SKENARIO C blok 8; 2012OBESITAS & GOUT ARTHRITIS15 Juni 2012dr.Liniyanti D.Oswari,MSc

Gout through the agesEgyptians : 2640 BC Hippocrates: 500 BC The unwalkable diseaseThe disease of kingsDerived from latin Gutta Drop ie, a drop of evil humour

B.C 400 HippocratesA.D 13th C Vielehardouin1679 Van Leeuwenhoek1814 1848 Garrod1950 Talbott et al1963GoutCrystals in tophicolchicineHyperuricemia probenecidallopurinolHistory of Gout1798 WollastoneUric acid in tophiUrate crystal1961 McCarty

Who, What, Where, When, Why, How?1-2% Uric acid crystal deposition1st MTP jointPolyarticular with increasing ageRenal involvementMiddle-AgeGenetics & LifestylePurine metabolism, overproduction (10%) or underexcretion (90%)

HyperuricemiaUrate crystalizationGenetic factorEnvironments

Inflammation to urate crystas

1.psd

2.psd

Presentation/DiagnosisAspiration of Synovial Fluidneedle-shaped monosodium urate crystals with negative birefringence.

Diagnosis24 hour uric acid level

>800 mg = overproduction

Definition of hyperuricemiaMean serum urate concentration in normal adult:

5.11.0mg/dl( ), 4.01.0mg/dl( )Limit of solubility of MSU

6.7mg/dl at 37 CHyperuricemia

> 7.0mg/dl( ), > 6.0mg/dl( )

The Old GoutA Musculoskeletal diseaseLow-Purine DietAvoid Vitamin CHigh Dose ColchicineAvoid HCT ( Hidrochlorthiazide): diuretic

Gout 2011Profound Metabolic Consequences!linked to obesity, hypertension, dyslipidemia, insulin resistance, hyperglycemia, and coronary artery disease.[3] NHANES III Metabolic Syndrome in 62.8% with gout vs. 25.4% withoutFramingham Study - independent 60% increased risk of coronary artery disease in men with gout, after controlling for other factors.[5]

Gout 2011: HPFSHealth Professionals Follow-up Study51, 529 men, 12-year, prospective studyRESULT55% increased risk of fatal myocardial infarction28% increased risk of all-cause mortality38% increased risk of death from cardiovascular disease.[6]

Gout 2011: HPFSindependent of agebody mass indexsmoking,family historydiabeteshyperlipidemiahypertension

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Mechanism?Elevated Uric Acid levelsActivate RASInhibit Nitric Oxide SynthaseIncrease Blood Pressure [7]

Gouty TophiIncidence has decreased over last few decadesSeen in 25-50% of untreated patients (after 10-20yrs)Location: Olecranon, bursae, digits, helix of earDamages bone, periarticular structures and soft tissuesPalpable measure of total body urate load

Other Extraarticular ComplicationsRenal 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

Chronic tophaceus goutTophi 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 arthritisAdvise to correct predisposing condition

Prophylactic colchicine or low dose NSAID Longterm urate lowering Tx Ix: frequent gouty attacks, tophi, urate nephropathy Goal: maintain serume urate at < 6.0mg/dl

Uric AcidRandom hyperuricemia gout (likely CRI, diuretic use)Acute attack: Urate levels may be normal, low or high40-49% of acute gouty attacks normouricemicMechanism: increased excretion of uric acidProbably mediated by IL-6, inflammationUrano W, et al. J Rheumatol 29:1950-3, 2002Schlesinger N, et al. J Rheumatol 24: 2265-6, 1997

Negative association between Gout RAFew reports of both coexisting in literatureRF preferentially binds MSU coated with IgG and inhibited neutrophil chemiluminescence (RF may block interaction of crystal bound IgG and Fc recpt)

The American Diet/fast food & its consequences

Obesity, Metabolic Syndrome and Gout~ 1/3 of Americans meet

criteria for obesity, ~2/3 overweightObesity and Increased Body Mass alone associated with HyperuricemiaInsulin Resistance Compounds the Problem

PRINCIPAL FEATURES OF METABOLIC SYNDROMEELEVATED CIRCULATING INSULIN LEVELSINSULIN RESISTANCE GLUCOSE INTOLERANCE OR TYPE II DMABDOMINAL (VISCERAL) OBESITY: defined as waist

circumference > 40 inches in men (>35 inches in females)DYSLIPIDEMIA (Hypertriglyceridemia&low HDL chol)HYPERTENSIONHYPERURICEMIAINCREASED RISK OF ATHEROSCLEROSIS AND

COAGULATIVE ARTERIAL OCCLUSIVE EVENTS

Renal Effects of Metabolic Syndrome Pertinent to GoutHyperinsulinemia Stimulates Increased Renal Sodium and Urate ReabsorptionA Mild Defect in Renal Ammonium Excretion Associated with IR Promotes Acid Milieu for Uric Acid Urolithiasis

relative risk of urolithiasisin men with diagnosis of gout:= 2.12Kramer et al . Kidney Int 2003

RENAL TRANSPORT OF URATERenal urate transport is typically explained by a 4-component model:

glomerular filtration,a near-complete reabsorption of filtered urate, subsequent secretion, andpostsecretory reabsorption in the remaining proximal tubule. This model evolved from an interpretation of the effects of uricosuric and antiuricosuric agents; drugs and compounds known to affect serum urate levels are summarized in the Table.

Clin exp Nephrol, 2005

SEVERAL POPULAR DIETS HIGH IN FAT AND LOW IN CARBOHYDRATES HAVE THE POTENTIAL TO PROMOTE HYPERURICEMIA VIA KETOSIS AND HIGH MEAT AND SEAFOOD INTAKE

Gout 2011: Lifestyle RXWeight LossAdiposity is associated with hyperuricemiaWeight loss leads to reductions in gout incidence.[8]Eat Less Red MeatPersons consuming higher amounts of beef, pork and lamb have a 41% increased risk of gout Selectively Consume SeafoodThose consuming higher amounts of seafood have a 51% increased risk of gout.[10]

Gout 2011: Lifestyle RXDrink Less Sweet Beverages and FructoseSugar 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]

Gout 2011: Lifestyle RXIncrease intake of Vegetables, legumes, Nuts, Vegetable ProteinsNo need to avoid Purine-rich vegetablesincreased intake of vegetable protein associated with up to 27% lower incidence of gout.[10]

Gout 2011: Lifestyle RXIncrease Omega-3 Fatty AcidsWalnuts, purslane, leafy greens, flax, small sustainably caught cold-water fishEPA inhibits gout-mediated inflammation

Gout 2011: Lifestyle RXLimit Alcohol to no more than 1-2 Drinks QDDrink Wine Rather than Beer or LiquorWine does not seem to correlate with incidence of gouteach 12 ounce beer consumed increases the risk of gout by 50% compared to non-beer-drinkers (on a daily basis)

Gout 2011: Lifestyle RXIncrease intake of Low-Fat DairyUp to 2 servings QDprotective effect on the incidence of gout.[10]RCT of milk confirmed its urate-lowering effect.[17] The mechanism related to the milk proteins casein and lactalbumin. [18]

Gout 2011: Lifestyle RXAlkalanize your Urinedirect correlation between urine pH and uric acid excretion, despite higher purine content of acidic diet. [21]

REVIEWPrevention PrescriptionEncourage weight loss and maintenance of a healthy body mass index.Decrease consumption of red meat and most seafood.Increase intake of vegetables, legumes, nuts, and vegetable proteins.Decrease intake of sugar-containing beverages and fructose.Limit alcohol to no more than 1-2 drinks per day and drink wine rather than beer or liquor.Increase intake of low-fat dairy, up to two servings per day.Maintain adequate hydration.

Gout 2011: Food RXVitamin C 500-1500mg QD45% less gout in persons consuming >1500mg QDDirect Association with Uric Acid levels and Vit C intakeDouble Blind RCT showed reductions in uric acid levels with 500mg supplementation

Fructose

present in honey and fruit50% of sugar (sucrose = 1 glucose + 1 fructose molecule)55% of HFCS ( high fructose corn sryup)

Results1 servings a day increased risk 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

Why does fructose affect uric acid. 1.infusion studies showfructoseFructose -1-phosphateADPATPAMPIMPURIC ACID

Fructokinase

Liver CellDecreasing Pi levels remove feedback onAMP Deaminase

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.

Hereditary Fructose IntolerancefructoseFructose -1-phosphateADPATPAMPIMPURIC ACID

Fructokinase

Liver CellDecreasing Pi levels remove feedback onAMP DeaminaseDHA -phosphate

Aldolase B

Management of acute gout

NSAIDs 1st choice Rapid acting (naproxen, indomethacine) preferred

Continued until 48h after absence of inflammation2. Colchicine Alternative, out-dated Time limit: effective between 12-36h of an attack

0.6mg q 1h up to 10 doses until relief of joint Sx or G-I Sx 3. Intraarticular corticosteroid: Effective in monoarticular gout 4. Systemic corticosteroid When NSAIDs are not effective or contraindicated

5. No urate lowering agents (allopurnol)

ColchicineEffective : within 24 hoursAdverse reactions: nausea, vomit, diarrhea,

abdominal pain, BM suppression, myopathy, alopecia Not use

: Combined renal and hepatic disease GFR

Corticosteroid P.O;20-40mg/day for 3-4days, then taper one to 2 weeksIntraarticular injection:

triamcinolone 10-40mg or deaxamethasone 2-10mg with lidocaineIn:

recalcitrant acute gout hepatopathy elderly patients with renal insufficiency

WBC 11000/mm3 (poly 75%), SUA 9.0mg/dl. Urine UA 500mg/daysynovial fluid analysis: WBC 10,000(Poly 70%), GS(-), AFB stain (-)

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 CMechanism: blocks reuptake and increase GFRBioflavonoids: HesperidinDOSE: increase citrus fruits, 500mg Vit C w/bioflavonoids, increase Rosemary

Gout 2011: Food RXEPA & GLASuppress inflammation in animal goutCardiovascular benefitAnti-inflammatory Diet

Dose: 500mg EPA or 3000mg Evening Primrose

Gout 2011: Food RXCherries and Cherry Juice280 g QD lowers plasma urate, increases urinary excretionDecreases CRP and NODouble Blind RCT of Cherry juice: less post-run painDOSE: pound of cherries or equivalent juice

Gout 2011: Food RXQuercetin Inhibits xanthine oxidaseDecreases BP and oxidized LDLonions, apples, berries, grapes, green and black tea, citrus fruits, capers, tomatoes, broccoli, and leafy greensSupplement with 500mg

TurmericEFAsGingerRosemaryNutsGreensTea

Gout 2011: Anti-Inflammatory Diet

Food RX: SummaryCitrusRosemaryCherriesCold-Water Fish, Flax, Walnuts, Leafy GreensOnions, apples, berries, tea, broccoli, tomatoes, grapes.Pineapple

AcupunctureNeedles Vs. Allopurinol + Indomethacin93% effective vs. 80% Greater reductions in serum uric acidFewer adverse effects

IceMost arthritic conditions benefit from heatpatients with gout prefer ice.[38]

Treatment: MEDSNSAID: 1st linePaucity of dataIndomethacin 50mg TID Ibuprofen 600mg TIDNaproxen 500mg BIDAvoid ASAincreases uric acid

Prevention

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SUMMARYThe disease burden of gout remains substantial and may be increasing.As more scientific data on modifiable risk factors and comorbidities of gout become available, integration of these data into gout care strategy may become essential, similar to the current care strategies for hypertension and type 2 diabetes.Recommendations for lifestyle modification to treat or to prevent gout are generally in line with those for the prevention or treatment of other major chronic disorders Weight control, limits on red meat consumption, and daily exercise are important foundations of lifestyle modification recommendations Plant-derived -3 fatty acids or supplements of eicosapentaenoic acid and docosahexanoic acid instead of consuming fish for cardiovascular benefits.

SUMMARYFurther riskbenefit assessments in each specific clinical context would be helpful.Daily consumption of nuts and legumes as recommended by the Harvard Healthy Eating Pyramid (32) may also provide important health benefits without increasing the risk for gout.Similarly, a daily glass of wine may benefit health without imposing an elevated risk for gout, especially in contrast to beer or liquor consumption.These lifestyle modifications are inexpensive and safe and, when combined with drug therapy, may result in better control of gout.

SUMMARYEffective management of gout risk factors (for example, hypertension) and the antihypertensive agents with uricosuric properties (for example, losartan or amlodipine could have a better risk benefit ratio than diuretics for hypertension in hypertensive patients with gout. Similarly, the uricosuric property of fenofibrate may be associated with a favorable risk benefit ratio among patients with gout and the metabolic syndrome.

SUMMARYThe recently elucidated molecular mechanism of renal urate transport has several important implications in conditions that are associated with high urate levels.In particular, the molecular characterization of the URAT1 anion exchanger has provided a specific target of action for well known substances affecting urate levels. Genetic variation in these renal transporters or upstream regulatory factors may explain the genetic tendency to develop 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.

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