Uric Acid Metabolism Flashcards
What are the purines?
Purines = Adenosine, Guanosine & Inosine
What do the purines act as?
o Genetic code markers (A & G)
o 2nd messengers for hormones (e.g. cAMP)
o Energy transfer (e.g. ATP)
How is allantoin made?
urines -> hypo-xanthine (Xanthine Oxidase / XO) -> Xanthine (XO) -> Urate (Urease) -> Allantoin
What is normal monosodium urate?
o Men = 0.12-0.42mmol/L
o Women = 0.12-0.36mmol/L
§ As temperature goes up, solubility (and thus, concentration) goes up
o Fractional Excretion of Uric Acid (FEUA) ~10% from kidneys (90% of urate is reabsorbed)
What causes Lesch Nyhan Syndrome?
HGPRT (Hypoxanthine-Guanine Phosphoibosyltransferase) Deficiency [if complete deficiency
What are the clinical features of Lesch Nyhan Syndrome?
o Normal at birth X-linked (male-dominant)
o Signs/symptoms:
§ Developmental delay (6/12) Hyperuricaemia
§ Choreiform movements (1yr) Spasticity, mental retardation
§ Self-mutilation (85%) (1-16yr)
o HPRT is usually used to recycle hypoxanthine and guanine back into DNA synthesis
What is the pathophysiology of Lesch Nyhan Syndrome?
There are different levels of urate homeostasis disorders – Lesch Nyhan Syndrome is a primary cause of increased urate production (a hyperuricaemia may be caused by decreased urate excretion, e.g. Down’s)
o No HPRT so no conversion of guanine back to GMP and less hypoxanthine back to IMP
o Less IMP and GMP -> LACK of inhibition on PAT and so de novo synthesis goes into overdrive
o Cells start to uncontrollably make IMP and this abundance of IMP -> abundance of urate
o PPRP also starts to build up -> driving further positive feedback of PAT
How are purines produced?
o 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
o Salvage synthesis – highly efficient and the predominant pathway
What is gout?
Gout (brought about by build-up of MSU crystals)
o Acute (Podagra) or chronic (Tophaceous)
o Male (0.5-3% prevalence) post-pubertal, female (0.1-0.6% prevalence) post-menopausal
What is acute gout?
o Rapid build-up of pain -> red, hot and swollen joint
o 1st MTP joint is the first affected in 50% (Podagra) -> MTP joint affected in 90% of all cases
What is the managment of acute goat?
Reducing inflammation [do NOT attempt to reduce plasma urate concentration] – ACUTE
§ NSAIDs (do not give if CKD is the cause of gout)
§ Glucocorticoids
§ Colchicine (inhibit microtubule assembly in neutrophils by inhibiting tuberculin)
· Inhibits mitosis and so reduces cell turnover
· Reduces neutrophil motility so less invasion and reaction with uric acid
What is the management of chronic gout?
§ Hydrate
§ Allopurinol (reduce synthesis; ok in CKD)
§ Probenecid (increase urate excretion; only give if GFR >50)
How do allopurinol and azathioprine act?
§ Azathioprine -> mercaptopurine -> thioinosinate
§ This interferes with purine metabolism
§ Allopurinol makes mercaptopurine last longer (more toxic on bone barrow)
§ NEVER give someone azathioprine if they are on allopurinol (and vice-versa)
How do you diagnose gout?
Tap effusion -> view under polarised light with red filter
What is the difference between gout and pseudogout?
o Gout = MSU crystals, needle-shaped, -ve birefringent
§ (i.e. needles are BLUE orientated left -> right)
o Pseudo-gout = pyrophosphate crystals, rhombus-shaped, +ve birefringent
§ Occurs in those with osteoarthritis
§ (i.e. needles are BLUE orientated right -> left)
