Biochem - Gout
Terms
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- what is gout?
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purine metabolism disorder manifested by:
deposition of monosodium urate crystals in/around joints
inflammation - what are tophi?
- accumulations of crystal aggregates in soft tissue
- what is uric acid and what is its form at physiological pH?
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end product of purine catabolism in humans
urate - where is uric acid found?
- uric acid is only in parts of the urinary tract where pH<5.7, otherwise it's found in it dissociated form
- what are the three requirements for gout?
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hyperuricemia (elevated blood urate)
precipitation of uric acid or monosodium urate crystals in tissues
inflammation (gouty arthritis) - when is the peak incidence for gout?
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after age 45 in men
after age 60 in women; postmenopausal
men 5X > women - what is hyperuricemia?
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males >7mg/dL
females >6mg/dL
solubility of urate in plasma at 37 deg Celsius is 6.5 mg/dL - how many people with hyperuricemia face gout?
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not very many (4.9% for >9mg/dL)
most people w/ hyperuricemia are ASYMPTOMATIC - what are serum urate levels influenced by?
- age, sex, ethnicity, weight, renal fxn, use of pharamcological agents (ex diuretics), metabolites (ex lactate, ketone bodies), use of ETOH, family history, diet
- what factors may precipitate urate crystal formation?
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drop in temp
changes in pH
trauma
stress - what parts of the body are frequently affected by gout?
- podagra > instep > ankle > heel > wrist
- how does the inflammatory response to urate crystals occur?
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crystals are coated w/ proteins that stimulat inflammatory mediators
mediators promote neutrophil recruitment and activation
activated neutrophils ingest urate crystals
lysosomal and cellular lysis -> augmentation of inflamm - describe acute intermittent gout
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develops from asymptomatic hyperuricemia
asymptomatic intervals of up to 10+ yrs; intervals of attack SHORTEN - describe chronic tophaceous gout
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is no treatment of urate crystals in joints...
destruction of joints
deformity
loss of function
rare because usually treated beforehand - how do you diagnose the presence of urate crystals?
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anthrocentesis
take out sample from synovial fluid of affected joint -> microscope - what do urolithiasis have to do with gout?
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urolithiasis are uric acid stones in the kidney
they can be seen at any of the clinical stages of gout - what is primary gout?
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gout is the major manifestation of an innate disorder
hereditary component; polygenic - what are the causes of >90% of primary gout?
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DECREASED EXCRETION rather than increased production
most cases are idiopathic - what are the known molecular defects of gout?
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increase availability of PRPP:
1. SUPER SYNTHETASE
PRPP synthetase variants w/ INCREASED activity; X-linked
2. Partial deficientcy of HGPRT - what happens when you increase PRPP availability?
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activation of rate-limiting, committed, and regulated step of purine de novo synthesis
purines that are made in excess must by degraded -> increase in uric acid - how does a partial deficiency of HGPRT affect a person?
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partial deficiency of HGPRT is >1.5% normal
increases availability of PRPP for de novo synthesis because little purine salvage is occuring - what is secondary gout?
- gout is a subordinate manifestation of an underlying disorder
- what are the examples of secondary gout?
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X-linked Lesch-Nyhan (total deficiency of HGPRT)
increased cell (nucleotide) turnover - leukemias, lymphomas, hemolytic disease, psoriasis
impairment of renal excretion - lead poisoning (saturnine gout)
increased conversion of ATP to AMP - chronic excessive alcohol ingestion, Type 1 glycogen storage disease, inborn errors of fructose metab and hypoxia - how is acute gout treated?
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antiinflamm agents (no effect on urate concentration)
1. colchicine - inhibit phagocytosis of urate crystals by neutrophils (depolarize MTs)
side effects are bad!
2. steroids
3. NSAID's - FIRST-LINE
also are analgesics
indomethacin is common
contraind: aspirin..competes w/ urate for excretion
GI bleeding - how is chronic gout treated?
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try to reduce urate conc to <6mg/dL by increasing excretion: URICOSURIC AGENTS
OR
by decreasing urate concentration: XANTHINE OXIDASE INHIBITOR - how do uricosuric agents work in treating chronic gout?
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INCREASE excretion
no effect on inflamm
inhibit proximal tubular reabsorption of urate; probenecidand sulfinpyruzone is common - how do xanthine oxidase inhibitors work in treating chronic gout?
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use allopurinol
treats both over-producers and under-excretors
allopurinol competitively inhibits oxidation of hypoxanthine
ULTIMATELY:
1. decreases UA production by directly inhibiting XO
2. decreases UA production by indirectly inhibiting purine de novo syntehsis (increases salvage) - what happens when XO is inhibited?
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xanthine and hypoxanthine accumulate
w/ normal HGPRT:
hypoxanthine can be salvaged to IMP, which will inhibit amidotransferase step of synthesis.
xanthine is excreted.
w/ deficient HGPRT:
hypoxanthine is still more soluble than urate, so less likely to precipitate - when trying to lower UA levels, what is used as prophylaxis against acute gout?
- NSAIDS and colchicine
- what is probenecid sulfinpyruzone?
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uricosuric agent
treats gout by increasing renal excretion