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Biochem - Gout


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what is gout?
purine metabolism disorder manifested by:
deposition of monosodium urate crystals in/around joints
what are tophi?
accumulations of crystal aggregates in soft tissue
what is uric acid and what is its form at physiological pH?
end product of purine catabolism in humans

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?
hyperuricemia (elevated blood urate)

precipitation of uric acid or monosodium urate crystals in tissues

inflammation (gouty arthritis)
when is the peak incidence for gout?
after age 45 in men
after age 60 in women; postmenopausal

men 5X > women
what is hyperuricemia?
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?
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?
drop in temp
changes in pH
what parts of the body are frequently affected by gout?
podagra > instep > ankle > heel > wrist
how does the inflammatory response to urate crystals occur?
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
develops from asymptomatic hyperuricemia

asymptomatic intervals of up to 10+ yrs; intervals of attack SHORTEN
describe chronic tophaceous gout
is no treatment of urate crystals in joints...

destruction of joints
loss of function

rare because usually treated beforehand
how do you diagnose the presence of urate crystals?

take out sample from synovial fluid of affected joint -> microscope
what do urolithiasis have to do with gout?
urolithiasis are uric acid stones in the kidney

they can be seen at any of the clinical stages of gout
what is primary gout?
gout is the major manifestation of an innate disorder

hereditary component; polygenic
what are the causes of >90% of primary gout?
DECREASED EXCRETION rather than increased production

most cases are idiopathic
what are the known molecular defects of gout?
increase availability of PRPP:

PRPP synthetase variants w/ INCREASED activity; X-linked

2. Partial deficientcy of HGPRT
what happens when you increase PRPP availability?
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?
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?
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?
antiinflamm agents (no effect on urate concentration)

1. colchicine - inhibit phagocytosis of urate crystals by neutrophils (depolarize MTs)
side effects are bad!

2. steroids

also are analgesics
indomethacin is common
contraind: aspirin..competes w/ urate for excretion
GI bleeding
how is chronic gout treated?
try to reduce urate conc to <6mg/dL by increasing excretion: URICOSURIC AGENTS


by decreasing urate concentration: XANTHINE OXIDASE INHIBITOR
how do uricosuric agents work in treating chronic gout?
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?
use allopurinol

treats both over-producers and under-excretors

allopurinol competitively inhibits oxidation of hypoxanthine

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?
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?
uricosuric agent
treats gout by increasing renal excretion

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