Chemical Patholgy - Uric acid metabolism Flashcards
Recall 3 roles of purines
- Base in DNA
- 2nd messengers for cAMP
- Form part of ATP
Recall the pathway of purine catabolism
Purines –> hypo-xanthine –> xanthine –> uric acid
Xanthine oxidase is involved in the production of both xanthine and urate
Recall the renal handling of urate
Urate is fairly insoluble
It is freely-filtered at the Bowman’s capsule
Bizzarely: it is both reabsorbed and re-excreted in the proximal convoluted tubule!
Name one disorder of inborn error of purine
metabolism. Outline the mechanism
Lesch Nyhan Syndrome = complete HPGRT deficiency causing increased urate production as PAT not inhibited
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 à abundance of urate
PPRP also starts to build up à driving further positive feedback of PAT
What is the inheritance pattern of Lesch Nyhan syndrome
X-linked
How does Lesch-Nyhan syndrome first present?
With developmental delay at 6-12 months
What is the mutation that causes Lesch-Nyhan syndrome?
HPRT - an enzyme that is key in purine recycling
Since there is no feedback inhibition on denovosynthesis of purines, plasma urate increases a LOT
What are 5 symptoms of Lesch-Nyhan syndrome?
Choreform movements, spasticity and UMN signs with mental retardation
Self-mutilation in 85% They bite their lips and digits with a great deal of force
What type of crystals cause gout?
Monosodium urate
What are the 2 clinical forms of gout?
Acute - “podagra”
Chronic - “tophaceous”
How should acute gout be treated?
Key thing is to reduce inflammation
1. NSAIDs (not if CKD is cause!)
1b. Colchicine (this is 2nd line, if NSAIDs contra-indicated)
1c. Glucocorticoids (if all else fails!!)
Nb: if you try to correct urate in the acute phase, you can actually make it worse!!
How should chronic gout be treated?
Need to manage the hyperuricaemia
- Hydration (water!)
- Reverse the factors driving urate up
- Allopurinol
- Probenecid (increase curate excretion, ok if GFR over 50)
What prescription drug can drive urate up?
Thiazide diuretics
What is the mechanism of action of allopurinol?
Inhibits xanthine oxidase
What is the mechanism of action of probenecid?
Increases renal excretion of urate
Recall one very important drug interaction to avoid when prescribing gout drugs
Allopurinol and azothioprine
The intermediary of azothioprine = mercaptopurine - which needs xanthine oxidase to be catabolised
Recall the diagnostic approach for gout
- History and examination should be sufficient
- If not clear: TAP effusion
How can gout crystrals be visualised?
View effusion material under polarised light - use RED filter
How can gout and pseudogout crystals be differenitated under the microscope?
Gout MSU crystals = negatively birefringent (BLUE, orientated left to right), needle shaped
Pseudogout calcium pyrophosphate crystals - positively birefringent, rhombus shaped, right to left
Which other condition predisposes to pseudogout?
Osteoarthritis
How long does pseudogout last?
1-3 weeks
2 pathways of purine synthesis
de novo = inefficient, done when high demanded, PAT is rate limiting step. PAT = Phosphoribosyl pyrophosphate amidotransferase
salvage = highly efficient, therefore predominant pathway
what drug should you never give someone if on allopurinol & vice versa
AZATHIOPRINE
distinguish between colour of gout and pseudogout crystals under polarised light
NEGATIVELY birefringent crystals will appear BLUE at 90 degrees (peperndicular) to the axis of the red compensator
POSITIVELY birefringent crystals will appear BLUE in the axis of the red compensator
