Uric acid metabolism Flashcards
What are the three main purines?
Adenosine
Guanosine
Inosine
What are the key roles of purines?
Genetic code (A, G) Messengers for hormone action (cAMP, cGMP) Energy transfer (ATP)
What enzyme breaks down hypoxanthine to xanthine?
Xanthine oxidase
What enzyme breaks down xanthine to urate?
Xanthine oxidase
What enzyme breaks down urate to allantoin?
Uricase
Which gender is gout more common in?
Males
Which enzyme in the urate metabolism process is inactive in humans?
URICASE
this means there is a buildup of urate
What concentration does urate circulate at in blood?
At the limit of solubility
Urate is INSOLUBLE
How does solubility of urate change based on temperature?
At colder temperatures, solubility DECREASES
What is the most commonly affected joint in gout? Why?
First metatarsophalangeal joint
Because it is at the extremity of the body > colder > urate is more likely to precipitate
Is urate reabsorbed/secreted by the kidney?
BOTH occur in the PCT
Only 10% of urate is filtered our
This is why urate concentration is so high
What is the fractional excretion of uric acid (FEUA)?
The fraction of filtered urate
The urate present in urine, so 10%
What are the two pathways for purine synthesis?
De novo purine metabolism
Salvage pathway
Compare metabolic demands of the two pathways for purine synthesis
De novo - VERY metabolic demanding, inefficient
Salvage - highly energy efficient
Which purine pathway predominates?
SALVAGE pathway
Where does the de novo pathway predominate?
in the bone marrow
due to high requirements
What is the rate limiting enzyme for the de novo pathway?
PAT
What exerts negative / positive feedback on PAT?
Neg feedback: AMP, GMP
Positive feedback: PPRP
What is the rate limiting enzyme in salvage pathway?
HPRT
What is Lesch–Nyhan syndrome?
ABSOLUTE DEFICIENCY in HGPRT
What is the method of vertical transmission of LNS?
X linked recessive
What are clinical features of LNS?
Normal at birth Development delay at 6m Hyperuricaemia Choreiform movements Spasticity, mental retardation SELF HARM
What is the biochemical basis of LNS?
Lack of HPRT > guanine not converted back to GMP > no GMP, AMP > no negative feedback
Also PPRP buildup
Overall, sends de novo pathway into overdrive
What are causes of secondary hyperuricaemia due to increased urate production? Why
Conditions lke Myeloproliferative disorders, Lyphoprolif disorders
Because there is an increase in cell turnover > excess urate > inability to excrete urate last enough
What toxin can cause gout?^
LEAD poisoning
causes saturnine gout
What drug can cause gout?
Diuretics, due to decreased urate excretion
What kind of crystals form in gout?
monosodium urate
What is the shape of crystals in gout?
needle shaped
What are the two diseases u can get from gout?
PODAGRA - acute
TOPHACEOUS gout - chronic
What are clinical features of gout?
Rapid build up of pain
Hot swollen painful joint
Typically 1st MTP (first to appear, most common)
How do gout crystals show up in polarised light?
NEGATIVE BIOREFRINGENCE (so perpendicular to compensator axis) and BLUE Parallel to compensator if YELLOW
How do pseudogout crystals show up in polarised light?
POSITIVE BIOREFRINGENCE (blue and parallel to compensator)
What substance are pseudo gout crystals made up of?
calcium pyrophosphate
What tx work for acute gout?
NSAID
Colchicine
Glujcocorticoid
What tx works for chronic gout=?
Allopurinol
Probenecid
What kind of medication is allopurinol?
XANTHINE OXIDASE inhibitor
so reduces urate synthesis
What medication must you never give with allopurinol?
AZATHIOPRINE
BECAUSE azathioprine is toxic to BM at high doses
Allopurinol blocks mercaptopurine secretion (mercaptopurine is product of azathioprine) thereby massively increasing its effecxt
What is the MOA of probenecid ?
URICOSURIC drug
increases secretion of urate in urine (increases FEUA)
describe what occurs in pseudogout
in patients with osteoarthritis
deposition of calcium pyrophorphate crystals
