Lifestyle Factors

Approach to Diet, Alcohol and Other Lifestyle

Recommendations on diet and on lifestyle factors (e.g., alcohol, tobacco, physical fitness) for life-threatening comorbidities in the gout patient (e.g., obesity, hypertension, diabetes, coronary artery disease, hyperlipidemia, chronic kidney disease (CKD)) typically supersede those for gout. Nevertheless, diet and lifestyle recommendations are among the most important and frequently discussed matters between patients and health care providers in the management of gout. In addition, there is a rich historical aspect to these issues, with astonishing accuracy of past assessments of diet, alcohol and gout disease development and acute flare risks (Table 7-1), well before the definitive work of Hyon Choi and colleagues. Table 7-2 summarizes the individual factors discussed below.

The impact of various dietary components for gout risk factors was clearly demonstrated in the Health Professionals Follow-up Study (HPFS) of middle-aged men without gout at the onset of the prospective observation period of 12 years. In this pioneering work of Choi and colleagues, the incidence of gout was associated with the daily intake of red meat and seafood (especially shellfish), which have high purine content (Figure 7-1). Subjects in the highest quintile of meat consumption had a 1.41 relative risk (RR) of developing gout compared with those who were in the lowest quintile. Similarly, those with high seafood intake had an RR=1.51 compared with the lowest consumers.

An internet-based case-crossover study of recurrent gout attacks in which 633 patients with gout were prospectively recruited and studied online for 1 year concluded that the odds ratio (OR) of recurrent gout attacks with increasing quintiles of purine intake from animal sources (over a 48-hour period) were 1.17, 1.38, 2.21 and 4.76. In contrast, with increasing quintiles of purine intake from plant sources, the OR was 1.12, 0.99, 1.32 and 1.39. In this study, the effects of purine intake persisted independent of subject gender, alcohol intake, or use of diuretics, allopurinol, NSAIDs and colchicine.

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Alcohol and Diet

Alcohol

In other data derived from the HPFS, Choi and collaborators demonstrated a significant association between new development of gout and alcohol consumption over a 12-year period. The RR of gout varied greatly between the types of alcohol beverages consumed (Figure 7-2). Beer, which has a high content of the soluble purine guanosine, had the most striking correlation, while wine had no observed association. However, wine drinkers may do more things correctly for good health than beer drinkers. In one study, wine drinkers had lower serum urate levels (in fact, serum urate levels comparable to nondrinkers) than did drinkers of other forms of alcoholic beverages. Nevertheless, all forms of alcohol promote hyperuricemia (Table 7-3).

In those with established gout, all forms of alcohol trigger acute gout flares, especially when more than one or two servings of alcohol are consumed in a 24-hour period (Table 7-4). Light beers have reduced carbohydrates and typically ~15% less alcohol than most regular beers, but the combined guanosine and alcohol content in light beers still induces considerable hyperuricemia.

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Sugar and the Particular Effects of Fructose

It is clinically advised that gout patients avoid excesses in:

• Sugar, in general, especially products enriched in fructose (e.g., food and beverages sweetened with high fructose corn syrup)
• All forms of sweetened sodas and energy beverages
• Consumption of most fruit juices (which are particularly rich in fructose).

Table sugar (sucrose) is a dimer of glucose and fructose. Fructose is a simple monosaccharide contained in honey and many fruits and other plants, where it frequently bound to glucose. Fruit juices are particularly enriched in fructose. Glucose, fructose and galactose monosaccharides are absorbed directly into the circulation in the digestive process.

High fructose corn syrup, made from corn and commonly used as a sweetener in sodas, energy drinks and many other dietary items the USA, contains up to 55% fructose. The particularly substantial ability of fructose to increase serum urate levels has been recognized for decades. The role of fructose-containing sugar and foods as a causative agent of hyperuricemia has been well defined. Absorbed fructose is transported to hepatocytes, where it is phosphorylated to fructose-1-phosphate by fructokinase. This enzymatic process results in hepatic intracellular adenosine triphosphate (ATP) consumption leading to increased uric acid production (Figure 7-3). Elevated fructose intake, including in the forms of high-fructose corn syrup or fruit juices, can cause sustained elevation of serum urate and increases the risk of incident gout. With acute fructose load, increased serum urate and renal fractional excretion of uric acid (FEUA) are observed. By contrast, with chronic increased dietary fructose, serum urate becomes elevated, but there is reduced FEUA. This effect is thought to be due to modulation of renal proximal tubule urate disposition by fructose. Interestingly, such effects may underlie varying influence, including in some ethnic and racial groups, of sugar sweetened beverages on serum urate levels and risk of gout in those with particular gout risk-modifying alleles of SLC2A9 and ABCG2 (Disease Definition and Overview).

Sugar consumption in the United States has more than doubled since the year 1900. There also has been an enormous rise in high-fructose corn syrup consumption in the United States over the last few decades due to economic factors that favor the use of this sweetener rather than cane sugar products. The rise in high-fructose corn syrup consumption in the United States is particularly noteworthy in adolescents, in which it comprises a large percentage of total calories from carbohydrates. Significantly, a major rise in obesity in the United States in the last half of the twentieth century started shortly after the start of robust use of high fructose corn syrup as a sweetener. Roles of not simply excess sugar, but also high fructose corn syrup by itself, have been proposed for increasing prevalence of gout, hyperuricemia, obesity, type 2 diabetes, nonalcoholic steatohepatitis (NASH, fatty liver) and hypertension in the United States. Effects of high fructose consumption that substantially increase hepatic uric acid production and promote loss of satiety signaling to the brain have been proposed as contributory mechanisms. However, this subject is not without controversy.

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Total Carbohydrate Quality, Quantity and the Glycemic Index

Clinical trial data from patients without gout suggest attention might be needed for the dietary glycemic index in those with gout. Specifically, the Omnicarb study analyzed effects of four different diets, all intended to be healthful, in 163 overweight or obese middle-aged adults, using a randomized crossover feeding trial design. The study was designed to ascertain whether plasma urate levels were affected by individual and combined effects of carbohydrate quality (glycemic index) and quantity (as the proportion of total daily energy, abbreviated “%carb”). Baseline mean serum urate was 4.7 mg/dL, approximately half the subjects were female and half were African-American. They studied four diets, tested over 5-week periods separated by 2-week washout blocks: 1) high glycemic index (glycemic index ≥65) with high %carb (58% kcal); 2) low glycemic index (glycemic index ≤45) with low %carb (40% kcal); 3) low glycemic index with high %carb; and 4) high glycemic index with low %carb. Body weight was kept constant in all groups. Plasma urate was lowered by diets with reduced glycemic index and low or high %carb (decrease of 0.24 mg/dL and 0.17 mg/dL, respectively) (Figure 7-4). The combination of lowering glycemic index and increasing the %carb dropped serum urate by -0.27 mg/dL, even adjusting for insulin sensitivity. These results would need to be assessed for robustness in a gout population, including patients with much higher serum urate and with and without background urate-lowering therapy (ULT), but they do suggest the possibility that attention to qualities, proportionate composition and total amount of carbohydrate intake might be a clinically meaningful dietary adjunct to ULT and have some impact on the potential for acute gout flares induced by diet.

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Omega-3 Fatty Acids

Anti-inflammatory effects of omega-3 fatty acids are substantial, include the capacity to limit experimental gout-like inflammation and in part are mediated suppression of activation of the NLRP3 inflammasome (as reviewed in Prophylaxis of Acute Gout Flares). This may explain preliminary evidence for increased acute gout flares linked to low omega-3 fatty acid levels.

Soy

A prospective study on data from the Singapore Chinese Health Study, using a cohort of middle-aged to elderly Chinese adults at recruitment, examined the relationship between the consumption of dietary protein from each of its major sources and the risk of gout in a Chinese population. In this study, hazard ratios (HRs) replicated increased risk for total protein, poultry and fish and shellfish; by contrast, soy food and non-soy legumes had decreased HRs for gout. Soy intake actually may raise serum urate to a slight degree. The mechanism for potential protective effect of soy for incident gout is not clear, but may reside in the anti-inflammatory properties of certain soy constituents, including isoflavones, saponins and anthocyanins.

Coffee and Caffeine

Coffee consumption (caffeinated or decaffeinated), but not tea or caffeine by itself in some studies, is associated with substantially decreased risk of developing gout in men and women, with additional studies showing a linkage of increased coffee consumption with lower serum urate levels in both genders in the general population. A meta-analysis of research studies done to date has suggested that women may need more coffee to significantly lower serum urate than do men (i.e., 4-6 cups/day vs 1-3 cups/day).

Caffeine is a methylxanthine that can inhibit xanthine oxidase activity. Unlike low-fat dairy products, which have an established direct uricosuric effect, coffee consumption has not yet been shown to have uricosuric activity. It is also important to note that daily intake of at least four cups of coffee was linked with mean serum urate level reduction of only 0.26 mg/dL. Moreover, caffeine has a diuretic effect that can promote decreased hydration. Elevated caffeine consumption from multiple sources, concentrated into repeated servings in one 24-hour period (e.g., four or more cups of coffee in a day) has been suggested by Neogi and coworkers to be a risk factor for acute gouty attacks (in preliminary results of an internet-based case-crossover study of subjects with gout). Therefore, those patients with gout who regularly consume coffee should be advised that they can continue, but caffeine overconsumption (or “binges”) should be avoided.

Cigarettes

Smoking is particularly high risk in the gout population, which already has higher associated cardiovascular disease risks. As such, the effects of smoking on developing gout are of substantial interest. In a large analysis of 54-year follow-up data from individuals gout-free at first assessment, as part of the Framingham Heart Study, incident gout was analyzed for possible association with cigarette smoking, with adjustments done for age, BMI, alcohol intake, hypertension, kidney disease and diabetes. In multivariable Cox models, cigarette smoking showed decreased association with gout in men (HR 0.68 [95% CI 0.49, 0.93] and not linked to BMI) and women (HR 0.92 [95% CI 0.60, 1.41] and potentially linked to BMI). The mechanism for these findings, which require replication cohort analyses, remains unclear.

Dairy Products

Low-fat dairy product consumption is associated with decreased development of incident gout and with modest urate-lowering. One clinical trial of milk product extracts suggested prophylactic benefit for gout attacks.

Ascorbate

Ascorbate (vitamin C), consumed as a supplement or from fruits or juices high in vitamin C, can have a beneficial impact on serum urate. In doses as low as 500 to 1000 mg/day, vitamin C supplements can lower serum urate levels by >0.6 mg/dL and as much as 1.5 mg/dL in subjects without gout. However, caution is needed since it is not known if the combined effects on urine pH, oxalate generation and uricosuria of high ascorbate intake can promote urolithiasis. Moreover, preliminary data from a randomized, controlled clinical trial of ascorbate 500 mg daily with or without allopurinol in gout patients did not suggest significant uric acid–lowering benefit of that dose of ascorbate. Further studies are needed, but would require higher doses of ascorbate.

Cherry Products

Cherry consumption (e.g., a regular serving of a half cup, which contains 10 to 12 cherries) has been touted as a folk remedy for gout. Moreover, cherries, cherry juice and cherry extracts are broadly available to patients, including on many commercial internet sites. Cherries contain ascorbate and large servings have been suggested to have a small effect on serum urate and cherry anthocyanins (in tart cherries, in particular) have anti-inflammatory properties. Cherries, especially of the sweet variety, also contain fructose. Therefore, it is valuable to look at cherries in high-quality studies.

A few, very small and short intervention studies, and a sizeable internet-based case-crossover study of subjects with gout, have suggested potential effects of cherry consumption on gout, particularly in prevention of gout flares. The internet study performed a multivariate analysis that took into account the use of alcohol, diuretic agents, NSAIDs, allopurinol and colchicine among study subjects. Cherry intake over a 2-day period was associated with a 35% lower risk of gout attacks compared with no intake (multivariate odds ratio [OR] = 0.65, 95% CI: 0.50-0.85), with cherry anti-gout benefits peaking at ~3 servings over a 2-day period and tending to attenuate in the next higher consumption level, although remaining protective. Cherry extract intake showed a similar inverse association with acute gout attacks (multivariate OR = 0.55, 95% CI: 0.30-0.98), but numbers were very small for cherry extract use. The effect of cherry intake on gout attacks persisted across subgroups by sex, BMI, purine intake, alcohol use, diuretic use and use of medications for gout. Moreover, when cherry intake was combined with allopurinol use, the risk of acute gout attacks was 75% lower than periods without either exposure (OR=0.25, 95% CI: 0.15-0.42) and this also held up in multivariate analysis.

Clearly, cherry fruit and cherry extract consumption in gout would benefit from increased investigation. However, the authors of the internet study and those in accompanying editorial, as well as the authors of this handbook, assess that it is too early to make specific dietary recommendations regarding cherry consumption as a complementary therapy strategy for gout patients.

Other Factors

Dehydration appears to be a substantial factor in increasing the risk of acute gout attacks (Prophylaxis of Acute Gout Flares)(Table 7-2). Hence, the need for regular fluid consumption during the day needs to be stressed in gout patient education.

In gout patients, decreased anti-inflammatory effects of gut microbiome-derived short chain fatty acid generation (e.g., butyrate generation) has been identified as a potential factor modulating the potential for flares, as discussed in detail in Prophylaxis of Acute Gout Flares. Maintenance of high dietary fiber has the potential to limit gouty inflammation by promoting butyrate generation, but this needs direct testing in prospective clinical trials, before specific recommendations can be made.

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Obesity, Physical Fitness and Hyperuricemia and Gout

Hyperuricemia and gout are highly correlated with body weight in both men and women. Subjects with gout are more commonly overweight than the population in general. Obesity is a common factor linking hyperuricemia, hypertension, hyperlipidemia and atherosclerosis. In another examination of the HPFS, Choi and colleagues demonstrated this correlation between rising BMI and incident gout in a very large middle-aged male patient population (Table 7-5). Importantly, The Multiple Risk Factor Intervention Trial (MRFIT) study determined an independent relation between history of gout and future risk of type 2 diabetes in men with elevated cardiovascular risk profile over a 6-year period. In MRFIT, the multivariate relative risk (RR) for incident type 2 diabetes among men with baseline gout (vs without gout) was 1.34 (95% CI 1.09, 1.64) and when further adjusted for serum urate levels, the association remained significant.

Last, as discussed in Prophylaxis of Acute Gout Flares, effects of some dietary gout flare triggers are potentially mediated through inhibition of activity of AMP-activated protein kinase (AMPK), a nutritional biosensor, which serves as a “master regulator” of gout-like inflammation in vivo. Not only caloric restraint, but also physical fitness and exercise increase tissue AMPK activity, whereas tissue AMPK activity is decreased in obesity, type 2 diabetes and metabolic syndrome. Hence, there is a mechanistic basis supportive of active maintenance of exercise and physical fitness, not simply caloric restraint, in gout patients.

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Overall Dietary and Lifestyle Strategy and Expectations for Management of Patients With Gout

Given the large impacts that alcohol, purine-rich foods, sugar and fructose and obesity have on hyperuricemia and gout, it seems perfectly reasonable that diets designed to reduce calories and purine content would have a beneficial effect on gout activity. An isocaloric, low-purine, low-protein diet can reduce serum urate by at least 1 mg/dL and up to 15% to 18%, especially if low alcohol consumption is a component. For example, in a study of 13 nondiabetic men with active gout, Dessein and colleagues demonstrated that a 1600-kcal diet composed of 40% carbohydrate, 30% protein and 30% monounsaturated and polyunsaturated fats had multiple beneficial effects. These patients had a 7.7-kg weight loss over the 16-week study, a 70% decrease in gout flares and a 1.5 mg/dL (approximately 18%) decrease in serum urate levels. However, diet is, by itself, rarely sufficient to lower serum urate to the ideal target level of <6 mg/dL in the average gout patient with a serum urate of >8 mg/dL. The usual practical expectation in the clinic is for diet to induce a maximal serum urate lowering of ~1 mg/dL.

How to Advise the Gout Patient on Diet and Alcohol

Core dietary recommendations for patients with hyperuricemia and gout are shown in Table 7-6. A prevailing principle is that each portion size and overall caloric content should be moderate; in this context, the average dinner plate size in the United States has increased steadily from 9 to 12 inches over the last few decades, and the larger plate size is associated with markedly increased caloric content (Figure 7-5). The concept of a smaller dinner plate size (or portions scaled to fit a smaller plate) is valuable for the patient. Last, appreciating a dietary pyramid can help the health care provider convey useful, specific dietary dos and don’ts for the gout patient (Figure 7-6).

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Take-Away Messages

• Dietary recommendations for life-threatening comorbidities in the gout patient (e.g., obesity, hypertension, diabetes, coronary artery disease, hyperlipidemia, CKD) typically supersede those for gout.
• In patients with overweight, sensible diets tailored to weight reduction to achieve ideal body weight (or close to it) are preferred.
• Moderation of each portion size is critical, as is avoiding large “feasts” and binge eating, especially with alcohol.
• The expected maximal serum urate lowering with diet alone is typically 1 mg/dL (and up to ~18%, especially if coupled with effective weight loss).
• All forms of alcohol promote hyperuricemia (and acute flares of arthritis in established gout).
• Low-purine diets are not palatable and exclude certain healthy vegetables with high purine content.
• Low-fat dairy products, and regular intake of fruits and vegetables are appropriate in gout patients.
• There is evidence that certain complementary measures through diet and dietary supplements (cherry products, omega-3 fatty acids) may be associated with fewer acute flares of gouty arthritis. However, there is insufficient data from prospective, randomized, controlled double-blind trials to make formal, evidence-based recommendations for gout clinical practice for these entities.