Uric acid metabolism

Question 1

What is a purine?
What is their role in the body?

Answer 1

3 main molecules: Adenosine, Guanusins and inosine

Make up A+G of DNA
Second messenger for hormones –> cAMP
energy transfere: ATP

Question 2

How are Purines broken down? (Explain purine catabolism)

Answer 2

Allantoin –> highly-soluble and easily excreted

However, humans have less uicase –> humans excrete urate –> less soluble –> already a slight increase in urate leads to too high concentration to be soluble and crystal formattion

Question 3

How is urate generally excreted?

Answer 3

Excreted renally, about 10%

Question 4

What are the 2 ways of synthesising purines?

Answer 4

1. De-novo synthetis –> active in bone marrow, otherwise usually supresssed as energy insufficient –> Green
2. Salvage or recyceling of other –> overally more energy effeicient and usually predominates –> Blue

Question 5

What is the rate-limiting steo of de-novo purine synthesis?

Answer 5

Conversion of PPRP to 5-phoyphoribosyl-1 amine

Enzyme: PAT

Controlled by negative feeback of AMP and GMP levels

Question 6

What is the main enzyme of the Salvage pathway of Purine metabolism?

Answer 6

H(G) PRT

–> Convert Xanthene or Guanine (Catabolic producs) back to Inosinic acid and Guanylic acid –> purine bases

Question 7

What is the pathophysiology of Lesh nyhan syndrome?

How does it present

Answer 7

X-linked recessive syndrome of purine metabolism
–> absoloute H(G)PRT deficiency –> no working salvage pathway of purine metabolism

Presentation
1. Developmental delay+ severe LD ?cause
2. Gout –> hyperuricaemia (no salvage pathway –> low guanine –> less negative feedback)
3. Self-mutilation in 85% aged 1-16 (bite of digits + chunks of lip)

Question 8

What are causes of hyperuricaemia?

Answer 8

1. Increased urate production
   Primary casues, e.g. Lesh Nyhan syndrome
   Secondary –> high cell turnover e.g. Myelo or lymphoproliferative disorders etc.
2. Decreased urinary excretion
   Primary very rare
   Secondary causes:
3. CKD
4. Diuretics

Question 9

What is the rational of management of acute attack of gout

Answer 9

Reduce the inflammation (DO NOT CHANGE PLASMA URATE concentration)

1. NSAIDs
2. Colchicine (reduces cell devision –> turnover long-term), **reduces neutrophil motility **
3. Glucocorticoids

Question 10

What is the principle of management of hyperuricaemia?

Answer 10

Not for acute gout
1. hydration (water, not beer or port)
2. Reverse factors putting up urate (e.g. thiazide diaretics)
3. Reduce synthesiss: allopurinol

Question 11

What are the side-effects and interactions of of allopurinol

Answer 11

Interaction with azathiprine –> makes it more toxic an bone marrow (aplastic anaemia)

Question 12

Name a drug used in the treatment of non-acute gout to reduce urate levels by increasing the fractional excretion of uric acid?

Answer 12

Probenecid