Uric Acid Metabolism Flashcards
What are the 3 main purines?
Adenosine
Guanine
Inosine
In humans, which enzyme/gene is inactive which leads to problems in purine metabolism?
Uricase (gene)
Why does uric acid tend to precipitate in the metatarsophalangeal joint?
It is at the periphery of the body so it is cooler.
What is the benefit of high urate levels?
Protection against oxidative stress
What are the two main ways of making purines?
De novo metabolism Salvage pathway (recycling)
Which is the predominant purine metabolism pathway?
Salvage pathway
In what conditions will de novo purine metabolism occur?
Very high demand for purines, e.g. in the bone marrow
What is the enzyme in the rate-limiting step in de novo purine metabolism?
PAT
What is the main enzyme of the salvage pathway?
HGPRT
Which condition results due to HGPRT deficiency?
Lesch-Nyhan syndrome
What is the genetic inheritance of Lesch-Nyhan syndrome?
X-linked
What are the key clinical features of Lesch-Nyhan syndrome?
Normal at birth Developmental delay at 6 months Hyperuricaemia (which is very rare in children) Choreiform movements at 1 yera Spasticity Intellectual disability Self-mutilation
What is the biological effect of HGPRT deficiency?
Less IMP and GMP produced means less inhibition of PAT
De novo pathway goes into overdrive
Lots of IMP being produced
The IMP is shunted down the catabolic pathway to try and reduce the amount
Leads to an accumulation of urate
Furthermore, less guanine is converted to GMP so PPRP also builds up, further driving PAT
Fundamentally, how can hyperuricaemia be caused?
Increased urate production
Decreased urate excretion
Give three examples of conditions causing secondary hyperuricaemia due to increased production.
Myeloproliferative disorders
Severe psoriasis
Chronic haemolytic anaemia
Give an example of a secondary condition affecting urate excretion.
Lead poisoning
Saturnine gout
What group of drugs can cause secondary hyperuricaemia through decreased excretion?
Diuretics
Which crystals are found in gout?
Monosodium urate
How is gout diagnosed?
View under polarised light using a red filter
Look for birefringence
Urate = needle-shaped and negatively birefringent
Calcium pyrophosphate = rhomboid-shaped and positively birefringent
What colour do the crystals appear under polarised light with a red filter?
Blue
What drugs are used in managing acute gout?
NSAIDs
Glucocorticoids
Colchicine
How does colchicine work?
Inhibits manufacture of tubulin - high dose colchicine can suppress cell turnover and reduce motility of neutrophils to the site
How is gout managed after the acute episode is over?
Drink lots of water
Reverse factors that are increasing uric acid
Allopurinol - xanthine oxidase inhibitor
Probenecid - increase renal excretion of uric acid
In combination with which drug should allopurinol NEVER be given?
Azathioprine
Interferes with metabolic pathway such that levels of azathioprine increase rapidly and become toxic.
