Accepted Manuscript

Update on Importance of Diet in Gout

Randall N. Beyl, Jr., MD, Dr. Laura Hughes, MD, MSPH, Dr. Sarah Morgan, MD, MS,
RD, FADA, FACP, CCD

PII: S0002-9343(16)30723-9
DOI: 10.1016/j.amjmed.2016.06.040
Reference: AJM 13610

To appear in: The American Journal of Medicine

Received Date: 18 April 2016

Revised Date: 13 June 2016
Accepted Date: 20 June 2016

Please cite this article as: Beyl RN Jr., Hughes L, Morgan S, Update on Importance of Diet in Gout, The
American Journal of Medicine (2016), doi: 10.1016/j.amjmed.2016.06.040.

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Randall N. Beyl Jr. MD

Review Article - Update on Importance of Diet in Gout

6/7/16

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Running Head: Update on Diet in Gout

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Keywords: Gout, Hyperuricemia, Metabolic syndrome, Dietary modification

Funding Sources – none

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Conflicts of Interest:

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Randall N. Beyl Jr. MD – none
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Dr. Laura Hughes MD, MSPH – none
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Dr. Sarah Morgan MD, MS, RD, FADA, FACP, CCD – none
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All Authors had access to and input in writing this manuscript. There were significant

contributions from each author in both the initial submitted version and the revision.
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Abstract

Gout is an inflammatory arthritis caused by deposition of monosodium urate crystals

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within synovial joints. Although it is most well-known for its arthritis, gout has an intimate

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relationship with many other cardiovascular and metabolic conditions. Current

recommendations support aggressive medical therapy to treat gout while dietary counseling

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has become less emphasized. This article argues for the absolute importance of dietary

counseling in gout and proves why this counseling may impact the long term well-being of a

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patient with gout.

Introduction
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Gout is an inflammatory arthritis caused by deposition of monosodium urate crystals

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within synovial joints as a result of elevated serum uric acid (SUA) levels (1). The classic
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symptoms described are recurrent “attacks” of severe pain, swelling, redness, and warmth in

one or a few joints; in some cases it can become chronic and polyarticular (2).
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In the United States the estimated prevalence of gout is 8 million individuals, which is an
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increase of approximately 1.2% over the last 20 years. (3-5) . When comparing two incidence
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cohorts from 1977-1978 and 1995-1996 in Minnesota, the incidence of primary gout was shown

to have increased from 42 to 62.3 per 100,000 (p=0.1) over the 20 year period (6). Other

studies have shown this trend to be worldwide. In New Zealand, where gout is especially

common, the prevalence is estimated at 2.69% and rose as high as 25% in elderly men (7).
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Because of new pharmacotheraputics targeting hyperuricemia, healthcare providers

often start medical therapy sooner and give dietary counseling less emphasis (8). With this

approach comes the inherent risk of drug toxicity, interactions, and polypharmacy in patients

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who often have multiple comorbidities. However, if the approach to gout treatment included

dietary therapy and lifestyle modification, it could lower uric acid levels as well as potentially

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mitigate the long term consequences of the metabolic syndrome which often coexist with gout

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(9, 10).

Gout and Metabolic Syndrome

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It has been well described that gout affects those who tend to be overindulgent; hence

the name “The Disease of Kings.” Although gout is not formally included in the metabolic
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syndrome definition, they share common conditions such as obesity, dyslipidemia, insulin

resistance, and hypertension. The prevalence of metabolic syndrome is 62.8% in patients with
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gout compared with 25.4% in non-gout patients (11). While 3.4% of people with weight below
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the 20th percentile are hyperuricemic, 11.4% of those above the 80th percentile have elevated
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serum urate (10). Hypertension was shown to be directly related to serum urate levels in mice

treated with uricase inhibitors; their blood pressure rose proportionally to their uric acid (12).
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Several recent small clinical trials have demonstrated that SUA-lowering agents such as
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allopurinol and probenecid can reduce blood pressure in adolescents (13) (14). Hyperlipidemia

has been found in 25-60% of gout patients while hypertriglyceridemia was seen in 53.7% of

gout patients versus 35.3% of non-gout patients (9). Insulin resistance has been found in 48.4-

76% of patients with gout, with the observed relative risk for incident type 2 diabetes mellitus
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in gout patients was 1.34 (95% Confidence Interval [CI] 1.09-1.64) compared to those without

gout (9, 10, 15). The prevalence of coronary heart disease is estimated at 25% of gout patients

in the UK and 18% in the US (9) . When compared to men without gout or coronary heart

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disease, men with gout had a relative risk 1.28 (95% CI 1.15-1.41) for total mortality and 1.55

(95% CI 1.24-1.93) for fatal coronary heart disease (16). In the Multiple Risk Factor Intervention

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Trial, MRFIT, gout patients had an increased risk of myocardial infarction of 26% and a 35% risk

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of coronary heart disease (9). Although gout is sometimes thought of as just an inflammatory

arthritis, it is not difficult to illustrate the relationship with other cardiovascular and metabolic

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conditions and long term poor outcomes.
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Dietary measures likely play a greater role than urate lowering therapy in the long term

management of metabolic syndrome commonly associated with gout. A self-reported incident

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gout trial found that men with a body mass index (BMI) over 27.5 were 16 times more likely to
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report gout flares than men with a BMI less than 20 (17). Compared to men with a BMI of 21-
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22.9, the relative risk of gout in a BMI of 25-29.9 was 1.95 (95% CI 1.44-2.65), BMI of 30-34.9

was 2.33 (1.62-3.36), and a BMI of at least 35 was 2.97 (95% CI 1.73-5.1) (18). In a small cohort
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of obese men with gout who were started on a moderate calorie and carbohydrate restriction
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diet for 16 weeks, there was an average weight loss of 5.4kg, an average decrease in monthly
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gout flares from 2.1 to 0.7 (p=0.002) and a decrease in serum urate of 0.57mg/dL to 0.47mg/dL

(p=0.001). Of the twelve men who initially had a high serum urate, seven became normalized

(19). In the MRFIT trial when compared with no weight change, the odds ratio for reaching

normal urate with a loss of 1 to 4.9 kg was 1.43 (95% CI 1.33-1.54) , 5 to 9.9kg was 2.17 (95% CI

1.95-2.4), and at least 10kg was 3.9 (95% CI 3.31-4.61). The decrease in serum urate levels for
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each bracket of weight loss was -0.12, -0.31, and -0.62 mg/dL respectively (20). Therefore,

obesity is associated with gouty flares and hyperuricemia, and weight loss is one of the most

important modifiable risk factors for gout.

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Single food / supplements effects on hyperuricemia and gout

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The National Health and Nutrition Examination Survey (NHANES) studies were designed to

assess the health and nutritional status of citizens in the United States. Questionnaires,

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examinations, vital signs, and laboratory data were collected over time in order to assess risk

factors for certain diseases. Much of the data in diet and gout comes from these studies. In

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each of the following foods that NHANES data is used there will description of certain

associations found, but given the design of the studies and the large number of variables there
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must be caution in assuming true causation.

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1. Alcohol
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The risk of hyperuricemia and gout differ both with amount and type of alcohol

ingested. NHANES data from men shows that when compared to no alcohol ingestion,
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beer was found to increase serum urate 0.46mg/dL per drink per day (95% CI 0.32-0.6)
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and liquor 0.29mg/dL per drink per day (0.14-0.45) (p<0.001). Wine was not found to be
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associated with increased urate (p<0.001). BMI was very similar among beer, liquor, and

wine drinkers in this study. In two different multivariate analyses, after adjusting for

BMI, the affect from each type of alcohol on serum urate remained(21). Cross sectional

data shows similar trends in women; each serving of beer per week increased serum

urate by 0.03mg/dL (22). A prospective cohort study of men followed for over 12 years
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showed that compared to non-drinkers, the relative risk of incident gout in drinkers was

1.32 (0.99-1.75) for 10 to 14.9 g/day, 1.49 (1.14-1.94) for 15 to 29.9g/day, 1.96 (0.48-

2.6) for 30-49.9 g/day, and 2.53 (1.73-3.7) for at least 50 g/day. The relative risk was

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1.49 (1.32-1.7) per 12-oz beer per day, 1.15 (1.04-1.28) per shot of liquor per day, and

found to be unassociated with wine intake 1.04 (0.88-1.22) (23). There have been many

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proposed mechanisms to explain how alcohol affects urate. An early study proposed

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that this was from increased ATP consumption causing eventual increased uric acid

production (24). Serum lactate was also recorded here and found to be elevated, which

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although since unproven, was postulated to decrease uric acid excretion (24) (25).
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Others have proposed that increased purine loads in beer cause increased uric acid

production (26). In a study of alcoholic versus non-alcoholic beer, both were found to
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increase serum urate levels, 6.5% vs 4.4% respectively, arguing that the ingestion of the
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purine load alone can increase uric acid levels (27).

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2. Purine-Rich Foods

Purine containing foods (such as meats, organ meat, seafood, legumes, yeast,
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mushrooms, and gravies) have been the target of many early gout diets based mainly on
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the concept that the biochemical degradation end product of purines is urate. More
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recent studies have found that this is not necessarily true. NHANES data shows that the

age-adjusted differences in serum urate between the lowest and highest intake of meat

was 0.48 mg/dL (0.34-0.61, p< 0.001) and 0.16 mg/dL for seafood (0.06-0.27, p=0.005).

Total protein intake was not found to be related to increasing urate levels (28). In a

similar prospective study, the relative risk for gout in men with the highest meat intake
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compared to the lowest was 1.41 (95% CI 1.07-1.8), while seafood was 1.51 (1.17-1.95).

Each additional serving of meat per day increased the risk of gout by 21% while each

additional weekly seafood serving increased risk by 7%. The intake of dried beans and

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greens is not associated with gouty flares, as shown by a relative risk of 0.73 (0.56-0.96)

(29).

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3. High Fructose Corn Syrup (HFCS) Sweetened Soft Drinks

Fructose is the only known carbohydrate to increase urate. Fructose and sugar intake

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also predispose to insulin resistance and metabolic syndrome, which further increase
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the risk of hyperuricemia (3). NHANES data shows a correlation between increasing

HFCS sweetened soft drink intake and serum urate levels. Compared with none, soft
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drink intake of < 0.5, 0.5-0.9, 1-3.9, and at least 4 servings per day lead to serum urate
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increases of 0.08, 0.15, 0.33, and 0.42 mg/dL (0.11-0.73, p< 0.001), and relative risks of
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gout of 1.01, 1.34, 1.51, and 1.82 respectively. This correlation was not found to be

significant with diet soft drinks. BMI was similar between the sugar sweetened and diet
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soft drink groups. Elevated BMI did not seem to be the cause of increased serum urate

in the sweetened soft drink group because serum urate was elevated similarly in
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individuals with both high and low BMI(30). In a prospective cohort of women similar
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findings were reported. The relative risk of gout for 1 serving of HFCS sweetened soft

drink per day was 1.74 (1.19-2.55) and for at least 2 servings per day was 2.39 (1.34-

4.26, p<0.001), while diet soda was not found to be correlated to risk of gout (31).
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4. Low-fat Dairy Intake

NHANES data shows that those who consumed at least 1 serving of milk a day had a

lower serum urate with a difference of -0.25mg/dL than those who did not (-0.4 to -

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0.09, p< 0.001). One serving of yogurt every other day had a difference of -0.26 (-0.41

to -0.12, p<0.001) compared with none (28). The incidence of gout seems to be

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inversely related to the intake of dairy products. The relative risk in men who took in the

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highest quintile of dairy compared to the lowest quintile was 0.56 (0.42-0.74, p< 0.001)

(28). A randomized control trial showed that each type of skim milk studied decreased

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serum uric acid by about 10% (p<0.001) (32). Another randomized control proof of
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concept trial compared lactose powder control, skim milk powder control, and skim milk

enriched with a whey protein, glycomacropeptide (GMP), and a fat extract, G600, that
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are naturally found in milk. GMP and G600 were hypothesized to be the active
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components of milk that decrease urate levels. There were significantly fewer gout
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flares over 3 months in the GMP / G600 skim milk group than the lactose powder group;

interestingly there was no difference between the lactose and skim milk powder control
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groups suggesting these supplemental compounds may actually reduce gout flares (33).

The presumed mechanism behind decreased urate levels is the uricosuric effect of the
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protein in dairy products (3) .

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5. Coffee / Tea

Coffee may affect serum urate in many ways, but few have been proven. NHANES data

shows that serum urate seemed to decrease with increasing levels of coffee intake.
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Compared with no coffee intake, 4-5 cups and at least 6 cups per day resulted in

reductions of urate of 0.26 mg/dL (0.11-0.41) and 0.43 mg/dL (0.23-0.65, p<0.001)

respectively. BMI was similar in all levels of coffee consumption. After adjusting for

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many variables, including BMI, higher levels of coffee intake still lead to lower SUA

levels. There was a similar inverse relationship between decaffeinated coffee and urate.

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Total caffeine levels were not associated with urate levels suggesting that something

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besides caffeine in coffee is driving this relationship. The odds ratio for hyperuricemia in

those who took in at least 6 cups of coffee a day compared with none was 0.57 (95% CI

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0.35-0.94, p=0.001). Increasing coffee intake decreased the relative risk for gout in a
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prospective trial. Relative risk for 0, < 1, 1-3, 4-5 and at least 6 cups of coffee daily were

1, 0.97, 0.92, 0.6 (0.41-0.87) and 0.41 respectively (95% CI 0.46-1.17, p=0.002). Again
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total caffeine consumption did not affect gout risk (34). Tea has not been shown to
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affect serum urate (35).

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6. Vitamin C
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A randomized control trial supplemented the intervention arm with 500mg/day Vitamin

C for 2 months. At the completion of the study the Vitamin C group had reduced urate
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with a mean change of -0.5mg/dL (-0.6 to -0.3) where there was no change in the
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control group (36). Later a prospective trial found that when compared to men with

Vitamin C intake less than 250mg/dL , men with intake of 500-999 mg/dL, 1,000-1499

mg/dL, and at least 1500 mg/dL had a relative risk of gout of 0.83 (95% CI 0.71-0.97),

0.66 (0.52-0.86), and 0.55 respectively (95% CI 0.38-0.80, p<0.001) (37). An

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observational study supported this by showing an inverse relationship between Vitamin

C dose and serum urate plateauing at 500mg/d (38). A recent meta-analysis of the 13

known RCT’s studying the effects of Vitamin C on serum urate showed that even though

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these studies were very heterogenic in design, there was a significant decrease in urate

with Vitamin C supplementation. The combined effect was reduction of -0.35 mg/dL (-

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0.66 to -0.03, p = 0.032) (39). In-vitro and animal studies show that Vitamin C has

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uricosuric effects, decreases urate production, and lowers serum urate levels (40).

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7. Cherry / Cherry Extract
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Small human and animal studies suggest that cherry extract can decrease serum urate.

A recent case-crossover observational study showed that patients that ingested cherries
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over a two day hazard period had 35% lower risk of gout flares than those not taking
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cherry products. There was also an inverse relationship between cherry intake and risk
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for flare found up to three servings (12 whole raw or ½ cup unsweetened canned per

serving) in two days (41). Although this data may suggest a benefit with cherry intake,
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there is a paucity of data needed to make this a strong recommendation to patients.

Cherry use remains an area of potential interest in future studies.

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Diet therapy for gout

Past guidelines recommended a rigid avoidance of purine rich foods. Challenges existed

with this approach including limited food choices and heightened long term metabolic risk with
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increased carbohydrate intake. Our proposed dietary strategy (figure 1) places less emphasis on

high purine avoidance while supporting choices that benefit the entire metabolic syndrome.

Clinicians should emphasize strategies that help increase insulin sensitivity, decrease

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triglycerides, improve blood pressure, and lower the risk for coronary heart disease (9).

Several specific diet plans have been well documented with the above approach in

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mind. In MRFIT compared to no weight change, the odds ratio of achieving normal urate for

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weight loss of 1-4.9kg was 1.43 (1.33-1.54), for 5-9.9kg was 2.17 (1.95-2.4), and for at least 10kg

was 3.9 (3.31-4.61) (p<0.001). The associated decrease in serum urate was -0.12, -0.31, and -

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0.62 mg/dL respectively suggesting weight loss alone can improve urate levels (20). In the
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Dietary Approaches to Stop Hypertension, DASH, trial patients were randomized to one of three

diets: control, healthy choice weight loss, and the DASH diet. Compared to the control group,
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the DASH diet resulted in increased HDL with decreased triglycerides, systolic and diastolic
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blood pressures, and weight while the healthy choice group only reduced triglycerides, systolic
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blood pressure and weight. It appeared that the addition of fresh fruits and vegetables

improved certain components of metabolic syndrome in addition to weight loss (42). The
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ATTICA study, a trial in the Grecian Province of Attica, investigated benefits of the
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Mediterranean diet in non-gout patients. Those with better self-reported compliance had lower
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serum uric acid levels. Serum urate positively correlated with meat intake, sugar sweetened

soft drinks, and legumes while urate was inversely related to fruit and dairy consumption.

Adherence was inversely related to serum urate and those with the highest level of compliance

had a 70% lower chance of hyperuricemia than those with the lowest compliance. Weight

change according to compliance was not specifically assessed, nor was the effect of weight
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change on serum urate levels. Thus, weight loss could be an explanation for the improved

serum urate levels in the ATTICA study. (43).

General recommendations and conclusion

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Although the current teaching is that health care professionals should concentrate on

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urate lowering therapy, diet remains a very important part of gout management. More

importantly than improving the arthritis associated with gout, diet gives the practitioner the

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opportunity to impact patients’ risk for morbidity and mortality from consequences of

metabolic syndrome.

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Strong evidence supports weight loss through diet as a foundation of lifestyle changes

needed in gout patients. Liberal intake of plant proteins, nuts, vegetables, legumes, whole
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grains, lower sugar fruits, and plant oils is supported while up to two servings daily of low fat
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dairy products is recommended. Although fish intake can increase serum urate, there may be
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greater overall cardiovascular benefit from the addition of moderate amounts of cold water,

oily fish such as tuna, salmon, and trout which are high in omega-3 fatty acids(9). Eggs and
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poultry are lower risk protein sources when used in moderation. One or less servings of red

meat or shellfish per week may be recommended. Avoidance of fructose sweetened food, beer,
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liquor, and starchy carbohydrates is highly recommended. Wine in moderation is acceptable.

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Up to six cups of coffee daily has been shown beneficial but warn that new initiation of coffee

may exacerbate gout flares (9). Supplementation with Vitamin C may be useful, but a dosing

range and long term safety recommendations have not been made. Cherry products may be

beneficial but better data is needed prior to making this a recommendation to patients. During
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an acute flare it is recommended to increase water intake to at least 8-16 cups per day and

avoid alcohol or meat.

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Figure 1 - General Dietary Recommendations for Gout Patients

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Diet Goals for Flares Long Term Diet Principles

• 8-16 cups of water a day • Weight loss and daily exercise

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• No Alcohol • Increase plant protein, nuts,
• Meat < 4-6oz / day fruit, whole grains

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• Protein from • 1-2 servings low fat dairy daily
• Low fat dairy • Decrease / eliminate beer,
• Tofu liquor and HFCS sweetend

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drinks
• Eggs
• Consider Vitamin C 500mg/day
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• Nut Butters
• If drinking coffee, continue up
to 6 cups daily
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Figure 2 – Gout Inverse Food Pyramid

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Plenty
Most meals: Whole grains, plant protein, fresh vegetables
2-3 servings a day: fresh fruits (less sweet when possible)

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1-3 servings a day: legumes, nuts
1-2 servings a day: low fat dairy

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Moderation (0-3 servings of each daily)
Oily fish (tuna, salmon, trout) , Chicken,

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eggs
Rare / Avoid
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-Red meat / Shell fish, HFCS, Refined Sugar,
Liquor, Beer
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Clinical Significance

-Gout is a prevalent disease

-Gout has strong associations with many comorbid conditions

-Diet is the common thread between these conditions

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-Dietary modifications can impact hyperuricemia and gout flares as well as metabolic syndrome,
hypertension, coronary artery disease, etc.

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-Certain foods and supplementation may improve hyperuricemia, gout flare control and prevention

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