Pathophysiology of gout and hyperuricaemia Flashcards
what is hyperuricaemia?
A condition associated with increased uric acid levels in the body
what two things cause hyperuricaemia?
- Increased intake or production of purines
* Impaired excretion of uric acid by kidneys
what is gout?
Inflammatory ‘metabolic’ arthritis associated with chronic hyperuricaemia which may be deposited in arteries as urate crystals.
what does uricase do?
convert uric acid to allantoin which is soluble
what is the dominant cause of hyperuricaemia in people with gout?
Underexcretion of urate
what do urate transportasome’s do?
they are reuptake transporters of urate from the filtered urine in the renal proximal tubule.
-so excess reuptake = hyperuricaemia
What effect does the multidrug transporter (ATP-binding cassette transporter G2; ABCG2) have on the urate excretion with reduced function?
- with reduced function, it blocks excretion and contributes to underexcretion
what is primary gout?
-not caused by another disorder and is often accompanied by other conditions e.g. obesity, alcohol, hypertension
what is secondary gout?
-Develops in course of other disorders e.g. Renal failure
what factors influence the precipitation of urate in joints?
- temperature
- pH
- cation concentration
- articular dehydration
- presence of insoluble collagen
- proteoglycans
what causes an acute flare of gout?
- The production of mature interleukin 1β (IL1β) after activation of NLRP3 (NALP3) inflammasome occurring after ingestion of crystals by monocytes
- this requires a second signal from toll-like receptor (TLRs).
how are flares resolved?
-the neutrophil extracellular trap (NET) binds to the crystals forming a tophi
what happens in chronic tophaceous gout?
there is a long period of silence before a flare reoccurs
What environmental factors influence gout formation?
- diet
- Alcohol intake
- Adiposity and Insulin resistance
how does diet affect gout?
-diets high in purine (e.g. meat and fish increases risk of gout as purine is used to make uric acid
what food high in purine is not associated with increased gout risk?
vegetables that are purine-rich
-reason is unknown
how does alcohol increase gout risk?
it increases uric acid production and decreases the amount excreted in urine and prevents metabolic acidosis
how does adiposity and Insulin Resistance increase gout risk?
-it increases uric acid levels as insulin reduces renal excretion of urate.
what are the two approaches to treating gout?
- Symptomatic Treatment (i.e. inflammation and pain)
2. Reduction of Uricaemia (by reducing uric acid production)
What drugs or drug class is used to prevent uric acid production?
Drug class = Xanthine oxidase inhibitors
Drugs = allopurinol, febuxostat
What drugs or drug class is used to prevent inflammation?
Drug class = inflammation inhibitors
Drugs = NSAIDs, colchicine, steroids, IL-1 inhibitors
What drugs or drug class is used to promote uric acid excretion in the urine as uricosuria?
Drug class = Uricosurics
Drugs = probenecid, benzbromarone
What drugs or drug class is used to promote the removal of excess uric acid in the blood and store as allantoin to remove from the body?
Drug class = Uricases
Drugs = rasburicase, pegloticase
how does colchicine help with gout?
- helps to prevent inflammation or further inflammation
- has no effect on the uric acid concentration itself
how does Xanthine Oxidase Inhibitors work to help with gout?
they prevent uric acid production by inhibiting xanthine oxidase from converting xanthine to uric acid
what’s the difference between febuxostat and allopurinol?
-febuxostat is not a purine analogue like allopurinol so it doesn’t affect any other enzyme in the purine metabolic pathways
what is the risk with taking sulfinpyrazone in the early stages of gout?
- there is a risk of precipitation of uric acid crystals in kidney
- can therefore block the kidney and form kidney stones
how do we reduce the risk of kidney stones in those taking sulfinpyrazone?
- maintain high fluid intake
- keep urine alkaline (uric acid+alkaline urine = neutralisation reaction = water is formed)
