SKENARIO C blok 8; 2012

OBESITAS & GOUT

ARTHRITIS
15 Juni 2012
dr.Liniyanti D.Oswari,MSc

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

allopurinol

probeneci
d
Hyperuricemia

colchicine

Crystals in tophi

Uric acid in tophi

1963
1961 McCarty

1950 Talbott et al
1848 Garrod

Gout

1814
1798 Wollastone

1679 Van Leeuwenhoek

A.D 13th C Vielehardouin

B.C 400 Hippocrates

Urate crystal

History of Gout

Who, What, Where, When, Why,

How?
1-2%
Uric acid crystal deposition
1st MTP joint
Polyarticular with increasing age
Renal involvement

Middle-Age
Genetics & Lifestyle
Purine metabolism, overproduction
(10%) or underexcretion (90%)

Inflammation to urate crystas

Urate crystalization

Hyperuricemia

Genetic factor
Environments

Presentation/Diagnosis
Aspiration of Synovial Fluid
needle-shaped monosodium urate
crystals with negative birefringence.

Diagnosis
24 hour uric acid level
>800 mg = overproduction
<600 mg = underexcretion
Normal uric acid in the blood:
( 2.5 6 mg/dl)

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(
)

The Old Gout

A Musculoskeletal disease
Low-Purine Diet
Avoid Vitamin C
High Dose Colchicine
Avoid HCT ( Hidrochlorthiazide):
diuretic

Gout 2011
Profound 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% without
Framingham Study - independent 60%
increased risk of coronary artery disease in
men with gout, after controlling for other
factors.[5]

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-cause
mortality
38% increased risk of death from
cardiovascular disease.[6]

Gout 2011: HPFS

independent of
age
body mass index
smoking,
family history
diabetes
hyperlipidemia
hypertension

Mechanism?

Elevated Uric Acid levels

Activate RAS
Inhibit Nitric Oxide Synthase
Increase Blood Pressure [7]

Gouty Tophi
Incidence has decreased over last few decades
Seen in 25-50% of untreated patients (after 1020yrs)
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

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

Management of
Chronic tophaceus arthritis
Advise 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 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 Gout RA

Few reports of both coexisting in literature
RF preferentially binds MSU coated with IgG and
inhibited neutrophil chemiluminescence (RF may block
interaction of crystal bound IgG and Fc recpt)

TheAmericanDiet/fastfood&itsconsequences

Obesity, Metabolic
Syndrome
and Gout

~ 1/3 of Americans meet

criteria for obesity, ~2/3
overweight
Obesity and Increased Body Mass
alone associated with
Hyperuricemia
Insulin Resistance Compounds the
Problem

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

Renal Effects of Metabolic

Syndrome Pertinent to
Gout
Hyperinsuline

mia Stimulates
Increased
Renal Sodium
and
Urate
Reabsorption
A Mild Defect
in Renal
Ammonium
Excretion
Associated
with IR
Promotes Acid
Milieu for Uric
Acid
Urolithiasis

Urate
pH

relative risk of urolithiasis

in men with diagnosis of gout:
= 2.12
Kramer et al . Kidney Int 2003

RENAL TRANSPORT OF URATE

1.
2.
3.
4.
.

Renal urate transport is typically

explained by a 4-component model:
glomerular filtration,
a near-complete reabsorption of filtered
urate,
subsequent secretion, and
postsecretory 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 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

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]

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]

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

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)

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 uratelowering effect.[17]
The mechanism related to the milk
proteins casein and lactalbumin. [18]

Gout 2011: Lifestyle RX

Alkalanize your Urine
direct correlation between urine pH
and uric acid excretion, despite
higher purine content of acidic diet.
[21]

REVIEW
Prevention Prescription

Encourage 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 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

Fructose
present in honey and fruit
50% of sugar (sucrose = 1 glucose +
1 fructose molecule)
55% of HFCS ( high fructose corn
sryup)

Results
1 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 show
Decreasing Pi
levels remove
feedback on

ATP

fructose
Fructokinase
Fructose -1-

ADP

AMP

phosphate

AMP
Deaminase

IMP
URIC ACID
Liver Cell

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 Intolerance

Decreasing Pi
levels remove
feedback on

ATP

fructose
Fructokinase
Fructose -1phosphate

ADP

AMP

AMP
Deaminase

IMP

Aldolase B
DHA phosphate

URIC ACID

Liver Cell

Management of acute gout

1.

NSAIDs
1st choice
Rapid acting (naproxen, indomethacine) preferred
Continued until 48h after absence of inflammation

2. 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)

Colchicine

Effective : within 24 hours

Adverse reactions: nausea, vomit, diarrhea,
abdominal pain, BM suppression, myopathy,
alopecia
Not use
: Combined renal and hepatic disease
GFR <10 mL/min
Extrahepatic biliary obstruction
Neutropenia

Corticosteroid
P.O;20-40mg/day for 34days, then taper one to
2 weeks
Intraarticular injection:
triamcinolone 10-40mg or
deaxamethasone 2-10mg
with lidocaine
In:
recalcitrant acute gout
hepatopathy
elderly patients with
renal insufficiency

WBC 11000/mm3 (poly 75%),

SUA 9.0mg/dl.
Urine UA 500mg/day
synovial fluid analysis:
WBC 10,000(Poly 70%), GS(-), AFB stain (-)

Correction of hyperuricemia

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)

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

Gout 2011: Food RX

EPA & GLA
Suppress inflammation in animal
gout
Cardiovascular benefit
Anti-inflammatory Diet
Dose: 500mg EPA or 3000mg
Evening Primrose

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

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

Gout 2011: AntiInflammatory Diet

Turmeric
EFAs
Ginger
Rosemary
Nuts
Greens
Tea

Food RX: Summary

Citrus
Rosemary
Cherries
Cold-Water Fish, Flax, Walnuts, Leafy
Greens
Onions, apples, berries, tea, broccoli,
tomatoes, grapes.
Pineapple

Acupuncture
Needles Vs. Allopurinol +
Indomethacin
93% effective vs. 80%
Greater reductions in serum uric acid
Fewer adverse effects

Ice
Most arthritic conditions benefit from
heat
patients with gout prefer ice.[38]

Treatment: MEDS

NSAID: 1st line

Paucity of data
Indomethacin 50mg TID
Ibuprofen 600mg TID
Naproxen 500mg BID
Avoid ASAincreases uric acid

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

SUMMARY
The 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.

SUMMARY
Further 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

SUMMARY
Effective 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.

SUMMARY
The 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.