Gout Pathophysiology Flashcards
What are the most common risk factors associated with gout?
(1) increase age
(2) male gender
(3) high BP
(4) high SCr/BUN
(5) high body weight
(6) alcohol intake
Describe the basic pathophysiology of gout.
Increased serum uric acid levels lead to deposits in the synovium of joints. It is a type of inflammatory arthritis.
A uric acid level above ______ is considered hyperuricemia.
6.8 mg/dL
The conversion of hypoxanthine to xanthine to uric acid is all catalyzed by what enzyme? What drugs target this enzyme and inhibit it in the treatment of gout?
xanthine oxidase
allopurinol and febuxostat
How do we normally get rid of uric acid? How can this be used therapeutically in its treatment?
normally renally excreted
this process can be accentuated therapeutically by uricosurics like probenecid
De novo synthesis of purines is accomplished by which enzyme?
PRPP synthetase
Decreased activity of which enzyme in the purine salvage pathway can result in increased uric acid levels?
HGPRTase
HGPRTase deficiency increases oxidation of hypoxanthine and increases de novo purine synthesis by PRPP.
Describe the basic inflammatory response that occurs in response to deposition of monosodium urate (MSU) crystals in the synovium.
MSU binds to TLRs on the surface of monocytes. They ingest the crystals and activate the inflammasome. IL-1 beta is released, resulting in release of pro-inflammatory mediators. This activates neutrophils and a positive inflammatory feedback loop.
What are the 4 developmental stages of gout?
(1) asymptomatic hyperuricemia
(2) acute gout
(3) intercritical phase (10% may never have another attack)
(4) chronic gout
How are each of the 4 developmental stages of gout treated?
(1) no treatment
(2) NSAIDS, colchicine, corticosteroids
(3) no treatment
(4) XOI, Pegloticase, Probenecid
What are two ways by which a patient can develop high uric acid levels? How can we tell which category the patient falls under?
either overproduction or under-excretion of uric acid
To distinguish, place patient on purine free diet for 3-5 days and measure the amount of uric acid excreted in the urine in 24 hours. If <600 mg on a purine free diet, the patient is an underexcretor. If >1000 mg on a normal diet, the patient is an overproducer.
Which classes of diuretics can cause hyperuricemia?
thiazides and loops
What is the gold standard diagnostic tool for gout?
actual visualization of tophi present in the joints
What are some clinical observations that can support a diagnosis of gout?
monoarticular involvement, pain/swelling/fever, big toe involvement, > 1 attack, hyperuricemia, peak inflammation w/in one day
Name and describe the long-term complications associated with gout.
(1) uric acid nephrolithiasis - low urine pH promotes crystal formation in urine resulting in stones
(2) acute or chronic gouty nephropathy - short or long term deposition of urate crystals in the renal system leading to acute renal failure, proteinuria, etc.
(3) tophaceous gout - deposition of MSU crystals in big toe, helix of ear, bursae, knees, wrists, hands resulting in joint pain and destruction
colchicine MOA
binds to intracellular protein tubulin and prohibits microtubule proliferation in immune cells to decrease migration and phagocytosis – decreased pain and inflammation
colchicine drug interactions
Cyclosporine, Tacrolimus, Verapamil
two drug classes used in treatment of acute gout
NSAIDs and corticosteroids
Why are NSAIDs preferred over colchicine?
less toxicity
Which corticosteroid is primarily used orally in acute gout treatment? Intra-articularly?
orally - prednisone
intra-articular - triamcinolone
What are the three main classes of drugs used in prevention of gout (urate lowering therapy)?
xanthine oxidase inhibitors (Allopurinol, Febuxostat)
Uricosurics (Probenecid)
Uricase agents (Pegloticase)
Explain how aspirin can precipitate an acute gout attack.
by competing with uricosurics for the anionic transporter in the renal tubules, they decrease the effects of uricosurics
salicylates in general interfere with the excretion of uric acid
Probenecid blocks the renal excretion of other drugs such as (name 3 classes)?
cephalosporins, penicillins, sulfonamides
Explain how cytotoxic drugs can precipitate an acute gout attack.
Cytotoxic agents cause cell death and the release of nucleic acids into the blood. This increases purine levels and eventually uric acid levels.
When may febuxostat be advantageous over allopurinol in gout patients?
patients who are hypersensitive to allopurinol, patients with poor renal function, patients not responding to high doses of allopurinol
Pegloticase is contraindicated in which patients?
those with G6P deficiency
Give two examples of uricase agents used in treatment of gout.
Pegloticase and Rasburicase
Lesinurad (Zurampic) MOA
selective blockade of the URAT1 (urate) transporter in the kidney, preventing reabsorption and enhancing excretion of uric acid
