purine metabolism

Question 1

Name the three (3) pathways that together ensure the continuing balanced supply of purine nucleotides to the cell. State which pathway is the most energy expensive (2)

Answer 1

Pathways: De novo synthesis, Salvage, Catabolism. Most energy expensive: De novo synthesis

Question 2

Briefly describe three (3) processes leading to uric acid excretion and where each process takes place (3)

Answer 2

Glomerular filtration 100% (Renal glomerulus), Active reabsorption almost 100% (Proximal convoluted tubule), Active secretion (PCT)

Question 3

Name the immediate metabolic complication (syndrome) that may arise following successful treatment of leukaemia with cytotoxic drugs (1)

Answer 3

TLS

Question 4

If a patient were to develop an acutely painful big toe within a week of treatment for leukaemia, name 2 possible diagnoses (2x½ = 1)

Answer 4

Gout, Septic arthritis

Question 5

List four (4) cardinal (main) biochemical features/ -abnormalities/ metabolic complications of TLS and explain the mechanisms behind these abnormalities [8x½ = 4] (Super NB)

Answer 5

Hyperkalaemia: From release of intracellular K+

Hyperphosphataemia: Tumour cell lysis leads to release of intracellular phosphate

Hypocalcaemia: Sequestration of plasma calcium in dead & dying tumour cells/ Precipitation with phosphate intracellular protein that has been released/ Calcium phosphate precipitation due to the raised phosphate concentration

Hyperuricaemia: Tumour cell lysis   DNA breakdown  increased purine catabolism  increased uric acid

Question 6

List the two (2) broad groups of causes (based on the mechanism for the biochemical derangement) for the derangement resulting in gout and two (2) causes from each group (6x½ = 3)

Answer 6

• Increased production of uric acid: Tumours, infection, chronic haemolytic anaemias, psoriasis, enzyme defects, obesity
• Decreased excretion of uric acid: Renal failure, renal tubular defect, competitors e.g. lactate, ketones, aspiri

Question 7

Choose the metabolic complication of TLS which is most readily preventable. Which organ is particularly at risk of damage from a raised level of this waste product (1)

Answer 7

Hyperuricaemia (uric acid). Kidney.

Question 8

Name the organ that is particularly susceptible to damage by TLS, and explain why it is so susceptible (3)

Answer 8

Kidney, mainly because of uric acid (urate nephropathy). Also possibly metastatic calcification induced by hyperphosphataemia

Question 9

Indicate two potential clinical consequences of TLS, & describe any steps that can be taken to minimise their impact [4] (NB)

Answer 9

Hyperkalaemia  Cardiac arrhythmias - treat with fluids, K+ losing diuretics, glucose + insulin

Hyperuricaemia  Gout, renal damage and/or stones (urate nephropathy) - treat by promoting diuresis, block urate production with allopurinol

Question 10

State two (2) possible clinical consequences of the elevated plasma uric acid, and explain the rationale for drug therapy aimed at reducing the plasma uric acid (4)

Answer 10

Acute gouty arthritis, acute renal failure (gouty nephropathy), urate kidney stones; allopurinol that inhibits formation of uric acid from purine precursor (hypoxanthine) OR uricosuric drugs that promote renal excretion of uric acid

Question 11

Outline the possible mechanisms for the development of renal failure in a patient with TLS (2)

Answer 11

Ca/ phosphate deposition  metastatic calcification in renal tubules. Uric acid crystal deposition in renal tubules

Question 12

Explain the mechanism by which allopurinol treatment may prevent TLS/ Discuss why it should be commenced prior to chemotherapy (2) (Super NB)

Answer 12

Inhibits xanthine oxidase (which converts hypoxanthine to uric acid), thereby preventing accumulation of uric acid from DNA released from tumour cells killed by chemotherapy (in the purine breakdown pathway)

Question 13

Explain why it is important to maintain a high urine flow rate and alkaline pH to prevent TLS (1)

Answer 13

To minimize precipitation of uric acid in the renal tubules (urate nephropathy)

Question 14

List four modalities used in the acute treatment of severe hyperkalaemia & for each state the mechanism (4x1½ = 6) (NB)

Answer 14

 Insulin and glucose  Increased cellular uptake of glucose, leading to glycolysis and phosphorylated intermediates which encourage potassium uptake by cells.

Beta 2 agonists  Stimulates glycogenolysis, in so doing, increasing phosphorylated intermediates and therefore promoting potassium uptake by cells.

Diuretics plus saline infusion: Promotes renal potassium excretion

Bicarbonate infusion  Induces alkalosis which promotes glycolysis, leading to potassium uptake by cells

Dialysis  Removes potassium (diffuses down concentration gradient into dialysis fluid)

Question 15

State the most likely biochemical cause for the inflamed joint (½)

Answer 15

Elevated uric acid

Question 16

In this particular patient, state the most likely clinical cause for this condition, and the mechanism (2½) [cancer - gout]

Answer 16

Leukaemia-associated tumour lysis, increased cell turnover leading to increased DNA breakdown and therefore increased production of uric acid.