Single Best Answers and EMQs in Clinical Pathology Flashcards
A patient with end stage renal failure presents with depression. He is on haemodialysis three times a week but feels it is not working anymore and is getting more tired lately. He says he has lost his appetite and consequently feels rather constipated too. He feels his mind is deteriorating and there is little worth in attending dialysis anymore. His doctor wants to exclude a reversible cause of his depression and orders some blood tests. The doctor finds the patient has a raised corrected calcium, normal phosphate levels and high parathyroid hormone levels. What is the diagnosis?
A Primary hyperparathyroidism B Secondary hyperparathyroidism C Tertiary hyperparathyroidism D Pseudohypoparathyroidism E Pseudopseudohypoparathyroidism
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 indi-rect, 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. As a result tertiary hyperparathyroidism gives a raised calcium with a very raised PTH, with normal or low phosphate. Serum alkaline phosphatase is also raised due to the osteoblast and osteoclast activity (note, osteoblasts produce alkaline phosphatase. This is why there is a normal alkaline phosphatase in myeloma, as it directly stimulates the osteoclasts). Treatment of tertiary hyperparathyroidism is subtotal parathyroidectomy.
Tertiary hyperparathyroidism is differentiated from primary hyperparathyroidism (A) by the presence of chronic renal failure but is otherwise difficult to distinguish biochemically. Primary hyperparathyroidism is most commonly caused by a solitary adenoma in the parathyroid gland. Surgeons sometimes use sestamibi technetium scintigraphy to locate the offending adenoma prior to surgical removal.
Secondary hyperparathyroidism (B) occurs where there is an appropriately increased PTH level responding to low calcium levels. This is commonly due to chronic renal failure or vitamin D deficiency but can be seen in any pathology resulting in reduced calcium or vitamin D absorption or hyperphosphataemia.
Pseudohypoparathyroidism (also known as Albright’s osteodystrophy) results from a PTH receptor insensitivity in the proximal convoluted tubule of the nephron. As a result, calcium resorption and phosphate excretion fail despite high PTH levels. Furthermore, other physical signs associated with this condition include short height, short 4th and 5th metacarpals, reduced intelligence, basal ganglia calcification, and endocrinopathies including diabetes mellitus, obesity, hypogonadism and hypothyroidism. Type 1 pseudohypoparathyroidism is inherited in an autosomal dominant manner where the renal adenylate cyclase G protein S alpha subunit is deficient, thus halting the intracellular messaging system activated by PTH.
Patients with pseudopseudohypoparathyroidism (E) have similar physical features pseudohypoparathyroidism but with no biochemical abnormalities of calcium present. This condition is a result of genetic imprinting where the phenotype expressed is dependent on not just what mutation is inherited but also from whom. In other words, inheriting the pseudo-hypoparathyroidism mutation from one’s mother leads to pseudohypo-parathyroidism, but inheriting it from one’s father leads to pseudo-pseudohypoparathyroidism. At the molecular level, this is signalled by differential methylation of genes thus providing a molecular off switch controlling its expression. Another example of genetic imprinting occurs in Prader–Willi syndrome and Angelman’s syndrome, caused by a microdeletion on chromosome 15
A 59-year-old man presents with a fall and haematemesis after a heavy night drinking at the local pub. This is his third admission in a month with alcohol-related problems. He has stopped vomiting, and on examination he is haemodynamically stable. He has digital clubbing, spider naevi and gynaecomastia. He is admitted for neurological observations overnight as he hit his head. The doctors notice the patient suffers from complex ophthalmoplegia, confusion and ataxia. Given his neurological symptoms which test would confirm the associated vitamin deficiency?
A Red cell folate B Red blood cell transketolase C Red blood cell glutathione reductase D Red blood cell aspartate aminotransferase activity E Carbohydrate deficient transferrin
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.
Folate (vitamin B9) is required for cell reproduction and DNA and RNA synthesis. It is particularly important in infancy and pregnancy where cell turnover is high and provides the rationale behind folate supplementation of pregnant women up to 12 weeks’ gestation where organogenesis is at its peak. Folic acid is found in high levels in green leafy vegetable, nuts, yeast and liver. Body stores last up to 4 months, therefore deficiency is not common given the fortification of foods. If one does become deficient, however, features include megaloblastic anaemia, diarrhoea, peripheral neuropathy and glossitis (classically giving a beefy tongue).
Red blood cell glutathione reductase (C) assay tests for riboflavin deficiency. Riboflavin (also known as vitamin B2) is named after its structure – it contains a ribose sugar with a flavin ring moiety which gives it its striking yellow colour. Riboflavin is important in energy metabolism including fats, ketone bodies, proteins and carbohydrates. The assay relies on glutathione reductase (GR), an important enzyme which regenerates glutathione which acts as a buffer against oxidative damage in erythrocytes. GR activity is reliant on riboflavin; GR activity is measured in-vitro before and after addition of riboflavin. An increased level of GR activity implies its activity is being limited by riboflavin deficiency. Clinically, riboflavin deficiency causes glossitis, mouth ulceration and dry skin. It is almost always associated with other vitamin deficiencies including iron. Treatment is with vitamin replacement.
Red cell aspartate aminotransferase (AST) activity (D) tests for pyridoxine levels (also known as vitamin B6). This vitamin is important in neurotransmitter synthesis, histamine synthesis, haemoglobin function and amino acid metabolism – this last function is exploited in the laboratory to test for deficiency. The enzyme activity is tested before and after the addition of pyridoxine, in a similar manner to the glutathione reductase and transketolase assays. Pyridoxine is found in meats, whole grain products and vegetables. It is absorbed in the jejunum and ileum and is water soluble. Deficiency causes a seborrhoeic dermatitis-like rash, angular cheilitis and neurological symptoms including confusion and neuropathy. Treatment is with replacement. Importantly, those on isoniazid for tuberculosis infection should be supplemented with pyridoxine to prevent these symptoms.
Carbohydrate deficient transferrin (E) is used in the detection of alcohol abuse. Transferrin, normally involved in plasma iron transport, has bound carbohydrate moieties making it a glycoprotein. People who abuse alcohol have a reduction in these bound carbohydrates therefore increasing their carbohydrate deficient transferrin. The test is around 70 percent sensitive but about 95 percent specific for alcohol abuse. Other tests for detecting increased alcohol consumption include the presence of a macrocytic anaemia, raised gamma glutamyl transferase as well as alanine aminotransferase and AST
A 75-year-old man presents with acute onset abdominal pain. The patient has not passed stools for 3 days and looks unwell. His past medical history includes bowel cancer which was treated with an abdominoperineal resection and chemotherapy 6 years ago. On examination, there is a large parastomal mass which is tender and irreducible. An arterial blood gas shows metabolic acidosis with a rasied lactate. The on-call doctor immediately starts normal saline fluids and prepares the patient for theatre. A strangulated hernia is diagnosed by the registrar and an emergency laparotomy is performed to resect the ischaemic bowel.
One day postoperatively the patient has the following blood results:
Hb 13.2 WCC 10.9 Platelets 234 Na 145 K 6.3 pH 7.38 Urea and creatinine normal
What is the most likely cause of hyperkalaemia?A Acute kidney injury B Tissue injury C Resolving metabolic acidosis D Adrenal failure from metastases E Overhydration from intravenous fluids
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 ischaemic 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.
Acute kidney injury (A) is not likely in this patient given the normal creatinine and urea, although this patient is at high risk of pre-renal failure. Bowel obstruction and infarction leads to so-called third space losses of fluids which can be up to litres in magnitude. The third space is within the bowel lumen where resorption of secretions has stopped owing to disrupted transport mechanisms. Acute renal failure would classically give a sharp rise in urea and creatinine and, if serious, leads to a hyperkalaemia with metabolic acidosis. This patient needs intravenous fluids with careful monitoring of input and output as well as monitoring electrolytes. Hyperkalaemia is important as it alters cardiac membrane stability making arrhythmias more likely.
The classical electrocardiographic features of hyperkalaemia include tall tented T waves, small P waves, widened QRS complexes, ST depression and QT narrowing. If severe, a sinusoidal pattern emerges at which point the patient needs urgent treatment to prevent a fatal dysrhythmia.
The patient’s metabolic acidosis (C) has resolved and usually the potassium abnormality associated with this resolves too. There is a close link between potassium concentration and pH – a lower pH is associated with hyperkalaemia as both K+ and H+ compete with each other for exchange with sodium. Thus a decreased pH means increased H+ concentration making it more available for exchange with sodium thus leaving K+ in the extracellular space. Once the metabolic acidosis resolves, this competition no longer exists and normal potassium homeostasis resumes.
Adrenal failure (D) from metastases could lead to Addison’s disease, a destruction of the zona glomerulosa and fasciculata resulting in lack of aldosterone and cortisol production. Addison’s disease classically presents biochemically with hyponatraemia, hyperkalaemia and hypercalcaemia. Aldosterone acts in the distal convoluted tube and collecting duct, its intracellular receptor (aldosterone mineralocorticoid receptor) acts with specific hormone response elements on the DNA to regulate gene transcription including N+/K+ pumps. The aldosterone receptor is also activated by cortisol which is produced in much higher concentrations physiologically. To prevent over-stimulation of the receptor, how-ever, a deactivating enzyme (11 beta hydroxysteroid dehydrogenase) co-localizes with the receptor to locally inactivate cortisol’s effect. In hypercortisolaemia (Cushing’s) this mechanism is overcome, resulting in excess aldosterone-like effects thus explaining the hypertension in these patients. Interestingly, licorice, which contains glycyrrhizic acid, inhibits this deactivating enzyme explaining its association with hypertension when eaten in excess.
Adrenal metastases, although possible in this patient, are unlikely given the biochemical disparity and lack of clinical information about metastatic disease.
Overhydration with intravenous fluids (E) can cause hyperkalaemia, but the on-call doctor in this question prescribed normal saline, which alone contains 154mmol/L sodium chloride only. Given the well known side effect of tissue injury postoperatively, some clinicians routinely omit potassium in the first postoperative bag of fluids to prevent hyperkalaemia. Hartmann’s has a more physiological biochemical profile and contains 5mmol/L potassium as well as 29mmol/L lactate. Patients on this fluid for maintenance fluid therapy can have falsely high lactates when arterial blood samples are analyzed.
A 54 year old with a background of hypertension, presents to the GP with a 2-week history of diarrhoea. He has been travelling in South East Asia recently and developed symptoms of diarrhoea 3 weeks ago. He went to the local doctor whilst in China who prescribed tetracycline, but his symptoms have persisted and only improved slightly. His past medical history includes an undisplaced parietal skull fracture he sustained when he was 10. He takes no other medications. The GP orders blood tests which show the following:
Na 148 K 4.8 Urea 13 Creatinine 112
What is the most likely cause of his hypernatraemia?
A Conn’s syndrome B Nephrogenic diabetes insipidus C Cranial diabetes insipidus D Tetracycline E Dehydration
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 extra-cellular 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 angio-tensin 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 intravas-cular volume with a normal osmolality.
Diabetes insipidus (DI) is caused by lack of ADH action. Craniogenic DI (C) implies a lack of production of ADH from the posterior pituitary whereas nephrogenic DI (B) implies a lack of sensitivity to ADH. Craniogenic DI classically follows head injury where over 80 per cent of the descending neurones from the paraventricular and supraoptic nuclei in the hypothalamus need to be destroyed to produce clinical symptoms. It is rare and probably would have manifested earlier with polydipsia and polyuria in this patient given the head injury was at the age of 10.
Nephrogenic DI is a result of renal resistance to ADH and has numerous aetiologies. Many intrinsic renal pathologies including interstitial nephritis, polycystic kidneys, sarcoid or amyloid can cause this. However, remember nephrogenic DI means a resistance to ADH action despite normal or high levels. This does not necessarily mean there is an intrinsic kidney problem – any cause of prolonged polyuria can cause solute washout in the renal medulla reducing the action of ADH. Another important cause of nephrogenic DI is drugs. The two classical drugs associated with this are lithium and demeclocycline. The latter is sometimes used therapeutically in patients with the syndrome of inappropriate ADH (SIADH). Here the excess ADH production is counter-acted by the demeclocycline which inhibits the renal response to ADH.
Although demeclocycline is a type of tetracycline, prescribed tetracycline (D) (rather confusingly) is a separate drug which is not associated with nephrogenic DI. Thus the treatment this man has received is unlikely to have caused the hypernatraemia.
Conn’s syndrome (A) is caused by an aldosterone secreting tumour leading to a hypertensive, hypokalaemic, metabolic alkalosis. It very rarely causes hypernatraemia. The causes of this disease include Adrenal adenoma, Bilateral nodular hyperplasia, Carcinoma of the adrenals or a Defective gene (glucocorticoid remediable aldosteronism, GRA). Adrenal ademona is by far the most common and presents with resistant hypertension and weakness (due to hypokalaemia). GRA is caused by a chimeric gene of aldosterone synthase with the 11 beta hydroxylase-1 promoter, resulting in an ACTH sensitive secretion of aldosterone. ACTH is under the negative feedback control of glucocorticoids. Exogenous administration of dexamethasone reduces ACTH levels thus reducing aldosterone expression, treating the disease
A 42-year-old woman with persistent polyuria and polydipsia is admitted for a water deprivation test. At the beginning of the test her weight, urine volume and osmolality and serum osmolality are measured and hourly thereafter for 8 hours. After 8 hours, she is given intramuscular desmopressin but drinks 3L of water before going to bed. Her blood is taken again the next morning (16 hours after beginning the test) and the results are as follows:
Start-8 hours-16 hours
Weight: 70kg - 67.8kg - 66.8kg
Urine volume (total): 0mL - 2200mL - 4000mL
Urine osmolality: 278 mosmol/kg - 872 mosmol/kg - 980 mosmol/kg
What is the most likely diagnosis? A Nephrogenic diabetes insipidus B Craniogenic diabetes insipidus C Psychogenic polydipsia D Invalid test E Normal
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.
The water deprivation test is a seldom used test nowadays but is useful to understand when considering these clinical problems. The test begins with the patient being completely deprived of water for 8 hours in which time the patient’s weight, blood and urine osmolality and urine volume are measured. A weight loss of more than 5 per cent in adults is an indication to stop the test.
After 8 hours, 2μg of desmopressin (a synthetic analogue of vasopressin) is given. The same measurements are taken for the next 8 hours. After the desmopressin is given the patient is allowed to drink up to 1.5 times the total urine output for the first 8 hours. In this patient’s case she had produced 2200mL of urine, but drank 3000mL of water. This therefore is acceptable and did not nullify the test making (D) an incorrect answer.
The patient’s urine osmolality increased above 800mOsmol/kg after 8 hours of water deprivation, indicating vasopressin action is functioning to appropriately retain water therefore concentrating the urine. A further 8 hours later, despite drinking 3L of fluid, the patient’s urine is still very concentrated implying the administered desmopressin and endogenous vasopressin are functioning.
In patients with craniogenic DI (B), the administration of desmopressin provides the water retention signal that the kidneys are failing to concentrate the urine. The typical result for patients with craniogenic DI is a dilute urine (800mOsmol/kg). Nephrogenic DI (A) would not respond to desmopressin and would likely leave the patient with dilute urine (
A 24-year-old previously fit and well woman presents with sudden onset abdominal pain the night after a party where she drank five units of alcohol. She complains of central abdominal pain, with nausea and vomiting. She also finds it difficult to control her bladder. On examination, she is tachycardic, hypertensive and is beginning to become confused. On looking back at her previous admissions, the doctor notices she has had similar episodes after drinking. This was also true for when she started the oral contraceptive pill and when she had tuberculosis which was treated with standard antibiotic treatments. She is also seeing a neurologist for peripheral neuropathy of unknown cause. The admitting doctor, an Imperial college graduate, suggests the possibility of acute intermittent porphyria. What enzyme deficiency is responsible for this disease?
A Porphobilinogen deaminase B Uroporphyrinogen synthase C Coproporphyrinogen oxidase D Protoporphyrinogen oxidase E Uroporphyrinogen decarboxylase
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.
The features of porphyria can be generally classified into neurological, cutaneous and microcytic anaemia. The exact combination of symptoms depends on where in the haem pathway the deficiency occurs. Neurological symptoms, including peripheral neuropathy, autonomic neuropathy and psychiatric features, are caused by the increase of porphyrin precursors 5 ALA and prophobilinogen (PBG). Cutaneous symptoms are due to photosensitive porphyrins which are produced later on in the sequence. Finally microcytic anaemia occurs due to the deficiency of haem production.
Acute intermittent porphyria (AIP) presents without cutaneous symptoms, this is because the enzyme deficiency is further upstream from the photosensitive porphyrins which cause the cutaneous symptoms. Instead neurological symptoms of the peripheral, autonomic and psychiatric systems predominate, as in this patient. The symptoms cluster in attacks if toxins induce ALA synthase or PBG deaminase activity. These include alcohol, the oral contraceptive pill and certain anti-biotics including rifampicin and pyrazinamide (two commonly used anti-tuberculosis drugs). Other common precipitants include surgery, infection and starvation. Investigations classically show urine which becomes brown or black upon standing in light as well as reduced erythrocyte PBG deaminase levels. Note there is no increase of faecal porphyrins in AIP. Treatment is to avoid precipitants as well as dextrose infusion and haem arginate intravenously which both inhibit ALA synthase activity.
Uroporphyrinogen synthase (B) results in congenital erythropoeitic porphyria which is one of the rarest inborn errors of metabolism. It is caused by a mutation on chromosome 10q26 and is inherited in an autosomal recessive fashion. Symptoms include vesicles, bullae and excessive lanugo hair as well as mutilating deformities of the limbs and face. Urine is classically burgundy red as well as patients having erythrodontia – red stained teeth. Treatment is to avoid sunlight and symptomatically treat the anaemia.
Coproporphyrinogen oxidase (C) causes hereditary coproporphyria and is another rare type of porphyria. The symptoms are predominantly neuro-visceral. Diagnosis is confirmed with increased faecal and urinary coproporphyrinogen.
Protoporphyrinogen oxidase deficiency (D) causes variegate porphyria which is caused by an autosomal dominant mutation of chromosome 14. It is relatively rare in the world except in South Africa where its incidence is as high as one in 300 (most probably due to the founder effect from early settlers). Attacks feature neuro-cutaneous features, although not necessarily together at the same time. It is almost always precipitated by drugs making it difficult to distinguish from AIP. In variegate porphyria, however, there is increased faecal protoporphyria as well as positive plasma fluorescence scanning.
Uroporphyrinogen decarboxylase (E) causes porphyria cutanea tarda and can be inherited in an autosomal dominant manner. It is characterized by cutaneous features including bullous reactions to light, hyperpigmentation, as well as liver disease. Non-inherited causes include alcohol, iron, infections (hepatitis C and HIV) and systemic lupus erythematosus (SLE). Investigations reveal abnormal liver function tests, raised ferritin (always) and increased urinary uroporphyrinogen. This gives a characteristic pink red fluorescence when illuminated with a Wood’s lamp. Treatment is to avoid precipitants as well as chloroquine which complexes with porphyrins and promotes uroporphyrin release from the liver.
A patient presents with an acutely painful, inflamed elbow. He has decreased range of movement passively and actively and the joint is tender, erythematous and warm. His past medical history includes hypertension, chronic lower back pain for which he takes aspirin, lymphoma for which he has just completed a course of chemotherapy and psoriasis which is well controlled. He is also a heavy drinker. A joint aspirate shows weakly negative birefringent crystals confirming the diagnosis of acute gout. Which factor in this patient is the least likely to contribute to this attack?
A Bendroflumethiazide B Chemotherapy C Alcohol D Psoriasis E Aspirin
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-inflammatory (e.g. diclofenac) in the acute phase or colchicine.
Aspirin (E) is avoided because it directly competes for urate acid excretion in the nephron therefore worsening hyperuricaemia. After the acute attack settles, long term xanthine oxidase inhibitors (the enzyme responsible for the final production of urate) can be inhibited by allopurinol. Alternatively, but less commonly, uricosuric drugs such as probenecid may be used (e.g. prevention of cidofovir nephropathy). Finally rasburicase, recombinant urate oxidase, is a newer pharmacological treatment in the setting of chemotherapy to prevent hyperuricaeamia.
Thiazide diuretics such as bendroflumethiazide (A) act by inhibiting NaCl transport in the distal convoluted tubule. They are contraindicated in gout as they increase uric acid concentration and are a well known precipitant of gout. Other diuretics do not have this property and therefore this patient should have his antihypertensive medication reviewed. Other side effects of thiazides include hyperglycaemia, hypercalcaemia and increased serum lipid concentrations.
Alcohol (C) increases urate levels in two ways – first it increases adenosine triphosphate turnover thus activating the salvage pathway producing more urate. It also decreases urate excretion in the kidney as it increases organic acids which compete for urate excretion in the nephron (much like aspirin).
Chemotherapy (B) involves the destruction of malignant cells, which release all of their intracellular contents into the blood stream including purines. Widespread malignancy treated with chemotherapy can dramatically increase urate concentration. Therefore some patients undergoing chemotherapy are given prophylactic allopurinal prevent this side effect as well as being encouraged to drink plenty of fluid to essentially dilute the urate produced.
Psoriasis (D) is a dermatological condition characterized by discrete patches of epithelial hyperproliferation. There are different types including flexural, extensor, guttate, erythrodermic and pustulopalmar. Some special clinical signs associated with this condition often asked about include Koebner’s phenomenon (appearance of psoriatic plaques at sites of injury) and Auspitz’s sign (dots of bleeding when a plaque is scratched off representing reticular dermis clubbing with capillary dilatation). Severe psoriasis results in T-cell mediated hyperproliferation and eventual breakdown of cells releasing their intracellular contents resulting in hyperuricaemia in much the same mechanism as chemotherapy. The treatment for psoriasis includes phototherapy with ultraviolet light, topical agents including tar and oral tablets including antiproliferatives
A patient has the following blood results; calculate the anion gap: Na 143mmol/L K 4mmol/L Cl 107mmol/L HCO3 25mmol/L PO4 1mmol/L Glucose 8mmol/L Urea 7mmol/L
A 14mmol/L B 15mmol/L C 16mmol/L D 17mmol/L E Not enough information
The anion gap is calculated using the following equation:
Anion gap = [Na+] + [K+] − [HCO3] − [Cl−]
It is a method of assessing the contribution of unmeasured anions in metabolic acidosis. The normal range varies between laboratories but the upper limit is usually between 10 and 18mmol/L. It is helpful to estimate the unmeasured anions such as phosphate, ketones and lactate which are difficult to measure normally.
Metabolic acidosis in the setting of a raised anion gap implies there is an increase production or reduced excretion of fixed or organic acids. The acid produced is buffered by bicarbonate thus increasing the anion gap. Causes include raised lactate (e.g. shock, infection or tissue ischaemia), urate (renal failure), ketones (diabetes mellitus) or drugs (methanol, aspirin). Furthermore there are two types of lactic acidosis – type A and type B. Type A is the most commonly associated with shock. Hypoperfusion of the tissues reduces the capacity of cells to continue aerobic respiration which leads to the formation of lactate via anaerobic respiration. Physiologically lactate concentration is around 1mM but can rise up to 10mM in extreme situations. It can also be falsely raised when replacing fluids which contain lactate (e.g. Hartmann’s solution – a common surgical fluid used to treat hypovolaemia). This is particularly important when dealing with suspected bowel ischaemia where fluid resuscitation is a vital initial management step. Lactate is often used to distinguish the presence of ischaemia which could be falsely elevated if using this fluid!. Type B lactic acidosis occurs in the absence of significant oxygen delivery problems and usually occurs secondary to drugs. Common culprits include metformin in a patient with renal failure, paracetamol overdose, ethanol or methanol poisoning or acute liver failure.
A useful and often quoted mnemonic to remember the causes of metabolic acidosis with a raised anion gap is MUDPILES: Methanol, Uraemia, Diabetic ketoacidosis, Propylene glycol, Isoniazid, Lactic acidosis, Ethylene glycol, Salicylates. Metabolic acidosis with a normal anion gap implies the loss of bicarbonate or ingestion of hydrogen ions. The loss of bicarbonate is compensated for by chloride thus normalizing the anion gap. This is why this type of acidosis is sometimes called hyperchloraemic acidosis. Alternatively excessive chloride load (e.g. ammonium chloride ingestion) can cause acidosis where bicarbonate concentration reduces to compensate. The causes of this type of acidosis are generally due to problems either in the kidneys, GI tract or secondary to drugs. In the kidneys, failure of acid secretion is the main problem. This may be due to an intrinsic problem in the tubules (called renal tubular acidosis (RTA)) or secondary to drugs manipulating the acid transport systems.
There are four types of RTA: type I is caused by the failure of acid secretion in the distal convoluted tubule. There is an inability to acidify urine despite systemic acidosis. Type II is caused by a bicarbonate leak in the proximal tubule which may be an isolated defect or associated with a generalized tubulopathy (Fanconi’s syndrome). In RTA type II there is an ability to acidify the urine during systemic acidosis because the kidney retains some bicarbonate transport function. There is often hypokalaemia due to the increased osmotic diuretic effect in the tubule caused by excessive bicarbonate, therefore increasing flow rate to the distal tubule. Type III RTA is a rare combination of type I and type II RTA. Type IV RTA is always due to an intrinsic problem in the tubules. There is lack of effective function of aldosterone which may be due to the lack of renin release (e.g. renal failure with parenchymal loss in the juxtaglomerular apparatus), hypoadrenalism (e.g. autoimmune disease or tuberculosis), renal resistance to aldosterone or drugs (e.g. ACE inhibitor, non-steroidal anti-inflammatory drugs, potassium sparing diuretics).
Gastrointestinal loss of bicarbonate is the other main cause of metabolic acidosis with a normal anion gap. Diarrhoea caused by any pathology can lead to this problem. It is particularly associated in the setting of VIPoma (vasoactive intestinal peptide–oma). Also known as Verner Morrison syndrome, this rare disease is due to a non-beta islet cell tumour, usually in the pancreas. It causes profound diarrhoea, hypokalaemia, achlorhydia and flushing. Note vomiting causes hypochloraemic alkalosis due to the loss of hydrogen chloride in the stomach. Other gastrointestinal causes include pancreatic or biliary fistulae, ileostomy or ureterosigmoidostomy.
One method to distinguish the different types of normal gap metabolic acidosis is the use of the urinary anion gap (UAG). The formula for this is:
Urinary anion gap = [Na+] + [K+] – [Cl-]
The UAG is a rough estimate of the bicarbonate concentration in the urine – the more negative the number, the higher the ammonium concentration and vice versa. This therefore helps distinguish the cause of the normal gap metabolic acidosis. If the bowel is responsible through bicarbonate loss, it would be sensible to assume the kidneys will try to compensate by increasing the ammonium excretion which is exchanged for hydrogen ions. The opposite is true for a loss of acid through the kidneys. A useful aide memoire is the word ‘neGUTive’. The negative urinary anion gap implies the gut is the culprit of the acidosis.
A patient has the following blood results: Na 143mmol/L K 4mmol/L Cl 107mmol/L HCO3 25mmol/L PO4 1mmol/L Glucose 8mmol/L Urea 7mmol/L
What is the estimated plasma osmolarity? A 309 B 279 C 426 D 294 E Not enough information
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 1kg, whereas the latter describes the same solute in 1L 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.
Estimating osmolarity is useful when calculating the osmolar gap. This is the difference between the estimated osmolarity and the laboratory osmolality. The difference is usually
A 67-year–old man with chronic renal failure presents with fatigue. He has been on haemodialysis three times per week for a decade. His past medical history includes diabetes mellitus, hypertension and gout. He has been increasingly tired the last few weeks although he cannot explain why. He has been attending his dialysis appointments and is compliant with his medications. The GP takes some bloods to investigate. Which of the following is NOT a common association with chronic renal failure?
A Acidosis B Anaemia C Hyperkalaemia D Hypocalcaemia E Hypophosphataemia
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.
Hyperkalaemia (C) is associated with chronic renal failure and is important as it can be potentially fatal. Hyperkalaemia changes cardiac membrane excitability making it more prone to arrhythmias. Resistant severe hyperkalaemia (>7mmol/L) is an indication for emergency renal dialysis, other indications include refractory pulmonary oedema, severe metabolic acidosis (pH
A 45-year-old woman presents feeling tired all of the time. She has been investigated for anaemia which reveals macrocytosis. She denies drinking excessively. She has recently moved house and the GP notices she has a croaky voice, peaches and cream complexion and a slowed reaction to his questions. He examines her and elicits slow relaxing ankle reflexes. He suspects hypothyroidism and orders some thyroid function tests. Which of the following results are consistent with primary hypothyroidism?
A Low TSH, raised free T4 and T3
B Low or normal TSH with low free T4 and T3
C Raised TSH with normal free T4 and T3
D Normal or raised TSH with raised T4 and T3
E None of the above
Thyroid function tests are relatively easy to interpret with a basic understanding of the hypothalamic–pituitary–thyroid axis of thyroid hormone control. The pituitary produces TSH (thyroid stimulating hormone) which is released from the anterior pituitary. It is under the control of the hypothalamus which releases thyroid releasing hormone (TRH) which signals to anterior pituitary cells to release TSH. TSH travels in the bloodstream and acts on thyrocytes in the thyroid gland to stimulate production of T4 and T3 hormone. Specifically TSH controls the rate of iodide uptake required for thyroid hormone production, thyroid peroxidase activity, iodotyrosine reuptake into the thyrocyte from colloid and iodotyrosine cleavage to form mature hormone.
T4 is the main circulatory hormone produced in about a 10:1 ratio compared with T3. However, free T3 has greater efficacy; in fact circulating T4 is converted into T3 within cells which then binds to its hormone receptor. TSH release is under negative feedback control of T4. In primary hypothyroidism, the thyroid does not have the ability to produce sufficient T4 or T3 to inhibit further TSH release. Therefore the biochemical abnormality found in primary hypothyroidism is a raised TSH with low T4 and T3, which is not one of the answer options (E).
A low TSH with raised free T4 and T3 (A) is seen in primary hyper-thyroidism, the most common cause of which is Graves’ disease. This is an autoimmune condition where stimulating antibodies bind to the TSH receptor to stimulate thyroid hormone production. The excessive T4 concentration negatively feedbacks onto the hypothalamus and pituitary to reduce TSH release. The other causes of this biochemical abnormality include multinodular goitre with functional tissue, toxic nodule (also known as Plummer’s disease), transient thyroiditis and De Quervain’s thyroiditis. Graves’ disease is unique in that it features extrathyroid features including pretibial myxoedema, exophthalmos and thyroid acropachy. Radioisotope scanning, a method using radioactive iodine to measure uptake in the thyroid gland, shows increased uptake throughout the gland.
A low or normal TSH with low free T4 and T3 (B) is frequently seen in patients with other non-thyroid illness. This is also known as sick euthyroid syndrome where the patient is unwell with another illness causing thyroid abnormalities. The cause is unclear but the role of inflammatory cytokines and reduced peripheral deiodination of T4 has been implicated. Another important differential for this combination of biochemical abnormalities is secondary hypothyroidism i.e. pituitary dysfunction causing low TSH and low thyroid hormones. This differential is serious as the associated hypoadrenalism could be fatal. A pituitary tumour must be excluded by imaging (MRI brain) and endocrinological stimulation tests (i.e. short synacthen test) to exclude Addison’s disease. Another explanation for these results not applicable in this patient is recently treated hyperthyroidism. There is sometimes a residual suppression of TSH following hyperthyroid treatment for up to 1 year, and if they are clinically hypothyroid replacement therapy should be prescribed.
A raised TSH with normal T4 and T3 (C) normally means the patient is suffering from subclinical hypothyroidism. This is an important finding as patients may have subtle symptoms and improve with treatment as well as possibly reducing deaths from cardiac events. People with TSH levels >10μ/L, positive thyroid antibodies, previously treated Graves’ disease or other organ specific autoimmunity (e.g. diabetes mellitus type I, myasthenia gravis) should be treated as they are at high risk of progression to clinical hypothyroidism. Other less common causes of this biochemical configuration include amiodarone therapy, recovery from sick euthyroid disease and thyroxine malabsorption in patients taking thyroxine therapy due to small bowel disease, cholestyramine or iron therapy.
A normal or raised TSH with raised T3 and T4 (D) is a rare disorder and usually means there is an artefact with the test. The results imply cen-tral hyperthyroidism with the hypothalamus inappropriately excreting excessive TSH stimulating the thyroid gland to overproduce T4 and T3. Rarely it can be caused by amiodarone therapy, thyroid receptor mutations, intermittent thyroxine overdose, or familial dysalbuminaemic hyperthyroxinaemia. This last condition is a rare abnormality of albumin which results in increased binding affinity of albumin for T4. This interferes with the assay and shows a normal TSH and T3 with appar-ently increased T4.
An 86-year-old woman presents to accident and emergency after a fall. She is a frequent faller but was unable to weight bear after the most recent incident. She has a history of rheumatoid arthritis which is controlled with low dose prednisolone. On examination her right leg is clinically shortened and externally rotated and a pelvic X-ray confirms the presence of a fractured neck of femur. The patient’s hip is fixed the next day. Her day one postoperative bloods show the following: Corrected calcium normal Phosphate normal Alkaline phosphatase raised Parathyroid hormone level normal Vitamin D level low
What is the most likely diagnosis? A Normal B Osteoporosis C Paget’s disease D Osteomalacia E Malignancy
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
The four risk factors NICE highlight are a low BMI (
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
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.
Galactose can enter the metabolic pathway through a number of steps. It must first be phosphorylated to allow its conversion into glucose-1-phosphate which eventually become glucose-6-phosphate to finally enter the metabolic cycle. Galactose-1-phosphate uridyltransferase converts galactose-1-phosphate into UDP galactose. This is the most common enzyme to be defective in galactosaemia. It is unclear exactly why the build up of galactose is so harmful, however one of the by products of its metabolism (galactitol produced by aldolase on galactose-1-phosphate) is responsible for cataract formation. The collection of gastrointestinal symptoms, hepatomegaly and cataracts on starting milk is very suggestive of this disease. Children with this disease are also more susceptible to sepsis with Escherichia coli. The Fehling’s and Benedict’s reagent tests are positive because galactose is a reducing sugar, the other important one being glucose which was excluded using glucose specific sticks. The investigation of choice is a red cell galactose-1-phosphate uridyltransferase level although this condition is sometimes screened for during the neonatal period in certain parts of the world. Treatment is to exclude milk from the child’s diet as well as eliminating other sources of galactose.
Galactokinase (C) deficiency is another cause of galactosaemia but much less common. It is due to a defective galactokinase gene on 17q24. Its function is to phosphorylate galactose to galactose-1-phosphate. Unlike classical galactosaemia as described above, severe symptoms in early life are less common. Instead, excess galactitol formation results in early cataract formation in homozygous infants. Treatment is similar to those with classical galactosaemia.
Fructose intolerance (A) is caused by fructose-1-phosphate aldolase deficiency which normally converts fructose-1-phosphate to dihydroacetone phosphate and glyceraldehyde. These products are further metabolized and can enter either glycolytic or gluconeogenesis path-ways depending on the energy state of the cell. The explanation is made more complicated by the fact that there are three isoenzymes of fructose-1-phosphate aldolase (A, B and C) of which B is expressed exclusively in the liver, kidney and intestine as well as metabolizing three different reactions. Aldolase B can produce triose phosphate com-pounds which are central to the glycolytic pathway, but this can also be reversed making it important in gluconeogenesis. A deficiency therefore explains the hypoglycaemia experienced by these patients. Furthermore, the reduced fructose metabolism increases its blood levels which conse-quently changes the ATP:ADP ratio. This increases purine metabolism resulting in excess uric acid production which competes for excretion in the kidney with lactic acid. The result is lactic acidosis, hyperuricaemia and hypoglycaemia. These is also severe hepatic dysfunction, the pathophysiology of which is relatively less well understood.
Tyrosinaemia (E) is another autosomal recessive inherited disorder of metabolism which has three subtypes – types I, II and III. Type I is the hereditary form which has a specifically high incidence in Quebec, Canada and is characterized by a defect in fumarylacetoacetate hydrolase. In its most severe form it presents with failure to thrive in the first few months, bloody stool, lethargy and jaundice. A distinctive cabbage-like odour is characteristic. On examination there is hepatomegaly with signs of liver failure and subsequent survival for less than 12 months if untreated. The investigation of choice is urinary succinylacetone and treatment is to restrict dietary tyrosine and phenylalanine and to treat the liver failure, sometimes with a transplant.
Urea cycle disorders (D) normally present with a non-infective encephalopathy, along with failure to thrive and hyperventilation in the neonatal period progressing to neurological symptoms associated with protein intake. The inability to metabolize urea leads to hyperammonaemia. A blood level above 300 μM/L is associated with encephalopathy. There are also associated increases in plasma amino acids, urine amino acids and organic acids. Enzyme studies are required to differentiate it from one of the ten potential defects responsible for this group of diseases. Treatment is to use benzoate or phenylacetate or extracorporeal dialysis to remove the ammonia and a low protein diet to prevent its build up
A 2-week-old neonate born at term with no gestational complications develops uncongutated jaundice. This was following a difficult birth where instrumentation was required after excessive delay in the second stage of labour. On examination, the neonate looks well in a normal flexed position with visible jaundice most noticeable in the soft palate. There are no abnormal facies but there is a visible large caput succedaneum with bruising. Urine dipstick is normal with no markers of infection present in the blood. What is the most likely cause of the jaundice?
A Urinary tract infection B Bruising C Haemolysis D Crigler–Najjar syndrome E Gilbert’s disease
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 450nm 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.
Other causes of jaundice include haemolysis (C), which may be congenital or acquired. Congenital causes include G6PD deficiency which can cause severe unconjugated jaundice. The mutation in this enzyme reduces erythrocyte ability to withstand oxidative stress which can be triggered by numerous drugs (classically anti-malarials) and fava beans (hence the alternative name for this condition is favism). Other causes of haemolysis include ABO incompability where blood type O mothers sometimes express IgG anti-A-haemolysins which can cross the placental barrier resulting in haemolysis. Treatment is supportive. Rhesus haemolytic disease is serious but fortunately rare with the implementation of anti-D immunization after significant events. In this situation, a mother has anti-D antibodies which cross the placental barrier resulting in profound haemolysis, hydrops and hepatosplenomegaly. This requires previous sensitization of the mother to rhesus D antigen either by previous pregnancy or blood transfusion. Therefore all pregnant women who are rhesus D negative receive prophylactic immunoglobulins during significant events in pregnancy which may release fetal blood into the maternal circulation, e.g. abortion. The immunoglobulins effectively neutralize the fetal blood and prevent an immune response from developing. Failure to do this will risk the next rhesus positive fetus.
Urinary tract infection (A) is a common cause of unconjugated jaundice in the neonate and must be excluded because if left untreated it can lead to complicated urinary tract infection involving the kidneys and urosepsis. Sepsis in neonates does not always present with fever but instead an inability to regulate body temperature. The most common pathogen is group B streptococcus, a common commensal in the vaginal tract of the mother.
Crigler–Najar syndrome (D) is caused by a genetic defect in glucoronyl transferase which is responsible for transporting bilirubin into the hepatocyte. There are two types – type I is characterized by a complete absence of this enzyme, type II is characterized by a partial reduction of this enzyme. Type I presents with severe neonatal jaundice with kernicterus, phototherapy can reduce the levels by half and liver transplantation is the only cure. Phenobarbitone is used only in type II Crigler–Najjar syndrome.
This disease is different from Gilbert’s disease (E) which is relatively common but also causes a mild unconjugated hyper-bilirubinaemia. The main defect is in biliribuin uridinediphosphate-glucuronyltransferase (UGT1A1) which is the enzyme responsible for conjugating bilirubin and is reduced by about 30 per cent in Gilbert’s disease. It does not cause liver damage and is relatively benign. Precipitating factors include stress, fasting, fever and dehydration. Investigations aim to prove an unconjugated jaundice without haemolysis and normal plasma bile acids. There is no bilirubinuria and no increase in urobilinogen either.
A 54-year-old man with a past history of alcohol abuse, recurrent severe epigastric pain with flatulence and steatorrhoea presents after a fall whilst out drinking with his friends. He had fallen onto his hip, has severe pain and inability to weight bear. On examination, his right lower limb is shortened and externally rotated. His liver function tests were normal apart from a raised alkaline phosphatase. A fractured neck of femur is diagnosed and is fixed that night. As part of a routine follow up, the fracture liaison nurse suspects vitamin D deficiency and orders a full set of vitamin D levels. What set of results would you expect in this man given his history?
A Low 25-hydroxycholecalciferol, low 1,25-dihydroxycholecalciferol, low parathyroid hormone
B Low 25-hydroxycholecalciferol, high 1,25-dihydroxycholecalciferol, high parathyroid hormone
C High 25-hydroxycholecalciferol, low 1,25-dihydroxycholecalciferol, high parathyroid hormone
D High 25-hydroxycholecalciferol, high 1,25-dihydroxycholecalciferol, high parathyroid hormone
E High 25-hydroxycholecalciferol, low 1,25-dihydroxycholecalciferol, low parathyroid hormone
B 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.
Vitamin D metabolism involves the skin, liver and kidneys as well as the bones and gastrointestinal tract. Sources of vitamin D include sun-light exposure and diet. Sunlight converts 7-dehydrocholesterol into cholecalciferol (vitamin D3). The latter product is what is consumed in the diet. This is then hydroxylated in the liver to form 25-hydroxy-cholecalciferol. This is then transported to the kidneys where the final hydroxylation by 1 alpha hydroxylase converts 25-hydroxy-cholecalciferol to 1,25-dihydroxycholecalciferol. This final step is stimulated by parathyroid hormone.
Therefore, this man has low 25-hydroxy-cholecalciferol levels due to reduced absorption of dietary vitamin D, but has a high level of 1,25-dihydroxy-cholecalciferol because of the reactive secondary hyperparathyroidism which converts any remaining 25-hydroxy-cholecalciferol to the activated form, hence the high levels (B).
Answer (A), where there are low levels of both forms of vitamin D, could also be present in this situation but there would be a high parathyroid hormone level making this answer incorrect.
A high 25-hydroxy-cholecalciferol, low 1,25-dihydroxy-cholecalciferol, high parathyroid hormone (C) would occur in patients with chronic renal failure where there is loss of parenchymal tissue to hydroxylyze 25-hydroxy-cholecalciferol to its final activated form. There is a secondary or tertiary hyperparathyroidism depending on the stage of renal failure. Secondary hyperparathyroidism occurs early on when the kidneys retain phosphate and appropriately stimulate PTH secretion. As the renal failure continues, the gland secretes PTH autonomously despite normal or high calcium levels.
A high 25-hydroxy-cholecalciferol, high 1,25-dihydroxy-cholecalciferol, high parathyroid hormone (D) would occur in patients with vitamin D resistance where there is normal production of vitamin D but there is reduced activity due to the inability to detect vitamin D. There are two types – type 2 vitamin D dependent rickets is autosomal recessive and is caused by an end organ resistance whereas type 1 is caused by a congenital lack of 1 alpha hydroxylase giving a similar biochemical profile to that seen in chronic renal failure. Parathyroid hormone levels are high despite high vitamin D levels because PTH is under negative feed-back control from calcium and phosphate levels, not vitamin D levels.Finally a high 25-hydroxy-cholecalciferol, low 1,25-dihydroxy-cholecalciferol, low parathyroid hormone may be seen in hypoparathyroidism of which the most common cause is post-surgical intervention. There is a low PTH level and therefore low stimulation of 1 alpha hydroxylase in the kidney to covert 25-hydroxy-cholecalciferol to 1,25-dihydroxy-cholecalciferol thus explaining their levels
Which of the following is not a cause of raised alkaline phosphatase levels? A Pregnancy B Paget’s C Congestive heart failure D Obstructive jaundice E Myeloma
E - 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.
This means although there are areas of lysis on X-rays, there is little osteoblast response leading to a normal alkaline phosphatase level. This may be complicated by a fracture which will stimulate osteoblast activity leading to a raised ALP in the setting of myeloma.
Paget’s disease, a syndrome characterized by abnormal remodelling, normally has a very elevated level of ALP caused by increased but disorganized remodelling of the bone. On X-rays there are patches of lucency and sclerosis. There are normally no calcium or phosphate abnormalities making it different from metastatic prostatic cancer which also gives a patchy sclerotic X-ray but would raise the calcium levels.
There are various isomers of ALP which are not distinguishable on a standard liver function assay without electrophoresis. In the third trimester of pregnancy (A), placental ALP is produced leading to raised levels if one were to measure them at this time. Another isoenzyme is found in the liver and bile ducts where it is used to distinguish between an obstructive and hepatic picture in liver disease. Here, obstruction or damage to the bile ducts cause a disproportionately raised ALP compared with the AST and ALT. Another way of distinguishing whether an isolated raised ALP is originating in the liver is to look at the GGT – this often rises with bile duct injury whereas it would be normal if the ALP were of bone or placental origin.
Finally congestive cardiac failure can cause a mildly raised ALP and may be due to reduced forward flow of blood causing congestion in the liver and release of ALP into the systemic circulation. The causes of a raised ALP are many and can be categorized into the following:
1 Liver related – cholestasis, hepatitis, fatty liver, tumour
2 Drugs – phenytoin, erythromycin, carbamezepine, verapamil
3 Bones
1 Bone disease – Paget’s disease, renal osteodystrophy, fracture
2 Non-bone disease – vitamin D deficiency, malignancy, secondary hyperparathyroidism
4 Cancer (different from metastases to bones) – breast, colon cancer and Hodgkin’s lymphoma
A 44-year-old African man is seen by a volunteer doctor in his village with skin changes around the neck. There are erythematous and pigmented areas around the neck in a necklace-like distribution. His family is also complaining of him becoming more forgetful and unable to perform normal daily tasks. This is made particularly distressing given his increase in bowel movements, although he cannot remember how many times he goes. He and his family, like many of the villagers, eat almost exclusively maize, and the doctor has treated several cases of kwashiorkor in the local area. What is the nutritional deficiency most likely to explain his symptoms? A Tocopherol B Riboflavin C Retinol D Vitamin B3 E Ascorbate
D - 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. Niacin is essential for most cellular processes but only usually affects those with severe malnutrition because tryptophan can also be converted into niacin, therefore a dual deficiency is required for the full syndrome to develop. The disease is remembered by the four Ds – dementia, diarrhoea, dermatitis and death. The neurological symptoms do not exclusively manifest as dementia – other symptoms also include depression, anxiety, tremor, delusions, psychosis and even coma. The diarrhoea occurs in about half of patients furthering the malnutrition problem. Dermatitis can affect the mouth, lips, hands, arms, legs and feet. The causes are primary niacin deficiency due to poor nutrition – this is the most likely case in this question given the maize diet and the suggestion of protein malnutrition by the presence of kwashiorkor in the local population. Secondary niacin deficiency may be secondary to malabsorptive problems including prolonged diarrhoea, inflammatory bowel disease and liver cirrhosis. Iatrogenic causes are well described – implicated drugs include isoniazid and azathioprine. Treatment is with niacin replacement therapy and treatment of underlying disease if it is secondary.
Tocopherol (A) is also known as vitamin E, its deficiency causes haemolytic anaemia, spinocerebellar degeneration and peripheral neuropathy. It is rare in humans. It is one of the fat soluble vitamins (the others being A, D and K) and is important in normal reproduction, muscular development and resistance to red cell haemolysis. It is stored in the liver, adipose tissue, muscle, pituitary gland, testes and adrenals. Its levels are directly measured in the plasma. Recently in the HOPE (Heart Outcomes Prevention Evaulation) study, vitamin E was found to have no evidence of benefit in preventing the development of cardiovascular disease.
Riboflavin deficiency (B), also known as vitamin B2, causes ariboflavinosis. Symptoms include dry mucous membranes affecting the mouth, eyes and genitalia along with a normocytic normochromic anaemia. It is usually associated with protein and energy malnutrition or alcoholism and is normally found in legumes, pulses and animal products. Riboflavin is an essential constituent in two molecules – flavin mononucleotide and flavin adenine dinucleotide (FAD). These molecules readily accept and donate electrons making them ideal coenzymes in redox metabolic reactions. Riboflavin is absorbed in the proximal small intestine, its deficiency can be tested for by assaying erythrocyte levels, or assaying the activity of erythrocyte glutathione reductase which requires FAD for its activity. Treatment of this deficiency is daily supplementation.
Retinol (C), also known as vitamin A, is another fat soluble vitamin whose function is necessary for normal epithelial tissue growth, polysaccharide synthesis and the formation of visual pigment, rhodopsin. Vitamin A deficiency can cause dry skin and hair as well as xerophthalmia (drying of the cornea with ulceration). Rarely, Bitot’s spots can develop and are seen on the conjunctiva and represent an accumulation of keratin. Vitamin A deficiency can also cause night blindness due to rhodopsin abnormalities as well as a distinctive skin rash called pityria-sis rubra pilaris. Treatment is with a balanced diet and supplementation. This is not without caution – vitamin A can be toxic: there are reports of Arctic explorers eating polar bear liver who developed headache, diarrhoea and dizziness. Vitamin A consumption, especially in liver, is also cautioned in pregnant women as it may be teratogenic.
Ascorbate (E) is also known as vitamin C which, if deficient, causes scurvy. The features of scurvy include anaemia, bleeding gums and induration of the calf and leg muscles. This is due to ascorbate’s role in the formation of collagen including that of bone, cartilage, teeth and intercellular substance of capillaries. This explains the defective ossification and bleeding tendency. Unsurprisingly, wound healing is also poor. Vitamin C also improves the efficacy of desferrioxime, an iron chelator used in states of iron overload, which may be due to vitamin C’s antioxidant action.
A 51-year-woman with epilepsy is admitted after suffering a seizure following non-compliance with her phenytoin. She admits to having problems at home and was finding it difficult to continue to take her medication regularly. She is restarted on phenytoin. How many half lives does it normally take for a drug to reach its steady state?
A 1–2 half lives B 3–5 half lives C 10–11 half lives D 50–60 half lives E 100–150 half lives
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 under-dosing 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. This figure can be calculated relatively simply. Let us consider we give a patient a single dose of a drug with a half life of 24 hours. This means 50 per cent of the medication will be eliminated in 24 hours, but 50 per cent will remain. On day 2, 24 hours after the first dose, we give another dose. On day 3 there is now 75 per cent of the original doses of drug in the patient’s circulation – the original dose which has been in the system for two half lives and therefore is at 25 per cent, and the second dose which has been in the system for one half life and is therefore at 50 per cent of the original dose – giving 75 per cent. Continuing this daily, the amount of drug in steady state by day 4 is 93.75 per cent, by day 5 it is around 97 per cent. This is for a drug with a half life of 24 hours (this is approximately phenytoin’s half life); but this holds true for any half life except those drugs with very short half lives.This also explains why loading doses are used. If, say, a drug has a half life of 1 week, then it would take up to 5 weeks for the patient to be within the therapeutic range. Therefore, loading doses are used to increase the initial blood concentration and reduce the time needed to reach steady state.
Drugs which require therapeutic drug monitoring include:
•Antibiotics, e.g. gentamicin, vancomycin
•Anticonvulsants, e.g. phenytoin, lamotrigine
•Immunosuppressives, e.g. methotrexate, mycophenolate, tacrolimus
•Lithium
•Digoxin
Unfortunately, determining drug efficacy is more complicated than simply measuring its plasma concentration. The efficacy depends on both pharmacokinetic and pharmacodynamic factors. Pharmacokinetic factors relate to the absorption, distribution, metabolism and excretion of the drug. Absorptive factors include water/fat solubility of the drug or specific transport mechanisms across the mucosal lining of the gut, e.g. grapefruit juice increases ciclosporin bioavailability. Distributive factors take into account the water solubility and fat solubility of the drug as well as the amount of fat or water the patient has. A useful method of measurement of this concept is the volume of distribution which describes the volume of water required to completely account for the administered drug at the given plasma concentration. If the drug has a high fat solubility, the concentration in the plasma will be relatively low, therefore it would require a high volume at the given concentration to account for the drug given. Metabolism factors include pharmacogenetic factors, e.g. thiopurine methyltransferase mutation affects the administration of azathioprine as reduced levels are more likely to lead to toxicity. These factors also include the phase I and phase II type reactions which are involved in oxidation/reduction and solubilization of the drug, respectively. Excretive factors are mostly to do with renal function; some drugs (e.g. digoxin) can accumulate in renal failure. The pharmacodynamic factors that must be considered include whether the drug is in the active form when administered. Some drugs are required to be metabolized before they have their therapeutic effect, e.g. azathiopurine (metabolized to mercaptopurine), enalapril (metabolized to enalaprilat) or carbimazole (metabolized to methimazole) or the drug is active but its metabolic products are also active, e.g. codeine and tramadol. Another important pharmacodynamic factor to consider is the degree of drug bound to protein. Traditionally drug levels are quoted as a total drug level which includes both bound and unbound drug but only the unbound drug is active. Drugs which are highly protein bound have an altered therapeutic effect in low protein states or if another drug has a higher protein affinity therefore displacing the former drug and increasing the proportional unbound active drug. Phenytoin is important to remember as it is highly protein bound (90–94 per cent). Others include mycophenolate and carbamazepine.
A 67-year-old Indian man presents with irritability, sweating and tremor which progresses to stupor. The admitting doctor sends for a laboratory glucose which comes back at 2.2mmol/L. The patient is resuscitated and given intravenous glucose. A history reveals that he does not suffer from diabetes, and his past medical history is remarkable only for vitiligo. On direct questioning he admits to feeling increasingly more tired, particularly after returning recently from India. His family arrive after which the doctor notices the patient’s unusually darker tan compared with his children. Further investigations reveal the patient has low insulin and low C peptide concentrations. What is the most likely diag-nosis?
A Pituitary failure
B Addison’s disease
C Alcohol induced
D Glycogen storage disease
E Medium chain acyl-CoA dehydrogenase deficiency (MCADD)
B 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.
In patients with hypoglycaemia, a plasma insulin and C peptide is diagnostically useful to elucidate the cause. Insulin is the main endogenous hypoglycaemic and is released from beta cells in the pancreas. C peptide is a by product of insulin production and therefore has a direct correlation with endogenous insulin production. Causes of raised insulin and C peptide concentrations are few and include islet cell hyperplasia (e.g. persistent hyperinsulinaemic hypoglycaemia of infancy, Beckwith Weidemann syndrome) or insulinoma. If insulin were exogenously administered, then the C peptide level would be low because endogenous production would be appropriately suppressed.
All of the answers given can cause hypoglycaemia with low insulin and C peptide levels.
Pituitary failure (A) with TSH and ACTH failure can cause hypoglycaemia. In this patient other symptoms and signs suggesting pituitary failure would manifest, e.g. sex hormone deficiency leading to loss of libido, menopause in women; lack of growth hormone leads to muscle atrophy, abdominal obesity; lack of dopaminergic inhibition to prolactin leads to galactorrhoea, amenorrhoea and infertility; lack of TSH leads to hypothyroidism.
Alcohol induced (C) hypoglycaemia occurs due to the increased production of cytosolic NADH from ethanol metabolism into acetaldehyde. NADH inhibits gluconeogenesis resulting in hypoglycaemia. Chronically, chronic alcoholism leads to malnutrition thus reducing the hepatic glycogen stores.
Glycogen storage disease (D), more specifically glycogen storage disease type I (Von Gierke’s disease) is caused by a mutation in the glucose-6-phosphatase enzyme. Phosphorylated glucose cannot cross cell membranes and therefore the lack of this enzyme essentially traps glucose from being transported. Patients present with stunted growth, hepatomegaly and have hypoglycaemia, lactic acidosis, high urate and high triglycerides (GLUT).
Finally medium chain acyl-CoA dehydrogenase deficiency (MCADD) is caused by a genetic defect in fatty acid beta oxidation. This is important in ketone body formation in hypoglycaemia, which the brain must use to preserve function as it cannot utilize fats directly in states of neuroglycopenia. This mutation leads to hypoketotic hypoglycaemia often with hepatomegaly and cardiomyopath
A 56-year-old presents with sudden onset, severe epigastric pain which radiates through to the back. The pain is relieved only partly by sitting forward and is associated with nausea. The admitting doctor suspects pancreatitis and sends for a serum amylase which is greatly raised. A diagnosis of acute pancreatitis is made. The following results come back following a blood test:
Haemoglobin 14.5g/dL White cells 14.2 Na 148 K 4.6 Urea 14 Creatinine 123 Calcium 2.98 (corrected) Cholesterol 5.5 Albumin 35g/L Glucose 8.8mmol/L
Which biochemical abnormality is not likely to be a consequence of acute pancreatitis? A Raised white cells B Raised sodium C Raised urea and creatinine D Raised calcium E Raised glucose
D Hypercalcaemia is not a common consequence of acute pancreatitis, indeed hypercalcaemia is one of the causes of acute pancreatitis. Other causes of pancreatitis can be remembered by the well known mnemonic ‘GET SMASHED’:
•Gallstones
•Ethanol
•Trauma
•Steroids
•Mumps
•Autoimmune (polyarteritis nodosa)
•Scorpion venom (Trinidadian scorpion)
•Hypercalcaemia/Hypertriglyceridaemia/Hypothermia
•Endoscopic retrograde cholangiopancreatogram
•Drugs (including thiazides, azathioprine, valproate, oestrogens)
Corrected calcium is used instead of calcium because the latter is dependent on albumin concentration which binds 40 per cent of plasma calcium and is normally quoted by laboratory studies. The ionized non-bound calcium is the important measurement clinicians are usually interested in; therefore the corrected value is used which takes into account albumin concentration. If the laboratory has not quoted a corrected calcium, one can calculate the corrected value by subtracting 0.1mmol/L from the calcium concentration for every 4g/L the albumin is below 40g/L.
The mechanism of aetiology related to hypercalcaemia is unknown. Some theorize that hypercalcaemia results in small intraductal stones in the pancreas causing blockage. Others believe hypercalcaemia directly increases pancreatic exogenous enzyme output or direct activation of trypsinogen. Pancreatitis is a potentially life-threatening disease with progression to systemic inflammatory response syndrome (SIRS) and multiorgan failure is a well recognized complication. Scoring systems which help to predict severity do exist, perhaps the most easily remembered is the modified Glasgow scoring system:
• PaO2 55 years
• Neutrophilia – white blood cells >15×109/L
• Calcium 16mmol/L
• Enzymes – LDH >600iu/L or AST >200ui/L
• Albumin 10mmol/L
Scoring three or more of these criteria within 48 hours of admission should prompt early intensive care unit referral. Inspecting this list, this patient’s other biochemical abnormalities can be explained from the inflammatory response to the pancreatitis.
A raised white cell count (A) is due to the response of necrotic tissue in the pancreas which is being degraded by the inappropriate activation of trypsin, a powerful protease enzyme. A raised white cell count can also be secondary to the SIRS response as well as infection of the necrotic tissue.
The raised sodium (B) and raised urea and creatinine (C) are likely to be secondary to dehydration which is multifactorial – nausea and vomiting and third space sequestration of fluid from the inflamed pancreas. Acute renal failure in pancreatitis is a devastating complication – one study found the risk factors for developing acute renal failure were previous renal disease, hypoxaemia and abdominal compartment syndrome. A raised glucose (E) is due to the pancreatic endocrine dysfunction where glucose monitoring and insulin release are impaired leading to hyperglycaemia. Hypocalcaemia is a complication of pancreatitis and is due to the fat saponification from the released enzymes
A 76-year-old man presents following a fall and is diagnosed with a pubic ramus fracture which is treated conservatively. He has a background of chronic renal failure and over the weekend starts to feel palpitations and lightheadedness. An electrocardiograph is performed which shows tenting of the T waves, suggestive of hyperkalaemia. A blood test is performed which confirms the diagnosis. Which of the following treatments does not lower plasma potassium levels? A Calcium resonium B Sodium bicarbonate C Calcium gluconate D Insulin E Salbutamol
C Hyperkalaemia over 6.5mmol/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 Pwaves, widened QRS complexes which eventually become sinusoidal and can degenerate into ventricular fibrillation.
10 millilitres of 10% 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.
Calcium resonium (A) can be given orally or per rectum and reduces the plasma potassium levels over the longer term (around hours). This is therefore not helpful in the acute situation this patient is in, but may be considered once the potassium level is controlled. It binds potassium within the gut to increase excretion of ingested potassium therefore lowering overall potassium absorption. Its side effects unsurprisingly include gastrointestinal upset, including nausea and vomiting.
Insulin (D) along with dextrose is the main treatment to reduce potassium concentration acutely. Insulin drives potassium into cells along with glucose. Insulin must not be given alone as one could precipitate hypoglycaemia, the mechanism of action is within 20–30 minutes.
Nebulized salbutamol (E) is an example of a beta-2 receptor agonist which reduces potassium plasma concentration by activating the sodium–potassium–ATPase pump. This ubiquitous enzyme uses energy to transfer sodium and potassium to the extracellular and intracellular spaces respectively. In one recent study, it was shown that more lipophilic beta 2 agonists such as formeterol were more efficacious at reducing potassium plasma levels.
Sodium bicarbonate (B) does not directly lower plasma potassium levels, but instead neutralizes any excess acid in the blood. Bicarbonate reacts with hydrogen ions to produce carbon dioxide and water by increasing the bicarbonate levels, excess hydrogen ions are used in this reaction which raises the pH. Hydrogen and potassium compete at the cell membrane for entry into the cell; if hydrogen ion concentration decreases, a relative abundance of potassium is present making it more likely to enter the cell. This therefore lowers potassium levels, hence sodium bicarbonate indirectly can affect potassium levels
A 54-year-old man is admitted for an elective shoulder repair. The day before his surgery he develops acute onset central crushing chest pain radiating to his left arm and up the jaw. He is also sweaty and feels nauseous. He has a past medical history of coronary artery bypass grafting and angina, and his father died from a heart attack aged 46. An electrocardiogram is performed which shows acute ST elevation in the inferior leads. He is diagnosed with acute coronary syndrome and treated appropriately. His surgery is delayed, but he presents with the same symptoms 2 days later with further ST changes in the lateral leads. Which cardiac enzyme is most useful to confirm re-infarction? A Troponin I B Troponin T C Aspartate transaminase D Creatine kinase muscle brain (MB) E Lactate dehydrogenase
D - 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 iso-enzyme 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.
AST (C) rises around 24 hours after an infarct and remains raised for 48 hours but is less sensitive and specific. It is also raised in liver disease, skeletal muscle damage (particularly in crush injury) and haemolysis. Similarly, LDH (E) rises around 48 hours after myocardial infarction and remains elevated for up to a week. It is also not very specific – it can be raised in liver disease, haemolysis, pulmonary embolism and tumour necrosis
A 35-year-old man presents to his GP with a 1-month history of increased tiredness. The patient also admits to diarrhoea and minor abdominal pain during this period. His blood tests reveal the following: Hb 9.5 (13–18g/dL) MCV 64 (76–96fL) Fe 12.2 (14–31μmol/L) TIBC 74 (45–66μmol/L) Ferritin 9.2 (12–200μg/L)
A Iron deficiency anaemia B β-Thalassaemia C Anaemia of chronic disease D Blood loss E Alcohol F Vitamin B12 deficiency G Renal failure H Aplastic anaemia I Lead poisoning
A- 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.
Anaemia: Men
A 56-year-old vagrant man presents to the accident and emergency department with weakness in his legs. The patient has a history of poorly controlled Crohn’s disease. His blood tests demonstrate Hb 9.4 (13–18g/dL) and MCV 121 (76–96fL). A blood film reveals the presence of hypersegmented neutrophils.
A Iron deficiency anaemia B β-Thalassaemia C Anaemia of chronic disease D Blood loss E Alcohol F Vitamin B12 deficiency G Renal failure H Aplastic anaemia I Lead poisoning
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.
Dietary source: meat and dairy products (large body stores)
Causes of deficiency:
- Dietary: vegans
- Malabsorption: Stomach - lack of IF (gastric parietal cells) - pernicious anaemia or post gastrectomy; or terminal ileum (reduced absorption) - due to ileal resection - Crohn’s disease, tropical sprue, tapeworms
Clinical Features:
- Mouth: glossitis, angular cheilosis
- Neuropsychiatric: irritability, depression, psychosis, dementia
- Neurological: paraesthesia, peripheral neuropathy (loss of vibration and proprioception first), absent ankle reflex, spastic paraparesis, SACD of spinal cord
Pernicious Anaemia: AI atrophic gastritis that leads to achlorhydria and lack of gastric intrinsic factor. Most common cause of a microcytic anaemia in Western countries.
Specific tests: parietal cell antibodies (90%), IF antibodies (50%), Schilling Test (outdated)
Treatment: replenish stores with IM hydroxycobalamin (B12)
A 65-year-old man is referred to the haematology department by his GP after initially presenting with tiredness, palpitations, petechiae and recent pneumonia. His blood tests reveal Hb 9.8 (13–18g/dL), MCV 128 (76–96fL), reticulocyte count 18 (25–100×109/L), 1.2 (2–7.5×109/L) and platelet count 125 (150–400×109/L)
A Iron deficiency anaemia B β-Thalassaemia C Anaemia of chronic disease D Blood loss E Alcohol F Vitamin B12 deficiency G Renal failure H Aplastic anaemia I Lead poisoning
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, plate-lets and bone marrow cellularity as well as a raised MCV. Macrocytosis results from the release of fetal haemoglobin in an attempt to compen-sate for reduced red cell production.
Aplastic Anaemia is the inability of the BM to produce adequate blood cells. Haemopoeitic stem cell numbers are reduced in BM trephines (hypo cellular BM). AA typically refers to anaemia, but patients can have a pancytopenia as well.
The symptoms and signs relate to each cytopenia. Closely linked with leukaemia and PNH (Ham’s Test).
Management: Supportive (transfusions, antibiotics, iron chelation)
Drugs - to promote marrow recovery: growth factors and oxymethalone (androgen)
Immunosuppressants - idiopathic AA
SCT
Inherited AA:
Fanconi Anaemia: AR, pancytopenia, presents at 5-10 years, skeletal abnormalities (radii, thumbs), renal malformations, microopthalmia, short stature, skin pigmentation - 30% MDS, 10% progress to AML
Dyskeratosis Congenita: X-linked, chromosome instability (telomere shortening), pancytopenia, skin pigmentation, nail dystrophy, oral leukoplakia, (triad) + BM failure
Schwachman-Diamond Syndrome: AR, primarily neutrophilia +/- others, skeletal abnormalities, exocrine dysfunction, pancreatic dysfunction, hepatic impairment, short stature, AML risk
Diamond-Blackfan Anaemia: Pure red cell aplasia, normal WCC and platelets, presents at 1 year/neontal. Dysmorphology.
A 56-year-old woman presents to her GP with increased tiredness in the past few weeks. A past medical history of rheumatoid arthritis is noted. Her blood tests demonstrate the following:
Hb 8.6 (11.5–16g/dL) MCV 62 (76–96fL) Fe 10.2 (11–30μmol/L) TIBC 38 (45–66μmol/L) Ferritin 220 (12–200μg/L)
A Iron deficiency anaemia B β-Thalassaemia C Anaemia of chronic disease D Blood loss E Alcohol F Vitamin B12 deficiency G Renal failure H Aplastic anaemia I Lead poisoning
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
- Cytokine driven inhibition of red cell production - decreased proliferation of precursors, suppression of endogenous EPO, impaired Fe utilisation.
- Ferritin (intracellular protein, iron store) is high in ACD: Fe is sequestered in macrophages to deprive the invading bacteria of Fe.
- In renal failure it is not cytokine driven but due to EPO deficiency.
A 12-year-old Mediterranean boy presents to his GP with increased tiredness over the past few weeks which is affecting his ability to concentrate at school. Examination is normal. Blood tests demonstrate the following:
Hb 9.5 (13–18g/dL) MCV 69 (76–96fL) Fe 18.2 (14–31μmol/L) TIBC 54 (45–66μmol/L) Ferritin 124 (12–200μg/L
A Iron deficiency anaemia B β-Thalassaemia C Anaemia of chronic disease D Blood loss E Alcohol F Vitamin B12 deficiency G Renal failure H Aplastic anaemia I Lead poisoning
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 (extra medullary erythropoiesis), severe anaemia, heart failure, gallstones
Diagnosis: Hb electrophoresis (Guthrie @ birth)
Treatment: blood transfusions and desferrioxamine to stop iron overload, plus folic acid.
Blood loss (D) will result in a normocytic anaemia as a consequence of a reduced number of circulating red blood cells. Common causes include gastrointestinal blood loss, heavy menstrual bleeding and certain surgi-cal procedures.
Chronic alcohol (E) consumption directly causes a non-megaloblastic macrocytic anaemia. A poor diet in such patients also leads to folate and vitamin B12 deficiency which exacerbates the anaemia.
Chronic renal failure (G) is caused by the reduced production of red blood cells due to diminished secretion of erythropoietin by the dam-aged kidneys. This results in a normocytic, normochromic anaemia.
Lead poisoning (I) causes dysfunctional haem synthesis resulting in a microcytic anaemia. Lead poisoning leads to basophilic stippling, reflecting RNA found in red blood cells due to defective erythropoiesis
A 48-year-old woman diagnosed with chronic lymphocytic leukaemia develops jaundice and on examination is found to have conjunctival pallor. Direct antiglobulin test is found to be positive at 37°C.
A Hereditary spherocytosis B Sickle cell anaemia C β-Thalassaemia D Glucose-6-phosphate dehydrogenase deficiency E Pyruvate kinase deficiency F Autoimmune haemolytic anaemia G Haemolytic disease of the newborn H Paroxysmal nocturnal haemoglobinuria I Microangiopathic haemolytic anaemia
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).
Management: steroids, splenectomy, immunosuppression
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.
Management: Underlying cause, avoid cold, chlorambucil (chemo)
Direct antiglobulin test (DAT) is positive in AIHA and spherocytes are seen on blood film
An 18-year-old man presents to accident and emergency after eating a meal containing Fava beans. He is evidently jaundiced and has signs suggestive of anaemia. The patient’s blood film reveals the presence of Heinz bodies
A Hereditary spherocytosis B Sickle cell anaemia C β-Thalassaemia D Glucose-6-phosphate dehydrogenase deficiency E Pyruvate kinase deficiency F Autoimmune haemolytic anaemia G Haemolytic disease of the newborn H Paroxysmal nocturnal haemoglobinuria I Microangiopathic haemolytic anaemia
Glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency; D) is caused by an X-linked recessive enzyme defect.
Commonest RBC enzyme defect.
Prevalent in areas of malarial endemicity (Africa, Mediterranean, Middle Eastern populations)
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 (blue deposits, oxidised Hb). Intravascular haemolysis leads to dark urine.
Diagnosis: enzyme assay 2-3 months after a crisis (young RBCs may have sufficient enzyme so results may appear normal)
Treatment: Avoid precipitants, transfuse if severe
A 10-year-old girl presents to accident and emergency with jaundice. Blood tests reveal uraemia and thrombocytopenia. A peripheral blood film demonstrates the presence of schistocytes.
A Hereditary spherocytosis B Sickle cell anaemia C β-Thalassaemia D Glucose-6-phosphate dehydrogenase deficiency E Pyruvate kinase deficiency F Autoimmune haemolytic anaemia G Haemolytic disease of the newborn H Paroxysmal nocturnal haemoglobinuria I Microangiopathic haemolytic anaemia
Microangiopathic haemolytic anaemia (I) is caused by the mechanical destruction of RBCs in circulation. Causes:
- Thrombotic thrombocytopenic pupura (TTP): AI platelet activation: pentad of MAHA, fever, renal impairment, neuro abnormalities, thrombocytopenia. Inhibition of vWF cleaving enzyme (ADAMTS13)
- Haemolytic uraemic syndrome (HUS; E. coli O157:57). E. coli toxin damages endothelial cells, leading to the formation of a fibrin mesh and RBC damage. Causes impaired renal function, MAHA, thrombocytopenia, diarrhoea, renal failure, but no neurological problems. Typically effects children and the elderly.
- Disseminated intravascular coagulation (DIC)
- Systemic lupus erythematosus (SLE).
In all underlying causes, the potentiation of coagulation pathways creates a mesh which leads to the intravascular destruction of RBCs and produces schistocytes (helmet cells). Schistocytes are broken down in the spleen, raising bilirubin levels and initiating jaundice
A 9-year-old boy from sub-Saharan Africa presents to accident and emergency with abdominal pain. On examination the child is found to have dactylitis. Blood haemoglobin is found to be 6.2g/dL and electrophoresis reveals the diagnosis.
A Hereditary spherocytosis B Sickle cell anaemia C β-Thalassaemia D Glucose-6-phosphate dehydrogenase deficiency E Pyruvate kinase deficiency F Autoimmune haemolytic anaemia G Haemolytic disease of the newborn H Paroxysmal nocturnal haemoglobinuria I Microangiopathic haemolytic anaemia
Sickle cell anaemia (B) is an autosomal recessive genetic haematological condition due to a point mutation at position 6 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 (severe) while heterozygotes (HbAS) have sickle cell trait - usually asymptotic. 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.
HbSC: one HbS and one HbC (defective beta-chain)
Sickle b thalassaemia - HbS/β: one HbS, one β-thal trait
Sickle cell anaemia manifests at 3-6 months (coincides with decreasing fetal Hb).
Any decrease in O2 tension leads to polymerisation and sickling.
Features:
- Haemolysis: anaemia (60-80g/L), splenomegaly, folate deficiency, gallstones, aplastic crises (parvovirus B19)
- Vaso-occlusion and infarction: painful crises, dactylitis, stroke, chest-crises, hyposplenism (autosplenectomy), renal papillary necrosis, retinopathy, mesenteric ischaemia, priaprism, sequestration crises (spleen/liver)
Diagnosis: sickle cells and target cells on blood film, sickle solubility test, Hb electrophoresis, Guthrie test (birth)
Treatment: Analgesia for painful crises, folic acid, penicillin V, pneumovax, HiB vaccination, hydroxycarbamide
A 1-day old baby has developed severe jaundice on the neonatal ward. The mother is rhesus negative and has had one previous pregnancy. Due to having her first baby abroad, she was not administered prophylactic anti-D.
A Hereditary spherocytosis B Sickle cell anaemia C β-Thalassaemia D Glucose-6-phosphate dehydrogenase deficiency E Pyruvate kinase deficiency F Autoimmune haemolytic anaemia G Haemolytic disease of the newborn H Paroxysmal nocturnal haemoglobinuria I Microangiopathic haemolytic anaemia
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 (jaundice and fetal anaemia). 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.
In RhD negative women give women IM anti-D Ig when at high risk of feto-maternal haemorrhage. Routine ante-natal prophylaxis is at 28 and 34 weeks. During pregnancy any sensitising events (abortion, miscarriage, abdominal trauma, ECV, amniocentesis, etc) require anti-D, and at delivery if baby is RhD positive.
Hereditary spherocytosis (A) and hereditary eliptocytosis are both autosomal dominant disorders that result in RBC membrane defects and extravascular haemolysis.
HS: Defects are in spectrum or ankyrin (membrane proteins). Patients have a susceptibility to gallstones and parvovirus B19. Extravascular homeless leads to splenomegaly. Dx: spherocytes on blood film, increased osmotic fragility (lysis in hypotonic solution), -ve DAT (Coombs) as not autoimmune Ab mediated. Tx: splenectomy, folic acid.
HE: Defects in spectrin, severity ranges from hydrops fetalis to asymptomatic, elliptical erythrocytes.
Hereditary Pyropoikilocytosis: AR, erythrocytes are abnormally sensitive to heat
β-Thalassaemia (C) results in defects of the globin chains of haemoglobin. As a consequence, there is damage to RBC membranes causing haemolysis within the bone marrow.
Point mutations: decrease in β-chain synthesis (spectrum of disease), excess alpha-chains, increased HbA2 and HbF. Skull bossing, maxillary hypertrophy, hairs on end skull x-ray, hepatosplenomegaly.
Minor: heterozygous, asymptomatic carrier, mild anaemia,
Intermedia: moderate anaemia, splenomegaly, bone deformity, gall stones
Major: homozygous, severe anaemia at 3-6 months, FTT, hepatosplenomegaly (extra medullary erythropoeisis), bony deformity, heart failure.
Diagnosis: Hb electrophoresis (Guthrie at birth)
Treatment: blood transfusions and desferrioxamine to stop iron overload, plus folic acid.
Pyruvate kinase deficiency (E) is an autosomal recessive genetic disorder that causes reduced ATP production within RBCs and therefore reduces survival - severe neonatal jaundice, splenomegaly, haemolytic anaemia
Paroxysmal nocturnal haemoglobinuria (H; PNH) is a rare stem cell disorder which results in intravascular haemolysis, haemoglobinuria (especially at night) and thrombophilia. Ham’s test is positive. Acquired loss of protective GPI markers on RBCs (platelets and neutrophils) leading to complement mediated lysis, causing chronic intravascular homeless, especially at night. This causes morning haemoglobinuria, thrombosis (Budd-Chiara syndrome - hepatic vein thrombosis).
Diagnosis: immunophenotype shows altered GPI, Ham’s test (in-vitro acid induced lysis).
A 34-year-old man, who has a past medical history of splenectomy following splenic trauma, presents to his GP with malaise 2 weeks after returning from abroad. Routine blood results are found to be normal but a blood film demonstrates inclusions within erythrocytes.
A Anisocytosis B Howell–Jolly bodies C Heinz bodies D Rouleaux formation E Spherocytes F Target cells G Cabot rings H Pappenheimer bodies I Tear-drop cells
Howell–Jolly bodies (B) are nuclear DNA remnants found in circulating erythrocytes. On haematoxylin and eosin stained blood film they appear as purple spheres within erythrocytes. In healthy individuals erythrocytes expel nuclear DNA during the maturation process within the bone marrow; the few erythrocytes containing Howell–Jolly bodies are removed by the spleen. Common causes of Howell–Jolly bodies include splenectomy secondary to trauma and autosplenectomy resulting from sickle cell disease.
A 66-year-old man has a gastroscopy and colonoscopy following a blood test which demonstrated a microcytic anaemia. The patient had complained of tiredness and significant weight loss over a 1-month period.
A Anisocytosis B Howell–Jolly bodies C Heinz bodies D Rouleaux formation E Spherocytes F Target cells G Cabot rings H Pappenheimer bodies I Tear-drop cells
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.
IDA: microcytic, hypochromic, anisocytosis, poikilocytosis, pencil cells
A 36-year-old woman presents to her GP after a 1-month history of tiredness and recurrent chest infections. Blood tests reveal a pancytopenia and a subsequent bone marrow aspirate reveals a dry tap.
A Anisocytosis B Howell–Jolly bodies C Heinz bodies D Rouleaux formation E Spherocytes F Target cells G Cabot rings H Pappenheimer bodies I Tear-drop cells
Tear-drop cells (I), also known as dacrocytes, are caused by myelofibrosis. The pathogenesis of myelofibrosis is defined by the bone marrow undergoing fibrosis and replacement with collagenous tissue, 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 (primitive cells), tear-drop cells and circulating megakaryocytes. Bone marrow aspirate is described as a ‘dry and bloody’ tap.
Clinical features: usually elderly, pancytopenia related symptoms, extra-medullary haematopoiesis, MASSIVE splenomegaly, can present with Budd-Chiari syndrome.
Treatment: support with blood products, splenectomy in some cases. Hydroxycarbamide, thalidomide, steroids, SCT are also used.
A 3-week-old neonate is found to have prolonged jaundice with serious risk of kernicterus. Blood film demonstrates the presence of ‘bite cells’ as well as inclusions within erythrocytes.
A Anisocytosis B Howell–Jolly bodies C Heinz bodies D Rouleaux formation E Spherocytes F Target cells G Cabot rings H Pappenheimer bodies I Tear-drop cells
Heinz bodies (C) are inclusion bodies found within erythrocytes that represent denatured haemoglobin as a result of reactive oxygen species. Heinz bodies are most commonly caused by erythrocyte enzyme deficiencies such as glucose-6-phosphate dehydrogenase (G6PD) deficiency, which may present in neonates with prolonged jaundice and NADPH deficiency (leading to accumulation of hydrogen peroxide), as well as chronic liver disease and α-thalassaemia. Damaged erythrocytes are removed in the spleen by macrophages leading to the formation of ‘bite cells’.
A 45-year-old woman with known Graves’ diseases presents to her GP with increased tiredness. She is found to have a megaloblastic anaemia.
A Anisocytosis B Howell–Jolly bodies C Heinz bodies D Rouleaux formation E Spherocytes F Target cells G Cabot rings H Pappenheimer bodies I Tear-drop cells
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 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.
Rouleaux (D) formation describes the stacks of erythrocytes that form in high plasma protein states, for example, multiple myeloma.
Spherocytes (E) are caused by hereditary spherocytosis (AD defect in membranous proteins, for example spectrin), which leads to haemolytic anaemia.
Target cells (F) are erythrocytes with a central area of staining, a ring of pallor and an outer ring of staining. They are formed in thalassaemia, asplenia and liver disease.
Pappenheimer bodies (H) are granules of iron found within erythrocytes. Causes include lead poisoning, sideroblastic anaemia and haemolytic anaemia.
A 4-year-old girl is seen by her GP due to recent onset petechiae on her feet and bleeding of her gums when she brushes her teeth. The child’s platelet count is found to be 12500 per μL. The GP prescribes prednisolone and reassures the child’s mother that the bleeding will resolve.
A Immune thrombocytopenic purpura
B Idiopathic thrombotic thrombocytopenic purpura
C Disseminated intravascular coagulation
D Glanzmann’s thrombasthenia
E Von Willebrand disease
F Haemophilia A
G Haemophilia B
H Hereditary haemorrhagic telangiectasia
I Bernard–Soulier syndrome
Immune thrombocytopenic purpura (ITP; A) may follow either an acute or chronic disease process. Acute ITP most commonly occurs in children, usually occurring 2 weeks after a viral illness. It is a type 2 hypersensitivity reaction, with IgG binding to virus-coated platelets. The fall in platelets is very low (less than 20×109/L) but is a self-limiting condition (few weeks). Chronic ITP is gradual in onset with no history of previous viral infection. It is also a type 2 hypersensitivity reaction with IgG targeting GLP-2b/3a
A 28-year-old man attends the haematology outpatient clinic regarding a long-standing condition he has suffered from. His disorder is related to a deficiency in factor 8 and therefore requires regular transfusions to replace this clotting factor
A Immune thrombocytopenic purpura
B Idiopathic thrombotic thrombocytopenic purpura
C Disseminated intravascular coagulation
D Glanzmann’s thrombasthenia
E Von Willebrand disease
F Haemophilia A
G Haemophilia B
H Hereditary haemorrhagic telangiectasia
I Bernard–Soulier syndrome
Haemophilia A (F) is an X-linked genetic disorder and hence only affects men. Haemophilia A is characterized by a deficiency in factor 8. Haemophilia A is diagnosed by a reduced APTT as well as reduced factor 8. Symptoms depend on severity of disease: mild disease features bleeding after surgery/trauma; moderate disease results in bleeding after minor trauma; severe disease causes frequent spontaneous bleeds. Clinical features include haemarthrosis (causing fixed joints) and muscle haematoma (causing atrophy and short tendons)
A 34-year-old man is taken to the local accident and emergency after suffering an episode of jaundice, fever and worsening headache. Blood tests reveal a low platelet count and blood film is suggestive of a microangiopathic haemolytic anaemia picture
A Immune thrombocytopenic purpura
B Idiopathic thrombotic thrombocytopenic purpura
C Disseminated intravascular coagulation
D Glanzmann’s thrombasthenia
E Von Willebrand disease
F Haemophilia A
G Haemophilia B
H Hereditary haemorrhagic telangiectasia
I Bernard–Soulier syndrome
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
