Uric acid metabolism Flashcards Preview

Chemical pathology > Uric acid metabolism > Flashcards

Flashcards in Uric acid metabolism Deck (26)
Loading flashcards...
1
Q

Uric acid synthesis

A

Purine breakdown product

Xanthine oxidase

2
Q

Why is it not uncommon for urate crystals to form?

A

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

3
Q

What happens to urate in the kidney?

A

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

4
Q

What is FEUA?

A

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

5
Q

What is the rate limiting step in purine synthesis?

A

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

6
Q

What are the 2 feedback mechanisms acting in purine synthesis?

A

Negative feedback - high IMP + AMP levels inhibit PAT

Positive feedback - high PPRP levels increase PAT activity

7
Q

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

A

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.

8
Q

What are the main functions of purines?

A

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

9
Q

What is the structure of a purine?

A

Pyrimidine ring fused to imidazole ring

10
Q

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

A
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)
11
Q

What is Lesch Nyhan syndrome?

A

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)

12
Q
Hyperuricaemia
Neurological symptoms (normal at birth - developmental delay by 6m -then lip biting, choreiform movements, spasticity, retardation)
HGPRT deficiency
A

Lesch-Nyhan syndrome

13
Q

HGPRT

A

Salvage pathway of purine synthesis

14
Q

How does Lesch Nyhan syndrome lead to hyperuricaemia?

A

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

15
Q

What are the two main causes of hyperuricaemia?

A

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)

16
Q

Monosodium urate crystals
Needle shaped
Negative birefringence under polarised light

A

Gout

Negative needles

17
Q

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

A

Pseudogout

Pseudo positive

18
Q

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

A

Acute gout (‘Podagra’)

19
Q

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

A

Chronic gout (‘Tophaceous’)

20
Q

Acute gout Tx

A
REDUCE INFLAMMATION (1st line NSAID, 2nd line colchicine, 3rd line prednisolone)
DON'T alter urate concentration
21
Q

MoA colchicine

A

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

22
Q

Chronic gout Tx

A
  1. Reduce factors raising urate levels (lifestyle, allopurinol)
  2. Increase renal excretion - uricosuric e.g. probenocid
23
Q

MoA allopurinol

A

Xanthine oxidase inhibitor

24
Q

MoA probenicid

A

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

25
Q

Main side effect allopurinol

A
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
26
Q

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

A

Lesch-Nyhan syndrome