- Email: [email protected]
Update on Importance of Diet in Gout
REVIEW
Update on Importance of Diet in Gout Randall N. Beyl, Jr, MD, Laura Hughes, MD, MSPH, Sarah Morgan, MD, MS, RD, FADA, CCD Division of Clinical Immunology and Rheumatology, The University of Alabama at Birmingham.
ABSTRACT Gout is an inflammatory arthritis caused by deposition of monosodium urate crystals within synovial joints. Although it is most well-known for its arthritis, gout has an intimate relationship with many other cardiovascular and metabolic conditions. Current recommendations support aggressive medical therapy to treat gout, whereas dietary counseling 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 wellbeing of a patient with gout. Ó 2016 Elsevier Inc. All rights reserved. The American Journal of Medicine (2016) 129, 1153-1158 KEYWORDS: Dietary modification; Gout; Hyperuricemia; Metabolic syndrome
Gout is an inflammatory arthritis caused by deposition of monosodium urate crystals within synovial joints as a result of elevated serum uric acid (SUA) levels.1 The classic 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 In the United States the estimated prevalence of gout is 8 million individuals, which is an increase of approximately 1.2% over the last 20 years.3-5 When comparing 2 incidence 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 ¼ .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 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 who often have multiple comorbidities. However, if the approach to gout treatment included dietary therapy and lifestyle modification, Funding: None. Conflict of Interest: None. Authorship: All authors had access to and input in writing this manuscript. Requests for reprints should be addressed to Randall N. Beyl, Jr, MD, Rheumatology, The University of Alabama at Birmingham, 510 20th Street, Faculty Office Tower Room 851, Birmingham, AL 35210. E-mail address: [email protected] or [email protected] 0002-9343/$ -see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2016.06.040
it could lower uric acid levels as well as potentially mitigate the long-term consequences of the metabolic syndrome that often coexist with gout.9,10
GOUT AND METABOLIC SYNDROME 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 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 gout, compared with 25.4% in nongout patients.11 Whereas 3.4% of people with weight below the 20th percentile are hyperuricemic, 11.4% of those above the 80th percentile have elevated 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 Several recent small clinical trials have demonstrated that SUA-lowering agents, such as allopurinol and probenecid, can reduce blood pressure in adolescents.13,14 Hyperlipidemia has been found in 25%-60% of gout patients, whereas hypertriglyceridemia was seen in 53.7% of gout patients versus 35.3% of nongout 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 in gout patients being 1.34 (95% confidence interval [CI] 1.09-1.64) compared with those without gout.9,10,15 The prevalence of coronary heart disease is estimated at 25% of gout patients in the United Kingdom and 18% in the United States.9 When compared
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with men without gout or coronary heart disease, men with design of the studies and the large number of variables, there gout had a relative risk of 1.28 (95% CI 1.15-1.41) for total must be caution in assuming true causation. mortality and 1.55 (95% CI 1.24-1.93) for fatal coronary heart disease.16 In the Multiple Risk Factor Intervention Alcohol Trial (MRFIT), gout patients had an increased risk of The risk of hyperuricemia and gout differ both with amount myocardial infarction of 26% and a 35% risk of coronary and type of alcohol ingested. National Health and Nutrition heart disease.9 Although gout is Examination Survey data from sometimes thought of as just an men show that when compared CLINICAL SIGNIFICANCE inflammatory arthritis, it is not with no alcohol ingestion, beer difficult to illustrate the relation Gout is a prevalent disease. was found to increase serum urate ship with other cardiovascular and 0.46 mg/dL per drink per day Gout has strong associations with many metabolic conditions and long(95% CI 0.32-0.6) and liquor 0.29 comorbid conditions. term poor outcomes. mg/dL per drink per day (95% CI Dietary measures likely play a 0.14-0.45) (P <.001). Wine was Diet is the common thread between greater role than urate-lowering not found to be associated with these conditions. therapy in the long-term manageincreased urate (P <.001). Body Dietary modifications can impact hyperment of metabolic syndrome mass index was very similar commonly associated with gout. A uricemia and gout flares, as well as among beer, liquor, and wine self-reported incident gout trial metabolic syndrome, hypertension, and drinkers in this study. In 2 found that men with a body mass coronary artery disease. different multivariate analyses, index (BMI) over 27.5 were 16 after adjusting for BMI, the affect Certain foods and supplementation may times more likely to report gout from each type of alcohol on improve hyperuricemia, gout flare conflares than men with a BMI <20 serum urate remained.21 Crosstrol, and prevention. kg/m2.17 Compared with men with sectional data show similar a BMI of 21-22.9 kg/m2, the relatrends in women: each serving of tive risk of gout for a BMI of beer per week increased serum 22 25-29.9 kg/m2 was 1.95 (95% CI 1.44-2.65), BMI of 30-34.9 urate by 0.03 mg/dL. A prospective cohort study of men kg/m2 was 2.33 (95% CI 1.62-3.36), and a BMI of 35 followed for over 12 years showed that compared with kg/m2 was 2.97 (95% CI 1.73-5.1).18 In a small cohort of nondrinkers, the relative risk of incident gout in drinkers obese men with gout who were started on a moderate calorie was 1.32 (95% CI 0.99-1.75) for 10-14.9 g/d, 1.49 (95% CI and carbohydrate restriction diet for 16 weeks, there was an 1.14-1.94) for 15-29.9 g/d, 1.96 (95% CI 0.48-2.6) for 30average weight loss of 5.4 kg, an average decrease in 49.9 g/d, and 2.53 (95% CI 1.73-3.7) for at 50 g/d. The monthly gout flares from 2.1 to 0.7 (P ¼ .002), and a relative risk was 1.49 (95% CI 1.32-1.7) per 12-oz beer per decrease in serum urate of 0.57 mg/dL to 0.47 mg/dL (P ¼ day, 1.15 (95% CI 1.04-1.28) per shot of liquor per day, and .001). Of the 12 men who initially had a high serum urate, 7 was found to be unassociated with wine intake, 1.04 (95% became normalized.19 In the MRFIT trial, when compared CI 0.88-1.22).23 There have been many proposed mechawith no weight change, the odds ratio for reaching normal nisms to explain how alcohol affects urate. An early study urate with a loss of 1-4.9 kg was 1.43 (95% CI 1.33-1.54), 5proposed that this was from increased adenosine triphos9.9 kg was 2.17 (95% CI 1.95-2.4), and 10 kg was 3.9 phate consumption, causing eventual increased uric acid (95% CI 3.31-4.61). The decrease in serum urate levels for production.24 Serum lactate was also recorded here and each bracket of weight loss was 0.12, 0.31, and 0.62 found to be elevated, which although since unproven, was mg/dL, respectively.20 Therefore, obesity is associated with postulated to decrease uric acid excretion.24,25 Others have gouty flares and hyperuricemia, and weight loss is one of the proposed that increased purine loads in beer cause increased most important modifiable risk factors for gout. uric acid production.26 In a study of alcoholic versus nonalcoholic beer, both were found to increase serum urate levels, 6.5% versus 4.4% respectively, arguing that the SINGLE FOOD/SUPPLEMENTS EFFECTS ON ingestion of the purine load alone can increase uric acid HYPERURICEMIA AND GOUT levels.27 The National Health and Nutrition Examination Survey studies were designed to assess the health and nutritional Purine-Rich Foods status of citizens in the United States. Questionnaires, examinations, vital signs, and laboratory data were collected Purine-containing foods (such as meats, organ meat, over time, to assess risk factors for certain diseases. Much of seafood, legumes, yeast, mushrooms, and gravies) have the data on diet and gout come from these studies. For each been the target of many early gout diets, mainly on the basis of the following foods for which National Health and of the concept that the biochemical degradation end product Nutrition Examination Survey data are used there will be a of purines is urate. More recent studies have found that this description of certain associations found, but given the is not necessarily true. National Health and Nutrition
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Update on Diet in Gout
Examination Survey data show that the age-adjusted differences in serum urate between the lowest and highest intake of meat was 0.48 mg/dL (95% CI 0.34-0.61 mg/dL, P <.001) and 0.16 mg/dL for seafood (95% CI 0.06-0.27 mg/dL, P ¼ .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 compared with the lowest was 1.41 (95% CI 1.071.8), whereas seafood was 1.51 (95% CI 1.17-1.95). Each additional serving of meat per day increased the risk of gout by 21%, whereas each additional weekly seafood serving increased risk by 7%. The intake of dried beans and greens is not associated with gouty flares, as shown by a relative risk of 0.73 (95% CI 0.56-0.96).29
High-Fructose Corn Syrup (HFCS)-Sweetened Soft Drinks Fructose is the only carbohydrate known to increase urate. Fructose and sugar intake also predispose to insulin resistance and metabolic syndrome, which further increase the risk of hyperuricemia.3 National Health and Nutrition Examination Survey data show a correlation between increasing HFCS-sweetened soft drink intake and serum urate levels. Compared with none, soft drink intake of <0.5, 0.5-0.9, 1-3.9, and 4 servings per day lead to serum urate increases of 0.08, 0.15, 0.33, and 0.42 mg/dL (95% CI 0.110.73 mg/dL, P <.001) and relative risks of gout of 1.01, 1.34, 1.51, and 1.82, respectively. This correlation was not found to be significant with diet soft drinks. Body mass index was similar between the sugar-sweetened and diet 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 individuals with both high and low BMI.30 In a prospective cohort of women similar findings were reported. The relative risk of gout for 1 serving of HFCS-sweetened soft drink per day was 1.74 (95% CI 1.19-2.55) and for at least 2 servings per day was 2.39 (95% CI 1.34-4.26, P <.001), whereas diet soda was not found to be correlated to risk of gout.31
1155 powder control, skim milk powder control, and skim milk enriched with a whey protein, glycomacropeptide, and a fat extract, G600, that are naturally found in milk. Glycomacropeptide and G600 were hypothesized to be the active components of milk that decrease urate levels. There were significantly fewer gout flares over 3 months in the glycomacropeptide/G600 skim milk group than in the lactose powder group; interestingly, there was no difference between the lactose and skim milk powder control groups, suggesting these supplemental compounds may actually reduce gout flares.33 The presumed mechanism behind decreased urate levels is the uricosuric effect of the protein in dairy products.3
Coffee/Tea Coffee may affect serum urate in many ways, but few have been proven. National Health and Nutrition Examination Survey data show that serum urate seemed to decrease with increasing levels of coffee intake. Compared with no coffee intake, 4-5 cups and 6 cups per day resulted in reductions of urate of 0.26 mg/dL (95% CI 0.11-0.41 mg/dL) and 0.43 mg/dL (95% CI 0.23-0.65 mg/dL, P <.001), respectively. Body mass index was similar in all levels of coffee consumption. After adjusting for many variables, including BMI, higher levels of coffee intake still led to lower SUA levels. There was a similar inverse relationship between decaffeinated coffee and urate. Total caffeine levels were not associated with urate levels, suggesting that something besides caffeine in coffee is driving this relationship. The odds ratio for hyperuricemia in those who took in 6 cups of coffee per day compared with none was 0.57 (95% CI 0.35-0.94, P ¼ .001). Increasing coffee intake decreased the relative risk for gout in a prospective trial. Relative risk for 0, <1, 1-3, 4-5, and 6 cups of coffee daily were 1, 0.97, 0.92, 0.6 (95% CI 0.41-0.87), and 0.41, respectively (95% CI 0.46-1.17, P ¼ .002). Again total caffeine consumption did not affect gout risk.34 Tea has not been shown to affect serum urate.35
Vitamin C Low-Fat Dairy Intake National Health and Nutrition Examination Survey data show that those who consumed at least 1 serving of milk per day had a lower serum urate, with a difference of 0.25 mg/ dL versus those who did not (95% CI 0.4 to 0.09, P <.001). One serving of yogurt every other day had a difference of 0.26 (95% CI 0.41 to 0.12, P <.001) compared with none.28 The incidence of gout seems to be inversely related to the intake of dairy products. The relative risk in men who took in the highest quintile of dairy compared with the lowest quintile was 0.56 (95% CI 0.420.74, P <.001).28 A randomized, controlled trial showed that each type of skim milk studied decreased serum uric acid by approximately 10% (P <.001).32 Another randomized, controlled proof of concept trial compared lactose
A randomized control trial supplemented the intervention arm with 500 mg/d vitamin C for 2 months. At the completion of the study the vitamin C group had reduced urate, with a mean change of 0.5 mg/dL (0.6 mg/dL to 0.3 mg/dL), whereas there was no change in the control group.36 Later, a prospective trial found that when compared with men with vitamin C intake <250 mg/dL, men with intake of 500-999 mg/dL, 1000-1499 mg/dL, and 1500 mg/dL had a relative risk of gout of 0.83 (95% CI 0.710.97), 0.66 (95% CI 0.52-0.86), and 0.55, respectively (95% CI 0.38-0.80, P <.001).37 An observational study supported this by showing an inverse relationship between vitamin C dose and serum urate plateauing at 500 mg/d.38 A recent meta-analysis of the 13 known randomized, controlled trials studying the effects of vitamin C on serum urate showed
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that even though 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 (0.66 mg/dL to 0.03 mg/dL, P ¼ .032).39 In vitro and animal studies show that vitamin C has uricosuric effects, decreases urate production, and lowers serum urate levels.40
Plenty Most meals: Whole grains, plant protein, fresh vegetables 2-3 servings a day: fresh fruits (less sweet when possible) 1-3 servings a day: legumes, nuts 1-2 servings a day: low fat dairy ModeraƟon (0-3 servings of each daily) Oily fish (tuna, salmon, trout) , Chicken, eggs Rare / Avoid -Red meat / Shell fish, HFCS, Refined Sugar, Liquor, Beer
Cherry/Cherry Extract Small human and animal studies suggest that cherry extract can decrease serum urate. A recent case-crossover observational study showed that patients who ingested cherries over a 2-day hazard period had 35% lower risk of gout flares than those not taking cherry products. An inverse relationship between cherry intake and risk for flare was also found for up to 3 servings (12 whole raw or ½ cup unsweetened canned per serving) in 2 days.41 Although these data may suggest a benefit with cherry intake, 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.
DIET THERAPY FOR GOUT Past guidelines recommended a rigid avoidance of purinerich foods. Challenges existed with this approach, including limited food choices and heightened long-term metabolic risk with 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 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 mind. In MRFIT compared with no weight change, the odds ratio of achieving normal urate for weight loss of 1-4.9 kg was 1.43 (95% CI 1.33-1.54), for 5-9.9 kg was 2.17 (95% CI 1.95-2.4), and for 10 kg was 3.9 (95% CI 3.31-4.61) (P <.001). The associated decrease in serum urate was 0.12, 0.31, and 0.62 mg/dL, respectively, suggesting weight loss alone can improve urate
Diet Goals for Flares • 8-16 cups of water a day • No Alcohol • Meat < 4-6oz / day • Protein from • Low fat dairy • Tofu • Eggs • Nut Buers
Figure 2 Gout inverse food pyramid. HFCS ¼ highfructose corn syrup.
levels.20 In the Dietary Approaches to Stop Hypertension (DASH) trial patients were randomized to 1 of 3 diets: control, healthy choice weight loss, and the DASH diet. Compared with the control group, the DASH diet resulted in increased high-density lipoprotein, with decreased triglycerides, systolic and diastolic blood pressures, and weight, whereas the healthy choice group only reduced triglycerides, systolic 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 ATTICA study, a trial in the Grecian Province of Attica, investigated benefits of the Mediterranean diet in non-gout patients. Those with better self-reported compliance had lower serum uric acid levels. Serum urate positively correlated with meat intake, sugarsweetened soft drinks, and legumes, whereas 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 change on serum urate levels. Thus, weight loss could be an explanation for the improved serum urate levels in the ATTICA study.43
Long Term Diet Principles • Weight loss and daily exercise • Increase plant protein, nuts, fruit, whole grains • 1-2 servings low fat dairy daily • Decrease / eliminate beer, liquor and HFCS sweetend drinks • Consider Vitamin C 500mg/day • If drinking coffee, connue up to 6 cups daily
Figure 1 General dietary recommendations for gout patients. HFCS ¼ high-fructose corn syrup.
GENERAL RECOMMENDATIONS AND CONCLUSION Although the current teaching is that health care professionals should concentrate on 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 opportunity to impact patients’ risk for morbidity and mortality from consequences of metabolic syndrome. 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,
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Update on Diet in Gout
whole grains, lower-sugar fruits, and plant oils is supported, and up to 2 servings daily of low-fat dairy products is recommended (Figure 2). Although fish intake can increase serum urate, there may be 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 poultry are lowerrisk protein sources when used in moderation. One or less serving(s) of red meat or shellfish per week may be recommended. Avoidance of fructose-sweetened food, beer, liquor, and starchy carbohydrates is highly recommended. Wine in moderation is acceptable. Up to 6 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 are needed before making this a recommendation to patients. During an acute flare it is recommended to increase water intake to at least 816 cups per day and avoid alcohol or meat.
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1157 17. Williams PT. Effects of diet, physical activity and performance, and body weight on incident gout in ostensibly healthy, vigorously active men. Am J Clin Nutr. 2008;87(5):1480-1487. 18. Choi HK, Atkinson K, Karlson EW, Curhan G. Obesity, weight change, hypertension, diuretic use, and risk of gout in men: the health professionals follow-up study. Arch Intern Med. 2005;165(7):742-748. 19. Dessein PH, Shipton EA, Stanwix AE, Joffe BI, Ramokgadi J. Beneficial effects of weight loss associated with moderate calorie/carbohydrate restriction, and increased proportional intake of protein and unsaturated fat on serum urate and lipoprotein levels in gout: a pilot study. Ann Rheum Dis. 2000;59(7):539-543. 20. Zhu Y, Zhang Y, Choi HK. The serum urate-lowering impact of weight loss among men with a high cardiovascular risk profile: the Multiple Risk Factor Intervention Trial. Rheumatology (Oxford). 2010;49(12): 2391-2399. 21. Choi HK, Curhan G. Beer, liquor, and wine consumption and serum uric acid level: the Third National Health and Nutrition Examination Survey. Arthritis Rheum. 2004;51(6):1023-1029. 22. Gaffo AL, Roseman JM, Jacobs DR Jr, et al. Serum urate and its relationship with alcoholic beverage intake in men and women: findings from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort. Ann Rheum Dis. 2010;69(11):1965-1970. 23. Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. Alcohol intake and risk of incident gout in men: a prospective study. Lancet. 2004;363(9417):1277-1281. 24. Faller J, Fox IH. Ethanol-induced hyperuricemia: evidence for increased urate production by activation of adenine nucleotide turnover. N Engl J Med. 1982;307(26):1598-1602. 25. Faller J, Fox IH. Ethanol induced alterations of uric acid metabolism. Adv Exp Med Biol. 1984;165 Pt A:457-462. 26. Gibson T, Rodgers AV, Simmonds HA, Toseland P. Beer drinking and its effect on uric acid. Br J Rheumatol. 1984;23(3):203-209. 27. Yamamoto T, Moriwaki Y, Takahashi S, et al. Effect of beer on the plasma concentrations of uridine and purine bases. Metabolism. 2002;51(10):1317-1323. 28. Choi HK, Liu S, Curhan G. Intake of purine-rich foods, protein, and dairy products and relationship to serum levels of uric acid: the Third National Health and Nutrition Examination Survey. Arthritis Rheum. 2005;52(1):283-289. 29. Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. Purine-rich foods, dairy and protein intake, and the risk of gout in men. N Engl J Med. 2004;350(11):1093-1103. 30. Choi JW, Ford ES, Gao X, Choi HK. Sugar-sweetened soft drinks, diet soft drinks, and serum uric acid level: the Third National Health and Nutrition Examination Survey. Arthritis Rheum. 2008;59(1):109-116. 31. Choi HK, Willett W, Curhan G. Fructose-rich beverages and risk of gout in women. JAMA. 2010;304(20):2270-2278. 32. Dalbeth N, Wong S, Gamble GD, et al. Acute effect of milk on serum urate concentrations: a randomised controlled crossover trial. Ann Rheum Dis. 2010;69(9):1677-1682. 33. Dalbeth N, Ames R, Gamble GD, et al. Effects of skim milk powder enriched with glycomacropeptide and G600 milk fat extract on frequency of gout flares: a proof-of-concept randomised controlled trial. Ann Rheum Dis. 2012;71(6):929-934. 34. Choi HK, Willett W, Curhan G. Coffee consumption and risk of incident gout in men: a prospective study. Arthritis Rheum. 2007;56(6):2049-2055. 35. Choi HK, Curhan G. Coffee, tea, and caffeine consumption and serum uric acid level: the third national health and nutrition examination survey. Arthritis Rheum. 2007;57(5):816-821. 36. Huang HY, Appel LJ, Choi MJ, et al. The effects of vitamin C supplementation on serum concentrations of uric acid: results of a randomized controlled trial. Arthritis Rheum. 2005;52(6):1843-1847. 37. Choi HK, Gao X, Curhan G. Vitamin C intake and the risk of gout in men: a prospective study. Arch Intern Med. 2009;169(5):502-507. 38. Gao X, Curhan G, Forman JP, Ascherio A, Choi HK. Vitamin C intake and serum uric acid concentration in men. J Rheumatol. 2008;35(9):1853-1858. 39. Juraschek SP, Miller ER 3rd, Gelber AC. Effect of oral vitamin C supplementation on serum uric acid: a meta-analysis of randomized
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controlled trials. Arthritis Care Res (Hoboken). 2011;63(9): 1295-1306. 40. Holick M, Shils M, Shike M, Ross A, Caballero B, Cousins R. Modern nutrition in health and disease. OJME 10th edition, 2006:329-345. 41. Zhang Y, Neogi T, Chen C, Chaisson C, Hunter DJ, Choi HK. Cherry consumption and decreased risk of recurrent gout attacks. Arthritis Rheum. 2012;64(12):4004-4011.
42. Azadbakht L, Mirmiran P, Esmaillzadeh A, Azizi T, Azizi F. Beneficial effects of a Dietary Approaches to Stop Hypertension eating plan on features of the metabolic syndrome. Diabetes Care. 2005;28(12): 2823-2831. 43. Kontogianni MD, Chrysohoou C, Panagiotakos DB, et al. Adherence to the Mediterranean diet and serum uric acid: the ATTICA study. Scand J Rheumatol. 2012;41(6):442-449.
Update on Importance of Diet in Gout Randall N. Beyl, Jr, MD, Laura Hughes, MD, MSPH, Sarah Morgan, MD, MS, RD, FADA, CCD Division of Clinical Immunology and Rheumatology, The University of Alabama at Birmingham.
ABSTRACT Gout is an inflammatory arthritis caused by deposition of monosodium urate crystals within synovial joints. Although it is most well-known for its arthritis, gout has an intimate relationship with many other cardiovascular and metabolic conditions. Current recommendations support aggressive medical therapy to treat gout, whereas dietary counseling 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 wellbeing of a patient with gout. Ó 2016 Elsevier Inc. All rights reserved. The American Journal of Medicine (2016) 129, 1153-1158 KEYWORDS: Dietary modification; Gout; Hyperuricemia; Metabolic syndrome
Gout is an inflammatory arthritis caused by deposition of monosodium urate crystals within synovial joints as a result of elevated serum uric acid (SUA) levels.1 The classic 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 In the United States the estimated prevalence of gout is 8 million individuals, which is an increase of approximately 1.2% over the last 20 years.3-5 When comparing 2 incidence 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 ¼ .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 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 who often have multiple comorbidities. However, if the approach to gout treatment included dietary therapy and lifestyle modification, Funding: None. Conflict of Interest: None. Authorship: All authors had access to and input in writing this manuscript. Requests for reprints should be addressed to Randall N. Beyl, Jr, MD, Rheumatology, The University of Alabama at Birmingham, 510 20th Street, Faculty Office Tower Room 851, Birmingham, AL 35210. E-mail address: [email protected] or [email protected] 0002-9343/$ -see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2016.06.040
it could lower uric acid levels as well as potentially mitigate the long-term consequences of the metabolic syndrome that often coexist with gout.9,10
GOUT AND METABOLIC SYNDROME 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 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 gout, compared with 25.4% in nongout patients.11 Whereas 3.4% of people with weight below the 20th percentile are hyperuricemic, 11.4% of those above the 80th percentile have elevated 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 Several recent small clinical trials have demonstrated that SUA-lowering agents, such as allopurinol and probenecid, can reduce blood pressure in adolescents.13,14 Hyperlipidemia has been found in 25%-60% of gout patients, whereas hypertriglyceridemia was seen in 53.7% of gout patients versus 35.3% of nongout 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 in gout patients being 1.34 (95% confidence interval [CI] 1.09-1.64) compared with those without gout.9,10,15 The prevalence of coronary heart disease is estimated at 25% of gout patients in the United Kingdom and 18% in the United States.9 When compared
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with men without gout or coronary heart disease, men with design of the studies and the large number of variables, there gout had a relative risk of 1.28 (95% CI 1.15-1.41) for total must be caution in assuming true causation. mortality and 1.55 (95% CI 1.24-1.93) for fatal coronary heart disease.16 In the Multiple Risk Factor Intervention Alcohol Trial (MRFIT), gout patients had an increased risk of The risk of hyperuricemia and gout differ both with amount myocardial infarction of 26% and a 35% risk of coronary and type of alcohol ingested. National Health and Nutrition heart disease.9 Although gout is Examination Survey data from sometimes thought of as just an men show that when compared CLINICAL SIGNIFICANCE inflammatory arthritis, it is not with no alcohol ingestion, beer difficult to illustrate the relation Gout is a prevalent disease. was found to increase serum urate ship with other cardiovascular and 0.46 mg/dL per drink per day Gout has strong associations with many metabolic conditions and long(95% CI 0.32-0.6) and liquor 0.29 comorbid conditions. term poor outcomes. mg/dL per drink per day (95% CI Dietary measures likely play a 0.14-0.45) (P <.001). Wine was Diet is the common thread between greater role than urate-lowering not found to be associated with these conditions. therapy in the long-term manageincreased urate (P <.001). Body Dietary modifications can impact hyperment of metabolic syndrome mass index was very similar commonly associated with gout. A uricemia and gout flares, as well as among beer, liquor, and wine self-reported incident gout trial metabolic syndrome, hypertension, and drinkers in this study. In 2 found that men with a body mass coronary artery disease. different multivariate analyses, index (BMI) over 27.5 were 16 after adjusting for BMI, the affect Certain foods and supplementation may times more likely to report gout from each type of alcohol on improve hyperuricemia, gout flare conflares than men with a BMI <20 serum urate remained.21 Crosstrol, and prevention. kg/m2.17 Compared with men with sectional data show similar a BMI of 21-22.9 kg/m2, the relatrends in women: each serving of tive risk of gout for a BMI of beer per week increased serum 22 25-29.9 kg/m2 was 1.95 (95% CI 1.44-2.65), BMI of 30-34.9 urate by 0.03 mg/dL. A prospective cohort study of men kg/m2 was 2.33 (95% CI 1.62-3.36), and a BMI of 35 followed for over 12 years showed that compared with kg/m2 was 2.97 (95% CI 1.73-5.1).18 In a small cohort of nondrinkers, the relative risk of incident gout in drinkers obese men with gout who were started on a moderate calorie was 1.32 (95% CI 0.99-1.75) for 10-14.9 g/d, 1.49 (95% CI and carbohydrate restriction diet for 16 weeks, there was an 1.14-1.94) for 15-29.9 g/d, 1.96 (95% CI 0.48-2.6) for 30average weight loss of 5.4 kg, an average decrease in 49.9 g/d, and 2.53 (95% CI 1.73-3.7) for at 50 g/d. The monthly gout flares from 2.1 to 0.7 (P ¼ .002), and a relative risk was 1.49 (95% CI 1.32-1.7) per 12-oz beer per decrease in serum urate of 0.57 mg/dL to 0.47 mg/dL (P ¼ day, 1.15 (95% CI 1.04-1.28) per shot of liquor per day, and .001). Of the 12 men who initially had a high serum urate, 7 was found to be unassociated with wine intake, 1.04 (95% became normalized.19 In the MRFIT trial, when compared CI 0.88-1.22).23 There have been many proposed mechawith no weight change, the odds ratio for reaching normal nisms to explain how alcohol affects urate. An early study urate with a loss of 1-4.9 kg was 1.43 (95% CI 1.33-1.54), 5proposed that this was from increased adenosine triphos9.9 kg was 2.17 (95% CI 1.95-2.4), and 10 kg was 3.9 phate consumption, causing eventual increased uric acid (95% CI 3.31-4.61). The decrease in serum urate levels for production.24 Serum lactate was also recorded here and each bracket of weight loss was 0.12, 0.31, and 0.62 found to be elevated, which although since unproven, was mg/dL, respectively.20 Therefore, obesity is associated with postulated to decrease uric acid excretion.24,25 Others have gouty flares and hyperuricemia, and weight loss is one of the proposed that increased purine loads in beer cause increased most important modifiable risk factors for gout. uric acid production.26 In a study of alcoholic versus nonalcoholic beer, both were found to increase serum urate levels, 6.5% versus 4.4% respectively, arguing that the SINGLE FOOD/SUPPLEMENTS EFFECTS ON ingestion of the purine load alone can increase uric acid HYPERURICEMIA AND GOUT levels.27 The National Health and Nutrition Examination Survey studies were designed to assess the health and nutritional Purine-Rich Foods status of citizens in the United States. Questionnaires, examinations, vital signs, and laboratory data were collected Purine-containing foods (such as meats, organ meat, over time, to assess risk factors for certain diseases. Much of seafood, legumes, yeast, mushrooms, and gravies) have the data on diet and gout come from these studies. For each been the target of many early gout diets, mainly on the basis of the following foods for which National Health and of the concept that the biochemical degradation end product Nutrition Examination Survey data are used there will be a of purines is urate. More recent studies have found that this description of certain associations found, but given the is not necessarily true. National Health and Nutrition
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Examination Survey data show that the age-adjusted differences in serum urate between the lowest and highest intake of meat was 0.48 mg/dL (95% CI 0.34-0.61 mg/dL, P <.001) and 0.16 mg/dL for seafood (95% CI 0.06-0.27 mg/dL, P ¼ .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 compared with the lowest was 1.41 (95% CI 1.071.8), whereas seafood was 1.51 (95% CI 1.17-1.95). Each additional serving of meat per day increased the risk of gout by 21%, whereas each additional weekly seafood serving increased risk by 7%. The intake of dried beans and greens is not associated with gouty flares, as shown by a relative risk of 0.73 (95% CI 0.56-0.96).29
High-Fructose Corn Syrup (HFCS)-Sweetened Soft Drinks Fructose is the only carbohydrate known to increase urate. Fructose and sugar intake also predispose to insulin resistance and metabolic syndrome, which further increase the risk of hyperuricemia.3 National Health and Nutrition Examination Survey data show a correlation between increasing HFCS-sweetened soft drink intake and serum urate levels. Compared with none, soft drink intake of <0.5, 0.5-0.9, 1-3.9, and 4 servings per day lead to serum urate increases of 0.08, 0.15, 0.33, and 0.42 mg/dL (95% CI 0.110.73 mg/dL, P <.001) and relative risks of gout of 1.01, 1.34, 1.51, and 1.82, respectively. This correlation was not found to be significant with diet soft drinks. Body mass index was similar between the sugar-sweetened and diet 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 individuals with both high and low BMI.30 In a prospective cohort of women similar findings were reported. The relative risk of gout for 1 serving of HFCS-sweetened soft drink per day was 1.74 (95% CI 1.19-2.55) and for at least 2 servings per day was 2.39 (95% CI 1.34-4.26, P <.001), whereas diet soda was not found to be correlated to risk of gout.31
1155 powder control, skim milk powder control, and skim milk enriched with a whey protein, glycomacropeptide, and a fat extract, G600, that are naturally found in milk. Glycomacropeptide and G600 were hypothesized to be the active components of milk that decrease urate levels. There were significantly fewer gout flares over 3 months in the glycomacropeptide/G600 skim milk group than in the lactose powder group; interestingly, there was no difference between the lactose and skim milk powder control groups, suggesting these supplemental compounds may actually reduce gout flares.33 The presumed mechanism behind decreased urate levels is the uricosuric effect of the protein in dairy products.3
Coffee/Tea Coffee may affect serum urate in many ways, but few have been proven. National Health and Nutrition Examination Survey data show that serum urate seemed to decrease with increasing levels of coffee intake. Compared with no coffee intake, 4-5 cups and 6 cups per day resulted in reductions of urate of 0.26 mg/dL (95% CI 0.11-0.41 mg/dL) and 0.43 mg/dL (95% CI 0.23-0.65 mg/dL, P <.001), respectively. Body mass index was similar in all levels of coffee consumption. After adjusting for many variables, including BMI, higher levels of coffee intake still led to lower SUA levels. There was a similar inverse relationship between decaffeinated coffee and urate. Total caffeine levels were not associated with urate levels, suggesting that something besides caffeine in coffee is driving this relationship. The odds ratio for hyperuricemia in those who took in 6 cups of coffee per day compared with none was 0.57 (95% CI 0.35-0.94, P ¼ .001). Increasing coffee intake decreased the relative risk for gout in a prospective trial. Relative risk for 0, <1, 1-3, 4-5, and 6 cups of coffee daily were 1, 0.97, 0.92, 0.6 (95% CI 0.41-0.87), and 0.41, respectively (95% CI 0.46-1.17, P ¼ .002). Again total caffeine consumption did not affect gout risk.34 Tea has not been shown to affect serum urate.35
Vitamin C Low-Fat Dairy Intake National Health and Nutrition Examination Survey data show that those who consumed at least 1 serving of milk per day had a lower serum urate, with a difference of 0.25 mg/ dL versus those who did not (95% CI 0.4 to 0.09, P <.001). One serving of yogurt every other day had a difference of 0.26 (95% CI 0.41 to 0.12, P <.001) compared with none.28 The incidence of gout seems to be inversely related to the intake of dairy products. The relative risk in men who took in the highest quintile of dairy compared with the lowest quintile was 0.56 (95% CI 0.420.74, P <.001).28 A randomized, controlled trial showed that each type of skim milk studied decreased serum uric acid by approximately 10% (P <.001).32 Another randomized, controlled proof of concept trial compared lactose
A randomized control trial supplemented the intervention arm with 500 mg/d vitamin C for 2 months. At the completion of the study the vitamin C group had reduced urate, with a mean change of 0.5 mg/dL (0.6 mg/dL to 0.3 mg/dL), whereas there was no change in the control group.36 Later, a prospective trial found that when compared with men with vitamin C intake <250 mg/dL, men with intake of 500-999 mg/dL, 1000-1499 mg/dL, and 1500 mg/dL had a relative risk of gout of 0.83 (95% CI 0.710.97), 0.66 (95% CI 0.52-0.86), and 0.55, respectively (95% CI 0.38-0.80, P <.001).37 An observational study supported this by showing an inverse relationship between vitamin C dose and serum urate plateauing at 500 mg/d.38 A recent meta-analysis of the 13 known randomized, controlled trials studying the effects of vitamin C on serum urate showed
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that even though 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 (0.66 mg/dL to 0.03 mg/dL, P ¼ .032).39 In vitro and animal studies show that vitamin C has uricosuric effects, decreases urate production, and lowers serum urate levels.40
Plenty Most meals: Whole grains, plant protein, fresh vegetables 2-3 servings a day: fresh fruits (less sweet when possible) 1-3 servings a day: legumes, nuts 1-2 servings a day: low fat dairy ModeraƟon (0-3 servings of each daily) Oily fish (tuna, salmon, trout) , Chicken, eggs Rare / Avoid -Red meat / Shell fish, HFCS, Refined Sugar, Liquor, Beer
Cherry/Cherry Extract Small human and animal studies suggest that cherry extract can decrease serum urate. A recent case-crossover observational study showed that patients who ingested cherries over a 2-day hazard period had 35% lower risk of gout flares than those not taking cherry products. An inverse relationship between cherry intake and risk for flare was also found for up to 3 servings (12 whole raw or ½ cup unsweetened canned per serving) in 2 days.41 Although these data may suggest a benefit with cherry intake, 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.
DIET THERAPY FOR GOUT Past guidelines recommended a rigid avoidance of purinerich foods. Challenges existed with this approach, including limited food choices and heightened long-term metabolic risk with 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 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 mind. In MRFIT compared with no weight change, the odds ratio of achieving normal urate for weight loss of 1-4.9 kg was 1.43 (95% CI 1.33-1.54), for 5-9.9 kg was 2.17 (95% CI 1.95-2.4), and for 10 kg was 3.9 (95% CI 3.31-4.61) (P <.001). The associated decrease in serum urate was 0.12, 0.31, and 0.62 mg/dL, respectively, suggesting weight loss alone can improve urate
Diet Goals for Flares • 8-16 cups of water a day • No Alcohol • Meat < 4-6oz / day • Protein from • Low fat dairy • Tofu • Eggs • Nut Buers
Figure 2 Gout inverse food pyramid. HFCS ¼ highfructose corn syrup.
levels.20 In the Dietary Approaches to Stop Hypertension (DASH) trial patients were randomized to 1 of 3 diets: control, healthy choice weight loss, and the DASH diet. Compared with the control group, the DASH diet resulted in increased high-density lipoprotein, with decreased triglycerides, systolic and diastolic blood pressures, and weight, whereas the healthy choice group only reduced triglycerides, systolic 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 ATTICA study, a trial in the Grecian Province of Attica, investigated benefits of the Mediterranean diet in non-gout patients. Those with better self-reported compliance had lower serum uric acid levels. Serum urate positively correlated with meat intake, sugarsweetened soft drinks, and legumes, whereas 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 change on serum urate levels. Thus, weight loss could be an explanation for the improved serum urate levels in the ATTICA study.43
Long Term Diet Principles • Weight loss and daily exercise • Increase plant protein, nuts, fruit, whole grains • 1-2 servings low fat dairy daily • Decrease / eliminate beer, liquor and HFCS sweetend drinks • Consider Vitamin C 500mg/day • If drinking coffee, connue up to 6 cups daily
Figure 1 General dietary recommendations for gout patients. HFCS ¼ high-fructose corn syrup.
GENERAL RECOMMENDATIONS AND CONCLUSION Although the current teaching is that health care professionals should concentrate on 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 opportunity to impact patients’ risk for morbidity and mortality from consequences of metabolic syndrome. 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,
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whole grains, lower-sugar fruits, and plant oils is supported, and up to 2 servings daily of low-fat dairy products is recommended (Figure 2). Although fish intake can increase serum urate, there may be 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 poultry are lowerrisk protein sources when used in moderation. One or less serving(s) of red meat or shellfish per week may be recommended. Avoidance of fructose-sweetened food, beer, liquor, and starchy carbohydrates is highly recommended. Wine in moderation is acceptable. Up to 6 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 are needed before making this a recommendation to patients. During an acute flare it is recommended to increase water intake to at least 816 cups per day and avoid alcohol or meat.
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42. Azadbakht L, Mirmiran P, Esmaillzadeh A, Azizi T, Azizi F. Beneficial effects of a Dietary Approaches to Stop Hypertension eating plan on features of the metabolic syndrome. Diabetes Care. 2005;28(12): 2823-2831. 43. Kontogianni MD, Chrysohoou C, Panagiotakos DB, et al. Adherence to the Mediterranean diet and serum uric acid: the ATTICA study. Scand J Rheumatol. 2012;41(6):442-449.