23. Pleno C, Gout Arthritis

8/13/2019 23. Pleno C, Gout Arthritis

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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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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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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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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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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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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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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.

23. Pleno C, Gout Arthritis

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