In The Name Of GOD DR PARIN HEDAYATI - PowerPoint Presentation

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In The Name Of GOD

DR PARIN HEDAYATI

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Lifestyle Change in Patients with

Hyperuricemia

Subtitle

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The amount of

urate

in the body,

depends

on the balance between dietary intake, synthesis,

and excretion.  Hyperuricemia results from the overproduction of uric acid (10%), underexcretion of uric acid (90%), or often a combination of the two.

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Uric

Acid Metabolism

Uric acid is the final product of 

purine

 metabolism in humans.

Purines are components of nucleosides.Purine nucleosides (adenosine and guanine) are used in the creation of other metabolically important factors as well, such as 

ATP,

the methyl

donor, and NADH; an important cofactor in energy production and antioxidation

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Excess

purine nucleosides are removed from the body by breakdown in the liver and excretion from the kidneys.

The

purines are first converted into the

uric acid

.5

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The levels of uric acid in the blood depend on two factors

The

first is the rate of uric acid synthesis in the liver

.

Since uric acid results from purine degradation, its levels are influenced by both the amount of purines synthesized in the body, as well as the amounts of purines absorbed from the diet .6

Slide7

…The levels of uric acid in the blood depend on two factors

The second is the rate of uric acid excretion from the kidneys. Excretion has the greatest effect on blood uric acid levels, with about 90% of

hyperuricemia

cases attributed to impaired renal excretion

.

Impaired excretion is most often due to abnormalities in the kidney urate transporter (called URAT1) or organic ion transporter (OAT), both of which control the movement of uric acid out of proximal kidney tubules and into urine.

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One of the most intriguing aspects of uric acid is that although it appears to be a "waste product" of purine metabolism, only about 10% of the uric acid that enters a normal human kidney is excreted from the body

.

The

reason for this is likely due to the role or uric acid as one of the most important antioxidants in body fluids, responsible for the neutralization of over 50% of the free radicals in the blood stream

.

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uric acid has a principle role in protecting high-oxygen tissues (like the brain) from damage, and low blood uric acid levels have been associated with the progression or increased risk of several neurological disorders, including Amyotrophic Lateral Sclerosis

, Multiple

sclerosis ,

and

Huntington's

,Parkinson's ,and Alzheimer's diseases .9

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Uric acid is a metabolic "waste product" with poor solubility in body fluids, yet its potential role as a primary antioxidant in body fluids suggests that it should be kept at sufficient levels in the blood

.

Clearly, these diametric properties of uric acid define a range for normal blood uric acid levels

.

Commonly, the upper limit of this range is taken as 8.6 mg/dl in men and 7.1 mg/dl in women, Uric acid levels above this limit are considered as hyperuricemia.

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Hyperuricemia

is a primary risk factor for the development of gout, although it is likely that many

hyperuricemic

individuals will not develop symptoms.

The

risk of a gout attack increases with blood uric acid. 11

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Hyperuricemia

without symptoms (asymptomatic

hyperuricemia

) is also a risk factor for other diseases

.

Although patients with asymptomatic hyperuricemic may never experience the symptoms of a gout attack, ultrasound studies have revealed that up to one-third may have urate deposits and evidence of inflammation in their joints and surrounding soft tissues .

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As local serum uric acid concentrations rise above their limit of solubility, monosodium

urate

can begin to precipitate out of the blood, forming needle-like crystals preferentially in cartilage and fibrous tissues. Here, the crystals may reside for years without causing problems

.

Urate

crystals within tissues have two fates; they can re-dissolve in body fluids and reenter circulation, or may be "shed" from the tissue. Shed monosodium urate crystals can enter nearby joint spaces or bursa provide cushioning between tendons and bones where they are quickly engulfed by immune cells. This activates a localized inflammatory response, leading to the characteristic arthritis of gout

.

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Although

hyperuricemia

is most often associated with gout, elevated blood levels of uric acid have also been associated with other diseases.

Hyperuricemia

and gout are both risk factors

for

urolithiasis

. Both conditions increase the

risk of

forming not only uric acid stones, but also the more common calcium oxalate stones.

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Deposits of monosodium

urate

crystals in kidney tissues can result in kidney damage (nephropathy), either acutely by formation of crystals within the tubules of the kidney, or through a chronic inflammatory response to

urate

deposits in other tissues of the kidney .

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Hyperuricemia

is a risk factor for

cardiovascular diseases

in high risk

groups

It is often seen in patients with hypertension; high blood pressure has long been thought to contribute to elevated blood uric acid, possibly due to reduced blood flow to the kidneys and lower urate excretion .This effect was more pronounced in women and young adults. Lowering of uric acid levels in hyperuricemic, hypertensive adolescents reduced their blood pressure as well

.

Ironically

, the increased risk of cardiovascular diseases associated with hyperuricemia may be due to increases in oxidative stress: xanthine oxidase, the enzyme that synthesizes uric acid, also produces free radicals in the process

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Hyperuricemia

is an integral part of

metabolic syndrome

, and

epidemiological studies have demonstrated that elevated uric acid levels substantially increase metabolic syndrome risk (and vice versa)

.Data from the Multiple Risk Factor Intervention Trial (MRFIT) showed that hyperuricemia was associated with increased risk of type 2 diabetes, and that male patients with gout had a 41% increased risk for the disease.

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The Guideline Revising Committee of Japanese Society of Gout and Nucleic Acid Metabolism

Slide19

Hyperuricemia

is the cause of

urate

depo­sition diseases (such as gouty arthritis and renal damage) and is defined as serum urate levels of more than 7.0 mg/dL. The disease affects

people of both genders and all ages

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Amongst women, the risk of lifestyle

dis­eases

increases with rises in serum

urate

levels,

even if serum urate levels are below 7.0 mg/dL. Testing for underlying diseases and lifestyle guidance are carried out, but uric acid lower­ing

drugs are not indicated.

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Treatment of hyperuricemia

What is most important in the treatment

of

hyperuricemia

is the improvement of

life­style habits that are related to the development of hyperuricemia and which also easily lead to the development of prognosis related complications such as obesity, hypertension,

and

lipid metabolism abnormalities.

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Drug therapy is indicated in cases where

gouty

arthritis occurs repeatedly or gouty

to­phus

is diagnosed, and maintenance of serum

urate levels of 6.0mg/dL or lower is desirable.

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Drug therapy for asymptomatic

hyperuri­cemia

is implemented when serum

urate

levels are 8.0 mg/dL or higher as a general indicator, but should be undertaken with caution.

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There is scant evidence regarding treatment

for

asymptomatic

hyperuricemia

and consensus

is also insufficient. First of all, patients undergo lifestyle guidance, and then if serum urate levels remain high, drug therapy is considered

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In cases of

hyperuricemia

/gout

complicated by

concomitant renal damage or urinary

lith­iasis, allopurinol is administered to lower uric acid levels.25

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As renal function declines, it is necessary

to

reduce the allopurinol dosage used

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Treatment

of

hyperuricemia

using

allopu­rinol

is helpful in maintaining renal function in CKD patients. 27

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Losartan

potassium is helpful in

controlling hypertension/

hyperuricemia

in renal transplant patients undergoing cyclosporine therapy.28

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Hyperphosphatemia

treatment with

seve­lamer

hydrochloride—used with maintenance

hemodialysis patients—also prevents/reduces hyperuricemia29

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Treatment

of

hyperuricemia

/gout with

concomitant urinary

lithiasisGuidance concerning water intake aims to ensure that patients drink 2,000 mL/day of water or more.

Allopurinol

is the drug of first choice for

the treatment of hyperuricemia complicated

by

concomitant urinary

lithiasis

.

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Because

uricosuric

drugs stimulate the

for­mation

of

urate stones, as a general rule they are not used in the treatment of hyperuricemia cases complicated by concomitant urinary lithiasis.

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Using mainly citric acid formulations, the

aim

of urine

alkalinization

is to maintain urine

ph between 6.0 and 7.0. Diet therapy, such as purine intake limitations, also needs to be implemented concurrently.

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Allopurinol and urine

alkalinization

drugs

are

effective in preventing the reoccurrence of

calcium oxalate stones associated with hyper­uricosuria. 33

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Treatment of hyperuricemia

/gout with

concomitant hypertension

For

hyperuricemia

patients with hyperten­sion complications, first of all lifestyle guid­ance is carried out with the aim of “avoiding risks to organs overall” by simultaneously improving lifestyle habits related to the

onset

of

hyperuricemia.

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Drug therapy prioritizes blood pressure management, and it is desirable to give priority as far as possible to the use of antihyperten­sive drugs that do not negatively impact uric acid metabolism.

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Even when lifestyle guidance and

anti­ hypertensive

drugs preferable for uric acid

metabolism

are used, commencing

admin­istration of uric acid lowering drugs is con­sidered in cases where serum urate levels are 8.0mg/dL

or higher. It is desirable to

main­tain

serum urate levels during treatment to

6.0

mg/

dL

or lower.

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Treatment of hyperuricemia

/gout with

concomitant hyperlipidemia

In addition to treating

hyperuricemia

, ther­apy also aims to treat hyperlipidemia—which is a factor in arteriosclerotic disease—and alleviate the arteriosclerotic disease.

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A diagnosis

of hyperlipidemia

is

made when

th

patient has LDL hypercho­ lesterolemia (LDL cholesterol≧140mg/dL),

HDL

hypocholesterolaemia

(HDLcholesterol

<

40mg/

dL

), or hypertriglyceridemia (

triglyc­erides≧150mg/

dL

)

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Treatment of hyperlipidemia

complicatin

hyperuricemia

/gout

is carried out in accor­dance with the Arteriosclerotic Disease Pre­vention Guidelines

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Some drugs used to treat hyperlipidemia

also

have an effect on serum

urate

levels, and

so these are considered. In particular, fenofibrate is an effective medicinal agent in cases complicated by hypertriglyceridemia and hyperuricemia, especially hyperuricemia causing a

decreased

uricosuric

effect.

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Lifestyle guidance for patients with

hyperuricemia

/gout

Hyperuricemia

and gout are

representa­tive lifestyle diseases. Lifestyle guidance is a non drug therapy aimed at correcting lifestyle

habits

and plays an important role in

treat­ment regardless of whether or not drug therapy is

implemented.

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Lifestyle guidance for

hyperuricemia

/gout

patients

centers on

diet therapy, limitation of alcohol intake, and encouragement of exercise, and reducing obesity is expected to have the effect of lowering serum urate

levels.

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In diet therapy, patients are advised about

correct

energy intake, limitations on excessive

purine

and fructose intake, and drinking

suf­ficient water. Physical activity can be encour­aged to improve various pathological condi­tions of metabolic syndrome.

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Exercise daily and reduce weight

Increased

adiposity is associated with higher uric acid levels and an increased future risk of gout, whereas weight loss is associated with lower uric acid levels and a decreased risk of

gout.

Many

patients with gout are overweight or obese, and weight reduction through gradual caloric restriction and exercise can substantially help lower uric acid levels and the risk of gout attacks, in addition to its beneficial effects on associated cardiovascular-metabolic commodities and sequelae.

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Limit red meat intake 

It

is associated with higher uric acid levels

.

 The mechanism behind this increased risk may be multifactorial. The

urate-raising effect of artificial short-term loading of purified purine has been well demonstrated Red meat is the main source of saturated fats, which are positively associated with insulin resistance, which reduces renal excretion of urate.

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Tailor seafood intake to the individual

Seafood

intake has been linked to higher serum uric acid levels and increased future risk of gout, which is likely due to its high purine

contents.

Increased

intake of oily fish, other fish, and shellfish was associated with an increased risk of gout. However, given the apparent cardiovascular benefits from fish products. particularly oily fish that are rich in omega-3 fatty acids, it would be difficult to justify a recommendation to avoid all fish intake considering only the risk of gouty flares.

Oily

fish

 may be allowed while implementing other lifestyle measures, particularly among gouty patients with cardiovascular comorbidities.

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…Tailor seafood intake to the individual

A

mong

patients with gout or

hyperuricemia

, the use of plant-derived omega-3 fatty acids or supplements of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) could be considered in the place of fish consumption. Diets enriched in both linolenic acid and EPA significantly suppress urate

crystal induced inflammation in a rat

model

 raising an intriguing potential protective role of these fatty acids against gout flares.

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Drink skim milk or consume other low-fat dairy products

 

Up

to two servings daily

.

Low-fat dairy consumption has been inversely associated with serum uric acid levels .Low-fat dairy foods have been linked to a lower incidence of CHD, premenopausal breast cancer, colon cancer, and type 2 diabetes.

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Consume vegetable protein, nuts, legumes, and purine-rich vegetables

They

do not increase the risk of

gout

 and these food items (especially, nuts and legumes) are excellent sources of protein, fiber, vitamins, and minerals.

Individuals who consumed vegetable protein in the highest quintile of intake actually had a 27% lower risk of gout compared with the lowest quintile.

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Nut consumption is associated with several important health benefits including a lower incidence of CHD, sudden cardiac deaths, gallstones, and type 2 diabetes. Legumes or dietary patterns with increased legume consumption have been linked to a lower incidence of coronary heart disease, stroke, certain types of

cancer,and

type 2 diabetes.

 The recent healthy eating pyramid recommends 1–3 times daily consumption of nuts and legumes  which appears readily applicable among patients with gout or

hyperuricemia

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Reduce alcoholic beverages

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Limit sugar-sweetened soft-drinks and beverages

Fructose

contained in these beverages increases serum uric acid levels

.

Fructose

intake has been linked to increased insulin resistance, a positive energy balance, weight gain, obesity, type 2 diabetes, an increased risk of certain cancers,and symptomatic gallstone disease

.

 

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Allow coffee drinking if already drinking coffee

Both

regular and decaffeinated coffee drinking have been associated with lower uric acid levels

Coffee

drinking has been linked to a lower risk of type 2 diabetes,  kidney stones,symptomatic gallstone disease, and Parkinson's disease

.

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Caffeine tends to promote calcium excretion in urine, and drinking a lot of coffee, about four or more cups per day, may increase the risk of fractures among women.

 Caffeine, being a xanthine likely exerts a protective effect against gout similar to allopurinol through xanthine oxidase

inhibition.This

means that intermittent use of coffee or acute introduction of a large amount coffee may trigger gout attacks as allopurinol introduction does.

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Consider taking vitamin C supplements

It

has been found to reduce serum uric acid levels in clinical

trials

 and has recently been linked to a reduced future risk of gout

. Data suggest that total vitamin C intake of 500 mg/day or more is associated with a reduced risk.Potential cardiovascular benefit of vitamin

C

 may also be relevant among gout patients, because of their increased risk of cardiovascular morbidity and mortality

. 

Given

the general safety profile associated with vitamin C intake, particularly within the generally consumed ranges (e.g. tolerable upper intake level of vitamin C <2000 mg in

adults),

 vitamin C may provide a useful option in the prevention of gout.

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Vitamin C

Vitamin C is an essential water-soluble antioxidant vitamin in humans, which has been shown in laboratory tests to exert a uric acid-lowering effect by inhibiting the enzyme xanthine oxidase

.

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Cherries

Cherries are a traditional gout treatment rich in polyphenol antioxidants

,and

a small set of clinical cases in the 1950's documented decreased duration and severity of gout attacks in three people on cherry-supplemented diets

.

Two more recent investigations have demonstrated a potential role of cherries in the management of gout, although they present conflicting mechanisms for this action. After a single dose of 280 g cherries, the blood urate levels in 10 healthy women dropped by 14% after 5 hrs, while urinary urate levels increased

.

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Fiber

An analysis of fiber intake data in 9,384 adults without cancer, diabetes or heart disease from the National Health and Nutrition Examination Survey (NHANES) 1999-2004 revealed a significant association between higher fiber intake and lower

hyperuricemia

risk.

While these mechanisms for this reduction is unknown, dietary fiber may inhibit purine or adenine absorption in the digestive system

.Fiber has also been shown to reduce other independent risk factors for gout, including hypertension and high cholesterol

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Folate

A small case-controlled study of 92 gout patients and 92 gout-free controls demonstrated a statistically significant reduction in the risk of gout amongst persons who consumed over 51.5 mcg/day of folate from food sources

No

significant effects on gout risk were observed for vitamins A, E, or the other B vitamins in this study.

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Chinese Herbs

Several Chinese medicinal plants have been tested for xanthine oxidase inhibitory activity.

The

most active was the methanol extract of Chinese cinnamon (

Cinnamomum

cassia), followed by Chrysanthemum indicum and Lycopus europaeus. Among water extracts, the strongest inhibition was observed with Polygonum

cuspidatum

, which is an excellent source of the polyphenol 

resveratrol .

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Flavonoids

Flavonoids may lower blood uric acid through their ability to inhibit the enzyme xanthine

oxaidase

; olive leaf constituents,

have

all shown this ability in laboratory experiments.62

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Drugs

Slide64

urate

-lowering therapy (ULT) should be considered in patients with 1 or more tophi, ≥2 attacks per year, chronic kidney disease (CKD; stage 2 or worse), or a history of

urolithiasis

.

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initiating ULT with either

allopurinol;

probenecid

is recommended as an alternative first-line agent when either allopurinol

is

contraindicated, or when a patient has demonstrated intolerance toallopurinol. ULT can be started during an acute gout attack; the serum urate level should be monitored every 2-5 weeks during ULT titration and every 6 months after the target serum level (<6 mg/dL) has been reached.

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Allopurinol Dosing

Starting

allopurinol dose should not exceed 100 mg/day, and patients with CKD of stage 4 or higher should be started at 50 mg/day. Dosages should be titrated up every 2-5 weeks to achieve target serum uric acid and can go above 300 mg/day as long as the patient is educated and monitored for adverse events.

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Uricosuric Therapy

When using a

uricosuric

as ULT monotherapy, the ACR TFP recommends

probenecid

. First-line use of probenecid is contraindicated in patients with a history of urolithiasis

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Thank you

Caption

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