ALL Flashcards

Question

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

Answer 1

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.

Answer 2

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.

Answer 3

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.

Answer 4

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.

Answer 5

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.

Answer 6

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.

Answer 7

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.

Answer 8

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.

Answer 9

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.

Answer 10

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.

Answer 11

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.

Answer 12

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.

Answer 13

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.

Answer 14

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.

Answer 15

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.

Answer 16

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.

Answer 17

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.

Answer 18

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.

Answer 19

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.

Answer 20

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.

Answer 21

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.

Answer 22

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.

Answer 23

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.

Answer 24

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.

Answer 25

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.

Answer 26

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.

Answer 27

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.

Answer 28

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.

Answer 29

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.

Answer 30

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.

Answer 31

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.

Answer 32

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).

Answer 33

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.

Answer 34

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.

Answer 35

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.

Answer 36

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.

Answer 37

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.

Answer 38

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.

Answer 39

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.

Answer 40

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.

Answer 41

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

Answer 42

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.

Answer 43

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.

Answer 44

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.

Answer 45

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.

Answer 46

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.

Answer 47

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.

Answer 48

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.

Answer 49

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

Answer 50

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.

Answer 51

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

Answer 52

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.

Answer 53

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.

Answer 54

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.

Answer 55

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.

Answer 56

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.

Answer 57

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.

Answer 58

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.

Answer 59

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.

Answer 60

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.

Answer 61

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.

Answer 62

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.

Answer 63

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.

Answer 64

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.

Answer 65

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’.

Answer 66

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.

Answer 67

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.

Answer 68

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).

Answer 69

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.

Answer 70

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).

Answer 71

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,

Answer 72

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.

Answer 73

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.

Answer 74

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.

Answer 75

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.

Answer 76

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).

Answer 77

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.

Answer 78

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.

Answer 79

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.

Answer 80

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.

Answer 81

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.

Answer 82

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.

Answer 83

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).

Answer 84

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.

Answer 85

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.

Answer 86

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).

Answer 87

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.

Answer 88

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.

Answer 89

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.

Answer 90

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.

Answer 91

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).

Answer 92

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.

Answer 93

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.

Answer 94

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.

Answer 95

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

Answer 96

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.

Answer 97

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).

Answer 98

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.

Answer 99

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).

Answer 100

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).

Answer 101

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).

Answer 102

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.

Answer 103

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.

Answer 104

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.

Answer 105

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.

Answer 106

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.

Answer 107

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

Answer 108

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.

Answer 109

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.

Answer 110

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.

Answer 111

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.

Answer 112

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.

Answer 113

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.

Answer 114

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).

Answer 115

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

Answer 116

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).

Answer 117

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).

Answer 118

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

Answer 119

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.

Answer 120

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.

Answer 121

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.

Answer 122

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.

Answer 123

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.

Answer 124

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.

Answer 125

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.

Answer 126

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.

Answer 127

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.

Answer 128

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.

Answer 129

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.

Answer 130

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).

Answer 131

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.

Answer 132

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.

Answer 133

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).

Answer 134

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.

Answer 135

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

Answer 136

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.

Answer 137

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.

Answer 138

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.

Answer 139

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.

Answer 140

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.

Answer 141

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.

Answer 142

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).

Answer 143

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.

Answer 144

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.

Answer 145

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.

Answer 146

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.

Answer 147

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.

Answer 148

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.

Answer 149

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.

Answer 150

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.

Answer 151

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.

Answer 152

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.

Answer 153

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.

Answer 154

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.

Answer 155

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.

Answer 156

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.

Answer 157

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.

Answer 158

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).

Answer 159

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.

Answer 160

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.

Answer 161

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.

Answer 162

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.

Answer 163

A Anti-mitochondrial Anti-mitochondrial (A) antibodies are associated with primary biliary cirrhosis (PBC), and are immunoglobulins against mitochondria in cells of the liver. PBC is an autoimmune disease of unknown cause characterized by lymphocytic destruction of the bile canaliculi of the liver; build-up of bile leads to fibrosis and eventually cirrhosis. Clinical features include pruritis (increased bile acids in circulation) as well as the effects of reduced absorption of fat soluble vitamins (vitamin D, osteomalacia; vitamin K, bruising; vitamin A, blindness).

Answer 164

E Anti-glutamic acid decarboxylase Anti-glutamic acid decarboxylase (anti-GAD; E) antibody is present in patients with type 1 diabetes mellitus (T1DM). The pathogenesis of T1DM involves the autoimmune destruction of β-cells in the islets of Langerhans in the pancreas. β-Cells are the primary storage site for insulin in the body, and so destruction of these cells leads to diminished insulin release and hyperglycaemia. GAD is an enzyme responsible for the conversion of glutamate to GABA; GABA is the neurotransmitter involved in the release of insulin from β-cells. Presenting features of T1DM include polyuria, polydipsia and weight loss.

Answer 165

B c-ANCA c-ANCA (cytoplasmic anti-neutrophil cytoplasmic antibodies; B) are common in patients with Wegener’s granulamatosis, a vasculitic disease that is in severe cases life threatening. c-ANCA is directed towards proteinase 3 (PR3) within the neutrophil cytoplasm. Wegner’s granulamatosis primarily affects the nose (saddle-nose deformity due to perforated septum; epistaxis), lungs (pulmonary haemorrhage) and kidneys (glomerulonephritis). Due to its fulminant course, patients require life-long immunosuppression, usually with corticosteroids.

Answer 166

I Anti-endomysial Anti-endomysium (I) is characteristic of coeliac disease, autoimmune disease of the small intestine that results from an immune reaction to gliadin (peptide found in wheat, barley and rye). The endomysium is in fact related to muscle fibres; although muscle fibres are not affected in coeliac disease, anti-endomysial antibodies are useful in the diagnosis of coeliac disease. Clinical features include diarrhoea, abdominal pain and mouth ulcers. Other autoantibodies that are used in the diagnosis of coeliac disease are anti-tissue transglutaminase antibody and antigliadin antibodies.

Answer 167

I Pancreatic β-cell proteins Pancreatic β-cell proteins (I) are the antigenic target for cytotoxic CD8+ T cells in type 1 diabetes mellitus (T1DM). T1DM is a type IV hypersensitivity reaction since it is T-cell mediated; the pathogenesis involves the destruction of β-cells in the islets of Langerhans in the pancreas by CD8+ T cells. β-cells are the storage site for insulin in the body, and so destruction of these cells leads to diminished insulin release and hyperglycaemia. Presenting features of T1DM include polyuria, polydipsia and weight loss. Antibodies to glutamate decarboxylase (GAD) as well as islet cells may also circulate in T1DM patients.

Answer 168

B Nuts Ingestion of nuts (B) can lead to a type I hypersensitivity, characterized by a strong CD4+ Th2 response which causes release of IL-4 and IL-13. This causes B cells to produce IgE, which in turn binds to Fc receptors on mast cells. On re-exposure to the allergen the IgE on mast cells cross-links, with resultant mast cell degranulation (release of histamine and tryptases) and arachidonic acid metabolism (producing leukotrienes and prostaglandins). Clinical features include erythema, rhinitis, urticaria, angio-oedema, bronchoconstriction and in severe cases anaphylactic shock.

Answer 169

G Mouldy hay Chronic exposure to mouldy hay (G) is the cause of farmer’s lung, an example of an extrinsic allergic alveolitis. Actinomycetes are the most common pathogen found in hay dust, which are subsequently inhaled. Inhalation over prolonged periods of time leads to immune complex formation as antibodies combine with the inhaled allergen (type III hypersensitivity reaction); the immune complexes are deposited in the walls of the alveoli. Chronic exposure leads to pulmonary fibrosis, with associated shortness of breath, cyanosis and cor pulmonale.

Answer 170

E Type IV collagen Type IV collagen (E), is the target of soluble IgG in Goodpasture’s disease (type II hypersensitivity reaction). Type IV collagen is present in the glomerular basement membrane and lung basement membrane. Pulmonary features include cough, dyspnoea and haemoptysis; renal features include haematuria, acute renal failure and nephrotic syndrome. Investigations reveal the presence of anti-type IV collagen antibodies in the circulation; immunofluorescence will show linear deposition of IgG along the glomerular basement membrane.

Answer 171

H Grass pollen Grass pollen (H) may cause allergic rhinitis via a type I hypersensitivity reaction. The allergen triggers IgE production, which bind to the cell surface of mast cells and basophils. On repeated exposure to pollen, the mast cells degranulate, releasing histamine as well as other mediators. This results in the characteristic features of allergic rhinitis such as a runny nose, sneezing, itchiness, watery eyes and nasal congestion.

Answer 172

F Peanuts Allergy to peanuts (F) causes a spectrum of clinical manifestations, from mild food allergy to severe anaphylaxis. The underlying pathogenesis is the binding of the allergen to IgE causing mast cell degranulation and histamine release (a potent vasodilator and bronchoconstrictor). In anaphylaxis, this release of histamine occurs throughout the body, leading to the clinical features of shortness of breath, wheeze, swollen lips and signs of shock. Anaphylaxis is a medical emergency and requires prompt administration of intramuscular adrenaline and urgent transfer to a hospital.

Answer 173

C Myelin basic protein Myelin basic protein (C) and proteolipid protein are oligodendrocyte proteins implicated in the pathogenesis of multiple sclerosis. Multiple sclerosis (MS) is a demyelinating disease in which the myelin sheaths surrounding neurons of the brain and spinal cord are destroyed. Associated with the disease process is the antigenic stimulation of CD4+ T cells which in turn activate CD8+ cytotoxic T cells and macrophages; these are directed at oligodendrocyte proteins (type IV hypersensitivity reaction) causing destruction of oligodendrocytes and myelin. Clinical features of MS include optic neuritis, urinary/bowel incontinence, weakness of the arms/legs and dysphagia.

Answer 174

D Rhesus antigens Rhesus antigens (D) are found on the surface of erythrocytes. The rhesus (Rh) blood group system is clinically the most important after the ABO system; the most commonly used Rh antigen is the D antigen, signifying whether a patient is Rh positive or negative. Antibodies directed against the Rh antigen results in autoimmune haemolytic anaemia (AIHA; type II hypersensitivity reaction). Most commonly the cause is idiopathic, however, chronic lymphocytic leukaemia, systemic lupus erythematosus and drugs (methyldopa and penicillin) can trigger AIHA. Direct antiglobulin test is positive.

Answer 175

B HBsAg HBsAg (B) may be associated with the development of polyarteritis nodosa (PAN), a vasculitis of small and medium sized vessels. Immune complexes (type III hypersensitivity reaction) are deposited within such vessels leading to fibrinoid necrosis and neutrophil infiltration; as a result the vessel walls weaken and there is aneurysm development. Investigations will reveal a raised ESR, CRP and immunoglobulin level. pANCA is also associated with PAN. Angiogram will reveal multiple aneurysms. Corticosteroids and cytotoxic agents are required to control disease progression.

Answer 176

E Glycoprotein IIb–IIIa Glycoprotein IIb–IIIa (E) on the surface of platelets is the target for IgG autoantibodies (type II hypersensitivity reaction) in autoimmune thrombocytopenic purpura (AITP). IgG directed at platelets makes them more susceptible to destruction by splenic macrophages and as a result the platelet count in affected individuals will be very low. Symptoms depend upon the platelet count:

Answer 177

A Cyclophosphamide Cyclophosphamide (A) is an alkylating agent, attaching an alkyl group to the guanine base of DNA. This causes damage to the DNA structure and therefore prevents cell replication; cyclophosphamide affects B-cell replication more than T cells. Indications include multisystem connective tissue disease and vasculitis such as systemic lupus erythematosus and Wegner’s granulomatosis. Cyclophosphamide also has a role in treating cancers such as leukaemia and lymphoma. Complications of therapy include bone marrow suppression, hair loss and it has carcinogenic properties which may cause transitional cell carcinoma of the bladder.

Answer 178

D Abatacept Abatacept (D) is a CTLA4–immunoglobulin fusion protein indicated in the treatment of rheumatoid arthritis (disease which has been resistant to treatment with disease modifying drugs). Abatacept prevents antigen presenting cells from delivering a co-stimulatory signal to T cells in order to activate them; this is achieved by abatacept binding with high affinity to the B7 protein (CD80 and CD86) on the cell surface of APCs. Side effects include increased risk of infection from TB, hepatitis B virus and hepatitis C virus.

Answer 179

B Mycophenolate mofetil Mycophenolate mofetil (B) is the prodrug of mycophenolic acid which inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme required in guanine synthesis; impaired guanine synthesis reduces the proliferation of both T and B cells, but T cells are affected to a greater extent. Mycophenolate mofetil is indicated as an immunosuppressive agent in transplant patients as well as an alternative to cyclophosphamide in the treatment of autoimmune diseases and vasculitides. Side effects include bone marrow suppression (particularly low white blood cells and platelets) as well as herpes virus reactivation.

Answer 180

G Infliximab Infliximab (G) is a TNF-α antagonist used in the treatment of rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease and psoriasis. Infliximab has a high affinity for TNF-α but does not bind to TNF-β. TNF-α has the physiological role of inducing pro-inflammatory cytokines as well as promoting leukocyte migration and endothelial adhesion. Toxicity may result in reduced protection against infection from TB, hepatitis B virus and hepatitis C virus, a lupus-like condition, demyelination and malignancy.

Answer 181

I Denosumab Denosumab (I) is an antibody directed towards the RANK ligand in bones. Osteoblasts are responsible for bone formation, whilst osteoclasts (which contain the cell surface receptor RANK) break down bone. Inhibition of RANK by denosumab therefore inhibits osteoclast function and differentiation, thereby preventing the breakdown of bone. Denosumab is indicated in the treatment of osteoporosis but is also used in the management of multiple myeloma and bone metastases. Toxicity can predispose to respiratory and urinary tract infections.

Answer 182

B Wegener’s granulomatosis Wegener’s granulamatosis (B) is a systemic vasculitis characterized clinically by epistaxis, haemoptysis and haematuria. Wegener’s granulomatosis is defined by the presence of cytoplasmic anti-neutrophil cytoplasmic antibodies (cANCA). c-ANCA is directed towards proteinase 3 (PR3), an enzyme normally present within the cytoplasm of neutrophils. It is proposed that an infection is the trigger for the disease, which causes circulating neutrophils to become adherent to the endothelium and upregulation of PR3 on the cell surface. Vasculitis is mediated by both direct effect of PR3 on the endothelium as well as cANCA–PR3 immune complex deposition.

Answer 183

E IgA nephropathy IgA nephropathy (Berger’s disease; E) is the most common cause of glomerunephritis in the developed world. The condition occurs after a gastrointestinal or upper respiratory infection; potential offenders are postulated to include Haemophilus influenzae, hepatitis B virus and cytomegalovirus. Antigenic targets for IgA are thought to include collagen, fibronectin and laminin. Characteristically there is mesangial proliferation with deposition of IgA together with alternative pathway factors C3 and properdin. Blood tests will reveal a raised IgA level. Henoch–Schonlein purpura has a similar pathogenesis to IgA nephropathy but presents in children and has extra-renal clinical features.

Answer 184

H Post-streptococcal glomerulonephritis Post-streptococcal glomerulonephritis (H) is usually caused by a preceding group A β haemolytic streptococcus pharyngitis. Anti-streptolysin O titre (ASOT) will be raised. Pathological hallmarks of post-streptococcal glomerulonephritis include diffuse hypercellularity and diffuse swelling of the mesangium and glomerular capillaries. Influx of neutrophils and macrophages may reveal crescent formation on histology. Direct immunofluorescence reveals the sub-epithelial deposition of IgG and C3. The condition usually subsides with supportive treatment, including antibiotic therapy to combat the outstanding infection.

Answer 185

G Rapidly progressive glomerulonephritis Rapidly progressive glomerulonephritis (RPGN; G) is the most aggressive of all glomerulonephritides, which may cause end-stage renal failure over a period of days. The three sub-types include immune complex disease, pauci-immune disease and anti-glomerular basement membrane disease, all of which demonstrate crescent formation on biopsy (proliferation of macrophages and parietal epithelial cells). Immunofluoresence of IgG/C3 distinguishes between the three sub-types: immune complex disease is characterized by granular staining, pauci-immune disease shows absent/scant staining, while anti-glomerular basement membrane disease demonstrates linear staining.

Answer 186

A Minimal change disease Minimal change disease (A) is the most common cause of nephrotic syndrome in children. Triggers include a recent allergic reaction such as a bee sting (type I hypersensitivity reaction). Histological characteristics of renal biopsy specimens include a lack of structural change visible on light microscopy, while electron microscopy will demonstrate podocyte effacement. Steroids are the primary treatment modality, which lead to remission of disease in the vast majority of cases.

Answer 187

H Western blot Western blot (H) is a technique used to detect specific proteins in a patient’s serum; it is used in the confirmatory HIV test to detect specific antibodies to HIV. The first step is to separate native proteins by gel electrophoresis. The proteins are subsequently transferred to a membrane on which specific antibodies present in the serum may bind to HIV proteins produced using recombinant DNA. Unbound antibodies are washed away. Enzyme-linked antibodies are then added; these determine to which protein the subject has antibodies.

Answer 188

F Kveim test Kveim test (F) is an investigation used to diagnose sarcoidosis. A sample of spleen from a patient with known sarcoid is injected intradermally into a suspected patient. A positive test is evidenced by the presence of non-caseating granuloma formation on biopsy of the site, 4–6 weeks after the initial injection. Although not used in the UK due to infection concerns (especially bovine spongiform encephalopathy), it is still available in many countries.

Answer 189

I Direct antiglobulin test Direct antiglobulin test (DAT; I) also known as direct Coombs test, is the investigation of choice for the diagnosis of autoimmune haemolytic anaemia (AIHA). Causes of AIHA include lymphoproliferative disorders, drugs (penicillin) and autoimmune diseases (SLE). The test involves the separation of RBCs from the serum which is subsequently incubated with anti-human globulin. In the case of AIHA, the anti-human globulin will agglutinate the RBCs, which is visualized as clumping of the cells.

Answer 190

G Skin prick test Skin prick test (G) is the gold standard for investigating such type I hypersensitivity reactions. The test involves a few drops of purified allergen being pricked onto the skin. Allergens which are tested for include foods, dust mites, pollen and dust. A positive test is indicated by wheal formation, caused by cross-linking of IgE on the mast cell surface leading to histamine release.

Answer 191

B Immunofluorescence Immunofluorescence (B) is an immunological technique used in conjunction with fluorescence microscope. Fluorophores (fluorescent chemical compounds) attached to specific antibodies are directed at antigens found within a biological specimen, most commonly a biopsy sample, to visualize patterns of staining. For example, in Henoch– Schönlein purpura, anti-IgA antibody will demonstrate IgA deposits in the capillary walls of the specimen. Immunofluorescence may be direct (use of a single antibody bound to a single fluorophore) or indirect (secondary antibody carrying the fluorophore binds to the primary antibody).

Answer 192

G Bruton’s agammaglobulinaemia Bruton’s agammaglobulinaemia (G) is an X-linked disease that presents in childhood. It is caused by a mutation of the BTK gene, which expresses a tyrosine kinase. This mutation inhibits B-cell maturation and therefore B-cell and immunoglobulin levels are diminished. Blood tests will reveal a normal T-cell count, but diminished B-cell count as well as IgA, IgM and IgG levels. Plasma cells will also be absent from the bone marrow and lymphatics.

Answer 193

B Immunofluorescence Immunofluorescence (B) is an immunological technique used in conjunction with fluorescence microscope. Fluorophores (fluorescent chemical compounds) attached to specific antibodies are directed at antigens found within a biological specimen, most commonly a biopsy sample, to visualize patterns of staining. For example, in Henoch– Schönlein purpura, anti-IgA antibody will demonstrate IgA deposits in the capillary walls of the specimen. Immunofluorescence may be direct (use of a single antibody bound to a single fluorophore) or indirect (secondary antibody carrying the fluorophore binds to the primary antibody).

Answer 194

G Skin prick test Skin prick test (G) is the gold standard for investigating such type I hypersensitivity reactions. The test involves a few drops of purified allergen being pricked onto the skin. Allergens which are tested for include foods, dust mites, pollen and dust. A positive test is indicated by wheal formation, caused by cross-linking of IgE on the mast cell surface leading to histamine release.

Answer 195

I Direct antiglobulin test Direct antiglobulin test (DAT; I) also known as direct Coombs test, is the investigation of choice for the diagnosis of autoimmune haemolytic anaemia (AIHA). Causes of AIHA include lymphoproliferative disorders, drugs (penicillin) and autoimmune diseases (SLE). The test involves the separation of RBCs from the serum which is subsequently incubated with anti-human globulin. In the case of AIHA, the anti-human globulin will agglutinate the RBCs, which is visualized as clumping of the cells.

Answer 196

F Kveim test Kveim test (F) is an investigation used to diagnose sarcoidosis. A sample of spleen from a patient with known sarcoid is injected intradermally into a suspected patient. A positive test is evidenced by the presence of non-caseating granuloma formation on biopsy of the site, 4–6 weeks after the initial injection. Although not used in the UK due to infection concerns (especially bovine spongiform encephalopathy), it is still available in many countries.

Answer 197

H Western blot Western blot (H) is a technique used to detect specific proteins in a patient’s serum; it is used in the confirmatory HIV test to detect specific antibodies to HIV. The first step is to separate native proteins by gel electrophoresis. The proteins are subsequently transferred to a membrane on which specific antibodies present in the serum may bind to HIV proteins produced using recombinant DNA. Unbound antibodies are washed away. Enzyme-linked antibodies are then added; these determine to which protein the subject has antibodies.

Answer 198

A Minimal change disease Minimal change disease (A) is the most common cause of nephrotic syndrome in children. Triggers include a recent allergic reaction such as a bee sting (type I hypersensitivity reaction). Histological characteristics of renal biopsy specimens include a lack of structural change visible on light microscopy, while electron microscopy will demonstrate podocyte effacement. Steroids are the primary treatment modality, which lead to remission of disease in the vast majority of cases.

Answer 199

G Rapidly progressive glomerulonephritis Rapidly progressive glomerulonephritis (RPGN; G) is the most aggressive of all glomerulonephritides, which may cause end-stage renal failure over a period of days. The three sub-types include immune complex disease, pauci-immune disease and anti-glomerular basement membrane disease, all of which demonstrate crescent formation on biopsy (proliferation of macrophages and parietal epithelial cells). Immunofluoresence of IgG/C3 distinguishes between the three sub-types: immune complex disease is characterized by granular staining, pauci-immune disease shows absent/scant staining, while anti-glomerular basement membrane disease demonstrates linear staining.

Answer 200

H Post-streptococcal glomerulonephritis Post-streptococcal glomerulonephritis (H) is usually caused by a preceding group A β haemolytic streptococcus pharyngitis. Anti-streptolysin O titre (ASOT) will be raised. Pathological hallmarks of post-streptococcal glomerulonephritis include diffuse hypercellularity and diffuse swelling of the mesangium and glomerular capillaries. Influx of neutrophils and macrophages may reveal crescent formation on histology. Direct immunofluorescence reveals the sub-epithelial deposition of IgG and C3. The condition usually subsides with supportive treatment, including antibiotic therapy to combat the outstanding infection.

Answer 201

E IgA nephropathy IgA nephropathy (Berger’s disease; E) is the most common cause of glomerunephritis in the developed world. The condition occurs after a gastrointestinal or upper respiratory infection; potential offenders are postulated to include Haemophilus influenzae, hepatitis B virus and cytomegalovirus. Antigenic targets for IgA are thought to include collagen, fibronectin and laminin. Characteristically there is mesangial proliferation with deposition of IgA together with alternative pathway factors C3 and properdin. Blood tests will reveal a raised IgA level. Henoch–Schonlein purpura has a similar pathogenesis to IgA nephropathy but presents in children and has extra-renal clinical features.

Answer 202

B Wegener’s granulomatosis Wegener’s granulamatosis (B) is a systemic vasculitis characterized clinically by epistaxis, haemoptysis and haematuria. Wegener’s granulomatosis is defined by the presence of cytoplasmic anti-neutrophil cytoplasmic antibodies (cANCA). c-ANCA is directed towards proteinase 3 (PR3), an enzyme normally present within the cytoplasm of neutrophils. It is proposed that an infection is the trigger for the disease, which causes circulating neutrophils to become adherent to the endothelium and upregulation of PR3 on the cell surface. Vasculitis is mediated by both direct effect of PR3 on the endothelium as well as cANCA–PR3 immune complex deposition.

Answer 203

I Denosumab Denosumab (I) is an antibody directed towards the RANK ligand in bones. Osteoblasts are responsible for bone formation, whilst osteoclasts (which contain the cell surface receptor RANK) break down bone. Inhibition of RANK by denosumab therefore inhibits osteoclast function and differentiation, thereby preventing the breakdown of bone. Denosumab is indicated in the treatment of osteoporosis but is also used in the management of multiple myeloma and bone metastases. Toxicity can predispose to respiratory and urinary tract infections.

Answer 204

G Infliximab Infliximab (G) is a TNF-α antagonist used in the treatment of rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease and psoriasis. Infliximab has a high affinity for TNF-α but does not bind to TNF-β. TNF-α has the physiological role of inducing pro-inflammatory cytokines as well as promoting leukocyte migration and endothelial adhesion. Toxicity may result in reduced protection against infection from TB, hepatitis B virus and hepatitis C virus, a lupus-like condition, demyelination and malignancy.

Answer 205

B Mycophenolate mofetil Mycophenolate mofetil (B) is the prodrug of mycophenolic acid which inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme required in guanine synthesis; impaired guanine synthesis reduces the proliferation of both T and B cells, but T cells are affected to a greater extent. Mycophenolate mofetil is indicated as an immunosuppressive agent in transplant patients as well as an alternative to cyclophosphamide in the treatment of autoimmune diseases and vasculitides. Side effects include bone marrow suppression (particularly low white blood cells and platelets) as well as herpes virus reactivation.

Answer 206

D Abatacept Abatacept (D) is a CTLA4–immunoglobulin fusion protein indicated in the treatment of rheumatoid arthritis (disease which has been resistant to treatment with disease modifying drugs). Abatacept prevents antigen presenting cells from delivering a co-stimulatory signal to T cells in order to activate them; this is achieved by abatacept binding with high affinity to the B7 protein (CD80 and CD86) on the cell surface of APCs. Side effects include increased risk of infection from TB, hepatitis B virus and hepatitis C virus.

Answer 207

A Cyclophosphamide Cyclophosphamide (A) is an alkylating agent, attaching an alkyl group to the guanine base of DNA. This causes damage to the DNA structure and therefore prevents cell replication; cyclophosphamide affects B-cell replication more than T cells. Indications include multisystem connective tissue disease and vasculitis such as systemic lupus erythematosus and Wegner’s granulomatosis. Cyclophosphamide also has a role in treating cancers such as leukaemia and lymphoma. Complications of therapy include bone marrow suppression, hair loss and it has carcinogenic properties which may cause transitional cell carcinoma of the bladder.

Answer 208

E Glycoprotein IIb–IIIa Glycoprotein IIb–IIIa (E) on the surface of platelets is the target for IgG autoantibodies (type II hypersensitivity reaction) in autoimmune thrombocytopenic purpura (AITP). IgG directed at platelets makes them more susceptible to destruction by splenic macrophages and as a result the platelet count in affected individuals will be very low. Symptoms depend upon the platelet count:

Answer 209

B HBsAg HBsAg (B) may be associated with the development of polyarteritis nodosa (PAN), a vasculitis of small and medium sized vessels. Immune complexes (type III hypersensitivity reaction) are deposited within such vessels leading to fibrinoid necrosis and neutrophil infiltration; as a result the vessel walls weaken and there is aneurysm development. Investigations will reveal a raised ESR, CRP and immunoglobulin level. pANCA is also associated with PAN. Angiogram will reveal multiple aneurysms. Corticosteroids and cytotoxic agents are required to control disease progression.

Answer 210

D Rhesus antigens Rhesus antigens (D) are found on the surface of erythrocytes. The rhesus (Rh) blood group system is clinically the most important after the ABO system; the most commonly used Rh antigen is the D antigen, signifying whether a patient is Rh positive or negative. Antibodies directed against the Rh antigen results in autoimmune haemolytic anaemia (AIHA; type II hypersensitivity reaction). Most commonly the cause is idiopathic, however, chronic lymphocytic leukaemia, systemic lupus erythematosus and drugs (methyldopa and penicillin) can trigger AIHA. Direct antiglobulin test is positive.

Answer 211

C Myelin basic protein Myelin basic protein (C) and proteolipid protein are oligodendrocyte proteins implicated in the pathogenesis of multiple sclerosis. Multiple sclerosis (MS) is a demyelinating disease in which the myelin sheaths surrounding neurons of the brain and spinal cord are destroyed. Associated with the disease process is the antigenic stimulation of CD4+ T cells which in turn activate CD8+ cytotoxic T cells and macrophages; these are directed at oligodendrocyte proteins (type IV hypersensitivity reaction) causing destruction of oligodendrocytes and myelin. Clinical features of MS include optic neuritis, urinary/bowel incontinence, weakness of the arms/legs and dysphagia.

Answer 212

F Peanuts Allergy to peanuts (F) causes a spectrum of clinical manifestations, from mild food allergy to severe anaphylaxis. The underlying pathogenesis is the binding of the allergen to IgE causing mast cell degranulation and histamine release (a potent vasodilator and bronchoconstrictor). In anaphylaxis, this release of histamine occurs throughout the body, leading to the clinical features of shortness of breath, wheeze, swollen lips and signs of shock. Anaphylaxis is a medical emergency and requires prompt administration of intramuscular adrenaline and urgent transfer to a hospital.

Answer 213

H Grass pollen Grass pollen (H) may cause allergic rhinitis via a type I hypersensitivity reaction. The allergen triggers IgE production, which bind to the cell surface of mast cells and basophils. On repeated exposure to pollen, the mast cells degranulate, releasing histamine as well as other mediators. This results in the characteristic features of allergic rhinitis such as a runny nose, sneezing, itchiness, watery eyes and nasal congestion.

Answer 214

E Type IV collagen Type IV collagen (E), is the target of soluble IgG in Goodpasture’s disease (type II hypersensitivity reaction). Type IV collagen is present in the glomerular basement membrane and lung basement membrane. Pulmonary features include cough, dyspnoea and haemoptysis; renal features include haematuria, acute renal failure and nephrotic syndrome. Investigations reveal the presence of anti-type IV collagen antibodies in the circulation; immunofluorescence will show linear deposition of IgG along the glomerular basement membrane.

Answer 215

G Mouldy hay Chronic exposure to mouldy hay (G) is the cause of farmer’s lung, an example of an extrinsic allergic alveolitis. Actinomycetes are the most common pathogen found in hay dust, which are subsequently inhaled. Inhalation over prolonged periods of time leads to immune complex formation as antibodies combine with the inhaled allergen (type III hypersensitivity reaction); the immune complexes are deposited in the walls of the alveoli. Chronic exposure leads to pulmonary fibrosis, with associated shortness of breath, cyanosis and cor pulmonale.

Answer 216

B Nuts Ingestion of nuts (B) can lead to a type I hypersensitivity, characterized by a strong CD4+ Th2 response which causes release of IL-4 and IL-13. This causes B cells to produce IgE, which in turn binds to Fc receptors on mast cells. On re-exposure to the allergen the IgE on mast cells cross-links, with resultant mast cell degranulation (release of histamine and tryptases) and arachidonic acid metabolism (producing leukotrienes and prostaglandins). Clinical features include erythema, rhinitis, urticaria, angio-oedema, bronchoconstriction and in severe cases anaphylactic shock.

Answer 217

I Pancreatic β-cell proteins Pancreatic β-cell proteins (I) are the antigenic target for cytotoxic CD8+ T cells in type 1 diabetes mellitus (T1DM). T1DM is a type IV hypersensitivity reaction since it is T-cell mediated; the pathogenesis involves the destruction of β-cells in the islets of Langerhans in the pancreas by CD8+ T cells. β-cells are the storage site for insulin in the body, and so destruction of these cells leads to diminished insulin release and hyperglycaemia. Presenting features of T1DM include polyuria, polydipsia and weight loss. Antibodies to glutamate decarboxylase (GAD) as well as islet cells may also circulate in T1DM patients.

Answer 218

I Anti-endomysial Anti-endomysium (I) is characteristic of coeliac disease, autoimmune disease of the small intestine that results from an immune reaction to gliadin (peptide found in wheat, barley and rye). The endomysium is in fact related to muscle fibres; although muscle fibres are not affected in coeliac disease, anti-endomysial antibodies are useful in the diagnosis of coeliac disease. Clinical features include diarrhoea, abdominal pain and mouth ulcers. Other autoantibodies that are used in the diagnosis of coeliac disease are anti-tissue transglutaminase antibody and antigliadin antibodies.

Answer 219

B c-ANCA c-ANCA (cytoplasmic anti-neutrophil cytoplasmic antibodies; B) are common in patients with Wegener’s granulamatosis, a vasculitic disease that is in severe cases life threatening. c-ANCA is directed towards proteinase 3 (PR3) within the neutrophil cytoplasm. Wegner’s granulamatosis primarily affects the nose (saddle-nose deformity due to perforated septum; epistaxis), lungs (pulmonary haemorrhage) and kidneys (glomerulonephritis). Due to its fulminant course, patients require life-long immunosuppression, usually with corticosteroids.

Answer 220

E Anti-glutamic acid decarboxylase Anti-glutamic acid decarboxylase (anti-GAD; E) antibody is present in patients with type 1 diabetes mellitus (T1DM). The pathogenesis of T1DM involves the autoimmune destruction of β-cells in the islets of Langerhans in the pancreas. β-Cells are the primary storage site for insulin in the body, and so destruction of these cells leads to diminished insulin release and hyperglycaemia. GAD is an enzyme responsible for the conversion of glutamate to GABA; GABA is the neurotransmitter involved in the release of insulin from β-cells. Presenting features of T1DM include polyuria, polydipsia and weight loss.

Answer 221

A Anti-mitochondrial Anti-mitochondrial (A) antibodies are associated with primary biliary cirrhosis (PBC), and are immunoglobulins against mitochondria in cells of the liver. PBC is an autoimmune disease of unknown cause characterized by lymphocytic destruction of the bile canaliculi of the liver; build-up of bile leads to fibrosis and eventually cirrhosis. Clinical features include pruritis (increased bile acids in circulation) as well as the effects of reduced absorption of fat soluble vitamins (vitamin D, osteomalacia; vitamin K, bruising; vitamin A, blindness).

Answer 222

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.

Answer 223

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.

Answer 224

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.

Answer 225

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.

Answer 226

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).

Answer 227

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.

Answer 228

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.

Answer 229

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.

Answer 230

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.

Answer 231

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.

Answer 232

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.

Answer 233

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.

Answer 234

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.

Answer 235

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.

Answer 236

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.

Answer 237

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.

Answer 238

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.

Answer 239

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.

Answer 240

G Bruton’s agammaglobulinaemia Bruton’s agammaglobulinaemia (G) is an X-linked disease that presents in childhood. It is caused by a mutation of the BTK gene, which expresses a tyrosine kinase. This mutation inhibits B-cell maturation and therefore B-cell and immunoglobulin levels are diminished. Blood tests will reveal a normal T-cell count, but diminished B-cell count as well as IgA, IgM and IgG levels. Plasma cells will also be absent from the bone marrow and lymphatics.

Answer 241

G Bruton’s agammaglobulinaemia Bruton’s agammaglobulinaemia (G) is an X-linked disease that presents in childhood. It is caused by a mutation of the BTK gene, which expresses a tyrosine kinase. This mutation inhibits B-cell maturation and therefore B-cell and immunoglobulin levels are diminished. Blood tests will reveal a normal T-cell count, but diminished B-cell count as well as IgA, IgM and IgG levels. Plasma cells will also be absent from the bone marrow and lymphatics.

Answer 242

B c-ANCA c-ANCA (cytoplasmic anti-neutrophil cytoplasmic antibodies; B) are common in patients with Wegener’s granulamatosis, a vasculitic disease that is in severe cases life threatening. c-ANCA is directed towards proteinase 3 (PR3) within the neutrophil cytoplasm. Wegner’s granulamatosis primarily affects the nose (saddle-nose deformity due to perforated septum; epistaxis), lungs (pulmonary haemorrhage) and kidneys (glomerulonephritis). Due to its fulminant course, patients require life-long immunosuppression, usually with corticosteroids.

Answer 243

B Immunofluorescence Immunofluorescence (B) is an immunological technique used in conjunction with fluorescence microscope. Fluorophores (fluorescent chemical compounds) attached to specific antibodies are directed at antigens found within a biological specimen, most commonly a biopsy sample, to visualize patterns of staining. For example, in Henoch– Schönlein purpura, anti-IgA antibody will demonstrate IgA deposits in the capillary walls of the specimen. Immunofluorescence may be direct (use of a single antibody bound to a single fluorophore) or indirect (secondary antibody carrying the fluorophore binds to the primary antibody).

Answer 244

G Skin prick test Skin prick test (G) is the gold standard for investigating such type I hypersensitivity reactions. The test involves a few drops of purified allergen being pricked onto the skin. Allergens which are tested for include foods, dust mites, pollen and dust. A positive test is indicated by wheal formation, caused by cross-linking of IgE on the mast cell surface leading to histamine release.

Answer 245

I Direct antiglobulin test Direct antiglobulin test (DAT; I) also known as direct Coombs test, is the investigation of choice for the diagnosis of autoimmune haemolytic anaemia (AIHA). Causes of AIHA include lymphoproliferative disorders, drugs (penicillin) and autoimmune diseases (SLE). The test involves the separation of RBCs from the serum which is subsequently incubated with anti-human globulin. In the case of AIHA, the anti-human globulin will agglutinate the RBCs, which is visualized as clumping of the cells.

Answer 246

F Kveim test Kveim test (F) is an investigation used to diagnose sarcoidosis. A sample of spleen from a patient with known sarcoid is injected intradermally into a suspected patient. A positive test is evidenced by the presence of non-caseating granuloma formation on biopsy of the site, 4–6 weeks after the initial injection. Although not used in the UK due to infection concerns (especially bovine spongiform encephalopathy), it is still available in many countries.

Answer 247

H Western blot Western blot (H) is a technique used to detect specific proteins in a patient’s serum; it is used in the confirmatory HIV test to detect specific antibodies to HIV. The first step is to separate native proteins by gel electrophoresis. The proteins are subsequently transferred to a membrane on which specific antibodies present in the serum may bind to HIV proteins produced using recombinant DNA. Unbound antibodies are washed away. Enzyme-linked antibodies are then added; these determine to which protein the subject has antibodies.

Answer 248

A Minimal change disease Minimal change disease (A) is the most common cause of nephrotic syndrome in children. Triggers include a recent allergic reaction such as a bee sting (type I hypersensitivity reaction). Histological characteristics of renal biopsy specimens include a lack of structural change visible on light microscopy, while electron microscopy will demonstrate podocyte effacement. Steroids are the primary treatment modality, which lead to remission of disease in the vast majority of cases.

Answer 249

G Rapidly progressive glomerulonephritis Rapidly progressive glomerulonephritis (RPGN; G) is the most aggressive of all glomerulonephritides, which may cause end-stage renal failure over a period of days. The three sub-types include immune complex disease, pauci-immune disease and anti-glomerular basement membrane disease, all of which demonstrate crescent formation on biopsy (proliferation of macrophages and parietal epithelial cells). Immunofluoresence of IgG/C3 distinguishes between the three sub-types: immune complex disease is characterized by granular staining, pauci-immune disease shows absent/scant staining, while anti-glomerular basement membrane disease demonstrates linear staining.

Answer 250

H Post-streptococcal glomerulonephritis Post-streptococcal glomerulonephritis (H) is usually caused by a preceding group A β haemolytic streptococcus pharyngitis. Anti-streptolysin O titre (ASOT) will be raised. Pathological hallmarks of post-streptococcal glomerulonephritis include diffuse hypercellularity and diffuse swelling of the mesangium and glomerular capillaries. Influx of neutrophils and macrophages may reveal crescent formation on histology. Direct immunofluorescence reveals the sub-epithelial deposition of IgG and C3. The condition usually subsides with supportive treatment, including antibiotic therapy to combat the outstanding infection.

Answer 251

E IgA nephropathy IgA nephropathy (Berger’s disease; E) is the most common cause of glomerunephritis in the developed world. The condition occurs after a gastrointestinal or upper respiratory infection; potential offenders are postulated to include Haemophilus influenzae, hepatitis B virus and cytomegalovirus. Antigenic targets for IgA are thought to include collagen, fibronectin and laminin. Characteristically there is mesangial proliferation with deposition of IgA together with alternative pathway factors C3 and properdin. Blood tests will reveal a raised IgA level. Henoch–Schonlein purpura has a similar pathogenesis to IgA nephropathy but presents in children and has extra-renal clinical features.

Answer 252

B Wegener’s granulomatosis Wegener’s granulamatosis (B) is a systemic vasculitis characterized clinically by epistaxis, haemoptysis and haematuria. Wegener’s granulomatosis is defined by the presence of cytoplasmic anti-neutrophil cytoplasmic antibodies (cANCA). c-ANCA is directed towards proteinase 3 (PR3), an enzyme normally present within the cytoplasm of neutrophils. It is proposed that an infection is the trigger for the disease, which causes circulating neutrophils to become adherent to the endothelium and upregulation of PR3 on the cell surface. Vasculitis is mediated by both direct effect of PR3 on the endothelium as well as cANCA–PR3 immune complex deposition.

Answer 253

I Denosumab Denosumab (I) is an antibody directed towards the RANK ligand in bones. Osteoblasts are responsible for bone formation, whilst osteoclasts (which contain the cell surface receptor RANK) break down bone. Inhibition of RANK by denosumab therefore inhibits osteoclast function and differentiation, thereby preventing the breakdown of bone. Denosumab is indicated in the treatment of osteoporosis but is also used in the management of multiple myeloma and bone metastases. Toxicity can predispose to respiratory and urinary tract infections.

Answer 254

G Infliximab Infliximab (G) is a TNF-α antagonist used in the treatment of rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease and psoriasis. Infliximab has a high affinity for TNF-α but does not bind to TNF-β. TNF-α has the physiological role of inducing pro-inflammatory cytokines as well as promoting leukocyte migration and endothelial adhesion. Toxicity may result in reduced protection against infection from TB, hepatitis B virus and hepatitis C virus, a lupus-like condition, demyelination and malignancy.

Answer 255

B Mycophenolate mofetil Mycophenolate mofetil (B) is the prodrug of mycophenolic acid which inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme required in guanine synthesis; impaired guanine synthesis reduces the proliferation of both T and B cells, but T cells are affected to a greater extent. Mycophenolate mofetil is indicated as an immunosuppressive agent in transplant patients as well as an alternative to cyclophosphamide in the treatment of autoimmune diseases and vasculitides. Side effects include bone marrow suppression (particularly low white blood cells and platelets) as well as herpes virus reactivation.

Answer 256

D Abatacept Abatacept (D) is a CTLA4–immunoglobulin fusion protein indicated in the treatment of rheumatoid arthritis (disease which has been resistant to treatment with disease modifying drugs). Abatacept prevents antigen presenting cells from delivering a co-stimulatory signal to T cells in order to activate them; this is achieved by abatacept binding with high affinity to the B7 protein (CD80 and CD86) on the cell surface of APCs. Side effects include increased risk of infection from TB, hepatitis B virus and hepatitis C virus.

Answer 257

A Cyclophosphamide Cyclophosphamide (A) is an alkylating agent, attaching an alkyl group to the guanine base of DNA. This causes damage to the DNA structure and therefore prevents cell replication; cyclophosphamide affects B-cell replication more than T cells. Indications include multisystem connective tissue disease and vasculitis such as systemic lupus erythematosus and Wegner’s granulomatosis. Cyclophosphamide also has a role in treating cancers such as leukaemia and lymphoma. Complications of therapy include bone marrow suppression, hair loss and it has carcinogenic properties which may cause transitional cell carcinoma of the bladder.

Answer 258

I Anti-endomysial Anti-endomysium (I) is characteristic of coeliac disease, autoimmune disease of the small intestine that results from an immune reaction to gliadin (peptide found in wheat, barley and rye). The endomysium is in fact related to muscle fibres; although muscle fibres are not affected in coeliac disease, anti-endomysial antibodies are useful in the diagnosis of coeliac disease. Clinical features include diarrhoea, abdominal pain and mouth ulcers. Other autoantibodies that are used in the diagnosis of coeliac disease are anti-tissue transglutaminase antibody and antigliadin antibodies.

Answer 259

E Glycoprotein IIb–IIIa Glycoprotein IIb–IIIa (E) on the surface of platelets is the target for IgG autoantibodies (type II hypersensitivity reaction) in autoimmune thrombocytopenic purpura (AITP). IgG directed at platelets makes them more susceptible to destruction by splenic macrophages and as a result the platelet count in affected individuals will be very low. Symptoms depend upon the platelet count:

Answer 260

B HBsAg HBsAg (B) may be associated with the development of polyarteritis nodosa (PAN), a vasculitis of small and medium sized vessels. Immune complexes (type III hypersensitivity reaction) are deposited within such vessels leading to fibrinoid necrosis and neutrophil infiltration; as a result the vessel walls weaken and there is aneurysm development. Investigations will reveal a raised ESR, CRP and immunoglobulin level. pANCA is also associated with PAN. Angiogram will reveal multiple aneurysms. Corticosteroids and cytotoxic agents are required to control disease progression.

Answer 261

D Rhesus antigens Rhesus antigens (D) are found on the surface of erythrocytes. The rhesus (Rh) blood group system is clinically the most important after the ABO system; the most commonly used Rh antigen is the D antigen, signifying whether a patient is Rh positive or negative. Antibodies directed against the Rh antigen results in autoimmune haemolytic anaemia (AIHA; type II hypersensitivity reaction). Most commonly the cause is idiopathic, however, chronic lymphocytic leukaemia, systemic lupus erythematosus and drugs (methyldopa and penicillin) can trigger AIHA. Direct antiglobulin test is positive.

Answer 262

C Myelin basic protein Myelin basic protein (C) and proteolipid protein are oligodendrocyte proteins implicated in the pathogenesis of multiple sclerosis. Multiple sclerosis (MS) is a demyelinating disease in which the myelin sheaths surrounding neurons of the brain and spinal cord are destroyed. Associated with the disease process is the antigenic stimulation of CD4+ T cells which in turn activate CD8+ cytotoxic T cells and macrophages; these are directed at oligodendrocyte proteins (type IV hypersensitivity reaction) causing destruction of oligodendrocytes and myelin. Clinical features of MS include optic neuritis, urinary/bowel incontinence, weakness of the arms/legs and dysphagia.

Answer 263

F Peanuts Allergy to peanuts (F) causes a spectrum of clinical manifestations, from mild food allergy to severe anaphylaxis. The underlying pathogenesis is the binding of the allergen to IgE causing mast cell degranulation and histamine release (a potent vasodilator and bronchoconstrictor). In anaphylaxis, this release of histamine occurs throughout the body, leading to the clinical features of shortness of breath, wheeze, swollen lips and signs of shock. Anaphylaxis is a medical emergency and requires prompt administration of intramuscular adrenaline and urgent transfer to a hospital.

Answer 264

H Grass pollen Grass pollen (H) may cause allergic rhinitis via a type I hypersensitivity reaction. The allergen triggers IgE production, which bind to the cell surface of mast cells and basophils. On repeated exposure to pollen, the mast cells degranulate, releasing histamine as well as other mediators. This results in the characteristic features of allergic rhinitis such as a runny nose, sneezing, itchiness, watery eyes and nasal congestion.

Answer 265

E Type IV collagen Type IV collagen (E), is the target of soluble IgG in Goodpasture’s disease (type II hypersensitivity reaction). Type IV collagen is present in the glomerular basement membrane and lung basement membrane. Pulmonary features include cough, dyspnoea and haemoptysis; renal features include haematuria, acute renal failure and nephrotic syndrome. Investigations reveal the presence of anti-type IV collagen antibodies in the circulation; immunofluorescence will show linear deposition of IgG along the glomerular basement membrane.

Answer 266

G Mouldy hay Chronic exposure to mouldy hay (G) is the cause of farmer’s lung, an example of an extrinsic allergic alveolitis. Actinomycetes are the most common pathogen found in hay dust, which are subsequently inhaled. Inhalation over prolonged periods of time leads to immune complex formation as antibodies combine with the inhaled allergen (type III hypersensitivity reaction); the immune complexes are deposited in the walls of the alveoli. Chronic exposure leads to pulmonary fibrosis, with associated shortness of breath, cyanosis and cor pulmonale.

Answer 267

B Nuts Ingestion of nuts (B) can lead to a type I hypersensitivity, characterized by a strong CD4+ Th2 response which causes release of IL-4 and IL-13. This causes B cells to produce IgE, which in turn binds to Fc receptors on mast cells. On re-exposure to the allergen the IgE on mast cells cross-links, with resultant mast cell degranulation (release of histamine and tryptases) and arachidonic acid metabolism (producing leukotrienes and prostaglandins). Clinical features include erythema, rhinitis, urticaria, angio-oedema, bronchoconstriction and in severe cases anaphylactic shock.

Answer 268

I Pancreatic β-cell proteins Pancreatic β-cell proteins (I) are the antigenic target for cytotoxic CD8+ T cells in type 1 diabetes mellitus (T1DM). T1DM is a type IV hypersensitivity reaction since it is T-cell mediated; the pathogenesis involves the destruction of β-cells in the islets of Langerhans in the pancreas by CD8+ T cells. β-cells are the storage site for insulin in the body, and so destruction of these cells leads to diminished insulin release and hyperglycaemia. Presenting features of T1DM include polyuria, polydipsia and weight loss. Antibodies to glutamate decarboxylase (GAD) as well as islet cells may also circulate in T1DM patients.

Answer 269

E Anti-glutamic acid decarboxylase Anti-glutamic acid decarboxylase (anti-GAD; E) antibody is present in patients with type 1 diabetes mellitus (T1DM). The pathogenesis of T1DM involves the autoimmune destruction of β-cells in the islets of Langerhans in the pancreas. β-Cells are the primary storage site for insulin in the body, and so destruction of these cells leads to diminished insulin release and hyperglycaemia. GAD is an enzyme responsible for the conversion of glutamate to GABA; GABA is the neurotransmitter involved in the release of insulin from β-cells. Presenting features of T1DM include polyuria, polydipsia and weight loss.

Answer 270

A Anti-mitochondrial Anti-mitochondrial (A) antibodies are associated with primary biliary cirrhosis (PBC), and are immunoglobulins against mitochondria in cells of the liver. PBC is an autoimmune disease of unknown cause characterized by lymphocytic destruction of the bile canaliculi of the liver; build-up of bile leads to fibrosis and eventually cirrhosis. Clinical features include pruritis (increased bile acids in circulation) as well as the effects of reduced absorption of fat soluble vitamins (vitamin D, osteomalacia; vitamin K, bruising; vitamin A, blindness).

Answer 271

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.

Answer 272

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.

Answer 273

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.

Answer 274

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.

Answer 275

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).

Answer 276

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.

Answer 277

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.

Answer 278

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.

Answer 279

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.

Answer 280

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.

Answer 281

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.

Answer 282

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.

Answer 283

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.

Answer 284

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.

Answer 285

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.

Answer 286

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.

Answer 287

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.

Answer 288

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.

Answer 289

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).

Answer 290

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.

Answer 291

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.

Answer 292

G Bruton’s agammaglobulinaemia Bruton’s agammaglobulinaemia (G) is an X-linked disease that presents in childhood. It is caused by a mutation of the BTK gene, which expresses a tyrosine kinase. This mutation inhibits B-cell maturation and therefore B-cell and immunoglobulin levels are diminished. Blood tests will reveal a normal T-cell count, but diminished B-cell count as well as IgA, IgM and IgG levels. Plasma cells will also be absent from the bone marrow and lymphatics.

Answer 293

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.

Answer 294

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.

Answer 295

B Immunofluorescence Immunofluorescence (B) is an immunological technique used in conjunction with fluorescence microscope. Fluorophores (fluorescent chemical compounds) attached to specific antibodies are directed at antigens found within a biological specimen, most commonly a biopsy sample, to visualize patterns of staining. For example, in Henoch– Schönlein purpura, anti-IgA antibody will demonstrate IgA deposits in the capillary walls of the specimen. Immunofluorescence may be direct (use of a single antibody bound to a single fluorophore) or indirect (secondary antibody carrying the fluorophore binds to the primary antibody).

Answer 296

G Skin prick test Skin prick test (G) is the gold standard for investigating such type I hypersensitivity reactions. The test involves a few drops of purified allergen being pricked onto the skin. Allergens which are tested for include foods, dust mites, pollen and dust. A positive test is indicated by wheal formation, caused by cross-linking of IgE on the mast cell surface leading to histamine release.

Answer 297

I Direct antiglobulin test Direct antiglobulin test (DAT; I) also known as direct Coombs test, is the investigation of choice for the diagnosis of autoimmune haemolytic anaemia (AIHA). Causes of AIHA include lymphoproliferative disorders, drugs (penicillin) and autoimmune diseases (SLE). The test involves the separation of RBCs from the serum which is subsequently incubated with anti-human globulin. In the case of AIHA, the anti-human globulin will agglutinate the RBCs, which is visualized as clumping of the cells.

Answer 298

F Kveim test Kveim test (F) is an investigation used to diagnose sarcoidosis. A sample of spleen from a patient with known sarcoid is injected intradermally into a suspected patient. A positive test is evidenced by the presence of non-caseating granuloma formation on biopsy of the site, 4–6 weeks after the initial injection. Although not used in the UK due to infection concerns (especially bovine spongiform encephalopathy), it is still available in many countries.

Answer 299

H Western blot Western blot (H) is a technique used to detect specific proteins in a patient’s serum; it is used in the confirmatory HIV test to detect specific antibodies to HIV. The first step is to separate native proteins by gel electrophoresis. The proteins are subsequently transferred to a membrane on which specific antibodies present in the serum may bind to HIV proteins produced using recombinant DNA. Unbound antibodies are washed away. Enzyme-linked antibodies are then added; these determine to which protein the subject has antibodies.

Answer 300

A Minimal change disease Minimal change disease (A) is the most common cause of nephrotic syndrome in children. Triggers include a recent allergic reaction such as a bee sting (type I hypersensitivity reaction). Histological characteristics of renal biopsy specimens include a lack of structural change visible on light microscopy, while electron microscopy will demonstrate podocyte effacement. Steroids are the primary treatment modality, which lead to remission of disease in the vast majority of cases.

Answer 301

G Rapidly progressive glomerulonephritis Rapidly progressive glomerulonephritis (RPGN; G) is the most aggressive of all glomerulonephritides, which may cause end-stage renal failure over a period of days. The three sub-types include immune complex disease, pauci-immune disease and anti-glomerular basement membrane disease, all of which demonstrate crescent formation on biopsy (proliferation of macrophages and parietal epithelial cells). Immunofluoresence of IgG/C3 distinguishes between the three sub-types: immune complex disease is characterized by granular staining, pauci-immune disease shows absent/scant staining, while anti-glomerular basement membrane disease demonstrates linear staining.

Answer 302

H Post-streptococcal glomerulonephritis Post-streptococcal glomerulonephritis (H) is usually caused by a preceding group A β haemolytic streptococcus pharyngitis. Anti-streptolysin O titre (ASOT) will be raised. Pathological hallmarks of post-streptococcal glomerulonephritis include diffuse hypercellularity and diffuse swelling of the mesangium and glomerular capillaries. Influx of neutrophils and macrophages may reveal crescent formation on histology. Direct immunofluorescence reveals the sub-epithelial deposition of IgG and C3. The condition usually subsides with supportive treatment, including antibiotic therapy to combat the outstanding infection.

Answer 303

E IgA nephropathy IgA nephropathy (Berger’s disease; E) is the most common cause of glomerunephritis in the developed world. The condition occurs after a gastrointestinal or upper respiratory infection; potential offenders are postulated to include Haemophilus influenzae, hepatitis B virus and cytomegalovirus. Antigenic targets for IgA are thought to include collagen, fibronectin and laminin. Characteristically there is mesangial proliferation with deposition of IgA together with alternative pathway factors C3 and properdin. Blood tests will reveal a raised IgA level. Henoch–Schonlein purpura has a similar pathogenesis to IgA nephropathy but presents in children and has extra-renal clinical features.

Answer 304

B Wegener’s granulomatosis Wegener’s granulamatosis (B) is a systemic vasculitis characterized clinically by epistaxis, haemoptysis and haematuria. Wegener’s granulomatosis is defined by the presence of cytoplasmic anti-neutrophil cytoplasmic antibodies (cANCA). c-ANCA is directed towards proteinase 3 (PR3), an enzyme normally present within the cytoplasm of neutrophils. It is proposed that an infection is the trigger for the disease, which causes circulating neutrophils to become adherent to the endothelium and upregulation of PR3 on the cell surface. Vasculitis is mediated by both direct effect of PR3 on the endothelium as well as cANCA–PR3 immune complex deposition.

Answer 305

I Denosumab Denosumab (I) is an antibody directed towards the RANK ligand in bones. Osteoblasts are responsible for bone formation, whilst osteoclasts (which contain the cell surface receptor RANK) break down bone. Inhibition of RANK by denosumab therefore inhibits osteoclast function and differentiation, thereby preventing the breakdown of bone. Denosumab is indicated in the treatment of osteoporosis but is also used in the management of multiple myeloma and bone metastases. Toxicity can predispose to respiratory and urinary tract infections.

Answer 306

G Infliximab Infliximab (G) is a TNF-α antagonist used in the treatment of rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease and psoriasis. Infliximab has a high affinity for TNF-α but does not bind to TNF-β. TNF-α has the physiological role of inducing pro-inflammatory cytokines as well as promoting leukocyte migration and endothelial adhesion. Toxicity may result in reduced protection against infection from TB, hepatitis B virus and hepatitis C virus, a lupus-like condition, demyelination and malignancy.

Answer 307

B Mycophenolate mofetil Mycophenolate mofetil (B) is the prodrug of mycophenolic acid which inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme required in guanine synthesis; impaired guanine synthesis reduces the proliferation of both T and B cells, but T cells are affected to a greater extent. Mycophenolate mofetil is indicated as an immunosuppressive agent in transplant patients as well as an alternative to cyclophosphamide in the treatment of autoimmune diseases and vasculitides. Side effects include bone marrow suppression (particularly low white blood cells and platelets) as well as herpes virus reactivation.

Answer 308

D Abatacept Abatacept (D) is a CTLA4–immunoglobulin fusion protein indicated in the treatment of rheumatoid arthritis (disease which has been resistant to treatment with disease modifying drugs). Abatacept prevents antigen presenting cells from delivering a co-stimulatory signal to T cells in order to activate them; this is achieved by abatacept binding with high affinity to the B7 protein (CD80 and CD86) on the cell surface of APCs. Side effects include increased risk of infection from TB, hepatitis B virus and hepatitis C virus.

Answer 309

A Cyclophosphamide Cyclophosphamide (A) is an alkylating agent, attaching an alkyl group to the guanine base of DNA. This causes damage to the DNA structure and therefore prevents cell replication; cyclophosphamide affects B-cell replication more than T cells. Indications include multisystem connective tissue disease and vasculitis such as systemic lupus erythematosus and Wegner’s granulomatosis. Cyclophosphamide also has a role in treating cancers such as leukaemia and lymphoma. Complications of therapy include bone marrow suppression, hair loss and it has carcinogenic properties which may cause transitional cell carcinoma of the bladder.

Answer 310

E Glycoprotein IIb–IIIa Glycoprotein IIb–IIIa (E) on the surface of platelets is the target for IgG autoantibodies (type II hypersensitivity reaction) in autoimmune thrombocytopenic purpura (AITP). IgG directed at platelets makes them more susceptible to destruction by splenic macrophages and as a result the platelet count in affected individuals will be very low. Symptoms depend upon the platelet count:

Answer 311

B HBsAg HBsAg (B) may be associated with the development of polyarteritis nodosa (PAN), a vasculitis of small and medium sized vessels. Immune complexes (type III hypersensitivity reaction) are deposited within such vessels leading to fibrinoid necrosis and neutrophil infiltration; as a result the vessel walls weaken and there is aneurysm development. Investigations will reveal a raised ESR, CRP and immunoglobulin level. pANCA is also associated with PAN. Angiogram will reveal multiple aneurysms. Corticosteroids and cytotoxic agents are required to control disease progression.

Answer 312

D Rhesus antigens Rhesus antigens (D) are found on the surface of erythrocytes. The rhesus (Rh) blood group system is clinically the most important after the ABO system; the most commonly used Rh antigen is the D antigen, signifying whether a patient is Rh positive or negative. Antibodies directed against the Rh antigen results in autoimmune haemolytic anaemia (AIHA; type II hypersensitivity reaction). Most commonly the cause is idiopathic, however, chronic lymphocytic leukaemia, systemic lupus erythematosus and drugs (methyldopa and penicillin) can trigger AIHA. Direct antiglobulin test is positive.

Answer 313

C Myelin basic protein Myelin basic protein (C) and proteolipid protein are oligodendrocyte proteins implicated in the pathogenesis of multiple sclerosis. Multiple sclerosis (MS) is a demyelinating disease in which the myelin sheaths surrounding neurons of the brain and spinal cord are destroyed. Associated with the disease process is the antigenic stimulation of CD4+ T cells which in turn activate CD8+ cytotoxic T cells and macrophages; these are directed at oligodendrocyte proteins (type IV hypersensitivity reaction) causing destruction of oligodendrocytes and myelin. Clinical features of MS include optic neuritis, urinary/bowel incontinence, weakness of the arms/legs and dysphagia.

Answer 314

F Peanuts Allergy to peanuts (F) causes a spectrum of clinical manifestations, from mild food allergy to severe anaphylaxis. The underlying pathogenesis is the binding of the allergen to IgE causing mast cell degranulation and histamine release (a potent vasodilator and bronchoconstrictor). In anaphylaxis, this release of histamine occurs throughout the body, leading to the clinical features of shortness of breath, wheeze, swollen lips and signs of shock. Anaphylaxis is a medical emergency and requires prompt administration of intramuscular adrenaline and urgent transfer to a hospital.

Answer 315

H Grass pollen Grass pollen (H) may cause allergic rhinitis via a type I hypersensitivity reaction. The allergen triggers IgE production, which bind to the cell surface of mast cells and basophils. On repeated exposure to pollen, the mast cells degranulate, releasing histamine as well as other mediators. This results in the characteristic features of allergic rhinitis such as a runny nose, sneezing, itchiness, watery eyes and nasal congestion.

Answer 316

E Type IV collagen Type IV collagen (E), is the target of soluble IgG in Goodpasture’s disease (type II hypersensitivity reaction). Type IV collagen is present in the glomerular basement membrane and lung basement membrane. Pulmonary features include cough, dyspnoea and haemoptysis; renal features include haematuria, acute renal failure and nephrotic syndrome. Investigations reveal the presence of anti-type IV collagen antibodies in the circulation; immunofluorescence will show linear deposition of IgG along the glomerular basement membrane.

Answer 317

G Mouldy hay Chronic exposure to mouldy hay (G) is the cause of farmer’s lung, an example of an extrinsic allergic alveolitis. Actinomycetes are the most common pathogen found in hay dust, which are subsequently inhaled. Inhalation over prolonged periods of time leads to immune complex formation as antibodies combine with the inhaled allergen (type III hypersensitivity reaction); the immune complexes are deposited in the walls of the alveoli. Chronic exposure leads to pulmonary fibrosis, with associated shortness of breath, cyanosis and cor pulmonale.

Answer 318

B Nuts Ingestion of nuts (B) can lead to a type I hypersensitivity, characterized by a strong CD4+ Th2 response which causes release of IL-4 and IL-13. This causes B cells to produce IgE, which in turn binds to Fc receptors on mast cells. On re-exposure to the allergen the IgE on mast cells cross-links, with resultant mast cell degranulation (release of histamine and tryptases) and arachidonic acid metabolism (producing leukotrienes and prostaglandins). Clinical features include erythema, rhinitis, urticaria, angio-oedema, bronchoconstriction and in severe cases anaphylactic shock.

Answer 319

I Pancreatic β-cell proteins Pancreatic β-cell proteins (I) are the antigenic target for cytotoxic CD8+ T cells in type 1 diabetes mellitus (T1DM). T1DM is a type IV hypersensitivity reaction since it is T-cell mediated; the pathogenesis involves the destruction of β-cells in the islets of Langerhans in the pancreas by CD8+ T cells. β-cells are the storage site for insulin in the body, and so destruction of these cells leads to diminished insulin release and hyperglycaemia. Presenting features of T1DM include polyuria, polydipsia and weight loss. Antibodies to glutamate decarboxylase (GAD) as well as islet cells may also circulate in T1DM patients.

Answer 320

I Anti-endomysial Anti-endomysium (I) is characteristic of coeliac disease, autoimmune disease of the small intestine that results from an immune reaction to gliadin (peptide found in wheat, barley and rye). The endomysium is in fact related to muscle fibres; although muscle fibres are not affected in coeliac disease, anti-endomysial antibodies are useful in the diagnosis of coeliac disease. Clinical features include diarrhoea, abdominal pain and mouth ulcers. Other autoantibodies that are used in the diagnosis of coeliac disease are anti-tissue transglutaminase antibody and antigliadin antibodies.

Answer 321

B c-ANCA c-ANCA (cytoplasmic anti-neutrophil cytoplasmic antibodies; B) are common in patients with Wegener’s granulamatosis, a vasculitic disease that is in severe cases life threatening. c-ANCA is directed towards proteinase 3 (PR3) within the neutrophil cytoplasm. Wegner’s granulamatosis primarily affects the nose (saddle-nose deformity due to perforated septum; epistaxis), lungs (pulmonary haemorrhage) and kidneys (glomerulonephritis). Due to its fulminant course, patients require life-long immunosuppression, usually with corticosteroids.

Answer 322

E Anti-glutamic acid decarboxylase Anti-glutamic acid decarboxylase (anti-GAD; E) antibody is present in patients with type 1 diabetes mellitus (T1DM). The pathogenesis of T1DM involves the autoimmune destruction of β-cells in the islets of Langerhans in the pancreas. β-Cells are the primary storage site for insulin in the body, and so destruction of these cells leads to diminished insulin release and hyperglycaemia. GAD is an enzyme responsible for the conversion of glutamate to GABA; GABA is the neurotransmitter involved in the release of insulin from β-cells. Presenting features of T1DM include polyuria, polydipsia and weight loss.

Answer 323

A Anti-mitochondrial Anti-mitochondrial (A) antibodies are associated with primary biliary cirrhosis (PBC), and are immunoglobulins against mitochondria in cells of the liver. PBC is an autoimmune disease of unknown cause characterized by lymphocytic destruction of the bile canaliculi of the liver; build-up of bile leads to fibrosis and eventually cirrhosis. Clinical features include pruritis (increased bile acids in circulation) as well as the effects of reduced absorption of fat soluble vitamins (vitamin D, osteomalacia; vitamin K, bruising; vitamin A, blindness).

Answer 324

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.

Answer 325

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.

Answer 326

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.

Answer 327

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.

Answer 328

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).

Answer 329

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.

Answer 330

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.

Answer 331

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.

Answer 332

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.

Answer 333

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.

Answer 334

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.

Answer 335

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.

Answer 336

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.

Answer 337

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.

Answer 338

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.

Answer 339

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.

Answer 340

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).

Answer 341

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).

Answer 342

B Immunofluorescence Immunofluorescence (B) is an immunological technique used in conjunction with fluorescence microscope. Fluorophores (fluorescent chemical compounds) attached to specific antibodies are directed at antigens found within a biological specimen, most commonly a biopsy sample, to visualize patterns of staining. For example, in Henoch– Schönlein purpura, anti-IgA antibody will demonstrate IgA deposits in the capillary walls of the specimen. Immunofluorescence may be direct (use of a single antibody bound to a single fluorophore) or indirect (secondary antibody carrying the fluorophore binds to the primary antibody).

Answer 343

G Skin prick test Skin prick test (G) is the gold standard for investigating such type I hypersensitivity reactions. The test involves a few drops of purified allergen being pricked onto the skin. Allergens which are tested for include foods, dust mites, pollen and dust. A positive test is indicated by wheal formation, caused by cross-linking of IgE on the mast cell surface leading to histamine release.

Answer 344

I Direct antiglobulin test Direct antiglobulin test (DAT; I) also known as direct Coombs test, is the investigation of choice for the diagnosis of autoimmune haemolytic anaemia (AIHA). Causes of AIHA include lymphoproliferative disorders, drugs (penicillin) and autoimmune diseases (SLE). The test involves the separation of RBCs from the serum which is subsequently incubated with anti-human globulin. In the case of AIHA, the anti-human globulin will agglutinate the RBCs, which is visualized as clumping of the cells.

Answer 345

F Kveim test Kveim test (F) is an investigation used to diagnose sarcoidosis. A sample of spleen from a patient with known sarcoid is injected intradermally into a suspected patient. A positive test is evidenced by the presence of non-caseating granuloma formation on biopsy of the site, 4–6 weeks after the initial injection. Although not used in the UK due to infection concerns (especially bovine spongiform encephalopathy), it is still available in many countries.

Answer 346

H Western blot Western blot (H) is a technique used to detect specific proteins in a patient’s serum; it is used in the confirmatory HIV test to detect specific antibodies to HIV. The first step is to separate native proteins by gel electrophoresis. The proteins are subsequently transferred to a membrane on which specific antibodies present in the serum may bind to HIV proteins produced using recombinant DNA. Unbound antibodies are washed away. Enzyme-linked antibodies are then added; these determine to which protein the subject has antibodies.

Answer 347

A Minimal change disease Minimal change disease (A) is the most common cause of nephrotic syndrome in children. Triggers include a recent allergic reaction such as a bee sting (type I hypersensitivity reaction). Histological characteristics of renal biopsy specimens include a lack of structural change visible on light microscopy, while electron microscopy will demonstrate podocyte effacement. Steroids are the primary treatment modality, which lead to remission of disease in the vast majority of cases.

Answer 348

G Rapidly progressive glomerulonephritis Rapidly progressive glomerulonephritis (RPGN; G) is the most aggressive of all glomerulonephritides, which may cause end-stage renal failure over a period of days. The three sub-types include immune complex disease, pauci-immune disease and anti-glomerular basement membrane disease, all of which demonstrate crescent formation on biopsy (proliferation of macrophages and parietal epithelial cells). Immunofluoresence of IgG/C3 distinguishes between the three sub-types: immune complex disease is characterized by granular staining, pauci-immune disease shows absent/scant staining, while anti-glomerular basement membrane disease demonstrates linear staining.

Answer 349

H Post-streptococcal glomerulonephritis Post-streptococcal glomerulonephritis (H) is usually caused by a preceding group A β haemolytic streptococcus pharyngitis. Anti-streptolysin O titre (ASOT) will be raised. Pathological hallmarks of post-streptococcal glomerulonephritis include diffuse hypercellularity and diffuse swelling of the mesangium and glomerular capillaries. Influx of neutrophils and macrophages may reveal crescent formation on histology. Direct immunofluorescence reveals the sub-epithelial deposition of IgG and C3. The condition usually subsides with supportive treatment, including antibiotic therapy to combat the outstanding infection.

Answer 350

E IgA nephropathy IgA nephropathy (Berger’s disease; E) is the most common cause of glomerunephritis in the developed world. The condition occurs after a gastrointestinal or upper respiratory infection; potential offenders are postulated to include Haemophilus influenzae, hepatitis B virus and cytomegalovirus. Antigenic targets for IgA are thought to include collagen, fibronectin and laminin. Characteristically there is mesangial proliferation with deposition of IgA together with alternative pathway factors C3 and properdin. Blood tests will reveal a raised IgA level. Henoch–Schonlein purpura has a similar pathogenesis to IgA nephropathy but presents in children and has extra-renal clinical features.

Answer 351

B Wegener’s granulomatosis Wegener’s granulamatosis (B) is a systemic vasculitis characterized clinically by epistaxis, haemoptysis and haematuria. Wegener’s granulomatosis is defined by the presence of cytoplasmic anti-neutrophil cytoplasmic antibodies (cANCA). c-ANCA is directed towards proteinase 3 (PR3), an enzyme normally present within the cytoplasm of neutrophils. It is proposed that an infection is the trigger for the disease, which causes circulating neutrophils to become adherent to the endothelium and upregulation of PR3 on the cell surface. Vasculitis is mediated by both direct effect of PR3 on the endothelium as well as cANCA–PR3 immune complex deposition.

Answer 352

I Denosumab Denosumab (I) is an antibody directed towards the RANK ligand in bones. Osteoblasts are responsible for bone formation, whilst osteoclasts (which contain the cell surface receptor RANK) break down bone. Inhibition of RANK by denosumab therefore inhibits osteoclast function and differentiation, thereby preventing the breakdown of bone. Denosumab is indicated in the treatment of osteoporosis but is also used in the management of multiple myeloma and bone metastases. Toxicity can predispose to respiratory and urinary tract infections.

Answer 353

G Infliximab Infliximab (G) is a TNF-α antagonist used in the treatment of rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease and psoriasis. Infliximab has a high affinity for TNF-α but does not bind to TNF-β. TNF-α has the physiological role of inducing pro-inflammatory cytokines as well as promoting leukocyte migration and endothelial adhesion. Toxicity may result in reduced protection against infection from TB, hepatitis B virus and hepatitis C virus, a lupus-like condition, demyelination and malignancy.

Answer 354

B Mycophenolate mofetil Mycophenolate mofetil (B) is the prodrug of mycophenolic acid which inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme required in guanine synthesis; impaired guanine synthesis reduces the proliferation of both T and B cells, but T cells are affected to a greater extent. Mycophenolate mofetil is indicated as an immunosuppressive agent in transplant patients as well as an alternative to cyclophosphamide in the treatment of autoimmune diseases and vasculitides. Side effects include bone marrow suppression (particularly low white blood cells and platelets) as well as herpes virus reactivation.

Answer 355

D Abatacept Abatacept (D) is a CTLA4–immunoglobulin fusion protein indicated in the treatment of rheumatoid arthritis (disease which has been resistant to treatment with disease modifying drugs). Abatacept prevents antigen presenting cells from delivering a co-stimulatory signal to T cells in order to activate them; this is achieved by abatacept binding with high affinity to the B7 protein (CD80 and CD86) on the cell surface of APCs. Side effects include increased risk of infection from TB, hepatitis B virus and hepatitis C virus.

Answer 356

A Cyclophosphamide Cyclophosphamide (A) is an alkylating agent, attaching an alkyl group to the guanine base of DNA. This causes damage to the DNA structure and therefore prevents cell replication; cyclophosphamide affects B-cell replication more than T cells. Indications include multisystem connective tissue disease and vasculitis such as systemic lupus erythematosus and Wegner’s granulomatosis. Cyclophosphamide also has a role in treating cancers such as leukaemia and lymphoma. Complications of therapy include bone marrow suppression, hair loss and it has carcinogenic properties which may cause transitional cell carcinoma of the bladder.

Answer 357

E Glycoprotein IIb–IIIa Glycoprotein IIb–IIIa (E) on the surface of platelets is the target for IgG autoantibodies (type II hypersensitivity reaction) in autoimmune thrombocytopenic purpura (AITP). IgG directed at platelets makes them more susceptible to destruction by splenic macrophages and as a result the platelet count in affected individuals will be very low. Symptoms depend upon the platelet count:

Answer 358

B HBsAg HBsAg (B) may be associated with the development of polyarteritis nodosa (PAN), a vasculitis of small and medium sized vessels. Immune complexes (type III hypersensitivity reaction) are deposited within such vessels leading to fibrinoid necrosis and neutrophil infiltration; as a result the vessel walls weaken and there is aneurysm development. Investigations will reveal a raised ESR, CRP and immunoglobulin level. pANCA is also associated with PAN. Angiogram will reveal multiple aneurysms. Corticosteroids and cytotoxic agents are required to control disease progression.

Answer 359

D Rhesus antigens Rhesus antigens (D) are found on the surface of erythrocytes. The rhesus (Rh) blood group system is clinically the most important after the ABO system; the most commonly used Rh antigen is the D antigen, signifying whether a patient is Rh positive or negative. Antibodies directed against the Rh antigen results in autoimmune haemolytic anaemia (AIHA; type II hypersensitivity reaction). Most commonly the cause is idiopathic, however, chronic lymphocytic leukaemia, systemic lupus erythematosus and drugs (methyldopa and penicillin) can trigger AIHA. Direct antiglobulin test is positive.

Answer 360

C Myelin basic protein Myelin basic protein (C) and proteolipid protein are oligodendrocyte proteins implicated in the pathogenesis of multiple sclerosis. Multiple sclerosis (MS) is a demyelinating disease in which the myelin sheaths surrounding neurons of the brain and spinal cord are destroyed. Associated with the disease process is the antigenic stimulation of CD4+ T cells which in turn activate CD8+ cytotoxic T cells and macrophages; these are directed at oligodendrocyte proteins (type IV hypersensitivity reaction) causing destruction of oligodendrocytes and myelin. Clinical features of MS include optic neuritis, urinary/bowel incontinence, weakness of the arms/legs and dysphagia.

Answer 361

F Peanuts Allergy to peanuts (F) causes a spectrum of clinical manifestations, from mild food allergy to severe anaphylaxis. The underlying pathogenesis is the binding of the allergen to IgE causing mast cell degranulation and histamine release (a potent vasodilator and bronchoconstrictor). In anaphylaxis, this release of histamine occurs throughout the body, leading to the clinical features of shortness of breath, wheeze, swollen lips and signs of shock. Anaphylaxis is a medical emergency and requires prompt administration of intramuscular adrenaline and urgent transfer to a hospital.

Answer 362

H Grass pollen Grass pollen (H) may cause allergic rhinitis via a type I hypersensitivity reaction. The allergen triggers IgE production, which bind to the cell surface of mast cells and basophils. On repeated exposure to pollen, the mast cells degranulate, releasing histamine as well as other mediators. This results in the characteristic features of allergic rhinitis such as a runny nose, sneezing, itchiness, watery eyes and nasal congestion.

Answer 363

E Type IV collagen Type IV collagen (E), is the target of soluble IgG in Goodpasture’s disease (type II hypersensitivity reaction). Type IV collagen is present in the glomerular basement membrane and lung basement membrane. Pulmonary features include cough, dyspnoea and haemoptysis; renal features include haematuria, acute renal failure and nephrotic syndrome. Investigations reveal the presence of anti-type IV collagen antibodies in the circulation; immunofluorescence will show linear deposition of IgG along the glomerular basement membrane.

Answer 364

G Mouldy hay Chronic exposure to mouldy hay (G) is the cause of farmer’s lung, an example of an extrinsic allergic alveolitis. Actinomycetes are the most common pathogen found in hay dust, which are subsequently inhaled. Inhalation over prolonged periods of time leads to immune complex formation as antibodies combine with the inhaled allergen (type III hypersensitivity reaction); the immune complexes are deposited in the walls of the alveoli. Chronic exposure leads to pulmonary fibrosis, with associated shortness of breath, cyanosis and cor pulmonale.

Answer 365

B Nuts Ingestion of nuts (B) can lead to a type I hypersensitivity, characterized by a strong CD4+ Th2 response which causes release of IL-4 and IL-13. This causes B cells to produce IgE, which in turn binds to Fc receptors on mast cells. On re-exposure to the allergen the IgE on mast cells cross-links, with resultant mast cell degranulation (release of histamine and tryptases) and arachidonic acid metabolism (producing leukotrienes and prostaglandins). Clinical features include erythema, rhinitis, urticaria, angio-oedema, bronchoconstriction and in severe cases anaphylactic shock.

Answer 366

I Pancreatic β-cell proteins Pancreatic β-cell proteins (I) are the antigenic target for cytotoxic CD8+ T cells in type 1 diabetes mellitus (T1DM). T1DM is a type IV hypersensitivity reaction since it is T-cell mediated; the pathogenesis involves the destruction of β-cells in the islets of Langerhans in the pancreas by CD8+ T cells. β-cells are the storage site for insulin in the body, and so destruction of these cells leads to diminished insulin release and hyperglycaemia. Presenting features of T1DM include polyuria, polydipsia and weight loss. Antibodies to glutamate decarboxylase (GAD) as well as islet cells may also circulate in T1DM patients.

Answer 367

I Anti-endomysial Anti-endomysium (I) is characteristic of coeliac disease, autoimmune disease of the small intestine that results from an immune reaction to gliadin (peptide found in wheat, barley and rye). The endomysium is in fact related to muscle fibres; although muscle fibres are not affected in coeliac disease, anti-endomysial antibodies are useful in the diagnosis of coeliac disease. Clinical features include diarrhoea, abdominal pain and mouth ulcers. Other autoantibodies that are used in the diagnosis of coeliac disease are anti-tissue transglutaminase antibody and antigliadin antibodies.

Answer 368

B c-ANCA c-ANCA (cytoplasmic anti-neutrophil cytoplasmic antibodies; B) are common in patients with Wegener’s granulamatosis, a vasculitic disease that is in severe cases life threatening. c-ANCA is directed towards proteinase 3 (PR3) within the neutrophil cytoplasm. Wegner’s granulamatosis primarily affects the nose (saddle-nose deformity due to perforated septum; epistaxis), lungs (pulmonary haemorrhage) and kidneys (glomerulonephritis). Due to its fulminant course, patients require life-long immunosuppression, usually with corticosteroids.

Answer 369

E Anti-glutamic acid decarboxylase Anti-glutamic acid decarboxylase (anti-GAD; E) antibody is present in patients with type 1 diabetes mellitus (T1DM). The pathogenesis of T1DM involves the autoimmune destruction of β-cells in the islets of Langerhans in the pancreas. β-Cells are the primary storage site for insulin in the body, and so destruction of these cells leads to diminished insulin release and hyperglycaemia. GAD is an enzyme responsible for the conversion of glutamate to GABA; GABA is the neurotransmitter involved in the release of insulin from β-cells. Presenting features of T1DM include polyuria, polydipsia and weight loss.

Answer 370

A Anti-mitochondrial Anti-mitochondrial (A) antibodies are associated with primary biliary cirrhosis (PBC), and are immunoglobulins against mitochondria in cells of the liver. PBC is an autoimmune disease of unknown cause characterized by lymphocytic destruction of the bile canaliculi of the liver; build-up of bile leads to fibrosis and eventually cirrhosis. Clinical features include pruritis (increased bile acids in circulation) as well as the effects of reduced absorption of fat soluble vitamins (vitamin D, osteomalacia; vitamin K, bruising; vitamin A, blindness).

Answer 371

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.

Answer 372

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.

Answer 373

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.

Answer 374

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.

Answer 375

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).

Answer 376

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.

Answer 377

B Immunofluorescence Immunofluorescence (B) is an immunological technique used in conjunction with fluorescence microscope. Fluorophores (fluorescent chemical compounds) attached to specific antibodies are directed at antigens found within a biological specimen, most commonly a biopsy sample, to visualize patterns of staining. For example, in Henoch– Schönlein purpura, anti-IgA antibody will demonstrate IgA deposits in the capillary walls of the specimen. Immunofluorescence may be direct (use of a single antibody bound to a single fluorophore) or indirect (secondary antibody carrying the fluorophore binds to the primary antibody).

Answer 378

G Skin prick test Skin prick test (G) is the gold standard for investigating such type I hypersensitivity reactions. The test involves a few drops of purified allergen being pricked onto the skin. Allergens which are tested for include foods, dust mites, pollen and dust. A positive test is indicated by wheal formation, caused by cross-linking of IgE on the mast cell surface leading to histamine release.

Answer 379

I Direct antiglobulin test Direct antiglobulin test (DAT; I) also known as direct Coombs test, is the investigation of choice for the diagnosis of autoimmune haemolytic anaemia (AIHA). Causes of AIHA include lymphoproliferative disorders, drugs (penicillin) and autoimmune diseases (SLE). The test involves the separation of RBCs from the serum which is subsequently incubated with anti-human globulin. In the case of AIHA, the anti-human globulin will agglutinate the RBCs, which is visualized as clumping of the cells.

Answer 380

F Kveim test Kveim test (F) is an investigation used to diagnose sarcoidosis. A sample of spleen from a patient with known sarcoid is injected intradermally into a suspected patient. A positive test is evidenced by the presence of non-caseating granuloma formation on biopsy of the site, 4–6 weeks after the initial injection. Although not used in the UK due to infection concerns (especially bovine spongiform encephalopathy), it is still available in many countries.

Answer 381

H Western blot Western blot (H) is a technique used to detect specific proteins in a patient’s serum; it is used in the confirmatory HIV test to detect specific antibodies to HIV. The first step is to separate native proteins by gel electrophoresis. The proteins are subsequently transferred to a membrane on which specific antibodies present in the serum may bind to HIV proteins produced using recombinant DNA. Unbound antibodies are washed away. Enzyme-linked antibodies are then added; these determine to which protein the subject has antibodies.

Answer 382

A Minimal change disease Minimal change disease (A) is the most common cause of nephrotic syndrome in children. Triggers include a recent allergic reaction such as a bee sting (type I hypersensitivity reaction). Histological characteristics of renal biopsy specimens include a lack of structural change visible on light microscopy, while electron microscopy will demonstrate podocyte effacement. Steroids are the primary treatment modality, which lead to remission of disease in the vast majority of cases.

Answer 383

G Rapidly progressive glomerulonephritis Rapidly progressive glomerulonephritis (RPGN; G) is the most aggressive of all glomerulonephritides, which may cause end-stage renal failure over a period of days. The three sub-types include immune complex disease, pauci-immune disease and anti-glomerular basement membrane disease, all of which demonstrate crescent formation on biopsy (proliferation of macrophages and parietal epithelial cells). Immunofluoresence of IgG/C3 distinguishes between the three sub-types: immune complex disease is characterized by granular staining, pauci-immune disease shows absent/scant staining, while anti-glomerular basement membrane disease demonstrates linear staining.

Answer 384

H Post-streptococcal glomerulonephritis Post-streptococcal glomerulonephritis (H) is usually caused by a preceding group A β haemolytic streptococcus pharyngitis. Anti-streptolysin O titre (ASOT) will be raised. Pathological hallmarks of post-streptococcal glomerulonephritis include diffuse hypercellularity and diffuse swelling of the mesangium and glomerular capillaries. Influx of neutrophils and macrophages may reveal crescent formation on histology. Direct immunofluorescence reveals the sub-epithelial deposition of IgG and C3. The condition usually subsides with supportive treatment, including antibiotic therapy to combat the outstanding infection.

Answer 385

E IgA nephropathy IgA nephropathy (Berger’s disease; E) is the most common cause of glomerunephritis in the developed world. The condition occurs after a gastrointestinal or upper respiratory infection; potential offenders are postulated to include Haemophilus influenzae, hepatitis B virus and cytomegalovirus. Antigenic targets for IgA are thought to include collagen, fibronectin and laminin. Characteristically there is mesangial proliferation with deposition of IgA together with alternative pathway factors C3 and properdin. Blood tests will reveal a raised IgA level. Henoch–Schonlein purpura has a similar pathogenesis to IgA nephropathy but presents in children and has extra-renal clinical features.

Answer 386

B Wegener’s granulomatosis Wegener’s granulamatosis (B) is a systemic vasculitis characterized clinically by epistaxis, haemoptysis and haematuria. Wegener’s granulomatosis is defined by the presence of cytoplasmic anti-neutrophil cytoplasmic antibodies (cANCA). c-ANCA is directed towards proteinase 3 (PR3), an enzyme normally present within the cytoplasm of neutrophils. It is proposed that an infection is the trigger for the disease, which causes circulating neutrophils to become adherent to the endothelium and upregulation of PR3 on the cell surface. Vasculitis is mediated by both direct effect of PR3 on the endothelium as well as cANCA–PR3 immune complex deposition.

Answer 387

I Denosumab Denosumab (I) is an antibody directed towards the RANK ligand in bones. Osteoblasts are responsible for bone formation, whilst osteoclasts (which contain the cell surface receptor RANK) break down bone. Inhibition of RANK by denosumab therefore inhibits osteoclast function and differentiation, thereby preventing the breakdown of bone. Denosumab is indicated in the treatment of osteoporosis but is also used in the management of multiple myeloma and bone metastases. Toxicity can predispose to respiratory and urinary tract infections.

Answer 388

G Infliximab Infliximab (G) is a TNF-α antagonist used in the treatment of rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease and psoriasis. Infliximab has a high affinity for TNF-α but does not bind to TNF-β. TNF-α has the physiological role of inducing pro-inflammatory cytokines as well as promoting leukocyte migration and endothelial adhesion. Toxicity may result in reduced protection against infection from TB, hepatitis B virus and hepatitis C virus, a lupus-like condition, demyelination and malignancy.

Answer 389

B Mycophenolate mofetil Mycophenolate mofetil (B) is the prodrug of mycophenolic acid which inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme required in guanine synthesis; impaired guanine synthesis reduces the proliferation of both T and B cells, but T cells are affected to a greater extent. Mycophenolate mofetil is indicated as an immunosuppressive agent in transplant patients as well as an alternative to cyclophosphamide in the treatment of autoimmune diseases and vasculitides. Side effects include bone marrow suppression (particularly low white blood cells and platelets) as well as herpes virus reactivation.

Answer 390

D Abatacept Abatacept (D) is a CTLA4–immunoglobulin fusion protein indicated in the treatment of rheumatoid arthritis (disease which has been resistant to treatment with disease modifying drugs). Abatacept prevents antigen presenting cells from delivering a co-stimulatory signal to T cells in order to activate them; this is achieved by abatacept binding with high affinity to the B7 protein (CD80 and CD86) on the cell surface of APCs. Side effects include increased risk of infection from TB, hepatitis B virus and hepatitis C virus.

Answer 391

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.

Answer 392

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.

Answer 393

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.

Answer 394

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.

Answer 395

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.

Answer 396

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.

Answer 397

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.

Answer 398

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.

Answer 399

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.

Answer 400

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.

Answer 401

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.

Answer 402

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.

Answer 403

G Bruton’s agammaglobulinaemia Bruton’s agammaglobulinaemia (G) is an X-linked disease that presents in childhood. It is caused by a mutation of the BTK gene, which expresses a tyrosine kinase. This mutation inhibits B-cell maturation and therefore B-cell and immunoglobulin levels are diminished. Blood tests will reveal a normal T-cell count, but diminished B-cell count as well as IgA, IgM and IgG levels. Plasma cells will also be absent from the bone marrow and lymphatics.

Answer 404

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.

Answer 405

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).

Answer 406

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).

Answer 407

A Cyclophosphamide Cyclophosphamide (A) is an alkylating agent, attaching an alkyl group to the guanine base of DNA. This causes damage to the DNA structure and therefore prevents cell replication; cyclophosphamide affects B-cell replication more than T cells. Indications include multisystem connective tissue disease and vasculitis such as systemic lupus erythematosus and Wegner’s granulomatosis. Cyclophosphamide also has a role in treating cancers such as leukaemia and lymphoma. Complications of therapy include bone marrow suppression, hair loss and it has carcinogenic properties which may cause transitional cell carcinoma of the bladder.

Answer 408

E Glycoprotein IIb–IIIa Glycoprotein IIb–IIIa (E) on the surface of platelets is the target for IgG autoantibodies (type II hypersensitivity reaction) in autoimmune thrombocytopenic purpura (AITP). IgG directed at platelets makes them more susceptible to destruction by splenic macrophages and as a result the platelet count in affected individuals will be very low. Symptoms depend upon the platelet count:

Answer 409

B HBsAg HBsAg (B) may be associated with the development of polyarteritis nodosa (PAN), a vasculitis of small and medium sized vessels. Immune complexes (type III hypersensitivity reaction) are deposited within such vessels leading to fibrinoid necrosis and neutrophil infiltration; as a result the vessel walls weaken and there is aneurysm development. Investigations will reveal a raised ESR, CRP and immunoglobulin level. pANCA is also associated with PAN. Angiogram will reveal multiple aneurysms. Corticosteroids and cytotoxic agents are required to control disease progression.

Answer 410

D Rhesus antigens Rhesus antigens (D) are found on the surface of erythrocytes. The rhesus (Rh) blood group system is clinically the most important after the ABO system; the most commonly used Rh antigen is the D antigen, signifying whether a patient is Rh positive or negative. Antibodies directed against the Rh antigen results in autoimmune haemolytic anaemia (AIHA; type II hypersensitivity reaction). Most commonly the cause is idiopathic, however, chronic lymphocytic leukaemia, systemic lupus erythematosus and drugs (methyldopa and penicillin) can trigger AIHA. Direct antiglobulin test is positive.

Answer 411

C Myelin basic protein Myelin basic protein (C) and proteolipid protein are oligodendrocyte proteins implicated in the pathogenesis of multiple sclerosis. Multiple sclerosis (MS) is a demyelinating disease in which the myelin sheaths surrounding neurons of the brain and spinal cord are destroyed. Associated with the disease process is the antigenic stimulation of CD4+ T cells which in turn activate CD8+ cytotoxic T cells and macrophages; these are directed at oligodendrocyte proteins (type IV hypersensitivity reaction) causing destruction of oligodendrocytes and myelin. Clinical features of MS include optic neuritis, urinary/bowel incontinence, weakness of the arms/legs and dysphagia.

Answer 412

F Peanuts Allergy to peanuts (F) causes a spectrum of clinical manifestations, from mild food allergy to severe anaphylaxis. The underlying pathogenesis is the binding of the allergen to IgE causing mast cell degranulation and histamine release (a potent vasodilator and bronchoconstrictor). In anaphylaxis, this release of histamine occurs throughout the body, leading to the clinical features of shortness of breath, wheeze, swollen lips and signs of shock. Anaphylaxis is a medical emergency and requires prompt administration of intramuscular adrenaline and urgent transfer to a hospital.

Answer 413

H Grass pollen Grass pollen (H) may cause allergic rhinitis via a type I hypersensitivity reaction. The allergen triggers IgE production, which bind to the cell surface of mast cells and basophils. On repeated exposure to pollen, the mast cells degranulate, releasing histamine as well as other mediators. This results in the characteristic features of allergic rhinitis such as a runny nose, sneezing, itchiness, watery eyes and nasal congestion.

Answer 414

E Type IV collagen Type IV collagen (E), is the target of soluble IgG in Goodpasture’s disease (type II hypersensitivity reaction). Type IV collagen is present in the glomerular basement membrane and lung basement membrane. Pulmonary features include cough, dyspnoea and haemoptysis; renal features include haematuria, acute renal failure and nephrotic syndrome. Investigations reveal the presence of anti-type IV collagen antibodies in the circulation; immunofluorescence will show linear deposition of IgG along the glomerular basement membrane.

Answer 415

G Mouldy hay Chronic exposure to mouldy hay (G) is the cause of farmer’s lung, an example of an extrinsic allergic alveolitis. Actinomycetes are the most common pathogen found in hay dust, which are subsequently inhaled. Inhalation over prolonged periods of time leads to immune complex formation as antibodies combine with the inhaled allergen (type III hypersensitivity reaction); the immune complexes are deposited in the walls of the alveoli. Chronic exposure leads to pulmonary fibrosis, with associated shortness of breath, cyanosis and cor pulmonale.

Answer 416

B Nuts Ingestion of nuts (B) can lead to a type I hypersensitivity, characterized by a strong CD4+ Th2 response which causes release of IL-4 and IL-13. This causes B cells to produce IgE, which in turn binds to Fc receptors on mast cells. On re-exposure to the allergen the IgE on mast cells cross-links, with resultant mast cell degranulation (release of histamine and tryptases) and arachidonic acid metabolism (producing leukotrienes and prostaglandins). Clinical features include erythema, rhinitis, urticaria, angio-oedema, bronchoconstriction and in severe cases anaphylactic shock.

Answer 417

I Pancreatic β-cell proteins Pancreatic β-cell proteins (I) are the antigenic target for cytotoxic CD8+ T cells in type 1 diabetes mellitus (T1DM). T1DM is a type IV hypersensitivity reaction since it is T-cell mediated; the pathogenesis involves the destruction of β-cells in the islets of Langerhans in the pancreas by CD8+ T cells. β-cells are the storage site for insulin in the body, and so destruction of these cells leads to diminished insulin release and hyperglycaemia. Presenting features of T1DM include polyuria, polydipsia and weight loss. Antibodies to glutamate decarboxylase (GAD) as well as islet cells may also circulate in T1DM patients.

Answer 418

I Anti-endomysial Anti-endomysium (I) is characteristic of coeliac disease, autoimmune disease of the small intestine that results from an immune reaction to gliadin (peptide found in wheat, barley and rye). The endomysium is in fact related to muscle fibres; although muscle fibres are not affected in coeliac disease, anti-endomysial antibodies are useful in the diagnosis of coeliac disease. Clinical features include diarrhoea, abdominal pain and mouth ulcers. Other autoantibodies that are used in the diagnosis of coeliac disease are anti-tissue transglutaminase antibody and antigliadin antibodies.

Answer 419

B c-ANCA c-ANCA (cytoplasmic anti-neutrophil cytoplasmic antibodies; B) are common in patients with Wegener’s granulamatosis, a vasculitic disease that is in severe cases life threatening. c-ANCA is directed towards proteinase 3 (PR3) within the neutrophil cytoplasm. Wegner’s granulamatosis primarily affects the nose (saddle-nose deformity due to perforated septum; epistaxis), lungs (pulmonary haemorrhage) and kidneys (glomerulonephritis). Due to its fulminant course, patients require life-long immunosuppression, usually with corticosteroids.

Answer 420

E Anti-glutamic acid decarboxylase Anti-glutamic acid decarboxylase (anti-GAD; E) antibody is present in patients with type 1 diabetes mellitus (T1DM). The pathogenesis of T1DM involves the autoimmune destruction of β-cells in the islets of Langerhans in the pancreas. β-Cells are the primary storage site for insulin in the body, and so destruction of these cells leads to diminished insulin release and hyperglycaemia. GAD is an enzyme responsible for the conversion of glutamate to GABA; GABA is the neurotransmitter involved in the release of insulin from β-cells. Presenting features of T1DM include polyuria, polydipsia and weight loss.

Answer 421

A Anti-mitochondrial Anti-mitochondrial (A) antibodies are associated with primary biliary cirrhosis (PBC), and are immunoglobulins against mitochondria in cells of the liver. PBC is an autoimmune disease of unknown cause characterized by lymphocytic destruction of the bile canaliculi of the liver; build-up of bile leads to fibrosis and eventually cirrhosis. Clinical features include pruritis (increased bile acids in circulation) as well as the effects of reduced absorption of fat soluble vitamins (vitamin D, osteomalacia; vitamin K, bruising; vitamin A, blindness).

Answer 422

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.

Answer 423

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.

Answer 424

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.

Answer 425

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.

Answer 426

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).

Answer 427

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.

Answer 428

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.

Answer 429

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.

Answer 430

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.

Answer 431

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.

Answer 432

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.

Answer 433

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.

Answer 434

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.

Answer 435

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.

Answer 436

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.

Answer 437

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.

Answer 438

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.

Answer 439

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.

Answer 440

G Bruton’s agammaglobulinaemia Bruton’s agammaglobulinaemia (G) is an X-linked disease that presents in childhood. It is caused by a mutation of the BTK gene, which expresses a tyrosine kinase. This mutation inhibits B-cell maturation and therefore B-cell and immunoglobulin levels are diminished. Blood tests will reveal a normal T-cell count, but diminished B-cell count as well as IgA, IgM and IgG levels. Plasma cells will also be absent from the bone marrow and lymphatics.

Answer 441

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.