Chemical Patholgy 1 - 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
Why are humans susceptible to gout?
Purines –> hypo-xanthine –> xanthine –> uric acid
Xanthine oxidase is involved in the production of both xanthine and uratet
humans are susceptible to gout because they don’t have the enzyme that. breaks down uric acid into soluble products (as is the case in animals)
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!
**most of it is actually reabsorbed into the bloodstream - urate is meant to be a beneficial antioxidant**
Name one disorder of inborn error of purine
metabolism
Lesch Nyhan Syndrome
*deficiency of HPRT enzyme (which is important in synthesising purines via salvage pathway*
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 dinovosynthesis of purines, plasma urate increases a LOT
What are the 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?
how doesit happen?
Monosodium urate
happens when the crystals are no longer soluble so they precipitate out of solution
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
1b. Colchicine (this is 2nd line, if NSAIDs contra-indicated) – this inhibits neutrophil action
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. - stop thiazide diuretics
- Allopurinol - xanthine oxidase inhibitor
- Probenecid - increases uric acid excretion via the urine
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 and view under a microscope using POLARISED LIGHT with a red filter
**analyse birefringence - ability of crystal to rotate the axis of polarised light
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 crystals = negatively birefringent (BLUE - this is perpendicular to compensator)
Pseudogout crystals - positively birefringent (red) - this is parallel to the compensator
Which other condition predisposes to pseudogout?
Osteoarthritis
How long does pseudogout last?
1-3 weeks
**it is self limiting unlike gout which needs to be treated
What are the 3 main purines?
guanosine
adenosine
inosine
Why is chance of gout lower in women than men?
Women have lower monosodium urate in the plasma
What factors influence the solubility of gout and how does that explain where you get gout
- Temperature - solubility is less at lower temperatures hence gout in peripheries
- acidosis - acidosis decreases solubility as well
What are the two main pathways of purine synthesis?
- de novo pathway
- energy inefficient
- mostly used by bone marrow where high demand for purines
- main enzyme= PAT - salvage pathway
- partially cataobolised purines are essentially recycled
- way more energy efficinet
- every cell is able to utilise this pathway
- main enzyme = HPRT
What are some triggers of gout?
ASPIRIN triggers gout
alcohol
chemo
dehydration
thiazides
AACDD
aspirin alcohol chemo diuretics dehydration
Characeristics of crystals in gout
yellow
needle shaped
negatively birefringent
What type of crystals do you have in psueodgout?
calcium pyrophosphate crystals
these are parallel and positively birefringent
