Uric acid metabolism

Question 1

Uric acid synthesis

Answer 1

Purine breakdown product

Xanthine oxidase

Question 2

Why is it not uncommon for urate crystals to form?

Answer 2

Plasma urate concentration is close to urate solubility threshold (0.4mmol/L)
Solubility = concentration above which crystals will form
Pt. in men

Question 3

What happens to urate in the kidney?

Answer 3

Urate is freely filtered by glomerulus
90% reabsorbed in PCT via URAT1 transporter
Only 10% is excreted

Question 4

What is FEUA?

Answer 4

Fractional excretion of uric acid
How much uric acid is excreted by the kidney expressed as a %
10%

Question 5

What is the rate limiting step in purine synthesis?

Answer 5

PAT - converts PPRP to 5-phosphoribosyl-1-amine in purine synthesis

Question 6

What are the 2 feedback mechanisms acting in purine synthesis?

Answer 6

Negative feedback - high IMP + AMP levels inhibit PAT

Positive feedback - high PPRP levels increase PAT activity

Question 7

What are the three key outputs of purine synthesis and how are they linked?

Answer 7

Nucleotides IMP (inosine), GMP (guanosine) and AMP (adenosine) (nucleotide = ribose sugar, single phosphate, purine(/pyrimidine) base). IMP is an intermediate between GMP and AMP. These molecules are then adapted - e.g. phosphate groups added to form ATP, which adenylate cyclase can then act on to form cAMP.

Question 8

What are the main functions of purines?

Answer 8

DNA/RNA synthesis
Secondary messengers (cAMP, cGMP)
ATP

Question 9

What is the structure of a purine?

Answer 9

Pyrimidine ring fused to imidazole ring

Question 10

What are the two ways in which purines can be formed?

Answer 10

De novo synthesis (metabolically hard work - only used when purines in high demand, e.g. high cell turnover in BM)
Salvage pathway (predominant - partially metabolised purines converted to IMP/GMP by HGPRT)

Question 11

What is Lesch Nyhan syndrome?

Answer 11

Complete HGPRT deficiency
(Mutation of HPRT gene; 2/3 AR inheritance, 1/3 de novo mutation; almost exclusively affects males)
= Hyperuricaemia
(HGPRT is used to salvage partially metabolised purines back into purines, reducing the amount of urate)

Question 12

Hyperuricaemia
Neurological symptoms (normal at birth - developmental delay by 6m -then lip biting, choreiform movements, spasticity, retardation)
HGPRT deficiency

Answer 12

Lesch-Nyhan syndrome

Question 13

HGPRT

Answer 13

Salvage pathway of purine synthesis

Question 14

How does Lesch Nyhan syndrome lead to hyperuricaemia?

Answer 14

HGPRT
Lack of salvage pathway forming GMP/IMP from partially metabolised purines
Lack of negative feedback on PAT drives de novo synthesis
Increased purine catabolism = increased urate

Question 15

What are the two main causes of hyperuricaemia?

Answer 15

Increased urate production (may be primary e.g. Lesch-Nyhan or secondary e.g. increased cell turnover/breakdown)
Decreased urate excretion (may be primary (FJHN) or secondary (e.g. CKD, kidney damage, diuretics - things affecting kidney function)

Question 16

Monosodium urate crystals
Needle shaped
Negative birefringence under polarised light

Answer 16

Gout

Negative needles

Question 17

Calcium pyrophosphate crystals
Rod shaped (blunt ended)
Positive birefringence under polarised light

Answer 17

Pseudogout

Pseudo positive

Question 18

Mono-articular hot swollen red joint
Sudden hyperuricaemia
Usually 1st MTP

Answer 18

Acute gout (‘Podagra’)

Question 19

Chronically elevated urate
Crystal deposition in joints, kidney, earlobes
Recurrent acute attacks predispose
Kidney stones

Answer 19

Chronic gout (‘Tophaceous’)

Question 20

Acute gout Tx

Answer 20

REDUCE INFLAMMATION (1st line NSAID, 2nd line colchicine, 3rd line prednisolone)
DON'T alter urate concentration

Question 21

MoA colchicine

Answer 21

Inhibits tubulin polymerisation - microtubule formation - reduced neutrophil migration to reduce inflammation

Question 22

Chronic gout Tx

Answer 22

1. Reduce factors raising urate levels (lifestyle, allopurinol)
2. Increase renal excretion - uricosuric e.g. probenocid

Question 23

MoA allopurinol

Answer 23

Xanthine oxidase inhibitor

Question 24

MoA probenicid

Answer 24

Uricosuric - increases urate excretion / decreases urate re-absorption in the kidney

Question 25

Main side effect allopurinol

Answer 25

Azathioprine reaction (steroid sparing immunosuppressant in IBD)
Azathioprine = pro drug > mercaptopurine > thioinosinate. Mercaptopurine stopped by XO so accumulates if XO is blocked
Too much active drug

Question 26

Orange coloured sand in baby’s nappy
Self-mutilation
Delayed motor development

Answer 26

Lesch-Nyhan syndrome