ALL Flashcards
Endocrine chemical pathology A Prolactinoma B Grave’s disease C Addison’s disease D Schmidst’s syndrome E Acromegaly F Conn’s syndrome G Kallman’s syndrome H Secondary hypoaldosteronism I De Quervain’s thyroiditis A 46-year-old man is seen by his GP after experiencing tremors, heat intolerance and weight loss. His wife complained that his eyes were bulging. Blood tests reveal T3 (1.2–3.0 nmol/L), T4 (70–140 nmol/L), TSH (0.5–5.7 mIU/L).
B Grave’s disease Grave’s disease (B) is an autoimmune condition resulting in the production of TSH-receptor antibodies, leading to elevated levels of T3 and T4. TSH levels will therefore be suppressed as a result of negative feedback. Clinical features will include exophthalmos, pretibial myxoedema, diffuse thyroid enlargement as well as other systemic features of hyperthyroiditis (tremor, excess sweating, heat intolerance and unintentional weight loss). There is a strong association with other autoimmune conditions such as vitiligo and type 1 diabetes mellitus.
Potassium handling A Spurious sample B Anorexia C Diarrhoea D Renal tubular acidosis E Insulin overdose F Bartter syndrome G Frusemide H Renal failure I ACE inhibitors A 68-year-old woman on the Care of the Elderly ward is found to have the following blood results: Na 138 (135–145 mmol/L) K 3.0 (3.5–5.0 mmol/L) Urea 4.2 (3.0–7.0 mmol/L) Creatinine 74 (60–120 mmol/L) pH 7.31 (7.35–7.45) HCO3 28 (22–28 mmol/L)
D Renal tubular acidosis Renal tubular acidosis (D) occurs when there is a defect in hydrogen ion secretion into the renal tubules. Potassium secretion into the renal tubules therefore increases to balance sodium reabsorption. This results in hypokalaemia with acidosis. Renal tubular acidosis is classified according to the location of the defect: type 1 (distal tubule), type 2 (proximal tubule), type 3 (both distal and proximal tubules). Type 4 results from a defect in the adrenal glands and is included in the classification as it results in a metabolic acidosis and hyperkalaemia.
Acid–base balance A Metabolic acidosis B Metabolic acidosis with respiratory compensation C Metabolic alkalosis D Metabolic alkalosis with respiratory compensation E Respiratory acidosis F Respiratory acidosis with metabolic compensation G Respiratory alkalosis H Respiratory alkalosis with metabolic compensation I Mixed metabolic and respiratory acidosis pH 7.31 (7.35–7.45) pO2 7.6 (10.6–13 kPa) pCO2 8.2 (4.7–6.0 kPa) HCO3 26 (22–28 mmol/L)
E Respiratory acidosis Respiratory acidosis (E) is defined by a low pH (acidosis) together with a high pCO2, due to carbon dioxide retention secondary to a pulmonary, neuromuscular or physical causes. There is no metabolic compensation in this case, suggesting this is an acute pathology; a compensatory metabolic rise in HCO3 from the kidneys can take hours or days. This patient is also hypoxic with a low pO2. Causes of an acute respiratory acidosis include an acute exacerbation of asthma, foreign body obstruction and cardiac arrest.
Plasma proteins A Bence–Jones protein B Carcino-embryonic antigen C Caeruloplasmin D Fibrinogen E Amylase F Ferritin G α-Fetoprotein H Albumin I CA125 A 62-year-old smoker with a history of ulcerative colitis presents to his GP with weight loss and tiredness. The patient admits noticing fresh blood mixed in with the stool.
A Bence–Jones protein Bence–Jones proteins (A) are monoclonal globular proteins that are a diagnostic feature of multiple myeloma. Multiple myeloma is defined as the proliferation of plasma cells in the bone marrow and is commonly associated with the elderly population. Malignant plasma cells produce monoclonal antibodies and/or κ or λ light chains (paraproteins). The light chains appear in the urine and can be detected by electrophoresis of a urine sample as a monoclonal band. Bence–Jones proteins are also a feature of Waldenstrom’s macroglobulinaemia and amyloid light chain amyloidosis.
Endocrine chemical pathology A Prolactinoma B Grave’s disease C Addison’s disease D Schmidst’s syndrome E Acromegaly F Conn’s syndrome G Kallman’s syndrome H Secondary hypoaldosteronism I De Quervain’s thyroiditis A 38-year-old woman is referred by her GP to the Endocrine Clinic for further tests after experiencing fatigue and orthostatic hypotension. After a positive short synACTHen test, a long synACTHen test reveals a cortisol of 750 nmol/L after 24 hours.
C Addison’s disease Addison’s disease (C) is caused by primary adrenal insufficiency resulting in a reduced production of cortisol and aldosterone. It is diagnosed using the synACTHen test. In the short synACTHen test, baseline plasma cortisol is measured at 0 minutes, the patient is given 250 μg of synthetic ACTH at 30 minutes and plasma cortisol is rechecked at 60 minutes; if the final plasma cortisol is
Inborn errors of metabolism A Phenylketonuria (PKU) B Peroxisomal disorders C Maple syrup urine disease D Short-chain acyl-coenzyme A dehydrogenase (SCAD) deficiency E Von Gierke’s disease F Fabry’s disease G Urea cycle disorder H Homocystinuria I Galactosaemia A 14-day-old girl of Jewish descent presents with lethargy, poor feeding and hypotonia. The paediatrician examining the child also notices excessively sweaty feet.
C Maple syrup urine disease Maple syrup urine disease (C) is an organic aciduria, a group of disorders that represent impaired metabolism of leucine, isoleucine and valine. As a result, toxic compounds accumulate causing toxic encephalopathy which manifests as lethargy, poor feeding, hypotonia and/or seizures. Characteristic of maple syrup urine disease are a sweet odour and sweaty feet. The gold standard diagnostic test is gas chromatography with mass spectrometry. Management involves the avoidance of the causative amino acids.
Therapeutic drug monitoring A Procainamide B Lithium C Methotrexate D Theophylline E Gentamicin F Carbamazepine G Cyclosporine H Phenytoin I Digoxin A 35-year-old man presents to accident and emergency with feelings of lightheadedness and slurred speech. His wife mentions that the patient has been walking around ‘like a drunk’. The man’s blood pressure is found to be low.
H Phenytoin Phenytoin (H) is a commonly used anti-epileptic agent. Serum levels of phenytoin must be monitored due to its narrow therapeutic range (10–20 μg/mL). Phenytoin also exhibits saturation kinetics; a small rise in dose may lead to saturation of metabolism by CYP enzymes in the liver, hence producing a large increase in drug concentration in the blood as well as associated toxic effects. Phenytoin toxicity can lead to hypotension, heart block, ventricular arrhythmias and ataxia.
Anion gap A patient has the following blood results; calculate the anion gap: Na 143 mmol/L K 4 mmol/L Cl 107 mmol/L HCO3 25 mmol/L PO4 1 mmol/L Glucose 8 mmol/L Urea 7 mmol/L A 14 mmol/L B 15 mmol/L C 16 mmol/L D 17 mmol/L E Not enough information
A 14 mmol/L The anion gap is calculated using the following equation: Anion gap = [Na+] + [K+] − [HCO3] − [Cl−] It is a method of assessing the contribution of unmeasured anions in metabolic acidosis. The normal range varies between laboratories but the upper limit is usually between 10 and 18 mmol/L. It is helpful to estimate the unmeasured anions such as phosphate, ketones and lactate which are difficult to measure normally.
Inborn errors of metabolism A Phenylketonuria (PKU) B Peroxisomal disorders C Maple syrup urine disease D Short-chain acyl-coenzyme A dehydrogenase (SCAD) deficiency E Von Gierke’s disease F Fabry’s disease G Urea cycle disorder H Homocystinuria I Galactosaemia A 5-month-old boy is seen by the community paediatrician due to concerns of developmental delay. On examination dysmorphic features are noted, as well as a ‘cherry-red spot’ on the baby’s trunk.
F Fabry’s disease Fabry’s disease (F) is a lysosomal storage disorder in which there is deficiency in α-galactosidase. Presentation is almost always a child with developmental delay together with dysmorphia. Other findings may involve movement abnormalities, seizures, deafness and/or blindness. On examination, hepatosplenomegaly, pulmonary and cardiac problems may be noted. The pathognomonic feature of lysosomal storage disorders is the presence of a ‘cherry-red spot’.
Endocrine chemical pathology A Prolactinoma B Grave’s disease C Addison’s disease D Schmidst’s syndrome E Acromegaly F Conn’s syndrome G Kallman’s syndrome H Secondary hypoaldosteronism I De Quervain’s thyroiditis A 48-year-old man visits his GP complaining of muscle pain and weakness. He is found to have raised blood pressure. Blood tests reveal Na 149 (135– 145 mmol/L) and K 3.1 (3.5–5.0 mmol/L).
F Conn’s syndrome Conn’s syndrome (F) is defined as primary hyperaldosteronism secondary to an aldosterone-producing adrenal adenoma. As a result of the high aldosterone levels produced there will be an increased excretion of potassium and reabsorption of sodium, leading to hypokalaemia and hypernatraemia. The increased delivery of sodium to the juxtaglomerular apparatus causes renin levels to be reduced. Plasma aldosterone will either be raised or inappropriately normal (as ACTH is suppressed, aldosterone should physiologically be reduced).
Acid–base balance A Metabolic acidosis B Metabolic acidosis with respiratory compensation C Metabolic alkalosis D Metabolic alkalosis with respiratory compensation E Respiratory acidosis F Respiratory acidosis with metabolic compensation G Respiratory alkalosis H Respiratory alkalosis with metabolic compensation I Mixed metabolic and respiratory acidosis pH 7.30 (7.35–7.45) pO2 8.2 (10.6–13 kPa) pCO2 7.2 (4.7–6.0 kPa) HCO3 19 (22–28 mmol/L)
I Mixed metabolic and respiratory acidosis Mixed metabolic and respiratory acidosis (I) occurs when there is a low pH and a simultaneous high pCO2 and low HCO3. In the case of a mixed metabolic and respiratory acidosis, the metabolic acidosis component may be due to conditions such as uraemia, ketones produced as a result of diabetes mellitus or renal tubular acidosis. The respiratory acidosis component may be due to any cause of respiratory failure. Hence, this mixed picture may occur in a COPD patient with concurrent diabetes mellitus.
Potassium handling A Spurious sample B Anorexia C Diarrhoea D Renal tubular acidosis E Insulin overdose F Bartter syndrome G Frusemide H Renal failure I ACE inhibitors A 15-year-old boy presents to accident and emergency with loss of consciousness. His blood sugars are found to be extremely low. Blood tests demonstrate the following: Na 138 (135–145 mmol/L) K 3.0 (3.5–5.0 mmol/L) Urea 4.2 (3.0–7.0 mmol/L) Creatinine 74 (60–120 mmol/L) pH 7.48 (7.35–7.45) HCO3 31 (22–28 mmol/L)
E Insulin overdose Insulin overdose (E) in a diabetic patient will cause a redistributive hypokalaemia and concurrent metabolic alkalosis. Insulin causes a shift of potassium ions from the extracellular space to the intracellular space, thereby lowering blood potassium levels. Metabolic alkalosis can also cause a redistributive hypokalaemia; a reduced hydrogen ion concentration in the blood causes increased intracellular hydrogen ion loss to increase extracellular levels via Na+/H+ ATPase; potassium ions therefore diffuse intracellularly to maintain the electrochemical potential. Adrenaline and re-feeding syndrome also cause redistributive hypokalaemia.
Therapeutic drug monitoring A Procainamide B Lithium C Methotrexate D Theophylline E Gentamicin F Carbamazepine G Cyclosporine H Phenytoin I Digoxin A 45-year-old man presents to his GP for a routine medications review. The patient complains of recent diarrhoea and headaches. The GP notes the patient was treated with erythromycin for a community acquired pneumonia 1 week previous to the consultation.
D Theophylline Theophylline (D) is a drug used in the treatment of asthma and COPD. A low therapeutic index and wide variation in metabolism between patients lead to requirement for drug monitoring. Toxicity may manifest in a number of ways including nausea, diarrhoea, tachycardia, arrhythmias and headaches. Severe toxicity may lead to seizures. The toxic effects of theophylline are potentiated by erythromycin and ciprofloxacin. Without monitoring, many patients would be under-treated.
Vitamin deficiencies A Vitamin A B Vitamin B1 C Vitamin B2 D Vitamin B6 E Vitamin B12 F Vitamin C G Vitamin D H Vitamin E I Vitamin K A 26-year-old man presents to his GP with a 5-month history of bleeding gums. Petechiae are also observed on the patient’s feet. The man admits he has had to visit his dentist recently due to poor dentition
F Vitamin C Vitamin C (F) is a water soluble vitamin, essential for the hydroxylation of collagen. When deficiency of vitamin C is present, collagen is unable to form a helical structure and hence cannot produce cross-links. As a consequence, damaged vessels and wounds are slow to heal. Vitamin C deficiency results in scurvy, which describes both bleeding (gums, skin and joints) and bone weakness (microfractures and brittle bones) tendencies. Gum disease is also a characteristic feature.
Thyroid function tests A 45-year-old woman presents feeling tired all of the time. She has been investigated for anaemia which reveals macrocytosis. She denies drinking excessively. She has recently moved house and the GP notices she has a croaky voice, peaches and cream complexion and a slowed reaction to his questions. He examines her and elicits slow relaxing ankle reflexes. He suspects hypothyroidism and orders some thyroid function tests. Which of the following results are consistent with primary hypothyroidism? A Low TSH, raised free T4 and T3 B Low or normal TSH with low free T4 and T3 C Raised TSH with normal free T4 and T3 D Normal or raised TSH with raised T4 and T3 E None of the above
E None of the above Thyroid function tests are relatively easy to interpret with a basic understanding of the hypothalamic–pituitary–thyroid axis of thyroid hormone control. The pituitary produces TSH (thyroid stimulating hormone) which is released from the anterior pituitary. It is under the control of the hypothalamus which releases thyroid releasing hormone (TRH) which signals to anterior pituitary cells to release TSH. TSH travels in the bloodstream and acts on thyrocytes in the thyroid gland to stimulate production of T4 and T3 hormone. Specifically TSH controls the rate of iodide uptake required for thyroid hormone production, thyroid peroxidase activity, iodotyrosine reuptake into the thyrocyte from colloid and iodotyrosine cleavage to form mature hormone. T4 is the main circulatory hormone produced in about a 10:1 ratio compared with T3. However, free T3 has greater efficacy; in fact circulating T4 is converted into T3 within cells which then binds to its hormone receptor. TSH release is under negative feedback control of T4. In primary hypothyroidism, the thyroid does not have the ability to produce sufficient T4 or T3 to inhibit further TSH release. Therefore the biochemical abnormality found in primary hypothyroidism is a raised TSH with low T4 and T3, which is not one of the answer options (E).
Sodium handling A Ethanol B SIADH C Frusemide D Chronic kidney disease E Conn’s syndrome F Diarrhoea G Congestive cardiac failure H Addison’s disease I Hyperlipidaemia A 30-year old woman is seen by her GP after a 5-day episode of productive cough and lethargy. The GP notes dullness on percussion of the patient’s left lower lung. Blood and urine tests reveal the following: Na 128 (135–145 mmol/L) K 4.1 (3.5–5.0 mmol/L) Urea 3.5 (3.0–7.0 mmol/L) Glucose 3.2 (2.2–5.5 mmol/L) Osmolality 265 (275–295 mOsm/kg) Urine osmolality 285 mOsm/kg
B SIADH The syndrome of inappropriate ADH secretion (B; SIADH) results from the excess release of ADH. In this case the clinical features suggest pneumonia is the cause, but the aetiologies of SIADH are numerous, including malignancy, meningitis and drugs (carbamazepine). Criteria to diagnose SIADH include the following: • Hyponatraemia 100 mmol/L • High urine sodium >20 mmol/L • Euvolaemia • No adrenal, renal or thyroid dysfunction Characteristically the urine osmolality is inappropriately high; in normal circumstances if the plasma osmolality is low, the urine osmolality will stop rising as reduced ADH secretion prevents water retention. As a rule of thumb in SIADH, urine osmolality is greater than plasma osmolality.
Calcium handling A Primary hyperparathyroidism B Secondary hyperparathyroidism C Tertiary hyperparathyroidism D Pseudohypoparathyroidism E Primary hypoparathyroidism F Osteoporosis G Osteomalacia H Paget’s disease I Familial benign hypercalcaemia Ca 1.8 (2.2–2.6 mmol/L) PTH 0.69 (0.8–8.5 pmol/L) ALP 89 (30–150 u/L) PO4 1.5 (0.8–1.2 mmol/L) Vitamin D 76 (60–105 nmol/L)
E Primary hypoparathyroidism Primary hypoparathyroidism (E) is defined as dysfunction of the parathyroid glands leading to reduced production of PTH. As a result, the actions of PTH are blunted leading to reduced bone resorption as well as renal and gut calcium reabsorption. As a consequence there is hypocalcaemia and hyperphosphataemia. Other causes of hypocalcaemia include pseudoparathyroidism, vitamin D deficiency, renal disease (unable to make 1,25-dihydroxyvitamin D3), magnesium deficiency (magnesium required for PTH rise) and post-surgical (neck surgery may damage parathyroid glands).
- Arterial blood gas sample A 67-year-old woman presents to accident and emergency after having a fall. She is diagnosed with a fractured neck of femur which is fixed with a hemiarthroplasty. She also suffers from metastatic breast cancer. Four days postoperatively, she develops shortness of breath with an increased respiratory rate of 24 breaths per minute. The doctor on call takes an arterial blood gas sample which shows the following results: pH 7.48 PaO2 15.4 kPa on 2 L of oxygen pCO2 2.6 kPa Base excess +1 Saturations 99 per cent What does the blood gas show? A Metabolic alkalosis with respiratory compensation B Metabolic alkalosis C Respiratory alkalosis with metabolic compensation D Respiratory alkalosis E None of the above
D Respiratory alkalosis This lady has most likely suffered a pulmonary embolism manifesting as an acute onset of shortness of breath. Acid–base questions are best approached in three steps: first, decide if the pH shows an alkalosis or an acidosis. Next look at the PaCO2 and decide if it is high or low. Carbon dioxide dissolves in water to form carbonic acid, a weak acid. Therefore, if the concentration of carbon dioxide is high, it will lower the pH. You must then decide if the PaCO2 is compounding or helping the patient’s pH – in other words, is it worsening an acidotic patient or compensating for an alkalotic patient? Finally, look at the base excess. A greater positive base excess implies a higher concentration of bicarbonate, which is a base. Unlike carbon dioxide, therefore, high levels of bicarbonate will raise the pH. In this scenario, the pH is 7.48 meaning the patient is alkalotic with a low PaCO2, implying a respiratory cause. There is no compensation as the base excess of +1 is within normal limits. Unlike respiratory compensation, metabolic compensation takes several days. Below is a table of common causes of the different acid–base abnormalities with the likely carbon dioxide and base excess values.
Therapeutic drug monitoring A Procainamide B Lithium C Methotrexate D Theophylline E Gentamicin F Carbamazepine G Cyclosporine H Phenytoin I Digoxin A 65-year-old man being treated as an inpatient develops sudden onset ‘ringing in his ears’ as well as difficulty hearing.
E Gentamicin Gentamicin (E) is an aminoglycoside antibiotic, particularly useful against Gram-negative bacteria. It exhibits a low therapeutic index. Factors that may potentiate toxicity include dosage, kidney function (gentamicin is excreted through the kidneys) and other medications such as vancomycin. Gentamicin is an ototoxic and nephrotoxic agent and hence toxicity can lead to deafness and renal failure. Toxic effects on the ear are not limited to hearing, as the vestibular system is also affected, which may cause problems with balance and vision.
Endocrine chemical pathology A Prolactinoma B Grave’s disease C Addison’s disease D Schmidst’s syndrome E Acromegaly F Conn’s syndrome G Kallman’s syndrome H Secondary hypoaldosteronism I De Quervain’s thyroiditis A 45-year-old woman is referred to an endocrinologist due to the appearance of enlarged hands and feet as well as a protruding jaw. After conducting an oral glucose tolerance test, growth hormone levels are found to be 5 mU/L (
E Acromegaly Acromegaly (E) is caused by the increased secretion of growth hormone as a result of a pituitary adenoma (rarely there may be ectopic production). Serum growth hormone levels are not a useful marker of acromegaly due to its pulsatile release from the pituitary. The diagnostic test for acromegaly is the oral glucose tolerance test with synchronous growth hormone measurement: 75 mg of glucose is administered to the patient; if growth hormone levels are not suppressed to below 2 mU/L, a diagnosis of acromegaly is made.
Sodium handling A Ethanol B SIADH C Frusemide D Chronic kidney disease E Conn’s syndrome F Diarrhoea G Congestive cardiac failure H Addison’s disease I Hyperlipidaemia A 50-year-old woman with known diabetes has a routine blood test which demonstrates the following: Na 130 (135–145 mmol/L) K 4.1 (3.5–5.0 mmol/L) Urea 4.2 (3.0–7.0 mmol/L) Glucose 3.1 (2.2–5.5 mmol/L) Osmolality 283 (275–295 mOsm/kg)
I Hyperlipidaemia Pseudo-hyponatraemia can occur in patients with hyperlipidaemia (I) or hyperproteinaemia. In such states, lipids and proteins will occupy a high proportion of the total serum volume. Although the sodium concentration in serum water is in fact normal, a lower sodium concentration will be detected due to dilution by increased lipids and protein molecules. As a consequence, there is an apparent hyponatraemia. A spurious result due to the sample being taken from the drip arm can also cause pseudo-hyponatraemia.
Potassium handling A Spurious sample B Anorexia C Diarrhoea D Renal tubular acidosis E Insulin overdose F Bartter syndrome G Frusemide H Renal failure I ACE inhibitors A 64-year-old man who is an inpatient on the Care of the Elderly ward is found to have the following blood results: Na 136 (135–145 mmol/L) K 5.5 (3.5–5.0 mmol/L) Urea 14.4 (3.0–7.0 mmol/L) Creatinine 165 (60–120 mmol/L) pH 7.44 (7.35–7.45) HCO3 27 (22–28 mmol/L)
H Renal failure Renal failure (H) can lead to hyperkalaemia secondary to reduced distal renal delivery of sodium ions. As a consequence, there is reduced exchange of potassium ions via the Na/K ATPase pump in the collecting duct, which thereby leads to accumulation of potassium ions in the blood and hence hyperkalaemia. An increase in aldosterone release will initially cause a compensatory loss of potassium ions; as renal failure progresses, this homeostatic mechanism will become decompensated and hyperkalaemia will result. Renal failure will also be reflected in the deranged urea and creatinine levels due to reduced excretion.
Acute pancreatitis A 56-year-old presents with sudden onset, severe epigastric pain which radiates through to the back. The pain is relieved only partly by sitting forward and is associated with nausea. The admitting doctor suspects pancreatitis and sends for a serum amylase which is greatly raised. A diagnosis of acute pancreatitis is made. The following results come back following a blood test: Haemoglobin 14.5 g/dL White cells 14.2 Na 148 K 4.6 Urea 14 Creatinine 123 Calcium 2.98 (corrected) Cholesterol 5.5 Albumin 35 g/L Glucose 8.8 mmol/L Which biochemical abnormality is not likely to be a consequence of acute pancreatitis? A Raised white cells B Raised sodium C Raised urea and creatinine D Raised calcium E Raised glucose
D Raised calcium Hypercalcaemia is not a common consequence of acute pancreatitis, indeed hypercalcaenia is one of the causes of acute pancreatitis. Other causes of pancreatitis can be remembered by the well known mnemonic ‘GET SMASHED’: • Gallstones • Ethanol • Trauma • Steroids • Mumps • Autoimmune (polyarteritis nodosa) • Scorpion venom (Trinidadian scorpion) •Hypercalcaemia/Hypertriglyceridaemia/Hypothermia • Endoscopic retrograde cholangiopancreatogram • Drugs (including thiazides, azathioprine, valproate, oestrogens)
Acid–base balance A Metabolic acidosis B Metabolic acidosis with respiratory compensation C Metabolic alkalosis D Metabolic alkalosis with respiratory compensation E Respiratory acidosis F Respiratory acidosis with metabolic compensation G Respiratory alkalosis H Respiratory alkalosis with metabolic compensation I Mixed metabolic and respiratory acidosis pH 7.36 (7.35–7.45) pO2 14.2 (10.6–13 kPa) pCO2 4.1 (4.7–6.0 kPa) HCO3 14 (22–28 mmol/L)
B Metabolic acidosis with respiratory compensation Metabolic acidosis with respiratory compensation (B) occurs when pH is low (acidosis) and HCO3 is low with concurrent respiratory compensation by decreasing pCO2. The anion gap can differentiate between causes of metabolic acidosis (anion gap = [Na++ K+] – [Cl−+ HCO3 −]; normal range between 10 and 18 mmol/L). Causes of a raised anion gap can be remembered by the mnemonic MUDPILES: methanol/metformin, uraemia, diabetic ketoacidosis, paraldehyde, iron, lactate, ethanol and salicylates. Causes of a normal anion gap include diarrhoea, Addison’s disease and renal tubular acidosis.
Inherited metabolic disorders A 42-year-old woman presents to maternity in labour. It is her first child and she delivers a baby boy at 42 weeks gestation. During the neonatal period, the child develops feeding difficulty with hypotonia and jaundice. On examination there is a conjugated hyperbilirubinaemia. The mother thinks this has started shortly after she has started feeding the child with milk. After a few months, the child develops cataracts. On testing the urine, there is positive Fehling’s and Benedict’s reagent tests with a negative glucose oxidase strip test. The milk is eliminated from the child’s diet and immediately some of the symptoms improve. What is the diagnosis? A Fructose intolerance B Galactosaemia C Galactokinase deficiency D Urea cycle disorder E Tyrosinaemia
B Galactosaemia This neonate, born with cataracts, poor feeding, lethargy, conjugated hyperbilirubinaemia with hepatomegaly and reducing sugars in the urine after starting milk, is likely to have galactosaemia (B). This is a rare autosomal recessive inherited condition most commonly due to a mutation in the galactose-1-phosphate uridyltransferase gene on chromosome 9p13. It results in excessive galactose concentrations when milk, which contains glucose and galactose, is introduced into the baby’s diet.
Vitamin deficiency tests A 59-year-old man presents with a fall and haematemesis after a heavy night drinking at the local pub. This is his third admission in a month with alcoholrelated problems. He has stopped vomiting, and on examination he is haemodynamically stable. He has digital clubbing, spider naevi and gynaecomastia. He is admitted for neurological observations overnight as he hit his head. The doctors notice the patient suffers from complex ophthalmoplegia, confusion and ataxia. Given his neurological symptoms which test would confirm the associated vitamin deficiency? A Red cell folate B Red blood cell transketolase C Red blood cell glutathione reductase D Red blood cell aspartate aminotransferase activity E Carbohydrate deficient transferrin
B Red blood cell transketolase This patient suffers from chronic alcohol abuse with signs of chronic liver disease. He also exhibits the classical triad of Wernicke’s encephalopathy caused by a thiamine (vitamin B1) deficiency. The test for this is measuring red blood cell transketolase activity (B). Red cell transketolase is a thiamine pyrophosphate requiring enzyme which catalyzes reactions in the pentose phosphate pathway essential for regenerating NADPH in erythrocytes. The test measures enzyme activity by adding thiamine pyrophosphate to a sample of haemolyzed red blood cells and measuring the effluent substances. By calculating the amount of product made and substrates consumed, one is able to calculate the increase of enzyme activity after thiamine addition. A marked increase in activity implies a thiamine deficiency as the other substrate (ribose 5 phosphate) is supplied in excess. Thiamine deficiency has a number of clinical sequelae including Wernicke’s encephalopathy, a reversible neurological manifestation characterized pathologically by haemorrhage in the mammillary bodies. If left untreated, this may progress to Korsakoff’s syndrome, an irreversible neurological disease characterized by severe memory loss, confabulation, lack of insight and apathy. Thiamine deficiency can also lead to wet beriberi syndrome leading to a high output cardiac failure.
Plasma proteins A Bence–Jones protein B Carcino-embryonic antigen C Caeruloplasmin D Fibrinogen E Amylase F Ferritin G α-Fetoprotein H Albumin I CA125 A 42-year-old woman presents to her GP with weight loss and abdominal pain. Bimanual examination reveals a mass in the left adnexa.
I CA125 CA-125 (cancer antigen 125; I) is a protein encoded by the MUC16 gene that may suggest the presence of ovarian cancer. Its low sensitivity and specificity prevents it from being a diagnostic marker but it is useful when used in conjunction with imaging modalities for the diagnosis of ovarian cancer. Many ovarian cancers are coelomic epithelial carcinomas and hence will express CA-125, which is a coelomic epithelium-related glycoprotein. CA-125 may be associated with endometrial, pancreatic and breast carcinomas but plasma levels are most elevated in ovarian cancer.
Calcium handling A Primary hyperparathyroidism B Secondary hyperparathyroidism C Tertiary hyperparathyroidism D Pseudohypoparathyroidism E Primary hypoparathyroidism F Osteoporosis G Osteomalacia H Paget’s disease I Familial benign hypercalcaemia Ca 3.1 (2.2–2.6 mmol/L) PTH 10.5 (0.8–8.5 pmol/L) ALP 165 (30–150 u/L) PO4 0.6 (0.8–1.2 mmol/L) Vitamin D 78 (60–105 nmol/L)
A Primary hyperparathyroidism Primary hyperparathyroidism (A) is caused by a parathyroid adenoma or parathyroid chief cell hyperplasia that leads to increased PTH production. Primary hyperparathyroidism leads to hypercalcaemia due to a raised PTH level. PTH achieves this by activating osteoclastic bone resorption (increasing blood ALP), stimulating calcium reabsorption in the kidney (with concurrent excretion of phosphate) and potentiating the action of the enzyme 1α hydroxylase in the kidney. 1α Hydroxylase acts on 25-hydroxyvitamin D3 to produce 1,25-dihydroxyvitamin D3 (calcitriol), which increases gut absorption of calcium.
Nutritional deficiency A 44-year-old African man is seen by a volunteer doctor in his village with skin changes around the neck. There are erythematous and pigmented areas around the neck in a necklace-like distribution. His family is also complaining of him becoming more forgetful and unable to perform normal daily tasks. This is made particularly distressing given his increase in bowel movements, although he cannot remember how many times he goes. He and his family, like many of the villagers, eat almost exclusively maize, and the doctor has treated several cases of kwashiorkor in the local area. What is the nutritional deficiency most likely to explain his symptoms? A Tocopherol B Riboflavin C Retinol D Vitamin B3 E Ascorbate
D Vitamin B3 This man with poor diet, dermatitis, dementia and diarrhoea most likely has a niacin deficiency leading to pellagra. The other name for niacin is vitamin B3 (D).The rash he describes is also known as Casal’s necklace – a distinctive erythematous, pigmented rash in the necklace distribution named after Gaspar Casal, a Spanish physician practising in the early 1700s.
Liver function tests A Alcohol abuse B Gilbert’s syndrome C Gallstones D Dublin–Johnson syndrome E Non-alcoholic fatty liver disease F Crigler–Najjar syndrome G Alcoholic liver disease H Paracetamol poisoning I Hepatocellular carcinoma AST 65 (3–35 IU/L) ALT 72 (3–35 IU/L) GGT 82 (11–51 IU/L) ALP 829 (35–51 IU/L) Total bilirubin 234 (3–17 μmol/L) Conjugated bilirubin 63 (1.0–5.1 μmol/L)
C Gallstones Gallstones (C) may be composed of cholesterol, bilirubin or mixed in nature. The major complication of gallstones is cholestasis, whereby the flow of bile is blocked from the liver to the duodenum. This results in right upper quadrant abdominal pain, nausea and vomiting. Other causes of cholestasis include primary biliary cirrhosis, primary sclerosing cholangitis and abdominal masses compressing the biliary tree. Biochemically, cholestasis is defined by rises in GGT and ALP (obstructive picture) that are greater than the rises in AST and ALT.
- Paradoxical aciduria A 19-year-old female student presents to the GP with low mood, lethargy and muscle weakness. She is anxious that she is putting on weight and admits to purging after meals to keep her weight under control for several months. She has a past history of depression and is taking citalopram. On examination, her body mass index is 18, she is clinically dehydrated with signs of anaemia including conjunctival pallor. She has bilateral parotidomegaly and the GP also notices erosions of the incisors. He orders some blood tests which reveal the following: Hb 9.5 White cells 7.8 Platelets 345 Na 143 K 3.1 Urea 8.5 Creatinine 64 Arterial pH 7.49 Urinalysis is normal except for acidic urine. The cause of this patient’s acidic urine is: A Acute renal failure B Renal tubular acidosis C Citalopram D Anaemia E Physiological
E Physiological This is a difficult question but the answer can be deduced with a basic knowledge of electrolyte physiology. This patient suffers from bulimia nervosa as characterized by the use of characteristic purging after meals to keep her weight under control. The main abnormalities in the investigations reveal a hypokalaemia with arterial alkalosis and paradoxical aciduria. The alkalosis is likely to be due to excessive purging leading to a loss of hydrogen ions. The hypokalaemia is secondary to the metabolic alkalosis as potassium and hydrogen are transported across cell membranes by the same transporter. The reduction of plasma hydrogen ions leads to increased potassium uptake leading to hypokalaemia. As part of a normal homeostatic mechanism, potassium is exchanged for hydrogen ions in the distal convoluted tubule of the nephron, resulting in an apparent paradoxical aciduria.
Vitamin D deficiency A 54-year-old man with a past history of alcohol abuse, recurrent severe epigastric pain with flatulence and steatorrhoea presents after a fall whilst out drinking with his friends. He had fallen onto his hip, has severe pain and inability to weight bear. On examination, his right lower limb is shortened and externally rotated. His liver function tests were normal apart from a raised alkaline phosphatase. A fractured neck of femur is diagnosed and is fixed that night. As part of a routine follow up, the fracture liaison nurse suspects vitamin D deficiency and orders a full set of vitamin D levels. What set of results would you expect in this man given his history? A Low 25-hydroxycholecalciferol, low 1,25-dihydroxycholecalciferol, low parathyroid hormone B Low 25-hydroxycholecalciferol, high 1,25-dihydroxycholecalciferol, high parathyroid hormone C High 25-hydroxycholecalciferol, low 1,25-dihydroxycholecalciferol, high parathyroid hormone D High 25-hydroxycholecalciferol, high 1,25-dihydroxycholecalciferol, high parathyroid hormone E High 25-hydroxycholecalciferol, low 1,25-dihydroxycholecalciferol, low parathyroid hormone
B Low 25-hydroxycholecalciferol, high 1,25-dihydroxycholecalciferol, high parathyroid hormone This man is highly likely to have osteomalacia given the history of chronic alcohol abuse and episodes consistent with chronic pancreatitis. This is significant because the pancreas is responsible for emulsification and digestion of fats which facilitate fat soluble vitamin absorption including vitamins A, D, E and K. The reduced vitamin D absorption has led to osteomalacia, the pathological syndrome caused by vitamin D deficiency after epiphyseal closure. If vitamin D deficiency occurred before epiphyseal closure, the patient would suffer from rickets.
Plasma proteins A Bence–Jones protein B Carcino-embryonic antigen C Caeruloplasmin D Fibrinogen E Amylase F Ferritin G α-Fetoprotein H Albumin I CA125 A 15-year-old boy is brought in by his mother who has noted a change in his behaviour as well as a tremor. On slit lamp examination, Keiser–Fleischer rings are noted around the iris.
C Caeruloplasmin Caeruloplasmin (C) is a copper carrying protein encoded by the CP gene. Low plasma caeruloplasmin levels are associated with Wilson’s disease, an autosomal recessive condition in which there is an accumulation of copper within organs due to a defect in the copper transporter ATP7B (linking copper to caeruloplasmin). As a result caeruloplasmin is degraded in the blood stream. Clinical manifestations include neurological and psychiatric symptoms, and copper accumulation within the iris of the eyes leading to Keiser–Fleischer rings is pathognomonic.
Biochemical abnormalities in chronic renal failure A 67-year–old man with chronic renal failure presents with fatigue. He has been on haemodialysis three times per week for a decade. His past medical history includes diabetes mellitus, hypertension and gout. He has been increasingly tired the last few weeks although he cannot explain why. He has been attending his dialysis appointments and is compliant with his medications. The GP takes some bloods to investigate. Which of the following is NOT a common association with chronic renal failure? A Acidosis B Anaemia C Hyperkalaemia D Hypocalcaemia E Hypophosphataemia
E Hypophosphataemia Patients with chronic renal failure normally suffer from hyperphosphataemia, not hypophosphataemia (E). This is due to renal impairment of calcium metabolism which is under the control of parathyroid hormone (PTH) and vitamin D. In the evolving stages of chronic renal failure, a secondary hyperparathyroidism exists to compensate for the inability of the kidney to retain calcium and excrete phosphate. Therefore hypocalcaemia (D) is associated with chronic renal failure. This stimulates a physiological secretion of PTH by the parathyroid glands in an attempt to retain calcium. PTH is also responsible for excreting phosphate in the kidney, which is impaired due to the failure. Hyperphosphataemia also increases PTH levels as part of a negative feedback loop designed to maintain its homeostasis. Patients with chronic renal failure usually take phosphate binders (e.g. Sevelamer) which act to reduce phosphate absorption. This reduces PTH production which also reduces bone resorption thus improving renal osteodystrophy, a complex metabolic bone pathology associated with chronic renal failure. It is also important to reduce phosphate concentration to reduce ectopic calcification – if this precipitates in the tubules, this may reduce what little function there is left.
Hypoglycaemia A 67-year-old Indian man presents with irritability, sweating and tremor which progresses to stupor. The admitting doctor sends for a laboratory glucose which comes back at 2.2 mmol/L. The patient is resuscitated and given intravenous glucose. A history reveals that he does not suffer from diabetes, and his past medical history is remarkable only for vitiligo. On direct questioning he admits to feeling increasingly more tired, particularly after returning recently from India. His family arrive after which the doctor notices the patient’s unusually darker tan compared with his children. Further investigations reveal the patient has low insulin and low C peptide concentrations. What is the most likely diagnosis? A Pituitary failure B Addison’s disease C Alcohol induced D Glycogen storage disease E Medium chain acyl-CoA dehydrogenase deficiency (MCADD)
B Addison’s disease This patient, presenting with hypoglycaemia, tiredness and hyperpigmentation with an associated autoimmune history of vitiligo, most probably has adrenal failure (Addison’s disease (B)). The adrenal glands are responsible for producing cortisol, aldosterone and sex hormones. Adrenal failure is potentially lethal due to the lack of cortisol, which is an important stress hormone as well as an important gluconeogenesis stimulant at times of hypoglycaemia. An important worldwide cause is tuberculosis but in the developed world, autoimmunity is more likely. Autoimmune conditions often segregate as in this man with vitiligo, an autoimmune disease causing destruction of melanin in the skin. The patient has a tan as a by product of the lack of negative feedback in the hypothalamic–pituitary–adrenal axis. The hypothalamus releases cortisol releasing hormone (CRH) to the anterior pituitary which in turn releases ACTH (adrenocorticotropic hormone). ACTH is produced from its precursor molecule POMC (pro-opiomelanocortin) which, when cleaved, also produces MSH (melanocyte stimulating hormone). This accounts for the increased tanning seen in patients with Addison’s.
Plasma proteins A Bence–Jones protein B Carcino-embryonic antigen C Caeruloplasmin D Fibrinogen E Amylase F Ferritin G α-Fetoprotein H Albumin I CA125 A 13-year-old boy presents to his GP with parotitis with pain in his testes. His previous history reveals an incomplete childhood vaccination record
E Amylase Amylase (E) is an enzyme that breaks down starch into maltose. Serum amylase levels are often elevated during inflammation involving the parotid glands (parotitis) as occurs in mumps. Amylase is produced in the salivary glands, the parotid gland being the largest producer of the enzyme. Inflammation of the parotid glands cause a release of amylase into the blood stream, hence elevating levels. Raised serum amylase levels are also used in the diagnosis of pancreatitis; the pancreas is another amylase producing site.
Calcium handling A Primary hyperparathyroidism B Secondary hyperparathyroidism C Tertiary hyperparathyroidism D Pseudohypoparathyroidism E Primary hypoparathyroidism F Osteoporosis G Osteomalacia H Paget’s disease I Familial benign hypercalcaemia Ca 2.4 (2.2–2.6 mmol/L) PTH 4.2 (0.8–8.5 pmol/L) ALP 250 (30–150 u/L) PO4 1.1 (0.8–1.2 mmol/L) Vitamin D 76 (60–105 nmol/L)
H Paget’s disease Paget’s disease (H) is a condition associated with impaired bone remodelling. New bone is larger but weak and prone to fracture. The pathogenesis has been postulated to be linked to paramyxovirus. All calcium blood studies will be normal apart from ALP, which will be raised. Paget’s disease is associated with extreme bone pain, bowing and chalk-stick fractures. Bossing of the skull may lead to an eighth cranial nerve palsy and hence hearing loss. X-ray findings include lytic and sclerotic lesions.
Inborn errors of metabolism A Phenylketonuria (PKU) B Peroxisomal disorders C Maple syrup urine disease D Short-chain acyl-coenzyme A dehydrogenase (SCAD) deficiency E Von Gierke’s disease F Fabry’s disease G Urea cycle disorder H Homocystinuria I Galactosaemia An 18-month-old girl is seen by the GP. Her mother is concerned by the child’s brittle hair and inability to walk. The mother reports her daughter has had two previous convulsions
H Homocystinuria Homocystinuria (H) is an amino acid disorder in which there is a deficiency in the enzyme cystathionine synthetase. This metabolic disorder presents in childhood with characteristic features such as very fair skin and brittle hair. The condition will usually lead to developmental delay or progressive learning difficulties. Convulsions, skeletal abnormalities and thrombotic episodes have also been reported. Management options include supplementing with vitamin B6 (pyridoxine) or maintaining the child on a low-methionine diet.
Potassium handling A Spurious sample B Anorexia C Diarrhoea D Renal tubular acidosis E Insulin overdose F Bartter syndrome G Frusemide H Renal failure I ACE inhibitors A 16-day-old baby girl is found to have low blood pressure. Urinary calcium levels are found to be elevated. Blood tests demonstrate the following results: Na 138 (135–145 mmol/L) K 2.8 (3.5–5.0 mmol/L) Urea 3.4 (3.0–7.0 mmol/L) Creatinine 62 (60–120 mmol/L) pH 7.51 (7.35–7.45) HCO3 33 (22–28mmol/L)
F Bartter syndrome Bartter syndrome (F) is an autosomal recessive condition due to a defect in the thick ascending limb of the loop of Henle. It is characterized by hypokalaemia, alkalosis and hypotension. The condition may also lead to increased calcium loss via the urine (hypercalcuria) and the kidneys (nephrocalcinosis). Various genetic defects have been discovered; neonatal Bartter syndrome is due to mutations in either the NKCC2 or ROMK genes. In the associated milder Gitelman syndrome, the potassium transporting defect is in the distal convoluted tubule of the kidney.
Myocardial infarction A 54-year-old man is admitted for an elective shoulder repair. The day before his surgery he develops acute onset central crushing chest pain radiating to his left arm and up the jaw. He is also sweaty and feels nauseous. He has a past medical history of coronary artery bypass grafting and angina, and his father died from a heart attack aged 46. An electrocardiogram is performed which shows acute ST elevation in the inferior leads. He is diagnosed with acute coronary syndrome and treated appropriately. His surgery is delayed, but he presents with the same symptoms 2 days later with further ST changes in the lateral leads. Which cardiac enzyme is most useful to confirm re-infarction? A Troponin I B Troponin T C Aspartate transaminase D Creatine kinase muscle brain (MB) E Lactate dehydrogenase
D Creatine kinase muscle brain (MB) This question is difficult as it requires both knowledge of the relative sensitivities of cardiac enzymes and their relative timelines at which they stay raised after a recent infarction. CK MB (D) is the heart isoenzyme creatine kinase which rises about 6–12 hours post-infarction and it usually peaks in concentration 24 hours later. It then reduces to normal within 48–72 hours. It is very sensitive and is diagnostic if it is >6 per cent of total creatine kinase or the CK MB mass is >99 percentile of normal. It is very useful in detecting re-infarction because of its sensitivity and rapid return to normal levels compared with troponin I and T (A and B). Troponin is the most sensitive and specific test for myocardial infarction and is traditionally taken 12 hours post-infarction. Troponin I is a better marker of myocardial infarction compared with troponin T (Trop I: sensitivity and specificity of 90 per cent at 8 hours and 95 per cent, respectively, trop T 84 per cent at 8 hours and 81 per cent, respectively). However, troponin levels take up to 10 days to normalize, making their use in re-infarction soon after a primary infarct limited. Another reason troponin is not the correct answer is that they are not strictly speaking cardiac enzymes, but rather a structural protein in the contractility mechanism. Interestingly, troponin T is also elevated in chronic kidney disease without troponin I elevation, for reasons unknown.
Hyperkalaemia A 75-year-old man presents with acute onset abdominal pain. The patient has not passed stools for 3 days and looks unwell. His past medical history includes bowel cancer which was treated with an abdominoperineal resection and chemotherapy 6 years ago. On examination, there is a large parastomal mass which is tender and irreducible. An arterial blood gas shows metabolic acidosis with a rasied lactate. The on-call doctor immediately starts normal saline fluids and prepares the patient for theatre. A strangulated hernia is diagnosed by the registrar and an emergency laparotomy is performed to resect the ischaemic bowel. One day postoperatively the patient has the following blood results: Hb 13.2 WCC 10.9 Platelets 234 Na 145 K 6.3 pH 7.38 Urea and creatinine normal What is the most likely cause of hyperkalaemia? A Acute kidney injury B Tissue injury C Resolving metabolic acidosis D Adrenal failure from metastases E Overhydration from intravenous fluids
B Tissue injury The most likely cause of this patient’s hyperkalaemia is secondary to tissue injury. Potassium is the principle intracellular cation whereas sodium is the principle extracellular cation. Na–K exchange pumps require a continuous supply of adenosine triphosphate (ATP) to supply the energy required to maintain the transcellular gradient. In iscliaemic conditions, where oxygen supply is limited, ATP production fails to meet demand via aerobic respiration alone. Therefore ATP is also generated via anaerobic respiration. This can only occur for a limited period as the anaerobic pathway is both less efficient and produces lactic acid, thereby reducing the local pH and reducing the efficiency of enzymatic activity. This patient has had a significant amount of infarcted bowel removed with a raised lactate implying anaerobic metabolism has both occurred and ultimately failed leading to cell necrosis. The cells are then unable to maintain the Na–K transporter activity leading to potassium release in the blood stream. Furthermore, surgery itself causing direct cell damage increases the intracellular potassium leak into the plasma.
Estimated plasma osmolarity A patient has the following blood results: Na 143 mmol/L K 4 mmol/L Cl 107 mmol/L HCO3 25 mmol/L PO4 1 mmol/L Glucose 8 mmol/L Urea 7 mmol/L What is the estimated plasma osmolarity? A 309 B 279 C 426 D 294 E Not enough information
A 309 Estimated plasma osmolarity is calculated using the following equation: Estimated plasma osmolarity = {[Na+] + [K+]} × 2 + [glucose] + [urea] The estimation of osmolarity is an approximation of the laboratory plasma osmolality which is always higher. The difference between osmolarity and osmolality is the quantity of solvent one is referring to – the former describes the osmoles of solute in 1 kg, whereas the latter describes the same solute in 1 L of solvent. Sodium and potassium are the main plasma cations, they are doubled to take into account the equal concentration of total anions present to maintain electrical neutrality. Glucose and urea are the other main osmolites even though urea has very little osmotic effect in the plasma. It is a very small molecule that can pass easily through cell membranes without affecting osmotic pressure.
Inborn errors of metabolism A Phenylketonuria (PKU) B Peroxisomal disorders C Maple syrup urine disease D Short-chain acyl-coenzyme A dehydrogenase (SCAD) deficiency E Von Gierke’s disease F Fabry’s disease G Urea cycle disorder H Homocystinuria I Galactosaemia A fair haired 8-month-old baby, born in Syria, is seen together with his mother in the paediatric outpatient clinic. He is found to have developmental delay and a musty smell is being given off by the baby.
A Phenylketonuria (PKU) Phenylketonuria (PKU; A) is also an amino acid disorder. Children classically lack the enzyme phenylalanine hydroxylase, but other co-factors may be aberrant. Since the 1960s PKU has been diagnosed at birth using the Guthrie test but in some countries the test may not be available. The child will be fair-haired and present with developmental delay between 6 and 12 months of age. Later in life, the child’s IQ will be severely impaired. Eczema and seizures have also been implicated in the disease process.
Vitamin deficiencies A Vitamin A B Vitamin B1 C Vitamin B2 D Vitamin B6 E Vitamin B12 F Vitamin C G Vitamin D H Vitamin E I Vitamin K A 40-year-old patient with a history of Graves’ disease presents with bilateral weakness of her legs. On examination she is Babinski sign positive and blood tests reveal a megaloblastic anaemia.
E Vitamin B12 Vitamin B12 (cobalamin; E) deficiency may result from pathologies affecting the stomach or ileum, as well as pernicious anaemia. In pernicious anaemia, autoantibodies exist against intrinsic factor. Pernicious anaemia is also commonly associated with other autoimmune conditions, such as Graves’ disease. Anaemia is a common manifestation of vitamin B12 deficiency, with raised mean cell volume and hypersegmented neutrophils evident. Subacute combined degeneration of the cord can also result, causing ataxia and progressive weakness in limbs and trunk; Babinski sign may be positive.
Neonatal jaundice A 2-week-old neonate born at term with no gestational complications develops uncongutated jaundice. This was following a difficult birth where instrumentation was required after excessive delay in the second stage of labour. On examination, the neonate looks well in a normal flexed position with visible jaundice most noticeable in the soft palate. There are no abnormal facies but there is a visible large caput succedaneum with bruising. Urine dipstick is normal with no markers of infection present in the blood. What is the most likely cause of the jaundice? A Urinary tract infection B Bruising C Haemolysis D Crigler–Najjar syndrome E Gilbert’s disease
B Bruising This child, with a large amount of bruising (B), most probably developed unconjugated jaundice from the excess breakdown products of erythrocytes. The difficult labour requiring instrumentation has led to a large collection of bruising in the scalp which is broken down and leads to unconjugated jaundice. Neonates are susceptible to jaundice for many different reasons – reduced erythrocyte half life with increased haemoglobin levels, reduced transport in the liver (reduced ligandin is responsible for this) and increased enterohepatic circulation. Investigation of this is to rule out other causes including urinary tract infection, other haemolytic anaemias and congenital hypothyroidism which is normally tested for by the heel prick Guthrie test. Treatment is usually via phototherapy which uses light at 450 nm wavelength to solubilize (NOT conjugate) the excess bilirubin for excretion through the kidneys. This prevents passage of bilirubin through the immature blood–brain barrier which can then deposit into the basal ganglia causing kernicterus. Another method of treatment includes exchange transfusion.
Exacerbating factors for gout A patient presents with an acutely painful, inflamed elbow. He has decreased range of movement passively and actively and the joint is tender, erythematous and warm. His past medical history includes hypertension, chronic lower back pain for which he takes aspirin, lymphoma for which he has just completed a course of chemotherapy and psoriasis which is well controlled. He is also a heavy drinker. A joint aspirate shows weakly negative birefringent crystals confirming the diagnosis of acute gout. Which factor in this patient is the least likely to contribute to this attack? A Bendroflumethiazide B Chemotherapy C Alcohol D Psoriasis E Aspirin
D Psoriasis Although all of these factors can contribute to hyperuricaeamia, well controlled psoriasis (D) in this patient is unlikely to contribute to this attack of gout. Gout may be acute or chronic and is caused by hyperuricaemia. Hyperuricaemia is caused either by increased urate production or decreased urate excretion. Uric acid is a product of purine metabolism and is produced in three main ways – metabolism of endogenous purines, exogenous dietary nucleic acid and de novo production. De novo production involves metabolizing purines to eventually produce hypoxanthine and xanthine. The rate limiting enzyme in this pathway is called phosphoribosyl pyrophosphate aminotransferase (PAT) which is under negative feedback by guanine and adenlyl monophosphate. The metabolism of exogenous and endogenous purines, however, is the predominant pathway for uric acid production. The serum concentration of urate is dependent on sex, temperature and pH. A patient with acute gout does not necessarily have an increased urate concentration, therefore making serum urate levels an inaccurate method of diagnosis. The diagnosis of acute gout, which most commonly affects the first metatarsophalangeal joint (‘podagra’) is best made by observing weakly negatively birefringent crystals in an aspirate of the affected joint. This test is performed with polarized light – urate crystals are rhomboid and illuminate weakly when polarized light is shone perpendicular to the orientation of the crystal (hence negative birefringence). This is in contrast with pseudogout which has positively birefringent, spindly crystals – these illuminate best when the polarized light is aligned with the crystals. X-ray of the affected joint shows soft tissue inflammation early on, but as the disease progresses, well defined ‘punched out’ lesions in the juxta-articular bone appear with a late loss of joint space. There is no sclerotic reaction. Treatment is with a non-steroidal anti-iflammatory (e.g. diclofenac) in the acute phase or colchicine.
Therapeutic drug monitoring A Procainamide B Lithium C Methotrexate D Theophylline E Gentamicin F Carbamazepine G Cyclosporine H Phenytoin I Digoxin A 45-year-old woman is seen by her GP for a routine medications review. The patient complains of recent onset abdominal pain and tiredness. An electrocardiogram (ECG) reveals prolonged PR interval.
I Digoxin Digoxin (I) is an anti-arrhythmic agent used in the treatment of atrial fibrillation and atrial flutter. Symptoms of under-treatment and toxicity are similar. Toxicity commonly arises due to the narrow therapeutic index of the agent. Non-specific symptoms of toxicity include tiredness, blurred vision, nausea, abdominal pain and confusion. ECG changes may include a prolonged PR interval and bradycardia. As digoxin is excreted via the kidneys, renal failure may cause accumulation of digoxin.
Vitamin deficiencies A Vitamin A B Vitamin B1 C Vitamin B2 D Vitamin B6 E Vitamin B12 F Vitamin C G Vitamin D H Vitamin E I Vitamin K A 5-year-old girl who is a known cystic fibrosis sufferer is noted by her mother to have developed poor coordination of her hands and on examination her reflexes are absent. Blood tests also reveal anaemia.
H Vitamin E Vitamin E (tocopherol; H) is an important anti-oxidant which acts to scavenge free radicals in the blood stream. Deficiency leads to haemolytic anaemia as red blood cells encounter oxidative damage and are consequently broken down in the spleen. Spino-cerebellar neuropathy is also a manifestation, which is characterized by ataxia and areflexia. Vitamin E deficiency has also been suggested to increase the risk of ischaemic heart disease in later life, as low-density lipoproteins become oxidized perpetuating the atherosclerotic process.
Treatment of hyperkalaemia A 76-year-old man presents following a fall and is diagnosed with a pubic ramus fracture which is treated conservatively. He has a background of chronic renal failure and over the weekend starts to feel palpitations and lightheadedness. An electrocardiograph is performed which shows tenting of the T waves, suggestive of hyperkalaemia. A blood test is performed which confirms the diagnosis. Which of the following treatments does not lower plasma potassium levels? A Calcium resonium B Sodium bicarbonate C Calcium gluconate D Insulin E Salbutamol
C Calcium gluconate Hyperkalaemia over 6.5 mmol/L is a medical emergency. High extracellular potassium levels increase cardiac excitability lowers the threshold of fatal dysrhythmia. Classical electrocardiographic changes include tall tented T waves, small P waves, widened QRS complexes which eventually become sinusoidal and can degenerate into ventricular fibrillation. Ten millilitres of 10 per cent calcium gluconate is the first line medication given to anyone with hyperkalaemia. It does not change the plasma potassium levels but stabilizes the myocardium to help prevent fatal dysyhythmia. It does so by increasing the threshold potential making the myocardium less excitable.
Acid–base balance A Metabolic acidosis B Metabolic acidosis with respiratory compensation C Metabolic alkalosis D Metabolic alkalosis with respiratory compensation E Respiratory acidosis F Respiratory acidosis with metabolic compensation G Respiratory alkalosis H Respiratory alkalosis with metabolic compensation I Mixed metabolic and respiratory acidosis pH 7.45 (7.35–7.45) pO2 10.2 (10.6–13 kPa) pCO2 7.2 (4.7–6.0 kPa) HCO3 32 (22–28 mmol/L)
D Metabolic alkalosis with respiratory compensation Metabolic alkalosis with respiratory compensation (D) occurs when pH is high (alkalosis) and HCO3 is high with a compensatory reduction in respiratory effort that increases pCO2. As respiratory effort is reduced there is the possibility of the patient becoming hypoxic. Causes of metabolic alkalosis include vomiting, potassium depletion secondary to diuretic use, burns and sodium bicarbonate ingestion. Respiratory compensation increase serum CO2 concentration, which reduces pH back towards normal.
Sodium handling A Ethanol B SIADH C Frusemide D Chronic kidney disease E Conn’s syndrome F Diarrhoea G Congestive cardiac failure H Addison’s disease I Hyperlipidaemia A 63-year-old man with chronic obstructive pulmonary disease (COPD) sees his GP due to oedematous ankles. His blood and urine tests show the following: Na 130 (135–145 mmol/L) K 4.4 (3.5–5.0 mmol/L) Urea 4.2 (3.0–7.0 mmol/L) Glucose 3.1 (2.2–5.5 mmol/L) Osmolality 268 (275–295 mOsm/kg) Urine osmolality 16–mmol/LmOsm/kg
G Congestive cardiac failure Congestive cardiac failure (G) may present with shortness of breath, pitting peripheral oedema and/or raised jugular venous pulse (JVP). In this scenario, shortness of breath may be masked by the patient’s COPD. The clinical picture together with the blood result demonstrating a low sodium and low osmolality suggest a hypervolaemic hyponatraemia. This scenario can be differentiated from hypervolaemia as a result of CKD (D) by the urine osmolality, which is less than 20 mmol/L in this instance, thereby suggesting a non-renal cause for the hyponatraemia Ethanol (A) may cause hyponatraemia in the context of a raised plasma osmolality (>295 mmol/L). Other low molecular weight solutes that can cause hyponatraemia (when osmolality is raised) include mannitol and glucose. Frusemide (C) and other diuretics cause a hypovolaemic hyponatraemia. As well as a low plasma sodium and osmolality, the urine osmolality will be greater than 20 mmol/L, signifying a renal cause of hyponatraemia. Conn’s syndrome (E), also known as primary aldosteronism, results from an aldosterone-producing adenoma producing excess aldosterone. Biochemical (and concurrent clinical) features include hypernatraemia (hypertension) and hypokalaemia (paraesthesia, tetany and weakness). Diarrhoea (F) leads to a hypovolaemic hyponatraemia (as does vomiting). Plasma sodium and osmolality will be low and urine osmolality will be lower than 20 mmol/L indicating an extra-renal cause of hyponatraemia.
Hypernatraemia A 54 year old with a background of hypertension, presents to the GP with a 2-week history of diarrhoea. He has been travelling in South East Asia recently and developed symptoms of diarrhoea 3 weeks ago. He went to the local doctor whilst in China who prescribed tetracycline, but his symptoms have persisted and only improved slightly. His past medical history includes an undisplaced parietal skull fracture he sustained when he was 10. He takes no other medications. The GP orders blood tests which show the following: Na 148 K 4.8 Urea 13 Creatinine 112 What is the most likely cause of his hypernatraemia? A Conn’s syndrome B Nephrogenic diabetes insipidus C Cranial diabetes insipidus D Tetracycline E Dehydration
E Dehydration The most likely cause of hypernatraemia in this man is dehydration (E). Gastroenteritis with diarrhoea for 3 weeks causes a high rate of free water loss resulting in increased concentration of sodium in the extracellular compartment. Sodium and intravascular volume are closely linked and controlled by the renin angiotensin system and antidiuretic hormone. A reduction in renal blood flow through loss of intravascular volume results in increased renin secretion from the juxtaglomerular apparatus in the kidneys. Renin converts angiotensinogen to angiotensin I which in turn is converted to angiotensin II by angiotensin converting enzyme (which is constitutively expressed in the lungs). Angiotensin II increases the release of aldosterone from the zona glomerulosa in the adrenal cortex which acts to increase sodium retention. Retained sodium increases plasma osmolality which stimulates antidiuretic hormone (ADH) release from the posterior pituitary. ADH acts to increase free water retention, the net result being an increased intravascular volume with a normal osmolality.
Sodium handling A Ethanol B SIADH C Frusemide D Chronic kidney disease E Conn’s syndrome F Diarrhoea G Congestive cardiac failure H Addison’s disease I Hyperlipidaemia A 30-year-old woman visits her GP due to pigmentation of her palmar creases. Two weeks later the following blood and urine tests are received: Na 128 (135–145 mmol/L) K 5.9 (3.5–5.0 mmol/L) Urea 5.2 (3.0–7.0 mmol/L) Glucose 1.8 (2.2–5.5 mmol/L) Osmolality 264 (275–295 mOsm/kg) Urine osmolality 24 mOsm/kg
H Addison’s disease Addison’s disease (H) is also known as primary adrenal insufficiency (reduced aldosterone and cortisol); consequently there is a rise in the production of adrenocorticotropic hormone (ACTH). An impaired synthesis of aldosterone reduces reabsorption of sodium and increases excretion of potassium in the distal convoluted tubule and collecting ducts of the kidney; this leads to a simultaneous hyponatraemia and hyperkalaemia. Reduced cortisol production causes hypoglycaemia due to impaired gluconeogenesis. Clinical features of Addison’s disease include hyperpigmentation, postural hypotension and weight loss.
Therapeutic drug monitoring A Procainamide B Lithium C Methotrexate D Theophylline E Gentamicin F Carbamazepine G Cyclosporine H Phenytoin I Digoxin A 45-year-old woman is told she may be demonstrating signs of toxicity, 12 hours after being given an initial dose of medication. She has a coarse tremor and complains of feeling nauseous.
B Lithium Lithium (B) is a therapeutic agent used in the treatment of bipolar disorder. Drug monitoring is essential (12 hours post dose) due to its low therapeutic index as well as the potential life-threatening effects of toxicity. Lithium is excreted via the kidneys and therefore serum drug levels may increase (with potential toxicity) in states of low glomerular filtration rate, sodium depletion and diuretic use. Features of lithium toxicity include diarrhoea, vomiting, dysarthria and coarse tremor. Severe toxicity may cause convulsions, renal failure and possibly death.
Inborn errors of metabolism A Phenylketonuria (PKU) B Peroxisomal disorders C Maple syrup urine disease D Short-chain acyl-coenzyme A dehydrogenase (SCAD) deficiency E Von Gierke’s disease F Fabry’s disease G Urea cycle disorder H Homocystinuria I Galactosaemia A 9-month-old baby is seen in accident and emergency as her mother has reported that she has become ‘floppy’. The baby is found to be hypoglycaemic and on examination an enlarged liver and kidneys are noted.
E Von Gierke’s disease Von Gierke’s disease (E) is one of nine glycogen storage disorders, in which a defect in the enzyme glucose-6-phosphate results in a failure of mobilization of glucose from glycogen. The metabolic disease presents in infancy with hypoglycaemia. The liver is usually significantly enlarged and kidney enlargement can also occur. Other glycogen storage disorders (and enzyme defects) include Pompe’s (lysosomal α-glucosidase), Cori’s (amylo-1,6-glucosidase) and McArdle’s (phosphorylase); each disorder presents with varying degrees of liver and muscle dysfunction.
Acid–base balance A Metabolic acidosis B Metabolic acidosis with respiratory compensation C Metabolic alkalosis D Metabolic alkalosis with respiratory compensation E Respiratory acidosis F Respiratory acidosis with metabolic compensation G Respiratory alkalosis H Respiratory alkalosis with metabolic compensation I Mixed metabolic and respiratory acidosis pH 7.49 (7.35–7.45) pO2 13.6 (10.6–13 kPa) pCO2 4.1 (4.7–6.0 kPa) HCO3 23 (22–28 mmol/L)
G Respiratory alkalosis Respiratory alkalosis (G) is biochemically defined by a raised pH (alkalosis) and reduced pCO2. As previously mentioned, metabolic compensation can take hours or days to occur. The primary pathology causing respiratory alkalosis is hyperventilation which causes increased CO2 to be lost via the lungs. Causes of hyperventilation may be due to central nervous system disease, for example stroke. Other causes of hyperventilation include anxiety (panic attack), pulmonary embolism and drugs (salicylates).
Calcium handling A Primary hyperparathyroidism B Secondary hyperparathyroidism C Tertiary hyperparathyroidism D Pseudohypoparathyroidism E Primary hypoparathyroidism F Osteoporosis G Osteomalacia H Paget’s disease I Familial benign hypercalcaemia Ca 1.8 (2.2–2.6 mmol/L) PTH 9.6 (0.8–8.5 pmol/L) ALP 50 (30–150 u/L) PO4 1.9 (0.8–1.2 mmol/L) Vitamin D 82 (60–105 nmol/L)
I Familial benign hypercalcaemia Familial benign hypercalcaemia (I) is a genetic condition leading to raised blood calcium levels. The disease results from a mutation in the calcium receptor located on the parathyroid glands and kidneys. This receptor defect therefore leads to underestimation of calcium, causing an increased production of PTH, despite the raised calcium levels. It is important to distinguish these patients from hyperparathyroid patients as the management of these conditions differs. Receptor failure in the kidneys reduces calcium excretion, leading to a hypocalcuric state.
Calcium handling A Primary hyperparathyroidism B Secondary hyperparathyroidism C Tertiary hyperparathyroidism D Pseudohypoparathyroidism E Primary hypoparathyroidism F Osteoporosis G Osteomalacia H Paget’s disease I Familial benign hypercalcaemia Ca 2.1 (2.2–2.6 mmol/L) PTH 10.4 (0.8–8.5 pmol/L) ALP 190 (30–150 u/L) PO4 0.69 (0.8–1.2 mmol/L) Vitamin D 41 (60–105 nmol/L)
G Osteomalacia Osteomalacia (G; rickets in children) results from insufficient bone mineralization, secondary to vitamin D or phosphate deficiency. Low vitamin D causes hypocalcaemia, due to reduced 1,25-dihydoxyvitamin D3 production, and hence reduced reabsorption of calcium from the gut. Low blood calcium levels cause an increase in production of PTH in an attempt to normalize calcium. Therefore, calcium levels will either be low or inappropriately normal. Increased bone resorption will cause ALP levels to rise.
Liver function tests A Alcohol abuse B Gilbert’s syndrome C Gallstones D Dublin–Johnson syndrome E Non-alcoholic fatty liver disease F Crigler–Najjar syndrome G Alcoholic liver disease H Paracetamol poisoning I Hepatocellular carcinoma AST 2321 (3–35 IU/L) ALT 2562 (3–35 IU/L) GGT 62 (11–51 IU/L) ALP 182 (35–51 IU/L) Total bilirubin 14 (3–17 μmol/L) Conjugated bilirubin 3.4 (1.0–5.1 μmol/L)
H Paracetamol poisoning Paracetamol poisoning (H) is a common cause of acute liver failure. The clinical features of acute liver failure reflect the diminished synthetic and metabolic functioning of the liver. Characteristics include reduced blood sugar level, metabolic acidosis, increased tendency to bleed and hepatic encephalopathy. Biochemical tests will reveal AST and ALT levels greater than 1000 IU/L. AST and ALT levels will be greater than GGT and ALP levels, reflecting the hepatic rather than obstructive picture of the pathology.
Vitamin deficiencies A Vitamin A B Vitamin B1 C Vitamin B2 D Vitamin B6 E Vitamin B12 F Vitamin C G Vitamin D H Vitamin E I Vitamin K A 40-year-old known alcoholic develops confusion and an unsteady gait. On examination bilateral lateral rectus palsy is noted.
B Vitamin B1 Vitamin B1 (thiamine; B) deficiency most commonly occurs in cases of alcoholism. The acute presentation of vitamin B1 deficiency is Wernicke’s encephalopathy, characterized by the triad of confusion, ophthalmoplegia and ataxia. Chronic alcoholism can lead to Korsakoff’s syndrome (amnesia and confabulation) and peripheral neuropathy. Beriberi can also occur, classified into wet and dry beriberi. Wet beriberi presents in a similar manner to heart failure, with cardiomegaly, oedema and dyspnoea. Dry beriberi involves an ascending impairment of nervous function involving both sensory (paraesthesia) and motor (foot drop, wrist drop and paralysis) components.
Liver function tests A Alcohol abuse B Gilbert’s syndrome C Gallstones D Dublin–Johnson syndrome E Non-alcoholic fatty liver disease F Crigler–Najjar syndrome G Alcoholic liver disease H Paracetamol poisoning I Hepatocellular carcinoma AST 34 (3–35 IU/L) ALT 32 (3–35 IU/L) GGT 134 (11–51 IU/L) ALP 123 (35–51 IU/L) Total bilirubin (3–17 μmol/L) Conjugated bilirubin (1.0–5.1 μmol/L)
A Alcohol abuse Alcohol abuse (A) can lead to deranged liver function tests. In the absence of underlying liver disease, biochemical investigation may demonstrate an isolated rise in GGT. There may also be mild elevations in AST and ALT, reflecting mild hepatic damage. Haematology results will show a macrocytic picture due to toxic effects of alcohol on the bone marrow. Isolated raised GGT levels may also occur due to the consumption of enzyme-inducing drugs such as phenytoin, carbamazepine and phenobarbitone.
Plasma proteins A Bence–Jones protein B Carcino-embryonic antigen C Caeruloplasmin D Fibrinogen E Amylase F Ferritin G α-Fetoprotein H Albumin I CA125 A 50-year-old patient who has a 4-week history of tiredness undergoes a colonoscopy. Bleeding is noted in the large intestine.
F Ferritin Ferritin (F) is an intracellular protein responsible for the safe storage of iron, as free iron can be toxic to cells. Gastrointestinal bleeding may cause iron deficiency anaemia (microcytic anaemia), characterized haematologically by a reduced serum iron, raised total iron binding capacity and reduced ferritin. Ferritin levels will distinguish between other causes of microcytic anaemia: anaemia of chronic disease (raised ferritin) and thalassaemia (normal ferritin). As ferritin is an acute-phase protein, it will also be raised secondary to inflammation.
Vitamin deficiencies A Vitamin A B Vitamin B1 C Vitamin B2 D Vitamin B6 E Vitamin B12 F Vitamin C G Vitamin D H Vitamin E I Vitamin K A 35-year-old man who is being treated for tuberculosis develops a rash on his trunk. Blood tests also reveal anaemia.
D Vitamin B6 Vitamin B6 (pyridoxine; D) is an essential co-factor in a number of metabolic pathways including the synthesis of amino acids and neurotransmitters. Common causes of deficiency include reduced dietary intake and isoniazid use for the treatment of tuberculosis. Vitamin B6 deficiency causes blood and skin abnormalities. Haematologically, vitamin B6 deficiency causes sideroblastic anaemia; dermatologically seborrhoeic dermatitis can occur. Diagnosis is made by determining erythrocyte levels of aspartate aminotransferase.
Potassium handling A Spurious sample B Anorexia C Diarrhoea D Renal tubular acidosis E Insulin overdose F Bartter syndrome G Frusemide H Renal failure I ACE inhibitors A 32-year-old man presents to his GP for a check-up. His serum aldosterone is found to be low. Blood tests reveal the following: Na 140 (135–145 mmol/L) K 5.6 (3.5–5.0 mmol/L) Urea 5.3 (3.0–7.0 mmol/L) Creatinine 92 (60–120 mmol/L) pH 7.38 (7.35–7.45) HCO3 24 (22–28 mmol/L)
I ACE inhibitors ACE inhibitors (I) will lead to hyperkalaemia due to reduced potassium excretion. ACE inhibitors antagonize the effect of angiotensin converting enzyme, the enzyme which catalyzes the production of angiotensin II from angiotensin I. A decreased level of angiotensin II reduces the production of aldosterone in the adrenal glands, a key hormone causing the excretion of potassium. Other causes of reduced excretion of potassium include Addison’s disease, renal failure and potassium sparing diuretics.
Liver function tests A Alcohol abuse B Gilbert’s syndrome C Gallstones D Dublin–Johnson syndrome E Non-alcoholic fatty liver disease F Crigler–Najjar syndrome G Alcoholic liver disease H Paracetamol poisoning I Hepatocellular carcinoma AST 1259 (3–35 IU/L) ALT 1563 (3–35 IU/L) GGT 73 (11–51 IU/L) ALP 46 (35–51 IU/L) Total bilirubin 15.2 (3–17 μmol/L) Conjugated bilirubin 4.2 (1.0–5.1 μmol/L)
E Non-alcoholic fatty liver disease Non-alcoholic fatty liver disease (NAFLD; E) is due to fatty deposits in the liver (steatosis), but where the underlying cause is not due to alcohol. In such circumstances, aetiological factors include obesity, diabetes, parenteral feeding and inherited metabolic disorders (glycogen storage disease type 1). NAFLD may present with right upper quadrant pain or may be asymptomatic. Liver function tests will reveal raised AST and ALT levels (AST:ALT ratio
Water deprivation test A 42-year-old woman with persistent polyuria and polydipsia is admitted for a water deprivation test. At the beginning of the test her weight, urine volume and osmolality and serum osmolality are measured and hourly thereafter for 8 hours. After 8 hours, she is given intramuscular desmopressin but drinks 3 L of water before going to bed. Her blood is taken again the next morning (16 hours after beginning the test) and the results are as follows: Start 8 hours 16 hours Weight 70 kg 67.8 kg 66.8 kg Urine volume (total) 0 mL 2200 mL 4000 mL Urine osmolality 278 mosmol/kg 872 mosmol/kg 980 mosmol/kg What is the most likely diagnosis? A Nephrogenic diabetes insipidus B Craniogenic diabetes insipidus C Psychogenic polydipsia D Invalid test E Normal
C Psychogenic polydipsia This patient is most likely suffering from psychogenic polydipsia, an uncommon condition where excessive water drinking occurs without the physiological stimulus to drink. It was classically described in patients with schizophrenia but also occurs in children. Chronic psychogenic polydipsia can result in mineral washout of the renal interstitium resulting in a physiological inability to concentrate urine, in other words a form of nephrogenic diabetes insipidus.
Hypercalcaemia A patient with end stage renal failure presents with depression. He is on haemodialysis three times a week but feels it is not working anymore and is getting more tired lately. He says he has lost his appetite and consequently feels rather constipated too. He feels his mind is deteriorating and there is little worth in attending dialysis anymore. His doctor wants to exclude a reversible cause of his depression and orders some blood tests. The doctor finds the patient has a raised corrected calcium, normal phosphate levels and high parathyroid hormone levels. What is the diagnosis? A Primary hyperparathyroidism B Secondary hyperparathyroidism C Tertiary hyperparathyroidism D Pseudohypoparathyroidism E Pseudopseudohypoparathyroidism
C Tertiary hyperparathyroidism This patient has tertiary hyperparathyroidism (C) given the presence of elevated calcium levels with high parathyroid levels in the presence of chronic renal failure. Plasma calcium levels are controlled via parathyroid hormone (PTH) which is produced in the parathyroid glands situated within the thyroid gland. Reduced ionized calcium concentration is detected by the parathyroid glands leading to a release of PTH which circulates in the blood stream. PTH increases calcium resorption from the kidneys whilst increasing phosphate excretion. PTH also stimulates 1-alpha hydroxylation of 25-vitamin D to make 1,25-vitamin D. Finally, PTH increases bone resorption of calcium via osteoclast activation. The sum effects of increased PTH levels are to increase plasma calcium concentration and to reduce phosphate concentration. PTH has an indirect, but very important, mechanism via 1,25-vitamin D which acts to increase gut absorption of calcium. Tertiary hyperparathyroidism (C) is seen in the setting of chronic renal failure and chronic secondary hyperparathyroidism leads to hyperplastic or adenomatous change in the parathyroid glands resulting in autonomous PTH secretion. The causes of calcium homeostasis dysregulation are multifactorial including tubular dysfunction leading to calcium leak, inability to excrete phosphate leading to increased PTH levels and parenchymal loss resulting in lower activated vitamin D levels.
Liver function tests A Alcohol abuse B Gilbert’s syndrome C Gallstones D Dublin–Johnson syndrome E Non-alcoholic fatty liver disease F Crigler–Najjar syndrome G Alcoholic liver disease H Paracetamol poisoning I Hepatocellular carcinoma AST 32 (3–35 IU/L) ALT 29 (3–35 IU/L) GGT 34 (11–51 IU/L) ALP 53 (35–51 IU/L) Total bilirubin 36 (3–17 μmol/L) Conjugated bilirubin 3.4 (1.0–5.1 μmol/L)
B Gilbert’s syndrome Gilbert’s syndrome (B) is an autosomal dominant condition in which there is a mutation in the enzyme UDP glucuronosyl transferase which reduces conjugation of bilirubin in the liver. As a consequence patients experience mild, intermittent jaundice. Jaundice in patients with Gilbert’s syndrome may be precipitated by infection or starved states. Biochemistry will reveal that all liver function tests are normal apart from an isolated raised unconjugated bilirubin level, while conjugated bilirubin is within the normal range.
Acute abdominal pain A 24-year-old previously fit and well woman presents with sudden onset abdominal pain the night after a party where she drank five units of alcohol. She complains of central abdominal pain, with nausea and vomiting. She also finds it difficult to control her bladder. On examination, she is tachycardic, hypertensive and is beginning to become confused. On looking back at her previous admissions, the doctor notices she has had similar episodes after drinking. This was also true for when she started the oral contraceptive pill and when she had tuberculosis which was treated with standard antibiotic treatments. She is also seeing a neurologist for peripheral neuropathy of unknown cause. The admitting doctor, an Imperial college graduate, suggests the possibility of acute intermittent porphyria. What enzyme deficiency is responsible for this disease? A Porphobilinogen deaminase B Uroporphyrinogen synthase C Coproporphyrinogen oxidase D Protoporphyrinogen oxidase E Uroporphyrinogen decarboxylase
A Porphobilinogen deaminase PBG deaminase deficiency (A) causes acute intermittent porphyria, which this patient suffers from. The porphyrias are a group of seven disorders caused by enzyme activity reduction in the haem biosynthetic pathway. Haem is manufactured in both the liver and bone marrow where branched chain amino acids together with succinyl CoA and glycine are needed. The first step involves 5 aminolevulinic acid (ALA) synthesis by ALA synthase. This is the rate limiting step which is under negative feedback from haem itself.
Sodium handling A Ethanol B SIADH C Frusemide D Chronic kidney disease E Conn’s syndrome F Diarrhoea G Congestive cardiac failure H Addison’s disease I Hyperlipidaemia A 45-year-old man is seen by his specialist. His last blood and urine tests demonstrated the following: Na 129 (135–145 mmol/L) K 5.5 (3.5–5.0 mmol/L) Urea 8.2 (3.0–7.0 mmol/L) Glucose 4.2 (2.2–5.5 mmol/L) Osmolality 265 (275–295 mOsm/kg) Urine osmolality 26 mOsm/kg
D Chronic kidney disease A true hyponatraemic state occurs when the osmolality is simultaneously low. Chronic kidney disease (CKD; D) results in urinary protein loss and hence oedema. A reduced circulating volume causes activation of the renin–angiotensin system, thereby raising blood sodium levels. This in turn causes release of antidiuretic hormone (ADH) from the posterior pituitary leading to water retention and hypervolaemic hyponatraemia. Water reabsorption in the renal tubules increases urine osmolality (>20 mmol/L indicates a renal cause of hyponatraemia). CKD is also associated with hyperkalaemia and azotaemia.
Endocrine chemical pathology A Prolactinoma B Grave’s disease C Addison’s disease D Schmidst’s syndrome E Acromegaly F Conn’s syndrome G Kallman’s syndrome H Secondary hypoaldosteronism I De Quervain’s thyroiditis A 39-year-old woman sees an endocrinologist due to recent onset galactorrhoea. She denies recent child birth. Thyroid function tests are found to be normal.
A Prolactinoma A prolactinoma (A) is a prolactin-producing tumour and is the most prevalent pituitary tumour. Prolactinomas are classified according to size: microprolactinoma 10 mm diameter. The clinical consequences of prolactinoma are divided into, first, those that occur as a result of increased prolactin production and, second, effects due to the mass effect of the tumour. Hormonal effects of prolactin include amenorrhoea, galactorrhoea and gynaecomastia in males. Mass effects of the tumour can lead to compression of pituitary cells producing other hormones such as thyroid stimulating hormone, growth hormone and ACTH.
Raised alkaline phosphatase Which of the following is not a cause of raised alkaline phosphatase levels? A Pregnancy B Paget’s C Congestive heart failure D Obstructive jaundice E Myeloma
E Myeloma Alkaline phosphatase (ALP) is an enzyme responsible for removing phosphate groups from various molecules. It is produced in the liver, bile duct, kidney, bone and placenta. It is commonly requested as part of the liver function test panel and is used diagnostically in the approach to various conditions. Of these answers, only myeloma does not classically cause a raised ALP. ALP is caused by osteoblast activation whereas in myeloma there is direct osteoclast activation through the release of various cytokines.
Therapeutic drug monitoring A 51-year-woman with epilepsy is admitted after suffering a seizure following non-compliance with her phenytoin. She admits to having problems at home and was finding it difficult to continue to take her medication regularly. She is restarted on phenytoin. How many half lives does it normally take for a drug to reach its steady state? A 1–2 half lives B 3–5 half lives C 10–11 half lives D 50–60 half lives E 100–150 half lives
B 3–5 half lives Usually, drugs take between 4 and 5 half lives to reach a steady state. The half life is the time it takes for the plasma concentration of the drug to halve. Drugs such as phenytoin are monitored because underdosing will lead to no effect but overdosing will lead to toxicity. Most drugs have a wide therapeutic window – that is the difference between the minimum effective concentration and minimum toxic concentration. Drugs with narrow therapeutic windows may be suitable for drug monitoring to optimize treatment
- Hyponatraemia A 55-year-old man with severe learning difficulties presents with shortness of breath on exertion, fever and a productive cough of rusty red sputum. On examination, there is increased bronchial breathing in the lower right zone with inspiratory crackles. The patient is clinically euvolaemic, and urine dipstick is normal. A chest X-ray demonstrates right lower zone consolidation with the presence of air bronchograms. He is on carbemezepine for epilepsy and risperidone. Blood tests reveal the following: Hb 13.4 White cell count 12.8 C reactive protein 23 Na 123 K 4.7 Urea 6 Creatinine 62 What is the most likely cause of hyponatraemia? A Pneumonia B Carbamezepine C Risperidone D Syndrome of inappropriate antidiuretic hormone (SIADH) E Cerebral salt wasting syndrome
B Carbamezepine This patient’s hyponatraemia is most likely secondary to Carbamezepine therapy (B), a well documented side effect of this antiepileptic medication. Carbamezepine stimulates the production of vasopressin, the mechanism of action of which will be discussed shortly. It is also one of the ‘terrible 3 Cs’ which cause aplastic anaemia, the other two being carbimazole and chloramphenicol. Any patient with signs of infection or bleeding must be taken very seriously as fulminant sepsis may ensue without prompt treatment. This patient, however, has mounted a white cell response with a normal platelet count therefore making aplastic anaemia unlikely. Pneumonia (A) does not normally cause a sodium abnormality on its own. Less commonly, Legionnaire’s disease caused by the bacterium Legionella pneumophilia can have extrapulmonary features including hyponatraemia, deranged liver function tests and lymphopenia. This is unlikely to be the case as this organism often colonizes water tanks in places with air conditioning and has a prodromal phase of dry cough with flu-like symptoms. The alternative indirect pulmonary cause of hyponatraemia is lung cancer producing a SIADH; the tumour predisposes the patient to pneumonia by obstructing the normal ciliary clearance of the bronchi. It is unlikely in this patient given the lack of smoking history or cachexia.
Biochemical abnormalities of metabolic bone disease An 86-year-old woman presents to accident and emergency after a fall. She is a frequent faller but was unable to weight bear after the most recent incident. She has a history of rheumatoid arthritis which is controlled with low dose prednisolone. On examination her right leg is clinically shortened and externally rotated and a pelvic X-ray confirms the presence of a fractured neck of femur. The patient’s hip is fixed the next day. Her day one postoperative bloods show the following: Corrected calcium normal Phosphate normal Alkaline phosphatase raised Parathyroid hormone level normal Vitamin D level low What is the most likely diagnosis? A Normal B Osteoporosis C Paget’s disease D Osteomalacia E Malignancy
B Osteoporosis Osteoporosis (B) is a common disease which affects women more than men. It is pathologically associated with a reduction in bone density but normal mineralization of bone. There are usually no biochemical abnormalities and therefore all of the parameters measured here should be normal. Given the nature of the fracture, the raised alkaline phosphatase is likely to be due to the fracture where osteoblast and osteoclast activation for remodelling and bone healing is required for bone union. Note osteoblasts produce alkaline phosphatase, not osteoclasts. The activation of the two is usually simultaneous, therefore any bone remodelling will lead to a rise in alkaline phosphatase concentration. An important exception is in myeloma where bone lysis occurs with no rise in alkalaline phosphatase because osteoclasts are directly activated without osteoblast activity. Recently the National Institute of Clinical Excellence (NICE) have published guidelines regarding osteoporosis and its management. The risk factors of osteoporosis include: 1 Genetic factors: woman, age, Caucasion/Asian, family history 2 Nutritional factors: excessive alcohol and caffeine, low body weight 3 Life style factors: inactivity, smoking 4 Hormonal factors: nulliparous women, late menarche/early menopause, oophorectomy, post menopausal women, amenorrhoea 5 Iatrogenic factors: thyroxine replacement, steroids
A Iron deficiency anaemia B β-Thalassaemia C Anaemia of chronic disease D Blood loss E Alcohol F Vitamin B12 deficiency G Renal failure H Aplastic anaemia I Lead poisoning A 35-year-old man presents to his GP with a 1-month history of increased tiredness. The patient also admits to diarrhoea and minor abdominal pain during this period. His blood tests reveal the following: Hb 9.5 (13–18 g/dL) MCV 64 (76–96 fL) Fe 12.2 (14–31 μmol/L) TIBC 74 (45–66 μmol/L) Ferritin 9.2 (12–200 μg/L)
A Iron deficiency anaemia Iron deficiency anaemia (IDA; A) causes a hypochromic (pallor of the red blood cells on blood film due to reduced Hb synthesis), microcytic (small size) anaemia (low haemoglobin). A reduction in serum iron can be caused by a number of factors, including inadequate intake, malabsorption (coeliac disease; most likely cause in this case given diarrhoea and abdominal pain), increased demand (pregnancy) and increased losses (bleeding and parasitic infections). Further studies are required to distinguish IDA from other causes of microcytic anaemia: serum ferritin will be low, while total iron binding capacity (TIBC) and transferrin will be high.
A Iron deficiency anaemia B β-Thalassaemia C Anaemia of chronic disease D Blood loss E Alcohol F Vitamin B12 deficiency G Renal failure H Aplastic anaemia I Lead poisoning A 56-year-old vagrant man presents to the accident and emergency department with weakness in his legs. The patient has a history of poorly controlled Crohn’s disease. His blood tests demonstrate Hb 9.4 (13–18 g/dL) and MCV 121 ( 76–96 fL). A blood film reveals the presence of hypersegmented neutrophils.
F Vitamin B12 deficiency The majority of cases of vitamin B12 deficiency (F) occur secondary to malabsorption: reduced intrinsic factor production due to pernicious anaemia or post-gastrectomy, as well as disease of the terminal ileum. Clinical features will be similar to those of anaemia in mild cases, progressing to neuropsychiatric symptoms and subacute degeneration of the spinal cord (SDSC) in severe cases. Vitamin B12 deficiency results in a macrocytic megaloblastic anaemia as a result of inhibited DNA synthesis (B12 is responsible for the production of thymidine). Hypersegmented neutrophils are pathognomonic of megaloblastic anaemia.
A Iron deficiency anaemia B β-Thalassaemia C Anaemia of chronic disease D Blood loss E Alcohol F Vitamin B12 deficiency G Renal failure H Aplastic anaemia I Lead poisoning A 65-year-old man is referred to the haematology department by his GP after initially presenting with tiredness, palpitations, petechiae and recent pneumonia. His blood tests reveal Hb 9.8 (13–18 g/dL), MCV 128 (76–96 fL), reticulocyte count 18 (25–100 × 109/L), 1.2 (2–7.5 × 109/L) and platelet count 125 (150–400 × 109/L).
H Aplastic anaemia Aplastic anaemia (H) is caused by failure of the bone marrow resulting in a pancytopenia and hypocellular bone marrow. Eighty per cent of cases are idiopathic, although 10 per cent are primary (dyskeratosis congenita and Fanconi anaemia) and 10 per cent are secondary (viruses, SLE, drugs and radiation). The pathological process involves CD8+/ HLA-DR+ T cell destruction of bone marrow resulting in fatty changes. Investigations will reveal reduced Hb, reticulocytes, neutrophils, platelets and bone marrow cellularity as well as a raised MCV. Macrocytosis results from the release of fetal haemoglobin in an attempt to compensate for reduced red cell production.
A Iron deficiency anaemia B β-Thalassaemia C Anaemia of chronic disease D Blood loss E Alcohol F Vitamin B12 deficiency G Renal failure H Aplastic anaemia I Lead poisoning A 56-year-old woman presents to her GP with increased tiredness in the past few weeks. A past medical history of rheumatoid arthritis is noted. Her blood tests demonstrate the following: Hb 8.6 (11.5–16 g/dL) MCV 62 (76–96 fL) Fe 10.2 (11–30 μmol/L) TIBC 38 (45–66 μmol/L) Ferritin 220 (12–200 μg/L)
C Anaemia of chronic disease Anaemia of chronic disease (ACD; C) occurs in states of chronic infection and inflammation, for example in tuberculosis (TB), rheumatoid arthritis, inflammatory bowel disease and malignant disease. ACD is mediated by IL-6 produced by macrophages which induces hepcidin production by the liver. Hepcidin has the effect of retaining iron in macrophages (reduced delivery to red blood cells for erythropoiesis) and reduces export from enterocytes (reduced plasma iron levels). Laboratory features of ACD include a microcytic hypochromic anaemia, rouleaux formation (increased plasma proteins), raised ferritin (acute phase protein) as well as reduced serum iron and TIBC.
A Iron deficiency anaemia B β-Thalassaemia C Anaemia of chronic disease D Blood loss E Alcohol F Vitamin B12 deficiency G Renal failure H Aplastic anaemia I Lead poisoning A 12-year-old Mediterranean boy presents to his GP with increased tiredness over the past few weeks which is affecting his ability to concentrate at school. Examination is normal. Blood tests demonstrate the following: Hb 9.5 (13–18 g/dL) MCV 69 (76–96 fL) Fe 18.2 (14–31 μmol/L) TIBC 54 (45–66 μmol/L) Ferritin 124 (12–200 μg/L)
B β-Thalassaemia β-Thalassaemia (B) is a genetic disorder characterized by the reduced or absent production of β-chains of haemoglobin. Mutations affecting the β-globin genes on chromosome 11 lead to a spectrum of clinical features depending on the combinations of chains affected. β-Thalassaemia minor affects one β-globin chain and is usually asymptomatic, but may present with mild features of anaemia. Haematological tests reveal a microcytic anaemia but iron studies will be normal, differentiating from iron deficiency anaemia. β-Thalassaemia major occurs due to defects of both β-globin chains and results in severe anaemia requiring regular blood transfusions, as well as skull bossing and hepatosplenomegaly.
A Hereditary sherocytosis B Sickle cell anaemia C β-Thalassaemia D Glucose-6-phosphate dehydrogenase deficiency E Pyruvate kinase deficiency F Autoimmune haemolytic anaemia G Haemolytic disease of the newborn H Paroxysmal nocturnal haemoglobinuria I Microangiopathic haemolytic anaemia A 48-year-old woman diagnosed with chronic lymphocytic leukaemia develops jaundice and on examination is found to have conjunctival pallor. Direct antiglobulin test is found to be positive at 37°C.
F Autoimmune haemolytic anaemia Autoimmune haemolytic anaemia (AIHA; F) is caused by autoantibodies that bind to red blood cells (RBCs) leading to splenic destruction. AIHA can be classified as either ‘warm’ or ‘cold’ depending on the temperature at which antibodies bind to RBCs. Warm AIHA is IgG mediated, which binds to RBCs at 37°C; causes include lymphoproliferative disorders, drugs (penicillin) and autoimmune diseases (SLE). Cold AIHA is IgM mediated which binds to RBCs at temperatures less than 4°C; this phenomenon usually occurs after an infection by mycoplasma or EBV. Direct antiglobulin test (DAT) is positive in AIHA and spherocytes are seen on blood film.
A Hereditary sherocytosis B Sickle cell anaemia C β-Thalassaemia D Glucose-6-phosphate dehydrogenase deficiency E Pyruvate kinase deficiency F Autoimmune haemolytic anaemia G Haemolytic disease of the newborn H Paroxysmal nocturnal haemoglobinuria I Microangiopathic haemolytic anaemia An 18-year-old man presents to accident and emergency after eating a meal containing Fava beans. He is evidently jaundiced and has signs suggestive of anaemia. The patient’s blood film reveals the presence of Heinz bodies.
D Glucose-6-phosphate Glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency; D) is caused by an X-linked recessive enzyme defect. G6PD is an essential enzyme in the red blood cell pentose phosphate pathway; the pathway maintains NADPH levels which in turn supply glutathione to neutralize free radicals that may otherwise cause oxidative damage. Therefore, G6PD deficient patients are at risk of oxidative crises which may be precipitated by certain drugs (primaquine, sulphonamides and aspirin), fava beans and henna. Attacks result in rapid anaemia, jaundice and a blood film will demonstrate the presence of bite cells and Heinz bodies.
A Hereditary sherocytosis B Sickle cell anaemia C β-Thalassaemia D Glucose-6-phosphate dehydrogenase deficiency E Pyruvate kinase deficiency F Autoimmune haemolytic anaemia G Haemolytic disease of the newborn H Paroxysmal nocturnal haemoglobinuria I Microangiopathic haemolytic anaemia A 10-year-old girl presents to accident and emergency with jaundice. Blood tests reveal uraemia and thrombocytopenia. A peripheral blood film demonstrates the presence of schistocytes.
I Microangiopathic haemolytic anaemia Microangiopathic haemolytic anaemia (I) is caused by the mechanical destruction of RBCs in circulation. Causes include thrombotic thrombocytopenic pupura (TTP), haemolytic uraemic syndrome (HUS; E. coli O157:57), disseminated intravascular coagulation (DIC) and systemic lupus erythematosus (SLE). In all underlying causes, the potentiation of coagulation pathways creates a mesh which leads to the intravascular destruction of RBCs and produces schistocytes (helmet cells). Schistocytes are broken down in the spleen, raising bilirubin levels and initiating jaundice.
A Hereditary sherocytosis B Sickle cell anaemia C β-Thalassaemia D Glucose-6-phosphate dehydrogenase deficiency E Pyruvate kinase deficiency F Autoimmune haemolytic anaemia G Haemolytic disease of the newborn H Paroxysmal nocturnal haemoglobinuria I Microangiopathic haemolytic anaemia A 9-year-old boy from sub-Saharan Africa presents to accident and emergency with abdominal pain. On examination the child is found to have dactylitis. Blood haemoglobin is found to be 6.2 g/dL and electrophoresis reveals the diagnosis.
B Sickle cell anaemia Sickle cell anaemia (B) is an autosomal recessive genetic haematological condition due to a point mutation in the β-globin chain of haemoglobin (chromosome 11); this mutation causes glumatic acid at position six to be substituted by valine. Homozygotes for the mutation (HbSS) have sickle cell anaemia while heterozygotes (HbAS) have sickle cell trait. The mutation results in reduced RBC elasticity; RBCs therefore assume a sickle shape which leads to the numerous complications associated with a crisis. Blood tests will reveal an anaemia, reticulocytosis and raised bilirubin. Haemoglobin electrophoresis will distinguish between HbSS and HbAS.
A Hereditary sherocytosis B Sickle cell anaemia C β-Thalassaemia D Glucose-6-phosphate dehydrogenase deficiency E Pyruvate kinase deficiency F Autoimmune haemolytic anaemia G Haemolytic disease of the newborn H Paroxysmal nocturnal haemoglobinuria I Microangiopathic haemolytic anaemia A 1-day old baby has developed severe jaundice on the neonatal ward. The mother is rhesus negative and has had one previous pregnancy. Due to having her first baby abroad, she was not administered prophylactic anti- D.
G Haemolytic disease of the newborn Haemolytic disease of the newborn (G) occurs when the mother’s blood is rhesus negative and the fetus’ blood is rhesus positive. A first pregnancy or a sensitizing event such as an abortion, miscarriage or antepartum haemorrhage leads to fetal red blood cells entering the maternal circulation resulting in the formation of anti-D IgG. In a second pregnancy, maternal anti-D IgG will cross the placenta and coat fetal red blood cells which are subsequently haemolyzed in the spleen and liver. Therefore, anti-D prophylaxis is given to at-risk mothers; anti-D will coat any fetal red blood cells in the maternal circulation causing them to be removed by the spleen prior to potentially harmful IgG production.
A Anisocytosis B Howell–Jolly bodies C Heinz bodies D Rouleaux formation E Spherocytes F Target cells G Cabot rings H Pappenheimer bodies I Tear-drop cells A 34-year-old man, who has a past medical history of splenectomy following splenic trauma, presents to his GP with malaise 2 weeks after returning from abroad. Routine blood results are found to be normal but a blood film demonstrates inclusions within erythrocytes.
B Howell–Jolly bodies Howell–Jolly bodies (B) are nuclear DNA remnants found in circulating erythrocytes. On haematoxylin and eosin stained blood film they appear as purple spheres within erythrocytes. In healthy individuals erythrocytes expel nuclear DNA during the maturation process within the bone marrow; the few erythrocytes containing Howell–Jolly bodies are removed by the spleen. Common causes of Howell–Jolly bodies include splenectomy secondary to trauma and autosplenectomy resulting from sickle cell disease.
A Anisocytosis B Howell–Jolly bodies C Heinz bodies D Rouleaux formation E Spherocytes F Target cells G Cabot rings H Pappenheimer bodies I Tear-drop cells A 66-year-old man has a gastroscopy and colonoscopy following a blood test which demonstrated a microcytic anaemia. The patient had complained of tiredness and significant weight loss over a 1-month period.
A Anisocytosis Anisocytosis (A) is defined as the variation in the size of circulating erythrocytes. The most common cause is iron deficiency anaemia (IDA), but thalassaemia, megaloblastic anaemia and sideroblastic anaemia are all causative. As well as blood film analysis, anisocytosis may be detected as a raised red cell distribution width (RDW), a measure of variation in size of red blood cells. In the case of IDA, anisocytosis results due to deficient iron supply to produce haemoglobin.
A Anisocytosis B Howell–Jolly bodies C Heinz bodies D Rouleaux formation E Spherocytes F Target cells G Cabot rings H Pappenheimer bodies I Tear-drop cells A 36-year-old woman presents to her GP after a 1-month history of tiredness and recurrent chest infections. Blood tests reveal a pancytopenia and a subsequent bone marrow aspirate reveals a dry tap.
I Tear-drop cells Tear-drop cells (I), also known as dacrocytes, are caused by myelofibrosis. The pathogenesis of myelofibrosis is defined by the bone marrow undergoing fibrosis, usually following a myeloproliferative disorder such as polycythaemia rubra vera or essential thrombocytosis. Bone marrow production of blood cells decreases resulting in a pancytopenia. The body compensates with extra-medullary haemopoiesis causing hepatosplenomegaly. Blood film will demonstrate leuko-erythroblasts, tear-drop cells and circulating megakaryocytes. Bone marrow aspirate is described as a ‘dry and bloody’ tap.
A Anisocytosis B Howell–Jolly bodies C Heinz bodies D Rouleaux formation E Spherocytes F Target cells G Cabot rings H Pappenheimer bodies I Tear-drop cells A 3-week-old neonate is found to have prolonged jaundice with serious risk of kernicterus. Blood film demonstrates the presence of ‘bite cells’ as well as inclusions within erythrocytes.
C Heinz bodies Heinz bodies (C) are inclusion bodies found within erythrocytes that represent denatured haemoglobin as a result of reactive oxygen species. Heinz bodies are most commonly caused by erythrocyte enzyme deficiencies such as glucose-6-phosphate dehydrogenase (G6PD) deficiency, which may present in neonates with prolonged jaundice and NADPH deficiency (leading to accumulation of hydrogen peroxide), as well as chronic liver disease and α-thalassaemia. Damaged erythrocytes are removed in the spleen by macrophages leading to the formation of ‘bite cells’.
A Anisocytosis B Howell–Jolly bodies C Heinz bodies D Rouleaux formation E Spherocytes F Target cells G Cabot rings H Pappenheimer bodies I Tear-drop cells A 45-year-old woman with known Graves’ diseases presents to her GP with increased tiredness. She is found to have a megaloblastic anaemia.
G Cabot rings Cabot rings (G) are looped structures found within erythrocytes which may be caused by megaloblastic anaemia, i.e. inhibition of erythrocyte production occurring as a result of reduced DNA synthesis secondary to vitamin B12 deficiency. Vitamin B12 deficiency is most commonly caused by intrinsic factor (a protein required for vitamin B12 absorption) deficiency as a result of pernicious anaemia. Pernicious anaemia is caused by antibody destruction of gastric parietal cells which produce intrinsic factor and may be associated with other autoimmune diseases.
A Immune thrombocytopenic purpura B Idiopathic thrombotic thrombocytopenic purpura C Disseminated intravascular coagulation D Glanzmann’s thrombasthenia E Von Willebrand disease F Haemophilia A G Haemophilia B H Hereditary haemorrhagic telangiectasia I Bernard–Soulier syndrome A 4-year-old girl is seen by her GP due to recent onset petechiae on her feet and bleeding of her gums when she brushes her teeth. The child’s platelet count is found to be 12 500 per μL. The GP prescribes prednisolone and reassures the child’s mother that the bleeding will resolve.
A Immune thrombocytopenic purpura Immune thrombocytopenic purpura (ITP; A) may follow either an acute or chronic disease process. Acute ITP most commonly occurs in children, usually occurring 2 weeks after a viral illness. It is a type 2 hypersensitivity reaction, with IgG binding to virus-coated platelets. The fall in platelets is very low (less than 20 × 109/L) but is a self-limiting condition (few weeks). Chronic ITP is gradual in onset with no history of previous viral infection. It is also a type 2 hypersensitivity reaction with IgG targeting GLP-2b/3a.
A Immune thrombocytopenic purpura B Idiopathic thrombotic thrombocytopenic purpura C Disseminated intravascular coagulation D Glanzmann’s thrombasthenia E Von Willebrand disease F Haemophilia A G Haemophilia B H Hereditary haemorrhagic telangiectasia I Bernard–Soulier syndrome A 28-year-old man attends the haematology outpatient clinic regarding a longstanding condition he has suffered from. His disorder is related to a deficiency in factor 8 and therefore requires regular transfusions to replace this clotting factor.
F Haemophilia A Haemophilia A (F) is an X-linked genetic disorder and hence only affects men. Haemophilia A is characterized by a deficiency in factor 8. Haemophilia A is diagnosed by a reduced APTT as well as reduced factor 8. Symptoms depend on severity of disease: mild disease features bleeding after surgery/trauma; moderate disease results in bleeding after minor trauma; severe disease causes frequent spontaneous bleeds. Clinical features include haemarthrosis (causing fixed joints) and muscle haematoma (causing atrophy and short tendons).
A Immune thrombocytopenic purpura B Idiopathic thrombotic thrombocytopenic purpura C Disseminated intravascular coagulation D Glanzmann’s thrombasthenia E Von Willebrand disease F Haemophilia A G Haemophilia B H Hereditary haemorrhagic telangiectasia I Bernard–Soulier syndrome A 34-year-old man is taken to the local accident and emergency after suffering an episode of jaundice, fever and worsening headache. Blood tests reveal a low platelet count and blood film is suggestive of a microangiopathic haemolytic anaemia picture.
B Idiopathic thrombotic thrombocytopenic purpura Idiopathic thrombotic thrombocytopenic purpura (B) occurs due to platelet microthrombi. Presenting features include microangiopathic haemolytic anaemia (red blood cells coming into contact with microscopic clots are damaged by shear stress), renal failure, thrombocytopenia, fever and neurological signs (hallucinations/stroke/headache). A mutation in the ADAM-ST13 gene, coding for a protease that cleaves von Willebrand factor (vWF) allows for the formation of vWF multimers enabling platelet thrombi to form causing organ damage.
A Immune thrombocytopenic purpura B Idiopathic thrombotic thrombocytopenic purpura C Disseminated intravascular coagulation D Glanzmann’s thrombasthenia E Von Willebrand disease F Haemophilia A G Haemophilia B H Hereditary haemorrhagic telangiectasia I Bernard–Soulier syndrome A 68-year-old man on the Care of the Elderly ward is confirmed to have Gramnegative sepsis. The patient is bleeding from his mouth and is in shock. Initial blood tests reveal a reduced platelet count, anaemia and renal failure.
C Disseminated intravascular coagulation Disseminated intravascular coagulation (DIC; C) may be caused by Gram-negative sepsis, malignancy, trauma, placental abruption or amniotic fluid embolus. Tissue factor is released which triggers the activation of the clotting cascade, leading to platelet activation (thrombosis in microcirculation) and fibrin deposition (haemolysis). The consumption of platelets and clotting factors predisposes to bleeding. Plasmin is also generated in DIC which causes fibrinolysis, perpetuating the bleeding risk. The clinical manifestations of DIC are therefore linked to microthombus production (renal failure and neurological signs) and reduced platelets, clotting factors and increased fibrinolysis (bruising, gastrointestinal bleeding and shock).
A Immune thrombocytopenic purpura B Idiopathic thrombotic thrombocytopenic purpura C Disseminated intravascular coagulation D Glanzmann’s thrombasthenia E Von Willebrand disease F Haemophilia A G Haemophilia B H Hereditary haemorrhagic telangiectasia I Bernard–Soulier syndrome A 2-year-old boy is taken to see the GP due to his mother noticing bruising on his arms and legs after playing in the park. The parent mentions that she has also noticed several recent nose bleeds in her son but thought he would ‘grow out of it’. Investigations reveal a low APTT, low factor 8 levels and low Ristocetein cofactor activity.
E Von Willebrand disease von Willebrand disease (vWD; E) is an autosomal dominant condition caused by a mutation on chromosome 12. Physiologically, von Willebrand factor (vWF) has two roles: platelet adhesion and factor 8 production. Therefore, in vWD, where there is a deficiency in vWF, there is a defect in platelet plug formation as well as low levels of factor 8. Clinically, patients will present with gum bleeding, epistaxis or prolonged bleeding after surgery. Investigations will reveal a high/ normal APTT, low factor 8 levels, low ristocetin cofactor activity, poor ristocetin aggregation and normal PTT,
A Factor V Leiden B Antiphospholipid syndrome C Malignancy D Protein S deficiency E Antithrombin deficiency F Prothrombin G20210A mutation G Oral contraceptive pill H Buerger’s disease I Chronic liver disease A 35-year-old Caucasian man presents to accident and emergency with deep pain and swelling in his left calf. His past medical history reveals history of recurrent DVTs. The patient’s notes reveal a letter from his haematologist who had diagnosed a condition caused by a substitution mutation.
F Prothrombin G20210A mutation Prothrombin G20210A (F) is an inherited thrombophilia caused by the substitution of guanine with adenine at the 20210 position of the prothrombin gene. Physiologically, prothrombin promotes clotting after a blood vessel has been damaged. The G20210A causes the amplification of prothrombin production thereby increasing the risk of clotting, and causing a predisposition to deep vein thrombosis and pulmonary embolism. The prevalence of the mutation is approximately 5 per cent in the Caucasian population, the race with the greatest preponderance.
A Factor V Leiden B Antiphospholipid syndrome C Malignancy D Protein S deficiency E Antithrombin deficiency F Prothrombin G20210A mutation G Oral contraceptive pill H Buerger’s disease I Chronic liver disease A 38-year-old woman presents to accident and emergency with abdominal pain as well as passing blood and tissue per vagina. Ectopic pregnancy is diagnosed after ultrasound. The patient’s past medical history includes a haematological condition in which a clotting factor is unable to be degraded by activated protein C.
A Factor V Leiden Factor V Leiden (A) is an autosomal dominant inherited thrombophilia. Under normal circumstances protein C inhibits factor 5. In Factor V Leiden a mutation of the F5 gene that codes for factor 5, whereby an arginine codon is substituted for a glutamine codon, results in impaired degradation of factor 5 by protein C. As a result, patients are at risk of deep vein thrombosis and miscarriage. Diagnostic tests determine the functionality of activated protein C.
A Factor V Leiden B Antiphospholipid syndrome C Malignancy D Protein S deficiency E Antithrombin deficiency F Prothrombin G20210A mutation G Oral contraceptive pill H Buerger’s disease I Chronic liver disease A 32-year-old woman is seen by her rheumatologist to follow up her longstanding systemic lupus erythematosus (SLE). The patient has a history of recurrent miscarriages. The woman is positive for anti-cardiolipin antibodies and lupus anticoagulant.
B Antiphospholipid syndrome Antiphospholipid syndrome (APLS; B) is an autoimmune disorder that may present with stroke (arterial thrombosis), deep vein thrombosis (venous thrombosis) and/or recurrent miscarriages. APLS may be primary (not associated with autoimmune disease) or secondary to autoimmune disease such as SLE. Anti-cardiolipin antibodies and lupus anticoagulant bind to phospholipids on cell surface membranes of cells causing the activation of the coagulation cascade and thereby promoting clot formation. Diagnosis involves demonstrating the presence of circulating anti-cardiolipin antibodies and lupus anticoagulant.
A Factor V Leiden B Antiphospholipid syndrome C Malignancy D Protein S deficiency E Antithrombin deficiency F Prothrombin G20210A mutation G Oral contraceptive pill H Buerger’s disease I Chronic liver disease A 45-year-old man, who has a 50 pack/year history of smoking, is referred to the vascular outpatient clinic by his GP after suffering intermittent claudication. A diagnostic angiogram reveals a corkscrew appearance of his lower limb arteries.
H Buerger’s disease Buerger’s disease (thromboangitis obliterans; H) is a vasculitis of small/ medium arteries and veins of the hands and feet; it is strongly related to smoking. Claudication may be the initial presentation but as the disease progresses there is an association with recurrent arterial and venous thrombosis leading to gangrene and amputation in severe cases. Angiograms of the upper and lower limbs are helpful in the diagnosis of Buerger’s disease; a corkscrew appearance of the arteries may arise due to persistent vascular damage.
A Factor V Leiden B Antiphospholipid syndrome C Malignancy D Protein S deficiency E Antithrombin deficiency F Prothrombin G20210A mutation G Oral contraceptive pill H Buerger’s disease I Chronic liver disease A 37-year-old man presents to accident and emergency with shortness of breath and severe pleuritic chest pain. A CTPA reveals the diagnosis of pulmonary embolism. The patient’s haematological records state the patient has a condition that leads to the persistence of factors 5a and 8a causing increased risk of venous thrombosis.
D Protein S deficiency Protein S deficiency (D) is associated with the impaired degradation of factors Va and VIIIa. Protein S and protein C are physiological anticoagulants. Deficiency of protein S leads to persistence of factors 5a and 8a in the circulation and hence patients have a susceptibility to venous thrombosis. Three types of protein S deficiency exist: type I (quantitative defect) and types II and III (qualitative defect). Since protein S is a vitamin K dependent anticoagulant, warfarin treatment and liver disease may also lead to venous thrombosis in rare cases (the majority of cases show increased bleeding).
A Immediate haemolytic transfusion reaction B Febrile non-haemolytic reaction C Iron overload D IgA deficiency E Transfusion related lung injury F Bacterial infection G Delayed haemolytic transfusion reaction H Fluid overload I Graft versus host disease An 82-year-old man has just received a blood transfusion following a low haemoglobin level on the Care of the Elderly ward. He is now short of breath and is coughing up pink frothy sputum.
H Fluid overload Fluid overload (H) is an immediate complication of blood transfusion. Clinical features suggestive of fluid overload will include dyspnoea, distended neck veins and pink frothy sputum. Usually fluid overload occurs in situations where the blood transfusion rate is too fast; a transfusion would generally have to run at more than 2 mL/kg/hour to induce fluid overload. Patients with pre-existing cardiac or renal failure are prone to fluid overload as a result of blood transfusion.
A Immediate haemolytic transfusion reaction B Febrile non-haemolytic reaction C Iron overload D IgA deficiency E Transfusion related lung injury F Bacterial infection G Delayed haemolytic transfusion reaction H Fluid overload I Graft versus host disease A 34-year-old HIV-positive man receives a regular blood transfusion as part of his beta-thalassaemia major treatment regimen. He soon develops diarrhoea and a maculopapular rash on his limbs.
I Graft versus host disease Graft versus host disease (GVHD; I) occurs due to the transfer of donor lymphocytes to the recipient in a blood transfusion in patients who are immunosuppressed. Normally, the immune system is strong enough to detect and destroy donor lymphocytes. However, in immunosuppression (stem cell transplant patients/chemotherapy/malignancy/HIV) the donor lymphocytes cannot be destroyed; these foreign lymphocytes persist and target host tissue, especially the gastrointestinal tract and skin. Symptoms of GVHD include diarrhoea, maculopapular rash and skin necrosis. To minimize GVHD, donor blood is irradiated to remove lymphocytes.
A Immediate haemolytic transfusion reaction B Febrile non-haemolytic reaction C Iron overload D IgA deficiency E Transfusion related lung injury F Bacterial infection G Delayed haemolytic transfusion reaction H Fluid overload I Graft versus host disease A 34-year-old man requires a blood transfusion following a road traffic accident. However, soon after the transfusion, the patient is dyspnoeic and hypotensive. Investigation into the patient’s past medical history reveals a history of recurrent chest and gastrointestinal infections.
D IgA deficiency IgA deficiency (D) leads to recurrent mild infections of the mucous membranes lining the airways and digestive tract. In affected patients serum IgA levels are undetectable but IgG and IgM levels are normal. IgA is found in mucous secretions from the respiratory and gastrointestinal tracts and plays a key role in mucosal immunity. IgA deficient patients are also predisposed to severe anaphylactic reactions to blood transfusions due to the presence of IgA in donor blood.
A Immediate haemolytic transfusion reaction B Febrile non-haemolytic reaction C Iron overload D IgA deficiency E Transfusion related lung injury F Bacterial infection G Delayed haemolytic transfusion reaction H Fluid overload I Graft versus host disease A 56-year-old man is given a blood transfusion following severe blood loss after a hip replacement operation. Three hours after the transfusion, the patient develops shortness of breath, a dry cough and a fever of 39°C.
E Transfusion related lung injury Transfusion-related lung injury (TRALI; E) is characterized by acute non-cardiogenic pulmonary oedema that occurs within 6 hours following blood transfusion. The pathogenesis of TRALI involves the presence of anti-white blood cell antibodies in the donor blood that attack host leukocytes; sensitizing events in donors include previous blood transfusion or transplantation. Clinical features of TRALI are dry cough, dyspnoea and fever.
A Immediate haemolytic transfusion reaction B Febrile non-haemolytic reaction C Iron overload D IgA deficiency E Transfusion related lung injury F Bacterial infection G Delayed haemolytic transfusion reaction H Fluid overload I Graft versus host disease A 29-year-old woman requires an immediate blood transfusion after suffering a post-partum haemorrhage. However, 30 minutes after her transfusion she develops abdominal pain, facial flushing and vomiting. Analysis of the woman’s urine reveals the presence of haemoglobin.
A Immediate haemolytic transfusion reaction Immediate haemolytic transfusion reaction (IHTR; A) is characterized by ABO incompatibility and occurs 1–2 hours post-transfusion. Clinical features include abdominal pain, loin pain, facial flushing, vomiting and haemoglobinuria. Host IgG and IgM target donor red blood cells which are subsequently removed by the reticuloendothelial system. The most severe reaction occurs if a group O patient is transfused with group A blood.
A Acute lymphoblastic leukaemia B Acute promyelocytic leukaemia C Chronic myeloid leukaemia D Chronic lymphocytic leukaemia E Hairy cell leukaemia F T-cell prolymphocytic leukaemia G Large granular lymphocytic leukaemia H Adult T-cell leukaemia I Acute myeloid leukaemia A 62-year-old woman is seen by a GP due to a recent chest infection that has been troubling her. Initial blood tests show an elevated white cell count with specifically raised granulocytes. Following referral to a haematologist, a bone marrow biopsy reveals a hypercellular bone marrow and cytogenetic screening suggests a translocation between chromosomes 9 and 22.
C Chronic myeloid leukaemia Chronic myeloid leukaemia (CML; C) is most prevalent in the elderly population and is commonly suspected secondary to routine blood tests. Blood results will show an elevated level of granulocytes (neutrophils, basophils and eosinophils). Blood film will demonstrate myeloid cells at different stages of maturation. Bone marrow biopsy in CML patients suggests hypercellularity. Ninety-five per cent of cases are caused by the Philadelphia chromosome, a chromosomal translocation between chromosomes 9 and 22; this results in the BCR-Abl fusion oncogene that has tyrosine kinase activity. Recent novel therapies for CML include imatinib, a BCR-Abl inhibitor.
A Acute lymphoblastic leukaemia B Acute promyelocytic leukaemia C Chronic myeloid leukaemia D Chronic lymphocytic leukaemia E Hairy cell leukaemia F T-cell prolymphocytic leukaemia G Large granular lymphocytic leukaemia H Adult T-cell leukaemia I Acute myeloid leukaemia A 41-year-old man is referred to a haematologist by his general practitioner after several recent chest infections and tiredness. On examination, bruises are seen on his lower limbs as well as splenomegaly. Initial blood tests reveal a pancytopenia. Further testing demonstrates the presence of tumour cells that express tartrate-resistant acid phosphatase.
E Hairy cell leukaemia Hairy cell leukaemia (HCL; E) is a haematological malignancy of B lymphocytes and a subtype of chronic lymphocytic leukaemia. It most commonly occurs in middle-aged men. The cancer derives its name from the fine hair-like projections that are seen on tumour cells on microscopy. Cell surface markers include CD25 (IL-2 receptor) and CD11c (adhesion molecule). Diagnosis can be confirmed by the presence of tartrate-resistant acid phosphatase (TRAP) on cytochemical analysis. Clinical features relate to invasion of the spleen (splenomegaly), liver (hepatomegaly) and bone marrow (pancytopenia).
A Acute lymphoblastic leukaemia B Acute promyelocytic leukaemia C Chronic myeloid leukaemia D Chronic lymphocytic leukaemia E Hairy cell leukaemia F T-cell prolymphocytic leukaemia G Large granular lymphocytic leukaemia H Adult T-cell leukaemia I Acute myeloid leukaemia A 60-year-old man presents to his GP with fever, malaise and cough. On examination, the man is found to have petechiae on his legs as well as gum hypertrophy. Blood tests reveal anaemia, leukocytopenia and thrombocytopenia. A blood film demonstrates the presence of Auer rods within blast cells.
I Acute myeloid leukaemia Acute myeloid leukaemia (AML; I) is characterized by more than 20 per cent myleoblasts in the bone marrow. AML also causes proliferation of megakaryocytes and erythrocytes. Mutations that can cause AML include internal tandem duplications of the FLT3 gene (coding for a tyrosine kinase) and t(8;21) (a translocation causing a compressor complex to inhibit haematopoietic differentiation. Primary causes include Down’s syndrome; secondary causes include myeloproliferative disease. Blood tests will reveal a variable white cell count, anaemia, thrombocytopenia and reduced neutrophil count. Auer rods on blood film are pathognomonic, which will also be leuko-erythroblastic. Immunophenotyping of CD13, CD33 or CD34 can also aid diagnosis.
A Acute lymphoblastic leukaemia B Acute promyelocytic leukaemia C Chronic myeloid leukaemia D Chronic lymphocytic leukaemia E Hairy cell leukaemia F T-cell prolymphocytic leukaemia G Large granular lymphocytic leukaemia H Adult T-cell leukaemia I Acute myeloid leukaemia A 42-year-old Japanese migrant presents to his GP with generalized lymphadenopathy and nodules on his arms. On examination the patient has hepatosplenomegaly. Blood tests reveal lymphocytosis and a raised calcium level.
H Adult T-cell leukaemia Adult T-cell leukaemia (adult T-cell lymphoma; ATL; H) is a rare haematological malignancy with poor prognosis. It is caused by human T-cell leukaemia virus type 1 (HTLV-1), endemic in Japan and the Caribbean. Tumour cells express the cell surface protein CD4 and will contain the HTLV-1 virus within; the nuclei of ATL cells have a characteristic cloverleaf appearance. Clinical features include lymphadenopathy, hepatosplenomegaly, skin lesions and hypercalcaemia.
A Acute lymphoblastic leukaemia B Acute promyelocytic leukaemia C Chronic myeloid leukaemia D Chronic lymphocytic leukaemia E Hairy cell leukaemia F T-cell prolymphocytic leukaemia G Large granular lymphocytic leukaemia H Adult T-cell leukaemia I Acute myeloid leukaemia A 70-year-old man is reviewed by his GP after having felt tired and experienced weight loss over a 2-month period. The patient has lymphadenopathy on examination. Blood tests demonstrates a lymphocytosis of 4500 cells per microlitre and smudge cells can be visualized on a peripheral blood film.
D Chronic lymphocytic leukaemia Chronic lymphocytic leukaemia (CLL; D) is a B-cell neoplasm characterized by a lymphocyte count of over 4000 cells per microlitre. CLL most commonly occurs in elderly men. The cancer presents primarily in the lymph nodes with small lymphocytes containing irregular nuclei mixed with larger prolymphocytes. Prolymphocytes may aggregate to form pathognomonic proliferation centres. Blood film may reveal the presence of smudge cells. Clinical features are non-specific and include tiredness and weight loss. Hypogammaglobulinaemia is an associated immune phenomenon. CLL may convert into more aggressive forms including prolymphocytic transformation and diffuse-large B-cell lymphoma (Richter’s syndrome).
A Diffuse large B-cell lymphoma B Burkitt lymphoma C Follicular lymphoma D Small lymphocytic leukaemia E Mantle cell lymphoma F Peripheral T-cell lymphoma G Mycosis fungoides H Angiocentric lymphoma I Hodgkin’s lymphoma A 5-year-old boy is seen by a volunteer doctor at an Ethiopian refugee camp. On examination the child has a prominent swelling on the left side of his jaw. A tissue sample of the mass demonstrates a ‘starry sky’ appearance on light microscopy.
B Burkitt lymphoma Burkitt lymphoma (BL; B) is a haematological cancer of B lymphocytes caused by latent Epstein–Barr viral (EBV) infection and is most prevalent in Africa, affecting children and teenagers. Subtypes of BL include endemic, sporadic and immunodeficiency-associated disease. Endemic BL presents with a mandibular mass whereas non-endemic types present with an abdominal mass. All forms are highly associated with translocations of the c-myc gene on chromosome 8 (the most common with the Ig heavy chain on chromosome 14). A ‘starry sky’ appearance is characteristic when viewing BL cells under microscopy.
A Diffuse large B-cell lymphoma B Burkitt lymphoma C Follicular lymphoma D Small lymphocytic leukaemia E Mantle cell lymphoma F Peripheral T-cell lymphoma G Mycosis fungoides H Angiocentric lymphoma I Hodgkin’s lymphoma A 52-year-old man presents to his GP with painless lymphadenopathy which he describes as having fluctuated in size over the past month, as well as experiencing night sweats and weight loss. He also mentions the lumps become painful when he drinks alcohol. Further biopsy of the lumps reveals the presence of Reed–Sternberg cells.
I Hodgkin’s lymphoma Hodgkin’s lymphoma (I) results from the proliferation of B cells from the germinal centre. The pathogenesis is linked to EBV infection which activates NF-κB, preventing apoptosis of infected cells. Release of IL-5 from B-cells activates eosinophils, prolonging the life of B cells further. Histologically, Hodgkin’s lymphoma is characterized by the presence of Reed–Sternberg cells (binucleate/multinucleate cells with abundant cytoplasm, inclusion-like nucleoli and surrounded by eosinophils). Lymphadenopathy associated with Hodgkin’s lymphoma is usually painless, asymmetrical, fluctuates in size and is painful with alcohol intake. Other clinical features include fever, night sweats, weight loss and Pel– Ebstein fever (intermittent fever every 2 weeks). Unlike non-Hodgkin’s lymphoma, extra-nodal involvement is rare.
A Diffuse large B-cell lymphoma B Burkitt lymphoma C Follicular lymphoma D Small lymphocytic leukaemia E Mantle cell lymphoma F Peripheral T-cell lymphoma G Mycosis fungoides H Angiocentric lymphoma I Hodgkin’s lymphoma A 60-year-old man presents to his GP with malaise, night sweats and weight loss. On examination the patient is found to have generalized lymphadenopathy and hepatomegaly. Cytogenetic investigation a few weeks later by a haematologist reveals a translocation between chromosomes 11 and 14, which has caused overexpression of the BCL-2 protein.
E Mantle cell lymphoma Mantle cell lymphoma (MCL; E) is an aggressive B-cell lymphoma primarily affecting elderly men. The most common cause is a translocation between chromosomes 11 and 14, involving the BCL-1 locus and Ig heavy chain locus, therefore leading to over-expression of cyclin D1. Over-expression of cyclin D1 leads to dysregulation of the cell cycle. Clinically, generalized lymphadenopathy, as well as bone marrow and liver infiltration, are common. Hodgkin’s lymphoma can be split into classical and lymphocyte predominant nodular (LPN) subtypes.
A Diffuse large B-cell lymphoma B Burkitt lymphoma C Follicular lymphoma D Small lymphocytic leukaemia E Mantle cell lymphoma F Peripheral T-cell lymphoma G Mycosis fungoides H Angiocentric lymphoma I Hodgkin’s lymphoma A 40-year-old woman is referred to a haematologist after she is found to have generalized, painless lymphadenopathy. A report on tumour cell morphology states the presence of both centrocytes and centroblasts.
C Follicular lymphoma Follicular lymphoma (C) is caused most commonly by a translocation between chromosomes 14 and 18, leading to over-expression of the BCL-2 protein. Over-expression of BCL-2 causes inhibition of apoptosis, promoting the survival of tumour cells. Tumour cells in follicular lymphoma are characterized by centrocytes (small B cells with irregular nuclei and reduced cytoplasm) and centroblasts (larger B cells with multiple nuclei). Clinical features include painless, generalized lymphadenopathy. Follicular lymphoma usually presents in middle-aged patients and has a non-aggressive course but is difficult to cure.
A Diffuse large B-cell lymphoma B Burkitt lymphoma C Follicular lymphoma D Small lymphocytic leukaemia E Mantle cell lymphoma F Peripheral T-cell lymphoma G Mycosis fungoides H Angiocentric lymphoma I Hodgkin’s lymphoma A 62-year-old HIV-positive man presents to a haematologist with a 3-month history of weight loss and tiredness. On examination, the patient has a mass on his neck which the patient states has been rapidly growing. Staining of biopsy tissue demonstrates the present of large B cells which are positive for EBV.
A Diffuse large B-cell lymphoma Diffuse large B-cell lymphoma (DLBL; A) is a haematological malignancy most commonly affecting the elderly, characterized by large lymphocytes which have a diffuse pattern of growth. Common chromosomal abnormalities which contribute to the development of DLBL include the t(14;18) translocation which is characteristic of follicular lymphoma; this suggests that follicular lymphoma may undergo a degree of transformation to cause DLBL in such circumstances. Tumour cells that have follicular lymphoma morphology may be present at other sites. Two subtypes of DLBL have been described, both of which are associated with immunodeficiency: immunodeficiency- associated large B-cell lymphoma (linked to latent EBV infection) and body cavity-based large cell lymphoma (linked to HHV8 infection).
A Essential thrombocythaemia B Myelofibrosis C Chronic myelo-monocytic leukaemia D Refractory anaemia with excess blasts E Polycythaemia rubravera F Refractory anaemia with ringed sideroblasts G Refractory anaemia H 5q-Syndrome I Multiple myeloma A 40-year-old man is referred to a haematologist after suffering an episode of petechiae on his legs followed by a burning sensation in his fingers and deep vein thrombosis a few weeks later. Blood tests reveal a platelet count of 850 × 109/L.
A Essential thrombocythaemia Essential thrombocythaemia (A) results in a high platelet count, which quickly become dysfunctional; it is characterized by periods of bleeding or thrombosis. Clinical features of bleeding events include gastrointestinal bleeding, bruising, petechiae and/or menorrhagia. Thrombotic events manifest as erythromelalgia (erythema, swelling, pain and/or burning sensation in the extremities), digital ischaemia, cerebrovascular accident, deep vein thrombosis and Budd–Chiari syndrome. Blood tests will demonstrate a platelet count of over 600 × 109/L and the bone marrow will be hypercellular with giant platelets, as well as megakaryocyte clustering and hyperplasia. Treatment options include hydroxyurea or anagrelide.
A Essential thrombocythaemia B Myelofibrosis C Chronic myelo-monocytic leukaemia D Refractory anaemia with excess blasts E Polycythaemia rubravera F Refractory anaemia with ringed sideroblasts G Refractory anaemia H 5q-Syndrome I Multiple myeloma A 52-year-old woman presents to her GP due to increased tiredness. The patient also reports easy bruising and numerous bouts of pneumonia which have occurred over the past 6 months. On examination, the patient has splenomegaly. Blood tests reveal a low white cell and platelet count. Blood film reveals the presence of tear drop cells and on bone marrow aspiration there is a ‘dry’ tap.
B Myelofibrosis In myelofibrosis (B) the bone marrow undergoes fibrosis, the cause of which is unknown. The body compensates with extra-medullary haemopoiesis causing enlargement of the spleen and liver. The underlying pathogenesis is related to abnormal megakaryocytes releasing PDGF and TGF-β which stimulate fibroblast proliferation. Blood tests will show an initial rise in white cell and platelet counts during the compensatory phase; as fibrosis progresses the bone marrow reduces white cell and platelet production. Blood film will be leukoerythroblastic, with tear-drop cells and circulating megakaryocytes (fibrosis causes ejection of megakaryocytes from the bone marrow). Bone marrow aspirate will demonstrate a ‘dry’ or bloody tap.
A Essential thrombocythaemia B Myelofibrosis C Chronic myelo-monocytic leukaemia D Refractory anaemia with excess blasts E Polycythaemia rubravera F Refractory anaemia with ringed sideroblasts G Refractory anaemia H 5q-Syndrome I Multiple myeloma A 60-year-old man is referred to a haematologist after complaining of back pain and tiredness as well as recent onset low mood. Urine tests reveal the presence of Bence–Jones proteins. An X-ray of the patient’s spine shows the presence of lytic lesions.
I Multiple myeloma Multiple myeloma (I) is defined as the proliferation of plasma cells in the bone marrow (>10 per cent plasma cells). Myeloma cells release monoclonal antibodies (most commonly IgG or IgA) and/or light chains (paraproteins); IgA production significantly increases the viscosity of the blood. Diagnosis is based on paraprotein bands of greater than 30 g/L on electrophoresis. Blood tests will demonstrate an increased ESR and calcium levels as well as rouleaux formation on blood film. Bence–Jones proteins (immunoglobulin light chains) may be present in the urine. Plasma cells visualized from bone marrow biopsy are atypical, with multiple nuclei, prominent nucleoli and cytoplasmic granules (containing immunoglobulin). X-rays may reveal punched-out lytic lesions.
A Essential thrombocythaemia B Myelofibrosis C Chronic myelo-monocytic leukaemia D Refractory anaemia with excess blasts E Polycythaemia rubravera F Refractory anaemia with ringed sideroblasts G Refractory anaemia H 5q-Syndrome I Multiple myeloma A 72-year-old man presents with a 1-month history of fever, night sweats and weight loss. Blood tests reveal a monocyte count of 1400/mm3 in the peripheral blood and a bone marrow biopsy demonstrates that myeloblasts constitute 16 per cent of his bone marrow
C Chronic myelo-monocytic Chronic myelo-monocytic leukaemia (CMML; C) is a myelodysplastic/ myeloproliferative disease which most commonly affects the elderly population, defined by a monocytosis of >1000/mm3 and increased number of monocytes in the bone marrow. Myeloblasts make up
A Essential thrombocythaemia B Myelofibrosis C Chronic myelo-monocytic leukaemia D Refractory anaemia with excess blasts E Polycythaemia rubravera F Refractory anaemia with ringed sideroblasts G Refractory anaemia H 5q-Syndrome I Multiple myeloma A 43-year-old woman presents to her general practitioner with headaches, episodes of dizziness and a strange itching sensation after she comes out of the bath. On examination a plethoric appearance is noted. Blood tests reveal a haemoglobin of 19 g/dL and erythropoietin levels are suppressed.
E Polycythaemia rubravera Polycythaemia rubra vera (PRV; E) is characterized by proliferation of erythroid, granulocytic and megakaryocyte lines. Many PRV cases are due to a V167F mutation on exon 2 of the JAK2 gene, leading to uncontrolled stem cell proliferation. Clinical features include hyperviscosity (headaches, dizziness and stroke), hyper-mast-cell degranulation (pruritis after hot baths, plethoric skin and peptic ulceration) and increased cell turnover (gout). Blood tests will reveal a haemoglobin concentration above 18 g/dL, leukocytosis and thrombocytosis. Erythropoietin levels are low due to a negative-feedback response from increased erythrocyte production.
A Temporal arteritis B Renal cell carcinoma C Colorectal cancer D Rheumatoid arthritis E Miliary tuberculosis F Acute pancreatitis G Schistosomiasis H Sarcoidosis I Epstein–Barr infection A 56-year-old woman visits her GP for a regular check-up for a chronic condition she suffers from. On examination, she has signs of long-term steroid therapy. There is ulnar deviation at her metacarpophalangeal joints. Blood tests reveal a microcytic hypochromic anaemia, low iron and total iron binding capacity, but a raised ferritin level.
D Rheumatoid arthritis Rheumatoid arthritis (RA; D) is an inflammatory disease that mainly affects the small joints of the hands but systemic involvement can be a feature, manifesting in the lungs (fibrosis), heart (pericarditis) and eyes (scleritis). RA is a cause of anaemia of chronic disease (ACD), which is mediated by IL-6 produced by macrophages. IL-6 induces hepcidin production by the liver which has the effect of retaining iron in macrophages (reduced delivery to red blood cells for erythropoiesis) and decreases export from enterocytes (reduced plasma iron levels). Laboratory features of ACD include a microcytic hypochromic anaemia, rouleaux formation and raised ferritin (acute phase protein).
A Temporal arteritis B Renal cell carcinoma C Colorectal cancer D Rheumatoid arthritis E Miliary tuberculosis F Acute pancreatitis G Schistosomiasis H Sarcoidosis I Epstein–Barr infection A 45-year-old man presents to accident and emergency with an excruciating headache. Blood tests show an erythrocyte sedimentation rate of 110 mm/hour.
A Temporal arteritis Temporal arteritis (A) is a vasculitis most commonly affecting the medium and large arteries of the head. It is also known as giant cell arteritis due to the inflammatory cells that are visualized on biopsy. Prominent temporal arteries with regional tenderness, coupled with an erythrocyte sedimentation rate (ESR) of more than 60 mm/hour is highly suggestive of temporal arteritis. ESR may be raised due to increase plasma proteins (fibrinogen, acute phase proteins or immunoglobulin) or due to reduced packing of red blood cells (anaemia). Other causes of a raised ESR include myeloma, polymyalgia rheumatica and autoimmune disease.
A Temporal arteritis B Renal cell carcinoma C Colorectal cancer D Rheumatoid arthritis E Miliary tuberculosis F Acute pancreatitis G Schistosomiasis H Sarcoidosis I Epstein–Barr infection A 38-year-old man from Nigeria presents to his GP with progressive shortness of breath, cough and painful rashes on his lower legs. Blood tests reveal a monocytosis. Chest X-ray demonstrates bihilar lymphadenopathy.
H Sarcoidosis Sarcoidosis (H) is a granulomatous disease characterized by the presence of non-caseating granulomas in multiple organs, most commonly affecting the lungs. Diagnosis of sarcoidosis is usually a matter of excluding other diseases but chest X-ray (bihilar lymphadenopathy), CT scanning and lung biopsy can all help. Blood tests commonly reveal a monocytosis; monocytes are contributory to the pathogenesis of granulomatous disease. Other causes of monocytosis include brucellosis, typhoid, varicella zoster infection and chronic myelo-monocytic leukaemia (CMML).
A Temporal arteritis B Renal cell carcinoma C Colorectal cancer D Rheumatoid arthritis E Miliary tuberculosis F Acute pancreatitis G Schistosomiasis H Sarcoidosis I Epstein–Barr infection A 66-year-old presents to his GP with severe weight loss over 1 month as well as tiredness. Blood tests reveal an increased erythrocyte, haemoglobin and erythropoietin count.
B Renal cell carcinoma Renal cell carcinoma (RCC; B) is the most common type of renal cancer. Secondary polycythaemia may be associated with RCC as a result of increased erythropoietin (EPO) production. Secondary polycythaemia can be distinguished from primary polycythaemia as in the former there is an increase in blood EPO levels, whereas in the latter EPO levels decrease. Other causes of secondary polycythaemia include chronic hypoxia (high altitude, smoking, lung disease, cyanotic heart disease), renal disease (cysts, renal artery stenosis, hydronephrosis) and solid tumours (renal cell carcinoma and hepatocellular carcinoma).
A Temporal arteritis B Renal cell carcinoma C Colorectal cancer D Rheumatoid arthritis E Miliary tuberculosis F Acute pancreatitis G Schistosomiasis H Sarcoidosis I Epstein–Barr infection A 24-year-old man has recently returned from a trip to Kenya. He presents to his GP with abdominal pain, fever and on examination has hepatosplenomegaly. Blood tests reveal a marked eosinophilia.
G Schistosomiasis Schistosomiasis (G) is a parasitic disease caused by Schistosoma spp. It is particularly common in Asia, Africa and South America. The risk of bladder cancer is increased in urinary forms of schistosomiasis. The immune response to parasitic infection involves eosinophils and hence a marked eosinophilia is characteristic. Other causes of eosinophilia besides parasitic infection include allergic disease (asthma, rheumatoid arthritis, polyarteritis), neoplasms (Hodgkin’s lymphoma, non-Hodgkin’s lymphoma) as well as certain drugs (NSAIDs).
A 22-year-old motorcyclist is involved in a road traffic accident, and is transfused two units of blood. Four hours later he develops acute shortness of breath and hypoxia, and despite attempts at ventilation deteriorates rapidly and goes into respiratory arrest. An autopsy shows evidence of massive pulmonary oedema with granulocyte aggregation within the pulmonary microvasculature. The most likely diagnosis is: A Anaphylaxis B ABO incompatible blood transfusion C Fluid overload D Transfusion related acute lung injury E Air embolism
D Transfusion related acute lung injury Transfusion related acute lung injury (TRALI) (D) is rare but is one of the leading causes of transfusion related mortality. It can present with acute shortness of break and hypoxia, as in this case, typically within 6 hours of receiving the transfusion. The classic presentation to look out for is that of non-cardiogenic pulmonary oedema, i.e. pulmonary oedema that is not due to fluid overload. The underlying mechanism is not fully understood, but it is thought to involve HLA antibodies in the blood donor reacting with corresponding HLA antigens on the patient’s white blood cells. This leads to the formation of aggregates of white blood cells which become stuck in small pulmonary capillaries. The release of proteolytic enzymes from neutrophils and toxic oxygen metabolites causes lung damage, and subsequent non-cardiogenic pulmonary oedema which can be fatal. Treatment is essentially supportive, and includes stopping the transfusion, giving IV fluids and ventilation if needed. TRALI can occur with platelets and FFP, as well as with packed red cells as in this case. You might find it helpful to remember the mechanism by rearranging ‘TRALI’ to form the word ‘TRAIL’, and think of the blood donor leaving a ‘trail’ of antibodies in the recipient.
A 43-year-old woman is transfused three units of blood as an emergency following prolonged haematemesis. A few minutes later she becomes restless, and complains of chest pain. On examination she is pyrexial and tachycardic with a blood pressure of 95/60. There is bleeding at the site where her cannula is inserted, and urinalysis reveals haemoglobinuria. The most likely diagnosis is: A Anaphylaxis B ABO incompatible blood transfusion C Myocardial infarction D Graft versus host disease E Bacterial contamination
B ABO incompatible blood transfusion An ABO incompatible blood transfusion (B) can occur immediately after a transfusion has been given. For example, if group A, B or AB blood is given to a group O patient, the patient’s anti-A and anti-B antibodies attack the blood cells in the donor blood. The most severe form of reaction is thought to occur if group A red cells are transfused to a group O patient. Even just a few millilitres of blood can trigger a severe reaction within a few minutes. These reactions can also occur with platelets or fresh frozen plasma because they also contain anti-red cell antibodies. Symptoms can include chills, fever, pain in the back, chest or along the IV line, hypotension, dark urine (intravascular haemolysis), and uncontrolled bleeding due to DIC. In this case, the management involves stopping the transfusion immediately and taking blood samples for FBC, biochemistry, coagulation, repeat x-match, blood cultures and direct antiglobulin test, and contacting the haematology doctor as soon as possible. The blood bank should also be urgently informed because another patient may have also been given incompatible blood. These patients require fluid resuscitation and possibly inotropic support. They should be transferred to ICU if possible.
An 83-year-old woman with myelodysplasia is found to have a haemoglobin of 6.2 on admission. She is transfused two units of blood, and is discharged 2 days later. Six days after her admission her carer calls the GP with concerns that she is feverish and her skin looks slightly yellow. She is readmitted to hospital where blood tests reveal the following: bilirubin 35, ALT 15 (N 5–35), ALP 82 (N 20–140), Hb 7.3 g/dL, platelets 264 × 109/L. The most likely diagnosis is: A Febrile haemolytic transfusion reaction B Hepatitis B C Graft versus host disease D Post-transfusion purpura E Delayed haemolytic transfusion reaction
E Delayed haemolytic transfusion reaction Delayed haemolytic transfusion reactions (E) can occur more than 24 hours after a transfusion is given. They occur when patients are sensitized from previous transfusions or pregnancies, and therefore have antibodies against red cell antigens which are not picked up by routine blood bank screening if they are below the detectable limits. The most frequent causes are the antibodies of the Kidd (Jk) and Rh systems. Clinical features might include falling haemoglobin concentration, a smaller rise in haemoglobin than expected following a transfusion as in this case, fever, jaundice and rarely haemoglobinuria or renal failure. A blood film may show a raised reticulocyte count. Management of these reactions includes monitoring renal function, sending a repeat group and antibody screen and cross-match and further transfusion if needed. The blood bank should be notified too, and further specific treatment might not be needed unless renal failure develops.
An 8-year-old boy is brought to his GP by his father, who reports that he has been feeling progressively more tired over the past few months. On examination the GP notices a slight yellowing of his sclera, and the presence of splenomegaly. His father recollects that he himself was told he had a problem with his blood cells as a child, but has never been affected by it. A peripheral blood film shows a raised reticulocyte count and spherocytes. He is likely to have a positive: A Coombs test B Osmotic fragility test C G6PD test D Sickle cell screen E Schilling test
B Osmotic fragility test Hereditary spherocytosis is a type of autosomal dominant inherited haemolytic anaemia. It occurs due to an increase in the fragility of the red blood cell membrane due to dysfunctional skeletal proteins in the membrane, such as spectrin, ankyrin and band 4.2. Most patients develop a haemolytic state that is partially compensated. Clinical features can include tiredness from anaemia, as in this case, and the presence of jaundice and splenomegaly on examination. They can also develop pigment gallstones from the haemolysis. As with this child, there is often a positive family history. A blood film can show the presence of spherocytes and reticulocytes, and a Coombs test is negative. They may have a positive osmotic fragility test (B), but remember that this is just used to confirm that there are spherocytes present, not that the cause is hereditary spherocytosis. With this test, because the membrane is more permeable to salt and water, the spherocytes rupture in a mildly hypotonic solution. Do not forget that spherocytes may also be found in autoimmune haemolytic anaemia.
A 33-year-old Turkish man presents with extreme tiredness and shortness of breath after being started on a course of anti-malarial tablets. A full blood count reveals an Hb of 6.8. His Coombs test is negative. The cell type most likely to be found on his blood film is: A Heinz bodies B Pencil cells C Target cells D Spherocytes E Sickle cells
A Heinz bodies This man is suffering from glucose-6-phosphate dehydrogenase (G6PD) deficiency, an X-linked recessive disorder that is common in people from the Mediterranean, South East Asia, Middle East and West Africa. This enzyme is responsible for maintaining levels of glutathione from the pentose phosphate pathway, which protects against oxidant free radicals. Oxidative stress, for example in the form of chemicals, food or infection, can put people with this condition at risk of severe haemolytic anaemia. Drugs to be avoided in these patients include anti-malarials, such as primaquine, and others such as sulphonamides, vitamin K and dapsone. The exam favourite of broad beans can lead to a reaction called favism in these patients.
A 25-year-old student is treated for infectious mononucleosis following a positive Paul Bunnell test. A blood film reveals target cells, Howell–Jolly bodies and atypical lymphocytes. Together, these suggest that he has features of: A Bone marrow suppression B Hyposplenism C Disseminated intravascular coagulation D Haemolytic anaemia E Liver failure
B Hyposplenism Up to half of all patients might develop splenomegaly in infectious mononucleosis. This does not often cause symptoms but can lead to splenic rupture, either spontaneously or following minor trauma, and may necessitate treatment with splenectomy. Postoperatively a combination of features on a blood film might suggest hyposplenism: • Howell–Jolly bodies: these are small fragments of non-functional nuclei that are normally removed by the spleen, so might be seen on a blood film in hyposplenism. They may also be seen in megaloblastic and iron-deficiency anaemias • Target cells: these have a central dense area with a ring of pallor, and can occur in the three Hs: hepatic pathology, hyposplenism and haemoglobinopathies • Occasional nucleated red blood cells • Lymphocytosis • Macrocytosis • Acanthocytes: spiculated red cells that are found in hyposplenism, α-β-lipoproteinaemia, chronic liver disease and α-thalassaemia trait
A 4-year-old Afro-Caribbean boy has chest and abdominal pain. His blood tests reveal an Hb of 6.1 g/dL, with an MCV of 65. A blood film shows the presence of sickle cells. The most likely diagnosis is: A Sickle cell trait B Sickle cell anaemia C Sickle cell/b-thalassaemia D Sickle cell/haemoglobin C E b-Thalassaemia
B Sickle cell anaemia This boy is suffering from sickle cell anaemia (B), an autosomal recessive haemoglobinopathy. The term sickle cell disease actually comprises several different states: sickle cell anaemia, but also compound heterozygous states including sickle cell/haemoglobin C (D) and sickle cell/b-thalassaemia (C). Do not forget that the haemoglobin molecule consists of four chains, and there are three different forms: haemaglobin A (α2β2), haemoglobin A2 (α2d2) and haemoglobin F (α2ϒ2). The proportions of the different forms vary with age – haemoglobin F predominates before birth, but concentrations of haemaglobin A and A2 increase after birth, with haemoglobin A predominating. In sickle-cell anaemia a point mutation in the β-globin chain of haemoglobin (found on chromosome 11) results in the hydrophilic amino acid glutamic acid being replaced by the hydrophobic amino acid valine at the sixth position. This promotes aggregation of the haemoglobin chains in conditions of low oxygen, distorting the red blood cells so they adopt a sickle shape. These cells become adherent to the endothelieum of post capillary venules, causing retrograde capillary obstruction which can lead to painful crises.
A 7-year-old child has known sickle cell disease. He presents with a 5-day history of fever, shortness of breath and extreme fatigue. His mother reports that his younger brother, who also has sickle cell disease, has been feeling unwell too recently. A blood test for the patient reveals a severe anaemia and low reticulocyte count. He has most likely developed: A Splenic sequestration B Pneumococcal infection C Vaso-occlusive crisis D Folic acid deficiency E Parvovirus B19 infection
E Parvovirus B19 infection Aplastic crises caused by parvovirus B19 infection (E) can occur in patients with sickle cell disease. They can present with acute worsening of the patient’s baseline anaemia, which might manifest as shortness of breath and fatigue as in this case. The fever points to an infectious cause. The virus affects erythropoiesis by invading erythrocyte precursors and destroying them. Infants and children with sickle cell disease initially have no immunity to parvovirus B19, and their first exposure can lead to pure red cell aplasia. In a normal individual the virus blocks red cell production for 2 or 3 days with little consequence, but it can be life threatening in sickle cell patients in whom the red cell life span is already shortened. This can lead to profound anaemia over the course of just a few days, and a dramatic drop in the reticulocyte count. Serum IgM antibodies to parvovirus B19 can confirm the diagnosis, and blood transfusion may be required.
A 26-year-old pregnant woman is found to have an Hb of 9.5 g/dL on a routine blood test, with an MCV of 70. Serum electrophoresis reveals an Hb A2 of 3.9 per cent and Hb A of 96.1 per cent. Her ferritin levels are normal. The most likely diagnosis is: A Iron deficiency anaemia B Cooley’s anaemia C b-Thalassaemia intermedia D b-Thalassaemia minor E a-Thalassaemia
D b-Thalassaemia minor In b-thalassaemia minor (D) only one of the b-globulin alleles is mutated, so these individuals usually only have a well-tolerated microcytic anaemia (Hb >9 g/dL) which is clinically asymptomatic. They might be picked up on a routine blood test, with a low MCH and significantly low MCV (3.5–4 per cent to compensate for the reduced amount of normal haemoglobin, and they might have a slight increase in Hb F. It can worsen in pregnancy, as in this case.
A 24-year-old unemployed man presents to his GP with a 4-week history of flu-like symptoms and a persistent dry cough. On examination he has a maculopapular rash. A blood film reveals a haemolytic anaemia, and he is positive for cold agglutinins. The most likely organism implicated is: A Streptococcus pneumoniae B Mycoplasma pneumoniae C Legionella pneumophilia D Chlamydophila psittaci E Borrelia burgdorferi
B Mycoplasma pneumoniae Autoimmune haemolytic anaemia is a form of mainly extravascular haemolysis, which is mediated by autoantibodies. It is classified into warm and cold autoimmune haemolytic anaemia, according to the optimal temperature at which the antibodies bind to red blood cells. This activates the classical pathway in the complement system, resulting in haemolysis. Cold AIHA is mediated by IgM antibodies, and as the name suggests these antibodies bind optimally at lower temperatures (28–31°C), resulting in anaemia that is aggravated in cold conditions. In severe cases, patients may suffer from Raynaud’s or acrocyanosis (purplish discolouration of peripheries). Most cases are idiopathic, but there are some specific causes worth remembering, as ‘Cold LID’: • Lymphoproliferative disease, e.g. CLL, lymphomas • Infections – mycoplasma, as in this case (B), EBV • Do not know, i.e. idiopathic! This patient has typical features of mycoplasma pneumonia including a protracted history of flu-like symptoms (such as myalgia, arthralgia, headache) and a non-productive cough. Treatment includes avoiding cold conditions, use of chlorambucil, and treating the underlying cause. The other infectious agents listed here do not typically cause a cold haemolytic anaemia.
A 7-year-old boy is taken ill from school on a cold December day, with a presumed viral infection. On returning home that day, he beings to feel even more unwell with a very high fever, headache and abdominal pain. His father begins to worry that his skin has taken on a yellow tinge, and the boy says his urine is now a dark reddy-brown colour. He is taken to the GP and after several tests the presence of ‘Donath–Landsteiner antibodies’ is reported. This child is suffering from: A Paroxysmal cold haemoglobinuria B Paroxysmal nocturnal haemoglobinuria C Sickle cell disease D Acute intermittent porphyria E Epstein–Barr virus
A Paroxysmal cold haemoglobinuria Paroxysmal cold haemoglobinuria (A) is a rare form of autoimmune haemolytic anaemia. It usually affects children in the acute setting after an infection, and the key in this case is the presence of sudden haemoglobinuria and jaundice after exposure to a cold temperatures. IgG autoantibodies usually form after an infection, and bind to red blood cell surface antigens, inducing variable degrees of intravascular haemolysis in the cold. The antibodies are known as ‘Donath–Landsteiner antibodies’. Analysis of the urine will confirm the presence of haemaglobinuria, and blood tests often reveal a normocytic or macrocytic anaemia. It is possible to test indirectly for the IgG antiglobulins at a low temperature, as in this case. Blood transfusion may be required if the anaemia is severe, but in children who have an acute onset with an antecedent infection, it is usually a transient and self limiting condition.
A 21-year-old student has recently been diagnosed with coeliac disease. She presents to her GP complaining of increased tiredness and shortness of breath on climbing stairs. Which of the following are most likely to be raised in this patient? A Serum iron B Haematocrit C Transferrin D Ferritin E Mean cell haemoglobin
C Transferrin This patient is suffering from iron deficiency anaemia, a common complication in coeliac disease. The tiredness and shortness of breath are common symptoms. Causes can include blood loss (e.g. upper or lower GI bleeding, menstruation), malabsorption (as in this case), dietary deficiency (rare in adults but can be seen in children) or infestation with parasitic worms (the most common cause worldwide). Blood tests characteristically reveal a low mean cell volume, mean cell haemoglobin (E) and mean cell haemoglobin concentration. A blood film may reveal hypochromic red blood cells with anisocytosis (variation in cell size) and poikilocytosis (variation in cell shape). The red blood cell distribution width (RDW) (a measure of the variation of the width of red blood cells) may be increased initially.
A 34-year-old woman with known Addison’s disease is brought to the GP by her husband, as he is concerned that she keeps falling over at night. On examination the GP notes that she has conjunctival pallor. A thorough neurological examination reveals absent knee jerks, absent ankle jerks and extensor plantars bilaterally. Which of the following is the most sensitive test for the condition she has developed? A Anti-intrinsic factor antibodies B Anti-endomysial cell antibodies C Anti-smooth muscle antibodies D Anti-parietal cell antibodies E Anti-voltage gated calcium channel antibodies
D Anti-parietal cell antibodies This woman has developed pernicious anaemia leading to vitamin B12 deficiency. It can be associated with other autoimmune conditions, such as Addison’s disease or thyroid disease. Specifically, she has developed a condition called subacute combined degeneration of the cord (SACD) which has led to symmetrical loss of dorsal columns (resulting in loss of touch and proprioception leading to ataxia, and LMN signs) and corticospinal tract loss (leading to UMN signs), with sparing of pain and temperature sensation (which is carried by spinothalamic tracts). The ataxia and loss of joint position sense have resulted in her falling at night, which may be exacerbated by optic atrophy – another manifestation of vitamin B12 deficiency. Remember that vitamin B12 is found in meat, fish and dairy products. More common causes of vitamin B12 deficiency can be related to diet (e.g. vegans) or to malabsorption. It is absorbed in the terminal ileum after binding to intrinsic factor produced by the parietal cells in the stomach. Causes of malabsorption can therefore be related to the stomach (e.g. post gastrectomy, pernicious anaemia), or due to the terminal ileum (e.g. Crohn’s, resection of the terminal ileum, bacterial overgrowth).
A 58-year-old woman is referred to a haematology clinic following repeated chest infections and epistaxis. On examination the doctor notes that she has conjunctival pallor and some petechial rashes on her forearms, but no organomegaly. Her blood tests reveal a pancytopenia, and an MCV of 112. Her drug history includes omeprazole, carbamazepine, gliclazide, metformin, paracetamol, and simvastatin. A bone marrow biopsy reveals a hypocellular marrow. The most likely diagnosis is: A Aplastic anaemia B Myelodysplasia C Hypothyroidism D Chronic myeloid leukaemia E Myeloma
A Aplastic anaemia 14 A Causes of macrocytosis can be divided into: 1 Megaloblastic, e.g. folate and B12 deficiency 2 Non-megalobastic, causes of which can be remembered as RALPH = reticulocytosis (e.g. in haemolysis), alcohol, liver disease, pregnancy and hypothyroidism) 3 Other haematological disorders, e.g. myelodysplasia, aplastic anaemia, myeloma, myeloproliferative disorders This woman is suffering from aplastic anaemia (A), where the bone marrow stops producing cells leading to a pancytopenia. Bone marrow examination is needed to confirm the diagnosis, and shows a hypocellular bone marrow. Causes of aplastic anaemia can be primary or secondary. Primary causes can be congenital (e.g. Fanconi’s anaemia) or idiopathic acquired aplastic anaemia. Secondary causes include drugs (all the Cs – cytotoxics, carbamazepine, chloramphenicol, anticonvulsants such as phenytoin), ionizing radiation and viruses (e.g. hepatitis, EBV). This woman’s aplastic anaemia is secondary to long-term carbamazepine therapy for hypothyroidism
A 50-year-old diabetic man sees his GP complaining of generalized tiredness and a painful right knee. He is found on examination to have five finger breadths of hepatomegaly. An X-ray of his right knee is reported as showing chondrocalcinosis. His blood tests are likely to reveal: A Raised MCV B Raised total iron binding capacity C Reduced serum ferritin D Reduced iron level E Raised transferrin saturation
E Raised transferrin saturation This man has hereditary haemachromatosis, an inherited disorder of iron metabolism. It is particularly common in those of Celtic descent, and the gene responsible for the majority of cases is the HFE gene on chromosome 6. Increased iron absorption leads to deposition to multiple organs including: • the liver (hepatomegaly, deranged LFTs) • joints (arthralgia, chondrocalcinosis) • pancreas (diabetes) • heart (dilated cardiomyopathy) • pituitary gland (hypogonadism and impotence) • adrenals (adrenal insufficiency) • skin (slate grey skin pigmentation) Blood tests can show deranged LFTs as in this case, as well as a raised serum ferritin, raised serum iron, reduced or normal total iron binding capacity and raised transferrin saturation (E) (>80 per cent).
A 64-year-old woman is seen in the haematology clinic with generalized bone pain and recurrent infections. Following a set of blood tests, a skeletal survey reveals multiple lytic lesions and a bone marrow biopsy reports the presence of >10 per cent plasma cells. Her blood tests are most likely to have shown: A Raised calcium, normal alkaline phosphatase, raised ESR B Normal calcium, raised alkaline phosphatase, normal ESR C Raised calcium, raised alkaline phosphatase, raised ESR D Raised calcium, normal alkaline phosphatase, raised CRP E Normal calcium, normal alkaline phosphatase, raised CRP
A Raised calcium, normal alkaline phosphatase, raised ESR This woman has multiple myeloma, a cancer of plasma cells. The symptoms can be remembered using the mnemonic BRAIN: Bone pain (due to osteoclast activation leading to hypercalcaemia and the presence of lytic lesions on a skeletal survey, characteristically with a ‘pepperpot skull’ appearance), Renal failure (which can be secondary to one or a combination of: hypercalcaemia, tubular damage from light chain secretion, or secondary amyloidosis), Anaemia (typically normocytic), Infections (particularly pneumonias and pyelonephritis), and Neurological symptoms (such as a headache and visual changes from hyperviscosity, or confusion and weakness from the hypercalcaemia). The diagnostic criteria for symptomatic myeloma are as follows: • Clonal plasma cells >10 per cent on bone marrow biopsy • A paraprotein in the serum or urine – most commonly IgG • Evidence of end-organ damage related to the plasma cell disorder (commonly referred to by the acronym ‘CRAB’): • Calcium – high • Renal insufficiency • Anaemia • Bone lesions (e.g. lytic lesions, or osteoporosis with compression factors) Blood tests may reveal a high calcium but the alkaline phosphatase is often normal (A) (in contrast to other malignancies, with osteolytic metastases and raised alkaline phosphatase).
A 67-year-old woman presented with polyuria and polydipsia on a background of ongoing bone pain. Her blood tests revealed a high calcium, and a serum electrophoresis was sent. Her serum paraprotein was 25 g/L and a bone marrow biopsy revealed 6 per cent clonal plasma cells. The most likely diagnosis is: A Plasma cell dyscrasia B Monoclonal gammopathy of undetermined significance C Smouldering myeloma D Multiple myeloma E Hypercalcaemia with no evidence of underlying malignancy
D Multiple myeloma This question tests your understanding of the diagnostic criteria for plasma cell disorders. Do not forget that: 1 Symptomatic myeloma (D): • Clonal plasma cells on bone marrow biopsy • Paraprotein in either serum or urine • Evidence of end-organ damage attributed to the plasma cell disorder, commonly remembered using the acronym ‘CRAB’ (Calcium – high, Renal insufficiency, Anaemia and Bone lesions) 2 Asymptomatic (smouldering) myeloma (C): • Serum paraprotein >30 g/L AND/OR • Clonal plasma cells >10 per cent on bone marrow biopsy AND • NO myeloma-related organ or tissue impairment 3 Monoclonal gammopathy of undetermined significance (MGUS) (B): • Serum paraprotein
A 39-year-old motorcyclist is admitted following a road traffic accident complicated by severe burns. Several days later he is due to go home, when oozing is noted from his cannula site and he has several nose bleeds. Repeat blood tests reveal an Hb of 12.2 g/dL, WCC of 11.2 × 109/L, and platelets of 28 × 109/L. A coagulation screen shows a prolonged APTT and PT. He also has a reduced fibrinogen and raised D-dimers. The most likely diagnosis is: A Liver failure B Disseminated intravascular coagulation C Thrombotic thrombocytopenic purpura D Aplastic anaemia E Heparin induced thrombocytopenia
B Disseminated intravascular coagulation This man has developed disseminated intravascular coagulation (DIC) (B) following his severe burns. DIC is widespread pathological activation of the clotting cascade in response to various insults. The cascade is activated in various ways: one mechanism is the release of a transmembrane glycoprotein called ‘tissue factor’ in response to cytokines or vascular damage. This results in fibrin formation, which can eventually cause occlusion of small and medium sized vessels and lead to organ failure. At the same time, depletion of platelets and coagulation proteins can result in bleeding (as in this case). It can be caused by a wide range of factors, which can be remembered using the mnemonic ‘I’M STONeD!’: Immunological (e.g. severe allergic reactions, haemolytic transfusion reactions), Miscellaneous (e.g. aortic aneurysm, liver disease), Sepsis, Trauma (including serious tissue injury, burns, extensive surgery), Obstetric (e.g. amniotic fluid embolism, placental abruption), Neoplastic (myeloproliferative disorders as well as solid tumours such as pancreatic cancer), and Drugs and toxins.
A 46-year-old woman is brought to accident and emergency by her daughter, who reports that she had been feeling unwell for a few days with a fever and is now hallucinating. On examination she has a temperature of 38.9°C, is noted to be pale and has widespread purpura over both arms. Blood tests reveal an Hb of 9.1 g/dL, platelet count of 60 × 109/L, creatinine of 226 and urea 16.7. A blood film is reported as showing the presence of shistocytes. The most likely diagnosis is: A Weil’s disease B Glandular fever C Idiopathic thrombocytopenic purpura D Thrombotic thombocytopenic purpura E Haemolytic uraemic syndrome
D Thrombotic thombocytopenic purpura This woman has thrombotic thrombocytopenic purpura (TTP) (D), a rare but potentially fatal haematological emergency. It consists of six key features: 1 MAHA 2 A fever 3 Renal failure 4 Fluctuating CNS signs, e.g. seizures, hallucinations, hemiparesis, decreased consciousness 5 Haematuria/proteinuria 6 Low platelet count You can remember these as ‘MARCH with low platelets’. TTP typically affects adults and is thought to occur due to a deficiency of a protease that is responsible for cleaving multimers of von Willebrand factor. The resulting formation of large vWF multimers stimulates platelet aggregation and fibrin deposition in small vessels. This in turn causes microthrombi to form in blood vessels, impeding the blood supply to major organs such as the kidneys, heart and brain. Haemolysis occurs and shistocytes form because of the sheer stress on red blood cells as they pass through the microscopic clots.
A 28-year-old woman in her 29th week of pregnancy comes to accident and emergency with epigastric pain, nausea and vomiting. She also complains that her hands and feet have been swelling up. On examination her blood pressure is 165/96, HR 125 bpm, and she is apyrexial. She is noted to have yellowing of her sclera and right upper quadrant tenderness. Blood tests reveal an Hb of 10.1, platelets 96, WCC 11.3, LDH 820 (N 70–250), AST 115 (N 5–35), and ALT 102 (N 5–35). Her coagulation screen is normal and a blood film is reported as showing the presence of schistocytes. The most likely diagnosis is: A Hepatitis B Thrombotic thrombocytopenic purpura C Pre-eclampsia D Acute fatty liver of pregnancy E HELLP syndrome
E HELLP syndrome ‘HELLP’ syndrome (E) is a potentially fatal occurrence in pregnancy, characterized by a triad of features: 1 H – haemolysis 2 EL – elevated liver enzymes 3 LP – low platelet count In a similar way to DIC, generalized activation of the clotting cascade is triggered which can only be terminated with delivery. Platelet consumption and MAHA occurs, and liver ischaemia can lead to periportal necrosis and, in severe cases, formation of a subcapsular haematoma which can rupture. It usually presents in the third trimester, but can happen even up to a week after delivery. Often patients with HELLP have had pregnancy-induced hypertension or pre-eclampsia prior to its development. Common symptoms are often vague, and can include nausea and vomiting, epigastric pain, peripheral swelling, paraesthesia, headaches and visual problems. On examination patients may be noted to have peripheral oedema, upper abdominal tenderness, jaundice and hepatomegaly. Complications can include liver and renal failure, pulmonary oedema, DIC and placental abruption. Clotting studies may be normal as in this case, unless DIC has occurred. The only effective treatment is delivery, but other supportive treatment includes control of the hypertension, seizure prophylaxis and corticosteroid use.
A 56-year-old woman with known cirrhosis presents with falls. On examination she is clinically jaundiced and rectal examination reveals malaena. Blood tests reveal an INR of 2.2. She is diagnosed with decompensated chronic liver disease. Which of the following is not a vitamin K dependent clotting factor? A Thrombin B Factor VII C Factor VIII D Protein C E Factor X
C Factor VIII The vitamin K dependent clotting factors include II, VII, IX and X. Vitamin K is also required for the production for protein C, protein S and protein Z, although these are strictly not clotting factors, rather anticoagulant factors. Vitamin K is a fat soluble vitamin found in green leafy vegetables such as spinach, cabbage and cauliflower. It is absorbed in the small bowel and is important in the production of functional clotting factors in the liver. This patient’s acute chronic liver failure has meant she is no longer producing functional clotting factors, represented as a raised INR. Vitamin K is recycled in the liver and its oxidation is coupled with the post-translational modification of glutamate residues to form gammacarboxyglutamate. Vitamin K is firstly reduced by vitamin K epoxide reductase to form vitamin K hydroquinone. This reduced form is oxidized by vitamin K dependent carboxylase to form vitamin K epoxide. This reaction is coupled with gamma-glutamyl carboxylase; the enzyme responsible for post-translational modification of the vitamin K dependent factors. Vitamin K epoxide is then reconverted to vitamin K by vitamin K epoxide reductase; thus completing the cycle. If the patient were to be given vitamin K metabolism antagonists, e.g. warfarin, the clotting factors produced would still be immunologically identical (these are also known as Proteins Induced by Vitamin K Absence/Antagonism – PIVKA) but would lack efficacy as they are unable to interact with calcium or platelet factor 3.
A 46-year-old man presents with pain and swelling in the right calf 2 weeks after being fitted with a plaster cast to his leg after a fall. The calf is tender, erythematous and swollen. He is also a heavy smoker and slightly overweight. His admitting physician suspects a deep vein thrombosis (DVT) and books an ultrasound of the calf. A deep vein thrombosis is confirmed and 5 mg warfarin is started the next day. Two days later, the same patient develops pain and swelling in the other calf, an ultrasound confirms a further deep vein thrombosis in the contralateral leg. What factor is least likely to contribute to the development of the second DVT? A Smoking B Warfarin C Previous DVT D Being slightly overweight E Plaster cast
D Being slightly overweight Although obesity is associated with risk of development of DVT, this man is described as slightly overweight (D). Thus, in comparison to the other risk factors presented, it probably represents the lowest attributable risk to the second DVT.
A 54-year-old man presents with haematemesis. He has known varices and is currently vomiting large amounts of bright red blood. The admitting doctor takes some blood for fast analysis and confirms a haemoglobin of 4 g/dL. The patient’s haematemesis continues and he is transfused a total of 20 units of blood and eight units of fresh frozen plasma in the next 24 hours. The patient underwent gastroscopy which revealed bleeding oesophageal varices which were successfully treated by endoscopic banding. His post-transfusion bloods are the following: Hb 9.2 g/dL White cells 8.0 × 109/L Platelets 57 × 109/L Prothrombin time normal Activated partial thromboplastin time normal Fibrinogen >1.0 g/L What is the most likely cause of his thrombocytopenia? A Disseminated intravascular coagulopathy B Alcohol excess C Massive blood transfusion D Megaloblastic anaemia E Hypersplenism
C Massive blood transfusion Although all of the given options are causes of thrombocytopenia, the most likely cause in this patient is massive blood transfusion without replacement of platelets (C). Massive blood loss may be defined as losing one’s entire circulating blood volume in 24 hours. Other definitions include losing 50 per cent of one’s blood volume in 3 hours or a rate of loss of greater than or equal to 150 mL/min. This patient has been transfused 20 units of blood in the space of 24 hours, thus fulfilling the criteria for massive haemorrhage. Massive transfusion has its own particular complications, including thrombocytopenia. This is because this patient was only given packed red cells and fresh frozen plasma. These two blood products contain very few platelets and in general, a platelet count of around 50 × 109/L is to be expected when approximately two blood volumes have been replaced, as is the case in this patient. In this situation, the expert consensus is to keep the platelet level above 50 × 109/L, but there is marked interindividual variation therefore some consider using 75 × 109/L as the trigger value for platelet transfusion.
Which of the following is not often associated with a very high (>100 mm/hour) erythrocyte sedimentation rate (ESR)? A Myeloma B Anaemia C Leukaemia D Aortic aneurysm E Malignant prostatic cancer
B Anaemia ESR is a commonly used laboratory test to detect the presence of inflammation in general. It is performed by adding a sample of anticoagulant to a blood sample and adding this mixture to a calibrated vertical tube (Westergren tube). As the red cells fall with gravity and accumulate, they lie in the bottom of the tube, and are called sediment. The rate at which they accumulate is therefore the erythrocyte sedimentation rate. Factors which influence the ESR include age, sex and pathological processes which increase plasma proteins or the number of red cells. Women generally have a higher ESR than men and it also increases with age. Depending on the exact reference range for your particular lab, women and men over 50 can have an ESR of up to 30 and 20 mm/ hour, respectively, and still be normal. Conditions which increase plasma proteins such as fibrinogen, acute phase proteins and immunoglobulins can increase the ESR as these proteins reduce the ionic resistance between erythrocytes leading to an increased fall rate. They also promote rouleaux formation of erythrocytes which is the characteristic stacking of erythrocytes seen under the microscope. The most important protein to promote rouleaux formation is fibrinogen. The number of red cells in a given volume also influences ESR; in severe anaemia ESR is falsely raised as the reduced ionic repulsion between erythrocytes allow faster sedimentation. However, this rarely leads to an ESR of >100 mm/ hour, making anaemia (B) the correct answer.
A 62-year-old man presents with shortness of breath. This has been gradually getting worse for the last few years and is associated with chronic productive cough. He is a heavy smoker. His chest X-ray reveals a hyperexpanded chest with no other abnormalities. His bloods tests are normal except for a raised haemoglobin and raised haematocrit. What is the most likely cause for this? A Polycythaemia rubra vera B Idiopathic erythrocytosis C Secondary polycythaemia D Gaisbock’s disease E Combined polycythaemia
E Combined polycythaemia Combined polycythaemia (E), also known as smoker’s polycythaemia, has multiple aetiological factors. Cigarettes contain high concentrations of carbon monoxide gas which bind avidly to haemoglobin, thus displacing oxygen. This leads to increased erythropoietin (EPO) secretion from the hypoxic renal interstitium. EPO promotes erythrocyte proliferation and differentiation and prevents their apoptosis in the bone marrow, thus increasing red cell mass. Smoking is also a significant risk factor for chronic obstructive pulmonary disease, which is what this man suffers from. The obstructed airways reduce oxygen delivery to the alveoli and pulmonary vessels they supply thus causing a reduction of oxygen supply furthering the hypoxia. Finally, smokers also have an associated reduced plasma volume, thus increasing the relative concentration of haemoglobin. This is therefore ‘combined’ because of the presence of both increased red cell mass and reduced plasma volume.
A 25-year-old black man develops jaundice and dark red urine 2 days after starting primaquine, an anti-malarial. His blood tests reveal a macrocytic anaemia with raised bilirubin and urine dipstick is positive for blood. A peripheral blood film reveals ‘bite cells’ and Heinz bodies. The most likely diagnosis is: A Hereditary spherocytosis B Glucose-6-phosphate dehydrogenase deficiency C Paroxysmal nocturnal haemoglobinuria D Microangiopathic haemolytic anaemia E Autoimmune haemolytic anaemia
B Glucose-6-phosphate dehydrogenase deficiency G6PD deficiency (B) (also known as favism) is an X-linked condition where the lack of this enzyme increases the oxidative damage sustained by red blood cells. It is part of the pentose phosphate pathway which maintains levels of reduced glutathione – an important erythrocyte antioxidant. People with this condition have erythrocytes with less reduced glutathione and are thus more sensitive to oxidative stress resulting in haemolysis. There are many variants of G6PD of differing severity. It is unlike some X-linked conditions where women can also be affected if they are homozygous. Precipitating factors include anti-malarials, primaquine, nitrofurantoin, dapsone, sulphonylureas and sulphonamides. Its alternate name, favism, relates to the fact that fava beans (broad beans) can trigger a haemolytic attack. The haemolysis released intracellular haemoglobin causing jaundice in this patient and haemoglobinuria, which caused a positive dipstick result. It is important to note that the differential for a positive dipstick for blood includes haemoglobinuria and myoglobinuria. Macrocytosis occurs from the raised reticulocyte production from increased bone marrow activity. Heinz bodies are seen due to the denatured haemoglobin which gets removed by macrophages in the spleen leaving ‘bite’ cells. A G6PD assay is useful in this patient but less so in the acute setting as the new reticulocytes can contain normal G6PD levels, thus giving a false negative result.
What are the likely laboratory findings for a patient with renal cell carcinoma with secondary polycythaemia who is not dehydrated? A Normal red cell count, normal red cell mass, increased erythropoietin concentration B Increased red cell count, increased red cell mass, increased erythropoietin concentration C Decreased red cell count, decreased red cell mass, normal erythropoietin concentration D Increased red cell count, decreased red cell mass, increased erythropoietin concentration E Decreased red cell count, increased red cell mass, decreased erythropoietin concentration
B Increased red cell count, increased red cell mass, increased erythropoietin concentration This question tests your understanding of erythropoeisis physiology and your understanding of laboratory measurements in a standard full blood count analysis. Red cell count is measured as the number of erythrocytes in a quantum of plasma, whereas red cell mass is determined by isotope studies quoted as mL/kg. It is a measure of absolute red cell mass and is therefore not affected if someone is dehydrated, for example, where the relative plasma volume is reduced giving a falsely high red cell concentration. There are many situations where the red cell concentration and red cell mass do not parallel each other, e.g. vomiting, diarrhoea or overuse of diuretics. If a patient has increased red cell concentration this may therefore be absolute or relative – the latter being secondary to reduced plasma volume thus making the polycythaemia secondary to haemoconcentration. Absolute polycythaemia may be primary or secondary. In this case there is secondary polycythaemia where the renal cell carcinoma is inappropriately producing too much EPO, thus overstimulating bone marrow erythropoeisis. Secondary polycythaemia is not always inappropriate – people with cyanotic heart disease, lung disease, haemoglobinopathies with high oxygen affinity or those living at altitude can get appropriate secondary polycythaemia as a physiological response to chronic hypoxaemia.
von Willebrand’s disease is characterized by abnormal platelet aggregation when they are exposed to: A Streptomycin B Aspirin C Fibrinogen D Collagen E Ristocetin
E Ristocetin von Willebrand’s disease (vWD) is characterized by a quantitive or qualititative defect in von Willebrand factor (vWF). Ristocetin, an antibiotic no longer used clinically, causes vWF to bind the platelet receptor glycoprotein Ib (GlpIb) through an unknown mechanism. If ristocetin is added to platelets with defective vWF or defective GlpIb (called Bernard–Soulier syndrome) then platelet aggregation does not occur. It will occur, however, with other pro-aggregative factors including collagen (D) and fibrinogen (C). If vWF or GlpIb is absent, aggregation does not occur with collagen as there is no molecular link between collagen and the platelet. However, this is the case with all patients with vWF. Furthermore, cryoprecipitate which contains vWF will correct defects in vWD but not in Bernard–Soulier syndrome.
An 18-month-old child with Down syndrome presents with recurrent infections and petechial bleeding. A blood film was analyzed showing a particular distinctive feature of haematological malignancy. What is the most likely diagnostically helpful finding seen in this patient? A Smudge cell B Reed Sternberg cell C Auer rod D Pelger Huet anomaly E Hairy cell
C Auer rod The Auer rod (C) is pathognomonic of acute myeloblastic leukaemia (AML). Children with Down syndrome are at higher risk of this disease due to chromosome 21 duplication where a ‘dosage’ effect is theorized to increase the expression of proto-oncogenes. This may also explain the increased risk of AML in Warkany syndrome type 2 (trisomy 8). Another dosage effect example, also in Down syndrome, is the increased risk of Alzheimer’s disease with beta amyloid, which accumulates in Alzheimer’s disease and is coded for on chromosome 21. Epidemiologically, children with Down syndrome are more likely to get AML than ALL in the first 3 years of their life, but thereafter are more likely to get ALL, similar to those without Down syndrome. Auer rod’s are pathognomonic for AML and are found in the cytoplasm. They represent stacked granules in myeloblasts and are azurophilic. They are particularly common in the M3 subtype of AML (according to the French American British classification).
An 8-year-old African boy presents with a large jaw mass which has been growing rapidly over the last few weeks. A histological sample was taken and a classical ‘starry sky’ appearance was observed. The most likely diagnosis is: A Follicular lymphoma B Marginal zone lymphoma C Burkitt’s lymphoma D Diffuse large B cell lymphoma E Mantle cell lymphoma
C Burkitt’s lymphoma Burkitt’s lymphoma (C) is one of the most aggressive malignancies known to man. It is a type of non-Hodgkin’s lymphoma (NHL) which arises from lymph node germinal centres. It is associated with Epstein–Barr virus and there are three subtypes – endemic, sporadic and immunodeficiency related. It is associated with translocation and dysregulation of the c-myc gene on chromosome 8 including t(8;14), t(2;8) and t(8;22). Histologically, there is profound proliferation. The starry sky appearance reflects islands of macrophages ingesting necrotic tumour cells as they have outgrown their own blood supply. Clinically, the endemic form affects younger men and classically presents with a jaw mass which spreads to extranodal sites including mesentery, ovary, testis, bone marrow and meninges.
A 35-year-old Afro-American man presents with painless lymphadenopathy which he noticed after shaving. He denies any recent infections, fevers, weight loss or night sweats. A biopsy is performed which shows lymphocytic and histiocytic cells. A haematologist calls to confirm the diagnosis of non-classical Hodgkin’s lymphoma. Which subtype is this? A Nodular sclerosis B Mixed cellularity C Nodular lymphocytic D Lymphocytic rich E Lymphocytic depleted
C Nodular lymphocytic Nodular lymphocytic (C) Hodgkin’s lymphoma is often called the nonclassical subtype of Hodgkin’s lymphoma. It is so called due to the atypical nature of the Reed–Sternberg cell which characterizes all Hodgkin’s lymphomas. This cell is known as the lymphocytic and histiocytic cell or L&H variant. Sometimes these cells are referred to as ‘popcorn’ cells because their nucleus resembles an exploded popcorn kernel. This subtype of HL accounts for 5 per cent of cases and has a bimodal age distribution – children and adults between the ages of 30 and 40. Unlike common HL, this type is more common in African American men compared with Caucasians in the US. Clinically, patients often present with peripheral lymphadenopathy without B symptoms (namely fever, night sweats and weight loss). It is generally thought of as a more indolent form of HL.
A 17-year-old boy with glucose-6-phosphate dehydrogenase (G6PD) deficiency presents with tiredness and is noticed to be jaundiced. These features have developed since he was diagnosed with a chest infection 1 week ago. What is the most likely haematological finding? A Positive direct antiglobulin test B Low mean cell volume C Reduced reticulocyte count D Haemoglobinuria E Increased haptoglobin concentration
D Haemoglobinuria This patient has glucose-6-phosphate dehydrogenase (G6PD) deficiency; a common X-linked condition where the reduction of G6PD function leads to haemolysis when erythrocytes are exposed to oxidative stress. Less commonly there is a chronic haemolysis when enzymatic activity is less than 10 per cent of normal. Unlike some other X-linked conditions, women can be affected due to the random nature of X chromosome inactivation (lyonization) which leads to some cells being vulnerable to oxidative stress. G6PD is important in the pentose phosphate shunt which critically regenerates NADPH, a cofactor important in glutathione metabolism. Reduced glutathione is the primary buffer against oxidative stress. Haemoglobinuria (D) occurs due to intravascular haemolysis in the face of oxidative stress in a susceptible patient. Red cells undergo intravascular and extravascular haemolysis leading to haemoglobinaemia and haemoglobinuria. Common precipitants include intercurrent infection but also drugs, the most notorious of which are dapsone, primaquine and nitrofurantoin. Classically, haemolysis can be triggered by fava beans (hence its alternate name ‘Favism’) as well as naphthalene (found in moth balls and henna).
A 35-year-old Asian woman presents with tiredness. The full blood count shows: Haemoglobin: 10.1 g/dL (11.5–16.5) Platelet count: 160 × 109 (150–400 × 109) White cell count: 6.6 × 109 (4–11 × 109) Mean cell volume: 62 fL (80–96 fL) Hb A2: 6.3 per cent (2–3 per cent) Which of the following is the most likely diagnosis? A Sickle cell disease B Acute myeloid leukaemia C b-Thalassaemia major D b-Thalassaemia trait E Hereditary spherocytosis
D b-Thalassaemia trait This woman presents with microcytic anaemia, the most common cause of which is iron deficiency. However, the mean cell volume is disproportionally reduced compared with the degree of anaemia indicating there might be a haemoglobinopathy present. The presence of increased Hb A2 confirms the diagnosis of b-thalassaemia trait. Unfortunately the nomenclature surrounding b-thalassaemia is relatively confusing but an attempt to clarify it will be made here. Firstly, thalassaemia is the reduction or absence of a type of globin gene. Normal haemoglobin is a tetramer of two alpha and two beta globin proteins. The ratio of alpha to non-alpha globin production is tightly controlled. There are two alpha genes located on chromosome 16, whereas only one beta gene on chromosome 11. b-Thalassaemia implies a reduction or absence of the beta chain. Beta (0) thalassaemia refers to an absence of beta globin production. This encompasses over 40 genetic mutations. Patients with this are often described as having b-thalassaemia major (C), however, confusingly some patients can produce beta globin genes but to such a poor extent they behave very similar clinically, as if they had no production. Within the first year of life they have profound life-long transfusion dependent anaemia. This is therefore not compatible in this patient’s case.
A 62-year-old man presents with bruising and tiredness. Examination reveals moderate splenomegly and his a reveal a normocytic anaemia with blood tests platelet count of 900 × 109/L, neutrophilia, basophilia, numerous myelocytes and 4 per cent myeloblasts. The neutrophils have low leukocyte alkaline phosphatase levels. Which of the following is likely to be present in this patient? A t(9;22) B t (8;14) C BCR-Abl fusion gene only D V617F point mutation in JAK2 E 5q-Syndrome
A t(9;22) This patient exhibits features of chronic myeloid leukaemia as evidenced by raised myeloid lineage cells including neutrophils, myelocytes and basophils. The neutrophils are morphologically normal but cytochemically different – a laboratory test sometimes used to differentiate between reactive or leukaemoid neutrophilia and CML is the leukocyte alkaline phosphatase. It is normal or high in the former, but characteristically low in CML. Absolute basophilia is a universal finding in CML, with absolute eosinophilia found in 90 per cent of cases. A raised platelet count is also common in CML; a low platelet count, however, should make one reconsider the diagnosis, e.g. myelodysplastic syndromes. Up to 95 per cent of patients with chronic myeloid leukaemia have the Philadelphia chromosome – a fusion chromosome between the long arms of chromosomes 9 and 22 (A). The formation of the BCR- Abl fusion gene acts as a constitutively active tyrosine kinase, but the induction of leukaemogenesis is complicated and mediated through both tyrosine dependent and independent pathways. It is known, however, that the tyrosine kinase activity of the BCR-Abl gene is absolutely required for transformation. BCR-Abl fusion genes alone (C) can occur without the t(9;22) translocation but this is much less common. This Robertsonian translocation is worth remembering as it is frequently asked about in examinations. The t(8;14) translocation occurs in Burkitt’s lymphoma: a highly aggressive lymphoma where cmyc, an oncogene, is under the influence of an immunoglobulin promoter, which is highly expressed. The V617F point mutation in JAK2 (D) is found in up to 99 per cent of cases of polycythaemia rubra vera. JAK2 is involved in downstream processing of the erythropoietin receptor signalling
Which of the following patients has the worse prognosis? A 25-year-old man with inguinal lymphadenopathy B 25-year-old woman with mediastinal and inguinal lymphadenopathy C 25-year-old woman with mediastinal and inguinal lymphadenopathy and night sweats D 25-year-old woman with mediastinal and inguinal lymphadenopathy with 5 per cent weight loss in last 6 months E 25-year-old man with cervical and mediastinal lymphadenopathy
C 25-year-old woman with mediastinal and inguinal lymphadenopathy and night sweats This question relies on the candidate’s knowledge and understanding of the Ann Arbor staging system. This clinical staging system is relatively intuitive – stages are between I and IV either in the absence or presence of ‘B symptoms’. A simplified version of the classification is as follows: • Stage I: involvement of a single lymph node region • Stage II: involvement of two or more lymph node regions on the same side of the diaphragm • Stage III: involvement of lymph nodes on both sides of the diaphragm • Stage IV: extranodal spread (not spleen however, this is taken as a lymph node) The definition of B symptoms includes significant unexplained fever, night sweats or unexplained weight loss of over 10 per cent during 6 months prior to diagnosis. The presence of B symptoms is denoted by a B subscript after the stage number, the absence is denoted by an A subscript. Patient A would therefore be classified as Ia, patient B as IIa, patient C as IIIb, patient D as IIIa, technically as she does not quite fulfil the 10 per cent loss in 6 months and finally patient E as stage IIa. Note that in Hodgkin’s lymphoma, the disease always spreads contiguously whereas in non-Hodgkin’s lymphoma this is not always the case. Further investigations for clinical staging include an upright chest X-ray, integrated positron emission tomography/computer tomography of the chest/abdomen/pelvis and sometimes a unilateral bone marrow aspirate and biopsy for those with stage III or IV with B symptoms.
A patient presents with acute promyelocytic leukaemia. What is the most likely mechanism of underlying leukaemogenesis? A Telomere shortening B Aberrant fusion of two genes C Impaired protein degredation D Over-expression of cellular oncogene E Post-translational modification
B Aberrant fusion of two genes Acute promyelocytic leukaemia is interesting for a number of reasons. There is a reciprocal translocation between the long arms of chromosomes 15 and 17 giving the PML-RARA fusion gene (B). This links the retinoic acid receptor alpha (RARA) gene on chromosome 17 with the promyelocytic leukaemia (PML) gene on chromosome 15. RARA is a member of a family of retinoin-binding transcription factors that regulate gene expression. It heterodimerizes with retinoid X receptor (RXR) and binds to retinoic acid response elements to influence gene transcription. In the absence of retinoic acid, the RARA/RXR dimer interacts with another protein (nuclear corepressor) to repress gene transcription. Therefore, addition of retinoic acid stimulates gene transcription. In the setting of promyelocytic leukaemia, retinoic acid induces myeloid differentiation which is abnormally halted thus providing remission by encouraging cell differentiation rather than cell death. The second reason this type of leukaemia is interesting is its association with disseminated intravascular coagulopathy. The pathogenesis is not completely understood but recognizing it early is important as treatment with retinoic acid plus supportive therapy can lead to rapid improvement in the coagulopathy.
A 64-year-old man presents with lethargy, weight loss and abdominal fullness. He is found to have chronic myeloid leukaemia. He is started on imatinib as part of the initial treatment to control his disease. What is the mechanism of action of imatinib? A Proteosome inhibitor B Tyrosine kinase inhibitor C IL-6 inhibitor D p53 inhibitor E Human epidermal growth factor receptor 2 protein inhibitor
B Tyrosine kinase inhibitor Imatinib is a tyrosine kinase inhibitor (B) and is used in the treatment of chronic myeloid leukaemia. It is a rational therapy which acts to inhibit the BCR-Abl tyrosine kinase thus blocking proliferation and inducing apoptosis in BCR-Abl positive cell lines. The BCR-Abl fusion is most commonly secondary to a balanced Robertsonian translocation between chromosomes 9 and 22. Imatinib is also used for gastrointestinal stromal tumour (GIST). Other tyrosine kinase inbitors include dasatinib and nilotinib. They do not cure CML but provide long-term control in the majority of patients, thus they are the initial treatment of choice for almost all newly diagnosed patients with CML.
A 16-year-old girl with mild von Willebrand’s disease is scheduled for a dental extraction. She has had one previously where she required two units of blood transfused. What is the most appropriate treatment for this patient prior to surgery? A Cryoprecipitate B Desmopressin C Fresh frozen plasma D Vitamin K E Recombinant factor VIII concentrate
B Desmopressin This woman has mild von Willebrand’s disease (vWD) which can be treated with desmopressin (B). There are three types of vWD – type I is a quantitative deficiency of von Willebrand Factor (vWF), type II is a qualitative defect in vWF whereas type III results in profound deficiency in vWF. There are four subtypes of type II vWF (2A, 2B, 2M and 2N). vWF is important in two ways; first it acts as a bridge between platelets and between platelets and subendothelial structures at the site of injury; and second it carries factor VIII which is a key molecule in the clotting cascade. Desmopressin acts to increase vWF and factor VIII concentration by encouraging its release from endothelial cell storage sites. Desmopressin is efficacious in type I and most type II disease but not in type III. This woman is known to have ‘mild’ disease thus making desmopressin a viable option. Interestingly, desmopressin in patients with type 2B will lead to a transient worsening of their thrombocytopenia. Patients with type 2B vWD have increased binding of the abnormal vWF to platelets causing sequestration and clearance of platelets. This is worsened for desmopressin, if only for a few hours. Despite this, there have been reports of patients benefiting from desmopressin.
An 80-year-old man presents with tiredness and lethargy. After initial work-up, a diagnosis of myelodysplastic syndrome is suspected. Which of the following is true about this condition? A A blood film will typically show neutrophil toxic granulation B If there are 1 per cent blasts of the total white cell count, this represents leukaemic transformation C Cytotoxic chemotherapy is first line treatment D Mortality is more likely to be from infection than leukaemic transformation E Absence of the short arm of chromosome 5 is a subtype
D Mortality is more likely to be from infection than leukaemic transformation The myelodysplastic syndromes are a heterogeneous group of conditions characterized by an abnormal clone of stem cells with impaired proliferation and differentiation. The result is a peripheral cytopenia, qualitative abnormalities in erythroid, myeloid and megakaryocyte maturation, as well as increased risk of leukaemic transformation. The abnormalities, both quantitative and qualitative, in neutrophils mean susceptibility to bacterial infection is high and thus a corresponding increased likelihood of mortality (D). Skin infections are particularly common and resistant to treatment.
A middle-aged woman comes to the dermatology clinic with a suspicious mole on her back. You decide excision is required and during the history she says ‘I have Factor V Leiden’. Which of the following best describes the pathophysiology of Factor V Leiden mutation? A Prothrombin mutation B Activated protein C resistance C Antithrombin III deficiency D Protein C deficiency E Protein S deficiency
B Activated protein C resistance Factor V Leiden is an autosomal dominantly inherited point mutation where arginine is replaced by glutamine in the 506th position. Factor V normally circulates in plasma as an inactivated factor and is activated by thrombin which then acts as a co-factor, with factor Xa, to convert prothrombin to thrombin. Factor Va is inactivated by cleavage of its heavy chain; firstly at position Arg506, which causes conformational change to reveal a further two cleavage sites (Arg306 and Arg 679). This inactivation is performed by the activated protein C complex, and thus the Leiden mutation confers resistance (B). The prothrombotic consequence of Factor V Leiden is actually two-fold – first Factor V is degraded more slowly thus there is more generation of thrombin in the prothrombinase complex and second, once factor V is cleaved at the first Arg506 site, it is thought to play a role, with protein S, to support activated protein C in Factor VIIIa degradation too.
A Kostmann syndrome B Severe combined immunodeficiency C Hyper IgM syndrome D Leukocyte adhesion deficiency E Protein-losing enteropathy F Cyclic neutropenia G Bruton’s agammaglobulinaemia H Di George’s syndrome I AIDS A 4-month-old girl is referred to a paediatrician with failure to thrive, after suffering from recurrent infections since birth, especially recurrent candida infections of her skin and mouth. Blood tests reveal a diminished T-cell count; further lymphocyte testing demonstrates non-functional B cells.
B Severe combined immunodeficiency Severe combined immunodeficiency (SCID; B) causes defects in both T cells and B cells. The most common subtypes can be categorized into an X-linked disease (mutation of IL-2 receptor) or an autosomal recessive condition (mutation of adenosine deaminase gene which leads to a build-up of toxins and hence compromised proliferation of lymphocytes). Characteristically, there is hypoplasia and atrophy of the thymus and mucosa-associated lymphoid tissue (MALT). Clinical features include diarrhoea, failure to thrive and skin disease (graft-versus-host induced, secondary to transplacental maternal T cells or blood transfusion- related caused by donor T cells).
A Kostmann syndrome B Severe combined immunodeficiency C Hyper IgM syndrome D Leukocyte adhesion deficiency E Protein-losing enteropathy F Cyclic neutropenia G Bruton’s agammaglobulinaemia H Di George’s syndrome I AIDS A 5-month-old boy is referred to a paediatrician after suffering with recurrent infections since his birth. His mother has noticed increased irritability. Blood tests reveal a neutrophil count of 350/μL. NBT test is normal.
A Kostmann syndrome Kostmann syndrome (severe congenital neutropenia; A) is a congenital neutropenia as a result of failure of neutrophil maturation. This results in a very low neutrophil count (less than 500/μL indicates severe neutropenia) and no pus formation. Kostmann syndrome is usually detected soon after birth. Presenting features may be non-specific in infants, including fever, irritability and infection. The nitro-blue-tetrazolium (NBT) test can help with diagnosis; the liquid turns blue due to the normal presence of NADPH. In Kostmann syndrome, NBT test is positive and therefore normal.
A Kostmann syndrome B Severe combined immunodeficiency C Hyper IgM syndrome D Leukocyte adhesion deficiency E Protein-losing enteropathy F Cyclic neutropenia G Bruton’s agammaglobulinaemia H Di George’s syndrome I AIDS A 5-month-old boy is referred to a paediatrician after suffering with recurrent infections since his birth. His mother has noticed increased irritability. Blood tests reveal a neutrophil count of 350/μL. NBT test is normal.
A Kostmann syndrome Kostmann syndrome (severe congenital neutropenia; A) is a congenital neutropenia as a result of failure of neutrophil maturation. This results in a very low neutrophil count (less than 500/μL indicates severe neutropenia) and no pus formation. Kostmann syndrome is usually detected soon after birth. Presenting features may be non-specific in infants, including fever, irritability and infection. The nitro-blue-tetrazolium (NBT) test can help with diagnosis; the liquid turns blue due to the normal presence of NADPH. In Kostmann syndrome, NBT test is positive and therefore normal.
A Kostmann syndrome B Severe combined immunodeficiency C Hyper IgM syndrome D Leukocyte adhesion deficiency E Protein-losing enteropathy F Cyclic neutropenia G Bruton’s agammaglobulinaemia H Di George’s syndrome I AIDS A 48-year-old woman presents to her GP with a history of diarrhoea for 3 weeks, which occasionally contains blood. She has felt increasingly tired and feverish. The patient has had similar episodes in the past which were treated with mesalazine. She also reports recurrent chest infections since her first episode of diarrhoea.
E Protein-losing enteropathy Protein-losing enteropathy (E) is defined as the severe loss of proteins via the gastrointestinal tract. The underlying pathophysiology may relate to mucosal disease, lymphatic obstruction or cell death leading to increased permeability to proteins. If more proteins are lost than synthesized in the body, hypoproteinaemia will result. Causes include Crohn’s disease, coeliac disease and rarely, Menetrier’s disease. Hypoproteinaemia secondary to such conditions results in fewer immunoglobulins being formed which diminishes the adaptive immune response.
A Kostmann syndrome B Severe combined immunodeficiency C Hyper IgM syndrome D Leukocyte adhesion deficiency E Protein-losing enteropathy F Cyclic neutropenia G Bruton’s agammaglobulinaemia H Di George’s syndrome I AIDS A 3-year-old girl is seen by a GP due to recurrent mild chest infections. The doctor notices the girl has a cleft lip. Blood tests reveal a reduced T-cell count as well as hypocalcaemia.
H Di George’s syndrome Di George’s syndrome (H) is caused by an embryological abnormality in the third and fourth branchial arches (pharyngeal pouches) due to a 22q11 deletion. The result is an absent or hypoplastic thymus, as well as a deficiency in T cells. There is a reduction or absence of CD4+ and CD8+ T cells as well as decreased production of IgG and IgA. B cell and IgM levels are normal. The features of Di George’s syndrome can be remembered by the mnemonic ‘CATCH’: cardiac abnormalities, atresia (oesophageal), thymic aplasia, cleft palate and hypocalcaemia.
A Selective IgA deficiency disease B Common variable immunodeficiency C Nephrotic syndrome D Bare lymphocyte syndrome deficiency E Sickle cell anaemia F Chronic granulomatous G Reticular dysgenesis H Wiskott–Aldrich syndrome I Interferon-gamma receptor A 4-year-old boy is referred to a paediatrician after suffering recurrent chest infections over the preceding few months. The boy has a history of eczema as well as recurrent nose bleeds. Blood tests reveal a reduced IgM level but raised IgA and IgE levels.
H Wiskott–Aldrich syndrome Wiskott–Aldrich syndrome (WAS; H) is an X-linked condition which is caused by a mutation in the WASp gene; the WAS protein is expressed in developing haematopoietic stem cells. WAS is linked to the development of lymphomas, thrombocytopenia and eczema. Clinical features include easy bruising, nose bleeds and gastrointestinal bleeds secondary to thrombocytopenia. Recurrent bacterial infections also result. Blood tests reveal a reduced IgM level and raised IgA and IgE levels. IgG levels may be normal, reduced or elevated.
A Selective IgA deficiency disease B Common variable immunodeficiency C Nephrotic syndrome D Bare lymphocyte syndrome deficiency E Sickle cell anaemia F Chronic granulomatous G Reticular dysgenesis H Wiskott–Aldrich syndrome I Interferon-gamma receptor A 20-year-old man presents to his GP with signs of a mild pneumonia. The patient states he has had several similar episodes in the past. Further investigations by an immunologist reveal the patient has a genetic condition caused by a mutation of MHC III.
B Common variable immunodeficiency Common variable immunodeficiency (CVID; B) presents in adulthood. A mutation of MHC III causes aberrant class switching, increasing the risk of lymphoma and granulomas. Patients with CVID also have a predisposition to developing autoimmune diseases. Recurrent infections caused by Haemophilus influenzae and Streptococcus pneumoniae are common. Clinical sequelae include bronchiectasis and sinusitis. Blood tests reveal a reduced B-cell count, a normal/reduced IgM level and decreased levels of IgA, IgG and IgE.
A Selective IgA deficiency disease B Common variable immunodeficiency C Nephrotic syndrome D Bare lymphocyte syndrome deficiency E Sickle cell anaemia F Chronic granulomatous G Reticular dysgenesis H Wiskott–Aldrich syndrome I Interferon-gamma receptor A 3-year-old girl is referred to a paediatrician after concerns about recurrent skin infections she has suffered from since birth. A nitro-blue-tetrazolium test is negative (remains colourless).
F Chronic granulomatous Chronic granulomatous disease (F) is an X-linked disorder causing deficiency of NADPH oxidase. As a result, neutrophils cannot produce the respiratory burst required to clear pathogens. The disease is characterized by chronic inflammation with non-caseating granulomas. Clinical features include recurrent skin infections (bacterial) as well as recurrent fungal infections. The disease is usually detected by the age of 5 and is diagnosed using the nitro-blue-tetrazolium (NBT) test, which remains colourless due to NADPH deficiency (if NADPH is present the solution turns blue). The patient will have a normal neutrophil count as there is no defect in neutrophil production.
A Selective IgA deficiency disease B Common variable immunodeficiency C Nephrotic syndrome D Bare lymphocyte syndrome deficiency E Sickle cell anaemia F Chronic granulomatous G Reticular dysgenesis H Wiskott–Aldrich syndrome I Interferon-gamma receptor A 4-year-old boy is referred to a paediatrician after a period of mild but chronic diarrhoea. On examination the child is found to have icteric sclera and hepatomegaly. Following blood tests, the doctor has a high suspicion that the child could have a defect in MHC I.
D Bare lymphocyte syndrome Bare lymphocyte syndrome (D) is caused by either deficiency in MHC I (type 1; all T cells become CD4+ T cells) or MHC II (type 2; all T cells become CD8+ T cells). Clinical manifestations include sclerosing cholangitis with hepatomegaly and jaundice.
A Selective IgA deficiency disease B Common variable immunodeficiency C Nephrotic syndrome D Bare lymphocyte syndrome deficiency E Sickle cell anaemia F Chronic granulomatous G Reticular dysgenesis H Wiskott–Aldrich syndrome I Interferon-gamma receptor A 22-year-old woman visits her GP after several chest infections in the past few years. As well as the chest infections, the patient reports that she has had several bouts of diarrhoea over the same time period.
A Selective IgA deficiency disease Selective IgA deficiency (A): IgA specifically provides mucosal immunity, primarily to the respiratory and gastrointestinal systems. Selective IgA deficiency results from a genetic inability to produce IgA and is characterized by recurrent mild respiratory and gastrointestinal infections. Patients with selective IgA deficiency are also at risk of anaphylaxis to blood transfusions due to the presence of donor IgA. This occurs especially after a second transfusion; antibodies having been created against IgA during the primary transfusion. Selective IgA deficiency is also linked to autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and coeliac disease.
A HLA-matching B Corticosteroids C Cyclosporine A D Azathioprine E Sirolimus F OKT3 G IL-2 receptor antibody H Tacrolimus I Anti-lymphocyte antibody A 48-year-old man has undergone a kidney transplant operation as a result of renal failure caused by long-standing diabetes mellitus. However, despite immunosuppression, signs of organ rejection become evident just 1 hour after the procedure.
A HLA-matching HLA-matching (tissue typing; A) is a preventative method of limiting the risk of organ transplant rejection. It is impractical to match all HLA loci and hence tissue typing focuses on major HLA antigens such as HLA-A and HLA-B. HLA-DR is also now routinely typed due to its role in activating recipient’s T-helper cells. HLA-matching greatly reduces the chance of hyperacute rejection caused by the presence of preformed antibodies against the graft. Pre-formed antibodies may occur as a result of previous blood transfusion or pregnancy.
A HLA-matching B Corticosteroids C Cyclosporine A D Azathioprine E Sirolimus F OKT3 G IL-2 receptor antibody H Tacrolimus I Anti-lymphocyte antibody A 45-year-old man undergoes a heart transplant due to end-stage heart failure. Seventy-two hours after the operation, the patient shows signs of organ rejection which is resistant to corticosteroid therapy. A mouse monoclonal antibody is administered to save the transplant.
F OKT3 OKT3 (muromonab-CD3; F) is a mouse monoclonal antibody targeted at the human CD3 molecule used to treat rejection episodes in patients who have undergone allograft transplantation. Administration of the antibody efficiently clears T cells from the recipient’s circulation, T cells being the major mediator of acute organ rejection. Primary indications include the acute corticosteroid-resistant rejection of renal, heart and liver transplants. Anaphylaxis can result given a murine protein is introduced to the recipient. OKT3 can also bind to CD3 on T cells, stimulating the release of TNF-α and IFN-γ causing cytokine release syndrome, which if severe, can be fatal.
A HLA-matching B Corticosteroids C Cyclosporine A D Azathioprine E Sirolimus F OKT3 G IL-2 receptor antibody H Tacrolimus I Anti-lymphocyte antibody A 32-year-old woman undergoes a bone marrow transplant for chronic lymphoblastic leukaemia. She is prescribed a medication that inhibits calcineurin. On examination, the patient has gum hyperplasia.
C Cyclosporine A Cyclosporine A (C) is an important immunosuppressive agent in the organ transplant arena, which inhibits the protein phosphatase calcineurin. This in turn inhibits IL-2 secretion from T cells, a cytokine which stimulates T cell proliferation. Another proposed mechanism of action involves the stimulation of TGF-β production. TGF-β is a growth-inhibitory cytokine, the production of T cells is reduced, hence minimizing organ rejection. Adverse effects include nephrotoxicity, hepatotoxicity, diarrhoea and pancreatitis. On examination, patients taking cyclosporine A may have gum hyperplasia.
A HLA-matching B Corticosteroids C Cyclosporine A D Azathioprine E Sirolimus F OKT3 G IL-2 receptor antibody H Tacrolimus I Anti-lymphocyte antibody A 62-year-old man who has undergone a kidney transplant was started on an immunosuppressive agent prior to the operation. The patient is warned that he will only be on the medication for a short period due to long-term side effects such as osteoporosis.
B Corticosteroids Corticosteroids (B) are used as an immunosuppressive agent in both the prevention and treatment of transplant rejection. Corticosteroids inhibit phospholipase A2 thereby blocking prostaglandin formation as well as a series of inflammatory mediators. The immunosuppressive effects of corticosteroids are numerous and include reducing the number of circulating B cells, inhibiting monocyte trafficking, inhibiting T-cell proliferation and reducing the expression of a number of cytokines, for example, IL-1, IL-2 and TNF-α. Prednisolone is used prophylactically before transplantation to prevent rejection; methylprednisolone is used in the treatment of rejection. Side effects are frequent, however, and include osteoporosis, diabetes mellitus and hypertension.
A HLA-matching B Corticosteroids C Cyclosporine A D Azathioprine E Sirolimus F OKT3 G IL-2 receptor antibody H Tacrolimus I Anti-lymphocyte antibody A 62-year-old man who is undergoing a liver transplant as a result of cirrhosis is prescribed a medication that inhibits DNA synthesis in an attempt to prevent proliferation of T cells.
D Azathioprine Azathioprine (D) is an antimetabolite agent used in immunosuppressive therapy. Azathioprine is metabolized into 6-mercaptopurine (6-MP), a purine analogue that prevents DNA synthesis, thereby inhibiting the proliferation of cells; lymphocytes are most affected. Antigen presenting cells present non-self proteins (from the allograft) to T cells which in turn produce IL-2 to stimulate T-cell proliferation. However, 6-MP inhibits this proliferation and so the reaction between T cells and the allograft is minimized. Important side effects include hepatotoxicity, hypersensitivity reactions and myelosuppression.
A Anti-smooth muscle B p-ANCA C Anti-Jo1 D Anti-cyclic citrullinated protein E Anti-centromere F Anti-double stranded DNA G Anti-parietal cell H Anti-thyroid stimulating hormone I Anti-topoisomerase A 56-year-old woman presents to the rheumatologist with pain in her hands. On examination there are obvious deformities of her proximal interphalyngeal joints and metacarpophalyngeal joints. Swan-neck deformities are seen but the patient has retained functionality of her fingers.
D Anti-cyclic citrullinated protein Anti-cyclic citrullinated protein (anti-CCP; D) antibody is associated with rheumatoid arthritis. The antibody is directed at the filament aggregating protein, filaggrin. Rheumatoid arthritis is a chronic systemic autoimmune disease that results in a symmetrical deforming polyarthritis. Clinical features include deformities of the hands (Boutonierre’s deformity, swan-neck deformity, Z-thumb and ulnar deviation of the fingers). The proximal interphalangeal joints are affected more than the distal interphalangeal joints. Extra-articular manifestations include pulmonary fibrosis, pericardial effusion, rheumatoid nodules and splenomegaly (Felty’s syndrome). Rheumatoid factor is another antibody measured in the investigation of rheumatoid arthritis, but is less sensitive and specific in comparison to anti-CCP.
A Anti-smooth muscle B p-ANCA C Anti-Jo1 D Anti-cyclic citrullinated protein E Anti-centromere F Anti-double stranded DNA G Anti-parietal cell H Anti-thyroid stimulating hormone I Anti-topoisomerase A 45-year-old woman is referred to a hepatologist after suffering an episode of jaundice, fatigue and fever. Liver function tests reveal an increased AST. Biopsy of the liver reveals cirrhosis and an autoimmune pathology is suspected.
A Anti-smooth muscle Anti-smooth muscle (A) antibody (anti-SMA) suggests the diagnosis of autoimmune hepatitis, but can also be present in patients with primary sclerosing cholangitis. Autoimmune hepatitis is characterized by inflammation, hepatocellular necrosis, fibrosis, with cirrhosis in severe cases. Diagnosis requires histological confirmation together with the presence of autoantibodies which may either be non-organ or liver-specific. Autoimmune hepatitis is classified into two major groups depending on the autoantibody present: type 1 is defined by the presence of anti-SMA and/or anti-nuclear antibody, whilst type 2 is characterized by the presence of anti-liver/kidney microsomal-1 antibody (anti-LKM-1).
A Anti-smooth muscle B p-ANCA C Anti-Jo1 D Anti-cyclic citrullinated protein E Anti-centromere F Anti-double stranded DNA G Anti-parietal cell H Anti-thyroid stimulating hormone I Anti-topoisomerase A 42-year-old woman presents to the rheumatologist with weakness in her proximal muscles and describes how she is finding it difficult to climb stairs. On examination, a rash is observed surrounding both eyes. A high resolution CT scan reveals a pulmonary fibrosis picture.
C Anti-Jo1 Anti-Jo1 (C) antibody is present in patients with dermatomyositis. Dermatomyositis is characterized by autoimmune inflammation of muscle fibres and skin. Clinical features include a heliotrope rash around the eyes, Gottron’s papules on the dorsum of finger joints as well as weakness of the proximal limb muscles which causes difficulty in climbing stairs and rising from a chair. Dermatomyositis is commonly associated with SLE and scleroderma. The presence of anti-Jo1 in dermatomyositis typically suggests interstitial pulmonary involvement. Blood tests reveal an increased ESR and raised creatine kinase level.
A Anti-smooth muscle B p-ANCA C Anti-Jo1 D Anti-cyclic citrullinated protein E Anti-centromere F Anti-double stranded DNA G Anti-parietal cell H Anti-thyroid stimulating hormone I Anti-topoisomerase A 43-year-old man is referred to the rheumatologist after experiencing paleness in his fingers, especially when exposed to cold weather. The patient also complains of recent onset difficulty in swallowing solid food.
E Anti-centromere Anti-centromere (E) antibody is associated with limited systemic scleroderma (CREST syndrome). CREST syndrome is characterized by calcinosis, Reynaud’s syndrome, oesophageal dysmotility, sclerodactyly and telangiectasia. The pathophysiology is defined by endothelial injury and chronic fibrosis (orchestrated by PDGF and TGF-β). Blood investigations will reveal a raised ESR, anaemia and hypergammaglobulinaemia. Anti-centromere antibodies detected in the presence of primary biliary cirrhosis indicate portal hypertension.
A Anti-smooth muscle B p-ANCA C Anti-Jo1 D Anti-cyclic citrullinated protein E Anti-centromere F Anti-double stranded DNA G Anti-parietal cell H Anti-thyroid stimulating hormone I Anti-topoisomerase A 42-year-old woman presents to the rheumatologist with joint pain and stiffness. On examination, the patient appears to have a tight mouth and fine end inspiratory crackles on auscultation of the lungs. The woman also has a widespread itchy rash on her body.
I Anti-topoisomerase Anti-topoisomerase (I) antibody is characteristic of diffuse systemic scleroderma. Diffuse systemic scleroderma shares some features of limited systemic scleroderma, however, it is more aggressive in its course, affecting large areas of the skin as well as involving the kidneys, heart and lungs. The pathogenesis of diffuse systemic scleroderma is similar to that of limited systemic scleroderma. The presence of anti-topoisomerase antibodies in diffuse systemic sclerosis is associated with pulmonary interstitial fibrosis.
A Anti-mitochondrial B c-ANCA C Anti-cardiolipin D Anti-ribonucleoprotein E Anti-glutamic acid decarboxylase F Anti-Ro G Anti-nuclear H Anti-intrinsic factor I Anti-endomysial A 25-year-old woman presents to her GP with a dry mouth and eyes for a period of 2 weeks. The patient also complains of joint pains over this time-course.
F Anti-Ro Anti-Ro (anti-SS-A; F) and Anti-La (anti-SS-B) antibodies are present in approximately 50 per cent of patients with Sjögren’s syndrome, as well as a lower proportion of patients with systemic lupus erythematosus. Sjögren’s syndrome is characterized by the destruction of the epithelial cells of exocrine glands. Salivary gland biopsy reveals an infiltrate of T and B cells; CD4+ T cells are most prominent. Clinical features include dryness of the eyes (confirmed by Schirmer’s test) and mouth, parotid swelling, fatigue, arthralgia and myalgia. Blood tests will demonstrate a raised ESR and occasionally a mild anaemia.
