1s: uric acid metabolism

Question 1

Purines: examples and role

Answer 1

Adenosine, Guanosine & Inosine; they act as…

• Genetic code markers (A & G)
• 2^nd messengers for hormones (e.g. cAMP)
• Energy transfer (e.g. ATP)

Question 2

How do purines turn into urate/uric acid

Answer 2

Purines → hypo-xanthine (Xanthine Oxidase / XO) → Xanthine (XO) Urate (Urease) →Allantoin

Question 3

MSU (monosodium urate plasma concentrations)

Answer 3

• Men = 0.12-0.42mmol/L
• Women = 0.12-0.36mmol/L

As temperature goes up, solubility (and thus, concentration) goes up

Fractional Excretion of Uric Acid (FEUA) ~10% from kidneys (90% of urate is reabsorbed)

Question 4

Give 4 purine metabolism conditions

Answer 4

Inborn errors = HGPRT Deficiency. If complete deficiency → Lesch Nyhan Syndrome (increased urate production)

Down’s syndrome = Decreased urate excretion -→ hypeuricaemia

Gout

Question 5

HGPRT deficiency

Answer 5

Normal at birth, X-linked

S+S:

• developmental delay (6/12)
• choreiform movements (1 yr) aka jerking/writhing movements
• self-mutilation (85%) (1-16 yr)
• hyperuricaemia, spasticity, mental retardation

HPRT is usually used to recycle hypoxanthine and guanine back into DNA synthesis

Question 6

Lesch Nyhan syndrome → increased urate production mechanism

Answer 6

Lesch Nyhan Syndrome is a primary cause of increased urate production

• No HPRT so no conversion of guanine back to GMP and less hypoxanthine back to IMP
• Less IMP and GMP → LACK of inhibition on PAT and so de novo synthesis goes into overdrive
• Cells start to uncontrollably make IMP and this abundance of IMP → abundance of urate
• PPRP also starts to build up → driving further positive feedback of PAT

Question 7

Production of purines

Answer 7

De novo synthesis – inefficient and only done when high demand (_PAT_ is rate-limiting step)

• Only dominant in the bone marrow; everywhere else, the salvage synthesis dominates

Salvage synthesis – highly efficient and the predominant pathway

Question 8

Gout what is it, what do you call acute gout and chronic gout

Answer 8

• Gout (brought about by build-up of MSU crystals)
  
  • Acute (Podagra) or chronic (Tophaceous)
  • Male (0.5-3% prevalence) post-pubertal, female (0.1-0.6% prevalence) post-menopausal
• Acute Gout:
  
  • Rapid build-up of pain  red, hot and swollen joint
  • 1^st MTP joint is the first affected in 50% (Podagra)  MTP joint affected in 90% of all cases

Question 9

Gout diagnosis

Answer 9

• Tap effusion  view under polarised light with red filter
• Gout = MSU crystals, needle-shaped, -ve birefringent
  
  • Left photo (i.e. needles are BLUE orientated left→right)
  • Pseudo-gout = pyrophosphate crystals, rhombus-shaped, +ve birefringent
    
    • Occurs in those with osteoarthritis
    • Right photo (i.e. needles are BLUE orientated right→left)
  • Overview:
    
    • NEGATIVELY birefringent crystals will appear BLUE and at 90 degrees to the axis of the red compensator
    • POSITIVELY birefringent crystals will appear BLUE in the axis of the red compensator
    • Summary of Assessing Crystals:
      
      • Look at the direction of the axis of the filter
      • Negatively birefringent crystals will be blue perpendicular to this

Question 10

Gout management

Answer 10

NSAIDS (CI: CKD), colchicine, allopurinol (reduce synthesis), probenecid (increase excretion, only give if GFR >50)

BEWARE ALLOPURINOL-AZATHIOPRINE INTERACTION