L43 Gout and Hyperuricemia Flashcards
Uric Acid, Urate, Monosodium Urate (concentration/formation/temp)
uric acid: prod of pur synth, pKa 5.4
-amphipathic (phil/phob)
Urate is conj base of uric acid
in blood, urate is predominant (pH 7.7
Na+ is abundant and there fore urate forms salt with Na as
MonoSodium Urate (MSU)
-much more soluble at 37
-solubility depends on Na and Urate concentrations
Ksp=[Na][Urate]= 4.5x10-5 7mg/dLUrate135mM Na
< no crysatls
>precipitation
in WATER: na low so urate can be high
in Blood: Na high so must keep urate lower
concentration can exceed 7mg/dL and not precipitate bc some urate is protein bound, therefore, not all hyperuricemia forms gout
Hyperuricemia
ab. night plasma or serum urate
ref range:
W 2.5-6.8 mg/dL
Men 3.9-7.9 mg/dL
-Hyperuricemia can result from unrelated metabolic diseases (type I GSD- Von Gierke) or fructose intolerance
if sustained, asymptomatic, predisposes to other problems ie gouty arthritis, rolithiasis, renal dysfunction
Uric acid/urate traits
limited solubility, limited secretion
urate is an antioxidant that can scavenge ROS
- high conc in blood (10x more than VitC)
- HYPOTHESIS-decrease in age specific cancter has offired in human as apposed to short lived mmals, antagonistic pleiotropy
Gout complaints? onset? who gets it? why? history?
mutlifactorial disease with genetic and env factors (diet & bp)
-painful big toes-50% of patients and 90% end up having problem with big toe
preceded by several decades of chronic hyperurecemia, precipitation of monosodium urate in synovial joints
-painful joint inflammation
male disease 40’s 50’s
HU present in all gout patients but not all HU will lead to gout
HISTORY: 2640 BC not treated till late 80s
arthritis of the rich
-middle age men of wealthy upper class
-mean MSU levels rising in men doubled from 1920-1970’s
risk of gout increased by diets high in meat (not in asia, rice and veggies low in dietary purines)
meat is highest source of nucleotides and then beer
MSU crystals
inflammation caused by MSU crystals called TOPHI
urate and Na slowly diffuses out of capillaries into interstitial fluid, hyperuricemia leads ot deposition of MSU crystals on articulate cartilage, INFLAM response to crystals
acute gouty arthritis: neutrophils and macrophages phagocytose the crystals , cell lysis, lysosomal enzymes lead to joint damage
temp of MSU changes solubility
37-7
30-4.5
knee temp: 34
toe temp: 32
PAINFUL TOES
HOmeostasis of Serum Urate
Production: defredation of purine nucleotides
Excretion: 2/3 in urine and 1.3 in bile (Urate is amphipathic) (so are both urate and uric acid amphipathic?)
Renal Excretion of MSU- four steps and clinical correlation with Von Gierkes
- urate is filtered at glomerulus with other low weight water soluble stuff
- 98-100 of the filtered urate is reabsorbed and returned to the blood (0-2% remains in proximal tubule) by SPECIFIC URATE TRANSPORTER
- Urate secreted from the blood to the lumen of the prox tubule by ORGANIC ANION PUMP. (50% of what was originally filtered) (pump also handles other organic compounts lactate, ketone bodies, aspirin) INcrease in ogorganic acids, will result in accumulation of urate in serum due to comp inhibition
- 40% reabsorbed
- urinary secretion is about 8-12% of what was originally filtered.
Van GierkeL hyperuricemic. Lactic acidemia, characteristic in this pathology, is goin got increase probablity of GOUT. BLOCKING ORGANIC ANION PUMP
Kidney Stones
5-10% of kidney stones composed of uric acid. NOT MSU ie NOT TOPHI
Uric acid very low conc in blood, but higher in urine (LOWER PH)
-more uric acid present, still less soluble in an aquous solution
Conditions leading to hyperuricemia and Gout
HypOuricemia: serum urate conc less than 2mg/dL (120mM) VERY UNCOMMON, no symptoms, no pathology, no therapy
herperuricemia: presne in 2-13% of ambulatory adults. present in all patients with gout.
-can be result of increased urate production (15% cases) or decreased renal clearance (85% cases)
distinction can be found in a 24 hour urine analysis
-decreased renal clearance: amounts are normal or less than normal
increased urate production: amounts are greater than normal
- decreased efficiency of purine salvage
- overactive PRPP synthetase
- increase rate of purine degredation
- increased cell death
decreaesd efficiency of purine salvage leads to increased urate production: how
salvage patheay (HGPRT) provides 90% of our purine nucleotides -if activity is reduced, purine bases that ouwl havve been salvaged now degraded to uric acid
-if HGPRT is 1-17%: kelly Seegmiller syntrome (hyperurecemia and premature gout)
-if HGPRT is 1% or lower: lesh nyhan syndrome
(patients campensate for dramatic decrease in salvage pathway with increasing denovo pathway- 10x higher.
uric acid production is equivalent to the incraese in denovo path
(in the urine ocntent SUPER high???) look at slide
-x linked recessive, premature GOUT, kidney stones 25%, low IQ, spastic cerebral palsy, self mutilation and aggression
overreactive PRPP synthetase leading to increased urate production and hyperuricemia: how does this work?
overreactive PRPP synthetase, renders enzyme with increase Vmax or Lower Km or insensitive feedback inhibition, hence increasing PRPP production
(GAIN OF FUNCTION MUTATION)
Glutamine PRPP aminotransferase, regulated allosterically, and by substrate availability, is activated by increase in PRPP, increased DENOVO path increasing urate production
increased rate of purine decredation leads to increased urate production, and hyperuricemia: how?
unusual physiological or pahtological states can provoke net ATP degredation, by exceeding capacity for ATP regeneration
- accellerated purine degredation: seen whenever AMP accumulates
- Increased ATP degradationL excesive ethanol consumption, strenous exercise, excessive fructose infusion, deficiences on G6Pase, FPBase, or aldolase,
Decreased ATP synthesisL tissue hypoxia, hypophospatemia
NO GOUT ALONE, aggravate existing GOUT
increased cell death leads to increased urate production adn hyperuricemia: how?
cancer chemo agents: cause cell death which increases DNA destruction and purine degredation
high urate levels lead to renal failure due to precip of uric acid crystals (NOT MSU) in teh kidney (tumor lysis syndrome) are these TOPHI? no
high uric acid levels need to be present for EXTENDED period of time before crystals develope. therefore would not cause GOUT by itself, but can aggravate gouty condition
Treatement of GOUT
- preventative
uricosuric agents
dietary purine restriction
xanthine oxidase inhibitors
-allopurinol: suicide inhibitor, XO converts it to Alloxanthine, decreases uric acid prod
excreted products of purine degredation are more water soluble
administered to those on CHEMO as prophylactic for high cell death and increased purines
-febuxostat(adenuric, uloric) new XO inhibitor
Recombinant urate oxidase
- convert uric acid to water soluble products
- rasburicase (elitek) 2002
- pegloticase (krystexxa) 2010
Treatement of gout attacksL reduce pain and inflammation, antiinflammatory meds
