Gout Flashcards
what type of an arthritis is gout?
a crystal arthritis
clinical syndrome of gout
monosodium urate (MSU) crystal deposition
physiologic syndrome of gout
hyperuricemia
hyperuricemia
excess urate in the plasma that may or may not result in precipitation of uric acid crystals. >6.8 mg/dl
most common form of inflammatory arthritis?
gout
who does gout mostly affect?
middle aged men
why doesn’t gout affect pre-menopasual women?
estrogen promotes renal uric acid excretion
risk factors for gout
obesity, metabolic syndrome, hypertension, insulin resistance, purine rich diet, alcohol
role of PRPP synthase
conversion of ribose 5P to PRPP
role of PRPP in gout
increased activity leads to increased PRPP (X linked mutation) that leads to increased uric acid (hyperuricemia)
HGPRT role
catalyzes single step salvage reaction for guanine and hypoxanthine.
HGPRT in gout
enzyme deficiency leads to higher levels of guanine and hypoxanthine –> hyperuricemia
uricase
enzyme not present in humans, catalyzes the conversion of uric acid to soluble allantion, leading to lower levels of uric acid
recombinant uricase used for gout treatment
pegloticase
xanthine oxidase role
catalyzes oxidation of hypothanxine to xanthine and xanthine to uric acid
xanthine oxidase in gout
inhibition decreases uric acid level
drugs targeting XO
allopurinol & febuxostat
circulating uric acid
urate anion
limit of solubility for serum urate anions
6.8mg/dL
where is uric acid produced?
liver (from degradation of purine compounds)
sources of urate production
not direct (always from liver metabolism of purine compounds). dietary intake, tissue nucleic acids, endogenous purine synthesis
urate excretion
GI (1/3) and renal (2/3)
URAT1 (urate/organic anion exchanger)
highly urate specific anion exchanger (organic anions) that is responsible for the reabsorption of filtered urate
where is URAT1?
on the luminal membrane of proximal renal tubular epithelial cells.
stimulation of URAT1
increased irate absorption and hyperuricemia
inhibition of URAT1
decreased irate absorption, hypouricemia
drug that inhibits URAT1 and causes more uric acid secretion in urine (uricosuria)
probenecid
is hyperuricemia more likely due to overproduction or under excretion?
90% underexcretion
causes of irate overproduction
primary and secondary hyperuricemia
primary hyperuricemia
inherited defects in regulation of purine nucleotide synthesis (HGPRT deficiency and PRPP synthetase super activity)
secondary hyperuricemia
dietary consumption, increased nucleic acid turnover (MPNs), accelerated ATP degradation
causes of irate underexcretion
kidney disease , medications, stimulation of URAT1
how does alcohol affect homeostasis of urate pool?
overproduction: increases plasma concentration of purines due to liver metabolism
underexcretion: stimulates URAT1 via increased lactic acid fro fermentation, dehydration inhibits excretion
pathogenesis of gout-basic version
uric acid crystals are mobilized and shed into synovial fluid, which causes a very strong inflammatory response
pathogenesis of gout- detailed version
crystal phagocytosis by synovial cells leads to the activation of the NALP3 inflammasome, which releases IL-1B, which binds to IL1 in synovial cells, which activates NF-kB which in turn increases secretion of cytokines that cause neutrophil activation and acute inflammation
IL-1B
inflammatory cytokine produced and released by NALP3 inflammasome complex
MSU crystals and complement
crystals can directly activate the C5b-9 complex that leads to mediator production involved in systemic symptoms like fever, high white count, etc
how does gout spontaneously resolve?
mediators either undergo death/deactivation/differentiation and lose inflammatory function, or up regulation of anti-inflammatory cytokines, or increased vascular permeability leads to urate transport out/increased entry of anti-inflammatory molecules
asymptomatic hyperuricemia
elevation of serum urate concentration in absence of signs of gout. 2/3s of hyperurimic patients
acute gout
acute onset, maximal severity within 12-24 hrs. severe pain, redness, swelling, disability. monoarticular
which joints are most commonly affected in acute gout?
hallux and knee
hallux involvement in gout
podagra
pseudogout
crystals of calcium pyrophosphate
chronic tophaceous gout
chronic hyperuricemia with recurrent acute flares. persistence of synovial fluid crystals with low grade inflammation. presence of tophi and erosions
tophi
deposits of MSU crystals. nests of crystals enveloped by granuloma like chronic inflammatory response with macrophages and multi nucleated giant cells, encased by dense connective tissue
urolithiasis
uric acid kidney stones. precipitation of crystals in the collecting ducts and ureters
acute uric acid nephropathy
uric acid precipitation within the renal tubules or interstititum. causes acute renal failure
synovial fluid aspirate diagnostic of gout
needle shaped, negatively birefringent (yellow=parallel, blue=perpendicular)
treatment for acute gout
control acute inflammation with non steroidal anti-inflammatory meds, colchicine, glucocorticoids
colchicine
blocks activation of NALP3 inflammasome, inhibits neutrophil activation in response to crystals
treatment from chronic gout
decrease uric acid levels with XO inhibitors (allopurinol), uricase (pegloticase), and URAT1 agents (probencid) or via lifestyle modification (decreased purine intake)
