23. pleno c, gout arthritis
TRANSCRIPT
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SKENARIO C blok 8; 2012
OBESITAS & GOUT ARTHRITIS15 Juni 2012
dr.Liniyanti D.Oswari,MSc
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Gout through the ages
Egyptians : 2640 BC
Hippocrates: 500 BC The unwalkable disease
The disease of kings
Derived from latin Gutta Drop
ie, a drop of evil humour
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B.C 400 Hippocrates
A.D13thC Vielehardouin
1679 Van Leeuwenhoek
1814
1848 Garrod
1950 Talbott et al
1963
Gout
Crystalsintophi
colchicine
Hype
ruricemia
prob
enecid
allopurinol
History of Gout
1798 Wollastone
Uricacid
intophi
Uratecrystal
1961 McCarty
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Who, What, Where, When, Why, How?
1-2%
Uric acid crystal deposition
1stMTP joint
Polyarticular with increasing age
Renal involvement
Middle-Age
Genetics & Lifestyle Purine metabolism, overproduction (10%) or
underexcretion (90%)
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Presentation/Diagnosis
Aspiration of Synovial Fluid
needle-shaped monosodium urate crystals with
negative birefringence.
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Diagnosis
24 hour uric acid level
>800 mg = overproduction
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Definition of hyperuricemia
Mean serum urate concentration in normal
adult:5.11.0mg/dl( ), 4.01.0mg/dl( )
Limit of solubility of MSU
6.7mg/dl at 37 C Hyperuricemia
> 7.0mg/dl( ), > 6.0mg/dl( )
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The Old Gout
A Musculoskeletal disease
Low-Purine Diet
Avoid Vitamin C
High Dose Colchicine
Avoid HCT ( Hidrochlorthiazide): diuretic
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Gout 2011
Profound Metabolic Consequences!
linked to obesity, hypertension, dyslipidemia,
insulin resistance, hyperglycemia, and coronary
artery disease.[3]
NHANES IIIMetabolic Syndrome in 62.8% with
gout vs. 25.4% without
Framingham Study - independent60% increasedrisk of coronary artery disease in men with gout,
after controlling for other factors.[5]
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Gout 2011: HPFS
Health Professionals Follow-up Study
51, 529 men, 12-year, prospective study
RESULT
55% increased risk of fatal myocardial
infarction
28% increased risk of all-causemortality 38% increased risk of death from
cardiovascular disease.[6]
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Gout 2011: HPFS
independent of
age
bodymass index
smoking,
family history
diabetes
hyperlipidemia
hypertension
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=
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Mechanism?
Elevated Uric Acid levels
Activate RAS
Inhibit Nitric Oxide Synthase
Increase Blood Pressure [7]
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Gouty Tophi Incidence has decreased over last few decades
Seen in 25-50% of untreated patients (after 10-20yrs)
Location: Olecranon, bursae, digits, helix of ear
Damages bone, periarticular structures and soft tissues
Palpable measure of total body urate load
Other Extraarticular Complications Renal
Uric acid calculi (seen in10-15% of gout pts)
Chronic urate nephropathy (in those with tophi)
Acute uric acid nephropathy (in pts undergoing chemotherapy) Hypertensive Renal disease is the most common cause of renal
disease in gout
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Chronic tophaceus gout
Tophi collections of solid urate in connective tissues,
creamy in appearance
Common sites: fingers, wrists, ears, knees, olecranon
bursa, ulnar aspect of forearm, Achilles tendon Increased prevalence of chronic tophaceous gout in
Persistent and excessive alcohol consumption
Persistent diuretics use
Non-compliance with therapy Organ transplant recipients treated with cyclosporine
Intolerance of uricosuric drug and allopurinol
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Management of
Chronic tophaceus arthritis
Advise to correct predisposing condition
Prophylactic colchicine or low doseNSAID
Longterm urate lowering Tx
Ix: frequent gouty attacks, tophi, uratenephropathy
Goal: maintain serume urate at < 6.0mg/dl
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Uric Acid
Random hyperuricemia gout (likely CRI, diuretic use)
Acute attack: Urate levels may be normal, low or high
40-49% of acute gouty attacks normouricemic
Mechanism: increased excretion of uric acid
Probably mediated by IL-6, inflammation Urano W, et al. J Rheumatol 29:1950-3, 2002
Schlesinger N, et al. J Rheumatol 24: 2265-6, 1997
Negative association between GoutRA Few reports of both coexisting in literature
RF preferentially binds MSU coated with IgG and inhibited neutrophilchemiluminescence (RF may block interaction of crystal bound IgG andFc recpt)
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The American Diet/fast food & its consequences
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Obesity, Metabolic Syndrome
and Gout
~ 1/3 of Americans meet
criteria for obesity, ~2/3 overweight
Obesity and Increased Body Mass aloneassociated with Hyperuricemia
Insulin Resistance Compounds the Problem
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PRINCIPAL FEATURES OF
METABOLIC SYNDROME
ELEVATED CIRCULATING INSULIN LEVELS
INSULIN RESISTANCE
GLUCOSE INTOLERANCE OR TYPE II DM
ABDOMINAL (VISCERAL) OBESITY: defined as waist
circumference > 40 inches in men (>35 inches in females)
DYSLIPIDEMIA (Hypertriglyceridemia&low HDL chol)HYPERTENSION
HYPERURICEMIA
INCREASED RISK OF ATHEROSCLEROSIS AND
COAGULATIVE ARTERIAL OCCLUSIVE EVENTS
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Renal Effects of Metabolic
Syndrome Pertinent to Gout HyperinsulinemiaStimulates
Increased RenalSodium andUrate Reabsorption
A Mild Defect inRenal AmmoniumExcretionAssociated with IRPromotes Acid
Milieu for Uric AcidUrolithiasis
pH
Urate
relative risk of urolithiasis
in men with diagnosis of gout:
= 2.12
Kramer et al . Kidney Int 2003
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RENAL TRANSPORT OF URATE
Renal urate transportis typically explained bya 4-component model:
1. glomerular filtration,
2. a near-complete reabsorption of filtered urate,
3. subsequent secretion, and4. postsecretory reabsorption in the remaining
proximal tubule.
This model evolved from an interpretation of the
effects of uricosuric and antiuricosuricagents; drugs and compounds known to affectserum urate levels are summarized in the Table.
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Clin exp Nephrol, 2005
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SEVERAL POPULAR DIETS
HIGH IN FAT AND LOW IN
CARBOHYDRATES HAVE
THE POTENTIAL TO
PROMOTE HYPERURICEMIAVIA KETOSIS AND HIGH
MEAT AND SEAFOOD
INTAKE
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Gout 2011: Lifestyle RX
Weight Loss
Adiposity is associated with hyperuricemia
Weight loss leads to reductions in gout
incidence.[8]
Eat Less Red Meat
Persons consuming higher amounts of beef, pork
and lamb have a 41% increased risk of gout
Selectively Consume Seafood
Those consuming higher amounts of seafood have
a 51% increased risk of gout.[10]
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Gout 2011: Lifestyle RX
Drink Less Sweet Beverages and Fructose
Sugar intake independently associated with
elevated uric acid levels in men. [11]
direct relationship between intake of fructose-
containing soft drinks and hyperuricemia as
well as gout.[12, 13]
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Gout 2011: Lifestyle RX
Increase intake of Vegetables, legumes, Nuts,
Vegetable Proteins
No need to avoid Purine-rich vegetables
increased intake of vegetable protein associated
with up to 27% lower incidence of gout.[10]
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Gout 2011: Lifestyle RX
Increase Omega-3 Fatty Acids
Walnuts, purslane, leafy greens, flax, small
sustainably caught cold-water fish
EPA inhibits gout-mediated inflammation
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Gout 2011: Lifestyle RX
Limit Alcohol to no more than 1-2 Drinks QD
Drink Wine Rather than Beer or Liquor
Wine does not seem to correlate with incidence of
gout
each 12 ounce beer consumed increases the
risk of gout by 50% compared to non-beer-
drinkers (on a daily basis)
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Gout 2011: Lifestyle RX
Increase intake of Low-Fat Dairy
Up to 2 servings QD
protective effect on the incidence of gout.[10]
RCT of milk confirmed its urate-lowering
effect.[17]
The mechanism related to the milk proteinscasein and lactalbumin. [18]
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Gout 2011: Lifestyle RX
Alkalanize your Urine
direct correlation between urine pH and uric
acid excretion, despite higher purine content
of acidic diet. [21]
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REVIEW
Prevention Prescription
Encourage weight loss and maintenance of a healthy body massindex.
Decrease consumption of red meat and most seafood.
Increase intake of vegetables, legumes, nuts, and vegetableproteins.
Decrease intake of sugar-containing beverages and fructose.
Limit alcohol to no more than 1-2 drinks per day and drink winerather than beer or liquor.
Increase intake of low-fat dairy, up to two servings per day. Maintain adequate hydration.
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Gout 2011: Food RX
Vitamin C 500-1500mg QD
45% less gout in persons consuming >1500mg
QD
Direct Association with Uric Acid levels and Vit
C intake
Double Blind RCT showed reductions in uric
acid levels with 500mg supplementation
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Fructose
present in honey and fruit
50% of sugar (sucrose = 1 glucose + 1
fructose molecule)
55% of HFCS ( high fructose corn sryup)
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Results
1 servings a day increasedrisk by 45%
BUT 2 or more servings a day
increased risk of gout by 85%
Suggests that the risk posed by free fructose intake , is as great as that of
the intake of purine rich food
Wh d f t ff t i id
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Why does fructose affect uric acid.
1.infusion studies show
fructose
Fructose-1-
phosphate
ADP
ATP
AMP
IMP
URIC ACID
Fructokinase
Liver Cell
Decreasing Pi
levels remove
feedback on
AMP
Deaminase
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Why does fructose affect uric acid.
Some fructose transporters in the kidney may
also be uric acid transporters and this may
affect the way the kidney handles uric acid.
Carriers of the defect hereditary fructose
intolerance also have high plasma uric acid.
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Hereditary Fructose Intolerance
fructose
Fructose-1-
phosphateADP
ATP
AMP
IMP
URIC ACID
Fructokinase
Liver Cell
Decreasing Pi
levels remove
feedback on
AMP
Deaminase
DHA-
phosphate
Aldolase B
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Management of acute gout
1. NSAIDs
1st choice Rapid acting (naproxen, indomethacine) preferredContinued until 48h after absence of inflammation
2. Colchicine
Alternative, out-dated Time limit: effective between 12-36h of an attack0.6mg q 1h up to 10 doses until relief of joint Sx or
G-I Sx3. Intraarticular corticosteroid:
Effective in monoarticular gout4. Systemic corticosteroid
When NSAIDs are not effective orcontraindicated
5. No urate lowering agents (allopurnol)
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Colchicine
Effective : within 24 hours
Adverse reactions: nausea, vomit, diarrhea,
abdominal pain, BM suppression, myopathy,
alopecia
Not use
: Combined renal and hepatic diseaseGFR
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Corticosteroid
P.O;20-40mg/day for 3-4days, then taper one to2 weeks
Intraarticular injection:
triamcinolone 10-40mg ordeaxamethasone 2-10mgwith lidocaine
In:
recalcitrant acute gouthepatopathyelderly patients withrenal insufficiency
12345678
Ice steroids Steroids
Painswelling
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Indications
More than two attacks per year
Tophaceous gout
Goal: less than 6mg/dl Antihyperuricemic agents
Decreasing urate production by inhibiting
xanthine oxidase (allopurinol) Promoting renal excretion of urate
(probenecid)
Correction of hyperuricemia
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Gout 2011: Prevention RX, Vit C
Mechanism: blocks reuptake and increase GFR
Bioflavonoids: Hesperidin
DOSE: increase citrus fruits, 500mg Vit C
w/bioflavonoids, increase Rosemary
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Gout 2011: Food RX
EPA & GLA
Suppress inflammation in animal gout
Cardiovascular benefit
Anti-inflammatory Diet
Dose: 500mg EPA or 3000mg Evening Primrose
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Gout 2011: Food RX
Cherries and Cherry Juice
280 g QD lowers plasma urate, increases
urinary excretion
Decreases CRP and NO
Double Blind RCT of Cherry juice: less post-run
pain
DOSE: pound of cherries or equivalent juice
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Gout 2011: Food RX
Quercetin
Inhibits xanthine oxidase
Decreases BP and oxidized LDL
onions, apples, berries, grapes, green and
black tea, citrus fruits, capers, tomatoes,
broccoli, and leafy greens
Supplement with 500mg
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Turmeric
EFAs
Ginger
Rosemary
Nuts
Greens Tea
Gout 2011: Anti-Inflammatory Diet
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Food RX: Summary
Citrus
Rosemary
Cherries
Cold-Water Fish, Flax, Walnuts, Leafy Greens
Onions, apples, berries, tea, broccoli,
tomatoes, grapes. Pineapple
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Acupuncture
Needles Vs. Allopurinol + Indomethacin
93% effective vs. 80%
Greater reductions in serum uric acid
Fewer adverse effects
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Ice
Most arthritic conditions benefit from heat
patients with gout prefer ice.[38]
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Treatment: MEDS
NSAID: 1stline
Paucity of data
Indomethacin 50mg TID
Ibuprofen 600mg TID
Naproxen 500mg BID
Avoid ASAincreases uric acid
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Prevention
An ounce of Prevention is worth a
pound of cure
Behold the rain which descends from
heaven upon our vineyards, there it
enters the roots of the vines, to be
changed into wine, a constant proof
that God loves us, and loves to see us
happy
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SUMMARY
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SUMMARY
The disease burdenof gout remains substantial and may be
increasing. As more scientific data on modifiable risk factors and
comorbidities of gout become available, integration of thesedata into gout care strategy may become essential, similar tothe current care strategies for hypertensionand type 2diabetes.
Recommendations for lifestyle modificationto treat or toprevent gout are generally in line with those for theprevention or treatment of other major chronic disorders
Weight control, limits on red meat consumption, and dailyexerciseare important foundations of lifestyle modificationrecommendations
Plant-derived -3 fatty acidsor supplements ofeicosapentaenoic acidand docosahexanoic acidinstead ofconsuming fish for cardiovascular benefits.
SUMMARY
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SUMMARY
Further riskbenefit assessmentsin each specific
clinical context would be helpful. Daily consumption of nuts and legumesas
recommended by the Harvard Healthy EatingPyramid (32)may also provide important healthbenefits without increasing the risk for gout.
Similarly, a daily glass of winemay benefit healthwithout imposing an elevated risk for gout, especiallyin contrast to beer or liquor consumption.
These lifestyle modificationsare inexpensive and safe
and, when combined with drug therapy, may resultin better control of gout.
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SUMMARY
Effective management of gout risk factors (for
example, hypertension) and the antihypertensive
agents with uricosuric properties (for example,
losartan or amlodipinecould have a better risk
benefit ratio than diureticsfor hypertension inhypertensive patients with gout.
Similarly, the uricosuric property offenofibrate may
be associated with a favorable riskbenefit ratio
among patients with gout and the metabolicsyndrome.
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SUMMARY
The recently elucidated molecular mechanism of renal uratetransporthas several important implications in conditionsthat are associated with high urate levels.
In particular, the molecular characterization of the URAT1
anion exchangerhas provided a specific target of action forwell known substances affecting urate levels.
Genetic variation in these renal transporters or upstreamregulatory factors may explain the genetic tendency todevelop conditions associated with high urate levels and a
patients particular response to medications. Furthermore, the transporters themselves may serve as
targets for future drug development.