ChemPath - Uric Acid Metabolism Flashcards
What are purines
Adenosine, guanosine, inosine
Genetic code markers, messengers of hormones and ATP
What is the urea cycle
Purine production
- De novo in bone marrow (inefficient)
- Salvage synthesis: HGPRT deficiency
Purines → (xanthine oxidase/XO) → hypo-xanthine
Hypo-xanthine → (XO) → xanthine
Xanthine → urease → urate
Urate → allantoin
What is the MOA of allopurinol
Inhibits xanthine oxidase (XO)
What is the MOA of azathioprine
6-mercaptopurine → purine analogue
Metabolised by the XO pathway OR TPMT → cleared
What is the prescribing consideration for azathioprine
Do not prescribe with allopurinol
If there is not TPMT, azathioprine will only be metabolised via the Xo pathway
Allopurinol = XO inhibitor → azathioprine lasts longer → toxic on bone marrow
What is Hypoxanthine-Guanine Phosphoibosyltransferase Deficiency (HGPRT deficiency)
Inborn error or purine metabolism
X-linked
No recycling of hypo-xanthine → purine → overloads the de novo purine synthesis pathway → reduced catabolic pathway → uncontrolled IMP production and accumulation → increased uric acid build up
What are the causes of HGPRT deficiency
Complete deficiency → increased urate production = Lesch Nyhan syndrome
Secondary:
Uricaemia
Chronic renal failure
Drugs e.g. diuretics
Increased cell turnover
Down’s syndrome (reduced urate excretion)
What are the signs and symptoms of HGPRT deficiency
Developmental delay
Choreiform movements
Self-mutilation
Hyperuricaemia
Spasticity, mental retardation
What is gout
Accumulation of MSU (monosodium urate) crystals
Acute (podagra) or chronic (tophaceous)
What are the features of acute gout
Rapid build-up of pain → red, hot swollen joint
First metatarsophalangeal joint (50%)
Male post-pubertal, female post-menopausal
How is gout diagnosed
Tap effusion → view under polarised light with red filter
- MSU crystals = needle-shaped
- NEGATIVE birefringerence
- Blue crystal, 90 degrees to red axis (orientated left → right)
How is pseudo-gout diagnosed
Tap effusion → view under polarised light with red filter
- Pyrophosphate crystals, rhombus shaped
- POSITIVE birefringerence
- Blue crystal, in the red axis (orientated right → left)
What is the management for acute gout
NSAIDs (do NOT give if CKD)
Glucocorticoids
Colchicine
What is the MOA of colchicine
Inhibits tuberculin → inhibits microtubule assembly in neutrophils
Inhibits mitosis → reduces cell turnover
Reduced neutrophil motility → less invasion → less reaction with uric acid
What is the management for non-acute/interval gout
Stay hydrated
Allopurinol
Probenecid (increases urate excretino)
