Key Points
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Lifestyle and dietary modifications can influence serum urate levels and the risk of gout and are the only acceptable options when urate-lowering medications are not yet indicated or are successfully terminated after durable remission of gout.
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Lifestyle modifications should continue as an adjunct measure to aid pharmacologic urate-lowering therapy regardless of the stage of gout, which is analogous to how hypertensive patients should continue lifestyle modifications in all stages of hypertension.
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Lifestyle modifications for gout patients should take into account both associated benefits and risks in a holistic manner, since gout is often associated with many important comorbidities including the metabolic syndrome and an increased future risk of cardiovascular disease and mortality.
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Reducing weight with daily exercise and limiting intake of red meat and sugary beverages would help reduce uric acid levels, the risk of gout, insulin resistance, and comorbidities.
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While heavy drinking should be avoided, moderate drinking, sweet fruits, and seafood intake, particularly oily fish, should be tailored to the individual, considering their anticipated health benefits against cardiovascular disease.
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Dairy products, vegetables, nuts, legumes, fruits (less sugary ones), and whole grains are healthy dietary choices for the comorbidities of gout and would likely help prevent gout by reducing insulin resistance and thus inducing urinary uric acid excretion.
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Coffee (regular or decaffeinated) and vitamin C supplementation may be considered as long-term preventive measures as they can lower urate levels as well as the risk of gout and some associated comorbidities.
Introduction
Historical descriptions of gout, including typical demographics, secular trends, and anecdotal observations, have all suggested that lifestyle factors substantially influence the risk of gout. Previous short-term purine feeding studies and the observed urate-lowering response associated with purine-restrictive diets have indicated a significant impact of dietary purine intake on serum urate levels. A less recognized but important point to consider is that long-term effects of lifestyle factors for insulin resistance syndrome are likely to have a considerable role in the risk of hyperuricemia and gout as well. Increasing trends in these lifestyle risk factors may help explain the increasing disease burden of gout that has been observed during the past several decades. Recent large-scale studies have confirmed some of the long-purported dietary risk factors for hyperuricemia and gout, including meat, seafood, beer, liquor, adiposity, and weight gain ( Fig. 11-1 ). Other putative risk factors, such as protein and purine-rich vegetables, were exonerated, and a potential protective effect of dairy products was newly identified. Furthermore, several other factors that had not been included in traditional lifestyle recommendations have been identified, including offending factors like fructose- and sugar-sweetened soft drinks and protective factors such as coffee and vitamin C supplements. Moreover, recent studies have identified the substantial comorbidity burden of cardiovascular-metabolic conditions among patients with hyperuricemia and gout.
Lifestyle and dietary recommendations are the only acceptable option when urate-lowering medications are not yet indicated or are successfully terminated after durable remission of gout ( Fig. 11-2 ). Furthermore, these recommendations should continue as an adjunct measure to aid pharmacologic urate-lowering therapy (ULT) regardless of the stage of gout, which is analogous to how hypertensive or diabetic patients should not give up lifestyle modifications in any stage of hypertension or type 2 diabetes. The application of scientific knowledge on the risk factors for hyperuricemia and gout into practice requires consideration of the health impact of these factors on the frequent comorbidities of hyperuricemia and gout. This is particularly relevant because a number of major cardiovascular-metabolic conditions often co-occur in these patients. In an extreme scenario, if a certain lifestyle modification can reduce the risk of gout but could also contribute to an increased risk of a major health outcome such as acute myocardial infarction or premature death, it would be difficult to justify its long-term implementation. Thus, it is important to consider holistic lifestyle recommendations that take into account both the impact on gout and relevant other relevant health outcomes, particularly cardiovascular-metabolic comorbidities of gout.
This chapter reviews the lifestyle risk factors for hyperuricemia and gout and attempts to provide holistic recommendations, considering both their impacts on the risk of gout and other potential health implications.
Historical Perspectives of Lifestyle Factors and Gout
Once known as a “disease of kings and king of diseases,” gout has affected important figures such as Alexander the Great, Charlemagne, Henry VIII, the Emperor Charles V, Benjamin Franklin, Alexander Hamilton, Tennyson, Coleridge, Voltaire, Isaac Newton, Charles Darwin, and Leonardo da Vinci. Also described by Hippocrates during the Golden Age of Greece, gout was previously considered a disease of the affluent, primarily observed in middle-aged men of the wealthy upper class (“the Patrician malady”). During the days of the Roman Empire, Seneca remarked that even women were getting gout, for “in this age, women now rival men in every kind of lasciviousness.” As is appreciable in these historical descriptions, gout had often afflicted the wealthy and the educated, and particularly those who not only could afford the comforts of life but also enjoyed its excesses, with habits that bordered on overindulgence, gluttony, and intemperance. As these lifestyles have become affordable and prevalent in the general public in the modern era, particularly in Western society with abundantly available foods and a strong tendency toward sedentary lifestyle, gout has changed its epidemiology from a “disease of kings” to a “disease of commoners.”
These historical observations and trends are consistent with the long-hypothesized notion about the links between excessive ingestion of purine-rich foods and alcohol and the development of gout. They are also in line with the conventional approach of limiting these factors in the lifestyle recommendations for gout management. Historically, other dietary approaches have also been proposed to help prevent gout. For example, a diet low in meat and high in dairy products was proposed as a means to prevent gout by the philosopher John Locke (1632-1704), who encouraged milk drinking and “eating very little flesh but abundance of herbs”; similar diets were proposed by George Cheyne in the 1700s and by Alexander Haig in the late 1800s. Also in the late 1800s, Sir William Osler prescribed diets low in fructose as means to prevent gout as he wrote in his 1892 textbook, The Principles and Practice of Medicine , that “The sugar should be reduced to a minimum. The sweeter fruits should not be taken.” These approaches have been supported by recent large-scale studies, which are discussed in detail later in this chapter.
Species Differences, Westernization, and Gout Trends
Humans are the only mammals that are known to develop gout spontaneously, probably because hyperuricemia commonly develops only in humans. In most fish, amphibians, and nonprimate mammals, uric acid generated from purine metabolism undergoes oxidative degradation via the uricase enzyme, which produces the more soluble compound allantoin. Thus, it is difficult to induce serum urate levels in rats unless an inhibitor of uricase is administered, whereas feeding meat to birds and many reptiles induces a substantial increase in serum urate levels as these species lack uricase, like humans. For example, gout has been observed in turkeys that were fed horse meat.
The impact of diet on the uric acid levels in species that lack uricase may also provide insight into why the serum urate levels in the great apes (1.5 to 3.0 mg/dl) are substantially lower than those in humans in the modern era (4.8 mg/dl among women and 6.1 mg/dl among men in the U.S. general population, 1999-2008). The great apes primarily consume fruit and vegetation while their animal protein intake is minimal. Early humans in indigenous scavenging and gathering societies who lived on traditional diets primarily derived from fruits and vegetables with sporadic additions of fish and game likely had serum urate levels similar to those of the great apes.
A number of epidemiologic studies from a diverse range of countries suggest that gout has increased in prevalence and incidence in the last few decades. This increase is likely explained in large part by trends in lifestyle factors associated with Westernization. For example, since the introduction of Western culture and dietary habits, gout has become an epidemic among some native peoples, such as the Maori of New Zealand. After the introduction of a diet high in fatty meats and carbohydrates and low in dairy products in the early 1900s, an epidemic of obesity and gout developed. Similarly, gout was rare among blacks in Africa, especially in rural areas where traditional agricultural and dairy-based diets were common, but its frequency has been increasing, particularly in urban communities. Gout was considered rare among African Americans in the early 1900s, but changes in diet have led to a rapid development of obesity, diabetes, and hypertension. Today, the mean serum urate levels are higher and gout is more common among African Americans than among whites. Furthermore, ecologic studies of Japanese and Filipino populations have found that U.S. immigrants from these countries had increases in serum urate levels, the incidence of gout, or both, compared with their offshore counterparts.
Pathophysiologic Considerations in Lifestyle Recommendations for Gout
The amount of urate in the body, the culprit in the causation of gout, depends on the balance among dietary intake, synthesis, and excretion. Hyperuricemia results from the underexcretion of uric acid in the vast majority of cases (90%), overproduction of uric acid, or a combination of the two. Thus, while lifestyle factors such as oral purine load can contribute to uric acid burden and the risk of gout to a certain extent, factors that can affect renal uric acid excretion or both production and excretion would likely have a substantial impact on uric acid burden and risk of gout. The purine-loading lifestyle factors (e.g., meat, seafood, alcohol, fructose-rich food) that affect serum urate levels can acutely increase the risk of urate crystal formation and gout attacks ( Fig. 11-3 ). In comparison, the factors that affect insulin resistance (e.g., adiposity, dairy intake, coffee) and the renal excretion of urate can improve urate levels and the risk of gout in a long-term manner ( Fig. 11-4 ). Traditional lifestyle approaches have almost exclusively focused on acute gout prevention with the purine-loading risk factors. However, since the insulin resistance syndrome is a highly prevalent comorbidity among gout patients and has cardiovascular-metabolic consequences, it is important to consider the factors that can improve insulin resistance, particularly in long-term lifestyle recommendations.
Gout Is a Metabolic Disorder Associated With Multiple Associated Comorbidities and Cardiovascular-Metabolic Sequelae
Although the cardinal feature of gout is inflammatory arthritis, it is a metabolic condition associated with elevated uric acid burden. A number of associated cardiovascular-metabolic conditions have been identified, including increased adiposity, hypertension, dyslipidemia, insulin resistance, hyperglycemia, certain renal conditions, and atherosclerotic cardiovascular disorders. Recent studies have quantified the magnitude of associations with these comorbid conditions. For example, in a representative sample of U.S. adult men and women (NHANES III), the prevalence of the metabolic syndrome, as defined by the revised National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP III), was 63% among individuals with gout and 25% among individuals without gout. Previous hospital-based case series reported that the prevalence of the metabolic syndrome was 82% in Mexican men and 44% in Korean men with gout. These quantitative population data indicate that the prevalence of the metabolic syndrome is remarkably high among individuals with hyperuricemia and gout. Correspondingly, the prevalence of the metabolic syndrome has been found to increase substantially with increasing levels of serum urate, from 19% for serum urate levels less than 6 mg/dl to 71% for levels of 10 mg/dl or greater. While more than 50% of gout patients have hypertension, coronary artery disease (CAD) has been observed in 25% of gout patients in the United Kingdom and in 18% of U.S. male health professionals with gout. Overweight and obese statuses have been observed in 71% and 14% of U.S. health professional men with gout, respectively, whereas obesity has been reported to be as high as 27.7% in a U.K. general practitioners’ population. The association with diabetes is generally weak, with a prevalence of 6% of gout patients in the United Kingdom and 5% among male health professionals with gout. The prevalence of kidney stones is 15% among male health professionals with gout and renal insufficiency was found to be 5% in the U.S. general population.
These cross-sectional associations have been consistently translated into increased future risk of relevant cardiovascular-metabolic sequelae. For example, the Framingham Heart Study found that gout was associated with a 60% increased risk of CAD in men, which was not explained by clinically measured risk factors. Also, in the Multiple Risk Factor Intervention Trial (MRFIT), participants with a history of gout had a 26% increased independent risk of myocardial infarction, a 33% increased risk of peripheral arterial disease, and a 35% increased risk of coronary heart disease (CHD) mortality. Similarly, the Health Professionals Follow-Up Study (HPFS) cohort showed a 59% increased risk of nonfatal myocardial infarction and a 55% increased risk of fatal myocardial infarction. Furthermore, in the HPFS, men with gout had a 28% higher risk of death from all causes, a 38% higher risk of death from cardiovascular disease (CVD), and a 55% higher risk of death from CHD. Finally, an analysis based on the MRFIT data showed that men with gout had a 41% increased risk of incident type 2 diabetes.
These comorbidities of gout and independent associations with future risks of CVD and mortality add to the overall burden of gout and provide strong support for serious consideration of these issues in determining appropriate lifestyle recommendations for gout patients.
Low-Purine Diet Versus a Dietary Approach Against the Metabolic Syndrome
The conventional dietary approach to gout management limits food or drinks that are known to potentially precipitate an acute gouty attack, such as large servings of meat and heavy beers. However, a rigid purine-restricted diet has been thought to be of dubious therapeutic value and can rarely be sustained for long. Furthermore, low-purine foods are often rich in both refined carbohydrates (including fructose) and saturated fat. These tend to further decrease insulin sensitivity, leading to higher plasma levels of insulin, glucose, triglycerides, and low-density lipoprotein cholesterol (LDL-C) levels and decreased levels of high-density lipoprotein cholesterol (HDL-C), thereby furthering the risk of the metabolic syndrome and its complications in these patients. In contrast, a diet aimed to lower insulin resistance can not only improve uric acid levels but also improve insulin sensitivity and decrease plasma glucose, insulin, and triglyceride levels, which would lead to a reduction in the incidence and mortality of CVD. Of note, the HPFS data on incident gout are largely consistent with the lifestyle recommendations against insulin resistance. For example, measures that are known to reduce insulin resistance like weight loss, higher dairy intake, lower fructose intake, and higher coffee intake have all been found to be protective against the risk of developing new cases of gout ( Fig. 11-4 , Table 11-1 ).
| Risk Factors | Direction of Risk | ||
|---|---|---|---|
| Risk of Hyperuricemia | Risk of Gout | References | |
| Adiposity | |||
| Body mass index | ↑ | ↑ | |
| Waist-to-hip ratio | ↑ | ↑ | |
| Weight gain | ↓ | ↓ | |
| Weight loss | ↓ | ↓ | |
| Purine-rich foods | |||
| Meats | ↑ | ↑ | |
| Seafoods | ↑ | ↑ | |
| Purine-rich vegetables/nuts | ↔ | ||
| Alcohol | ↑ | ↑ | |
| Fructose | ↑ | ↑ | |
| Sugar-sweetened beverages | ↑ | ↑ | |
| Sweet fruits/fruit juices | ↑ | ↑ | |
| Coffee/decaffeinated coffee | ↓ | ↓ | |
| Dairy products | |||
| Low-fat dairy products | ↓ | ↓ | |
| High-fat dairy products | ↔ | ||
| Vitamin C supplements | ↓ | ↓ | |
Furthermore, the fact that previously forbidden items such as purine-rich vegetables, nuts, legumes, and vegetable protein are, despite their high purine content, not associated with an increase in gout risk also supports their overall beneficial effects in gout patients, likely through lowering insulin resistance. (In fact, individuals who consumed a larger amount of vegetable protein [the highest quintile] had a 27% lower risk of gout compared with the lowest quintile. ) These approaches could not only reduce uric acid levels and the risk of gout in the long run but could also lower the major consequences of insulin resistance. In other words, the overall risk-benefit ratio of the diet approach against the metabolic syndrome would likely yield a more favorable net outcome in the long run than the traditional low-purine diet. Furthermore, as compared with the less palatable low-purine diet, a dietary approach against the metabolic syndrome may achieve higher long-term compliance. A formal comparison of these dietary approaches would be valuable.
Long-term Versus Short-term Implications of Lifestyle Interventions
Certain lifestyle interventions may have differential short-term versus long-term effects on the risk of gout, similar to the paradoxical short-term flares versus long-term benefits of ULT. For example, the more potent and immediate the urate-lowering effect of a certain lifestyle factor, the more likely it is that these paradoxical flares are expected, just as with potent pharmacologic ULTs. This means that if a certain lifestyle factor is associated with short-term flares but long-term benefits, physicians and patients should be aware of such effects, and its initiation among gout patients may require a gradual introduction, similar to ULT. Regardless, since ULTs are continued beyond the initial phase of paradoxical flares when indicated, lifestyle modifications may also be appropriately sustained beyond this initial phase in order to lower uric acid levels. The advantage of lifestyle modifications over ULT use is that one needs not consider adverse events and costs of drugs, as lifestyle approaches are generally healthy and affordable.
A similar analogy can be found in the use of exercise as a preventive measure against the risk of myocardial infarction. Although acute exertion associated with exercise can lead to a short-term increased risk of myocardial infarction, individuals who exercise regularly have a lower risk of developing myocardial infarction, and thus regular exercise is recommended as a CVD prevention measure. This is because the long-term benefits of exercise outweigh the short-term risk, particularly when the exercise regimen is gradually initiated. In the case of gout, a similar example might be that a burst of high consumption of caffeinated beverages may induce a short-term gout attack by promoting a decrease in both serum urate and hydration, but the long-term effects of steady consumption may be beneficial by lowering uric acid levels and the risk of developing gout. Thus, if a patient with gout chooses to try regular coffee intake to help reduce serum urate levels, its initiation may need to be similar to that of gradually implementing an exercise program in CVD prevention or initiating ULT. Alternatively, decaffeinated coffee may be considered without risking paradoxical flares associated with initiation.
Short-term Feeding Studies for Serum Uric Acid Levels
The long-suspected role of purine-rich food of animal origin on the risk of gout had been supported by metabolic experiments in animals and humans that examined the impact of artificial short-term loading of purified purine on the serum uric acid level (not gouty arthritis per se). While these studies provided a basis for the potential long-term effects of purine-rich food items, such as red or organ meat, on hyperuricemia and, conceivably, on the eventual development of gout in the long run, several hurdles existed before such a conclusion could be drawn. First, little has been known about the precise identity and quantity of individual purines in most foods, especially when cooked or processed. Additionally, the bioavailability of various purines contained in different foods varies substantially. For example, dietary substitution-addition experiments showed that RNA has a greater effect than an equivalent amount of DNA, ribomononucleotides have a greater effect than nucleic acid, and adenine has a greater effect than guanine. Finally, the outcome of interest in these studies was hyperuricemia, rather than gout, and a substantial proportion of hyperuricemic patients do not develop gouty arthritis. Thus, these short-term feeding studies are informative, but based on these studies alone, it is difficult to conclude whether a certain “purine-rich” food or food group actually affects the risk of gout per se.
Long-term, Prospective Cohort Studies of Lifestyle Factors for Gout
The limitations of short-term feeding studies can be addressed by long-term, prospective studies that collect dietary and other lifestyle information and track the development of gout among individuals without existing gout at baseline. These studies can examine the relation between actual foods or food groups (as opposed to purified purines) and the risk of developing gout on a long-term basis and can provide practical information. While the data from these studies are directly relevant to prevention of new cases of gout, these observations are likely applicable to patients with preexisting gout as well. In fact, the effects could be even more exaggerated as absorption of dietary purines causes a steeper rise in blood urate levels in these patients than in normouricemic individuals due to the relative impairment of renal uric acid clearance in the majority of these patients.
Several earlier prospective cohort studies that examined the risk factors for gout had a relatively small number of incident cases of gout (range of 60 to 102) and lacked comprehensive dietary information, including The Johns Hopkins Precursor Study, the Normative Aging Study, and the Framingham Heart Study. Thus, their ability to detect risk factors was somewhat limited to more obvious and common factors such as increased adiposity. More recently, two large prospective studies comprehensively gathered dietary and lifestyle information and had a large number of incident cases of gout during follow-up (730 men and 889 women with gout by 1998 and 2006, respectively). As the substantial amount of the data discussed in this chapter are based on these two prospective studies, relevant study specifics are summarized next, before individual risk factors are discussed.
Health Professionals Follow-Up Study
The HPFS is an ongoing longitudinal study of 51,529 male dentists, optometrists, osteopaths, pharmacists, podiatrists, and veterinarians who were 40 to 75 years of age in 1986. While there were no exclusions by race, 1% were African American and 2% were Asian. The participants returned a mailed questionnaire in 1986 concerning diet, medical history, and medications. To assess dietary intake, a validated food-frequency questionnaire was used to inquire about the average use of more than 130 foods and beverages during the previous year. The baseline dietary questionnaire was completed in 1986 and was updated every 4 years. Nutrient intake was computed from the reported frequency of consumption of each specified unit of food or beverage and from published data on the nutrient content of the specified portions. Food and nutrient intakes assessed by this dietary questionnaire have been validated previously against two 1-week diet records in this cohort. At baseline, and every 2 years thereafter, the participants provided information on weight, regular use of medications (including diuretics), and medical conditions (including hypertension and chronic renal failure). The follow-up for this cohort has exceeded 90%.
Beginning in 1986, biennial questionnaires asked whether participants had ever received a physician diagnosis of gout and, if so, the date of first occurrence. If the participant reported that gout had been diagnosed in 1986 (when dietary information was first collected) or later, we mailed a supplementary questionnaire to confirm the diagnosis according to the American College of Rheumatology (ACR) survey gout criteria, the age of occurrence, family history of gout, and other relevant information including treatment for gout. The response rate to the supplementary questionnaire was approximately 80%. To confirm the validity of the ACR survey gout criteria in this cohort, two board-certified rheumatologists reviewed the medical records of a sample of 76 men who had reported having gout and had consented to the release of their medical records. Of these 76 men, 26 did not have relevant and complete records. Among the remaining 50 men, the rate of concordance between the diagnosis of gout according to the ACR criteria and the diagnosis of gout according to our review of the medical records was 94%. Of note, the incidence rate in this cohort was very close to that of male physicians in the Johns Hopkins Precursor Study that used the same ACR gout definition.
Nurses’ Health Study (NHS) Cohorts
In 1976, 121,700 female U.S. registered nurses between the ages of 30 and 55 years, residing in 11 large U.S. states, completed an initial NHS questionnaire. The NHS population is predominantly white, reflecting the ethnic background of women entering nursing in the United States in the 1950s and 1960s. The 1992 questionnaire indicated the following ethnic composition: 1.2% African American, 0.6% Hispanic, 0.8% Asian, 17% southern European or Mediterranean, 7% Scandinavian, 60% other white, and 4% other ancestry. Similar to HPFS, the NHS cohort has been followed by mailed questionnaires sent every 2 years to update exposure information and to ascertain incident diseases. The participation rate has been very high. The follow-up for this cohort has exceeded 90% as well.
In 1982, 1984, 1986, 1988, 2002, and thereafter, biennial questionnaires asked whether participants had received a physician diagnosis of gout and, if so, the date of first occurrence. If the participant reported that gout had been diagnosed in 1980 (when dietary information was first collected) or later, a supplementary questionnaire was mailed to confirm the diagnosis according to the ACR survey gout criteria, the age of occurrence, family history, the type of symptoms, other relevant medical conditions, and treatment. The overall response rate for the supplementary gout questionnaire was 81%, similar to that observed in the HPFS. The concordance rate between the ACR criteria and medical records was greater than 90% based on 56 medical records.
The restriction to registered health professionals and nurses in these cohorts is both a strength and a limitation. The cohort of well-educated individuals minimizes potential for confounding associated with socioeconomic status, and investigators were able to obtain high-quality data with minimal loss to follow-up. Although the absolute rates of health outcomes and distribution of respective exposure intake may not be representative of a random sample of U.S. adults, their biological effects should be similar. These two prospective cohorts have provided a series of studies regarding lifestyle factors for the risk of gout, and those factors are discussed in detail next.
Individual Dietary and Lifestyle Factors and the Risk of Gout
Meat Intake
Meat intake could contribute to an increased risk of gout, likely because its high purine content raises serum urate levels, as was demonstrated by short-term metabolic experiments of purine loading in animals and humans. Furthermore, red meat is a key source of saturated fats, which are positively associated with insulin resistance, which reduces the renal excretion of uric acid. Indeed, a nationally representative sample of U.S. men and women indicated that higher levels of meat were associated with higher serum urate levels.
The HPFS showed that men in the highest quintile of meat intake had a 41% higher risk of gout compared with the lowest quintile. Specifically, the intake of two or more weekly servings of beef, pork, or lamb as a main dish was associated with a 50% increased risk of gout compared with less than one serving per month ( p for trend = .01). Saturated fats in red meat also increase LDL cholesterol levels more than HDL cholesterol, adding to a negative net health effect. Higher levels of these fats and red meat consumption have been linked to major disorders such as CAD, type 2 diabetes, and certain types of cancer. Thus, it would be beneficial for patients with gout to limit red and organ meat intake to help reduce the risk of both gout and associated major comorbidities (see Fig. 11-4 ).
Seafood and Omega-3 Fatty Acids
Seafood intake can also increase the risk of gout through its high purine content, despite not being associated with increased insulin resistance like red meat. The same nationally representative study showed higher levels of seafood consumption were associated with higher serum urate levels. The HPFS found that men in the highest quintile of seafood intake had a 51% higher risk compared with the lowest quintile. Increased intakes of tuna, dark fish, other fish; and shrimp, lobster, or scallops were all associated with an increased risk of gout ( p for trend <.05 for all items).
The recommendation regarding seafood in prevention of gout is not as straightforward as that for meat intake, because oily fish and omega-3 fatty acids reduce the incidence of cardiovascular disorders, according to many studies and clinical trials. Based on these data, the American Heart Association ( www.americanheart.org ) concludes that omega-3 fatty acids benefit the hearts of healthy people and those at high risk of—or who suffer from—CVD and currently recommends eating fish (particularly oily fish) at least twice weekly. Prospective secondary prevention studies suggest that eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplementation ranging from 0.5 to 1.8 g/d (either as fatty fish or supplements) significantly reduces subsequent cardiac and all-cause mortality. Similarly, total intakes of 1.5 to 3 g/d of α-linolenic acid seem beneficial. These apparent cardiovascular benefits from fish products make it difficult to justify a long-term recommendation to avoid all fish intake, considering the risk of gouty flares only. Cardiovascular prevention is likely more relevant among gouty patients, since the associated comorbidities of gout (e.g., insulin resistance syndrome, hypertension) or gout itself may pose an increased risk of CVD.
Patients with gout or hyperuricemia could consider the use of plant-derived omega-3 fatty acids or supplements of EPA and DHA in the place of fish consumption, for their cardiovascular prevention effects. This approach would provide the benefit of omega-3 fatty acids and avoid the increased risk of gout from the purine load contained in seafood. Further, diets enriched in both linolenic acid and EPA significantly suppress urate crystal–induced inflammation in a rat model, raising an intriguing potential protective role of these fatty acids against gout flares.
Dairy Intake
Dairy products may exert their urate-lowering effects without the concomitant purine load contained in other animal protein sources such as meat and seafood. Ingestion of milk proteins (casein and lactalbumin) has been shown to decrease serum urate levels in healthy subjects via the uricosuric effect of these proteins. Furthermore, a recent randomized trial has shown that milk intake has an acute urate-lowering effect via its low purine content in combination with increased excretion of uric acid in response to a protein load. Conversely, a previous 4-week randomized clinical trial showed a significant increase in uric acid level was induced by a dairy-free diet. In terms of nationally representative data on this link, dairy consumption was inversely associated with serum urate levels.
For the risk of gout, men in the highest quintile of dairy intake in the HPFS had a 44% lower risk compared with the lowest quintile, and the inverse association was limited to low-fat dairy consumption. Men in the highest quintile of dairy protein intake had a 48% lower risk of gout compared with the lowest quintile. The absence of the inverse association with high-fat dairy products could result from the counteracting effect of saturated fats contained in high-fat dairy products. Studies have suggested that low-fat dairy foods are associated with several potential health benefits, including a lower incidence of CHD, premenopausal breast cancer, colon cancer, and type 2 diabetes. Further, low-fat dairy foods have been one of the main components of the Dietary Approaches to Stop Hypertension (DASH) diet, which has been shown to substantially lower blood pressure. However, dairy consumption, including low-fat dairy foods, has been implicated in possible increases in prostate cancer. Weighing these benefits and risks, the recent healthy lifestyle pyramid recommends one to two daily servings of dairy products (see Fig. 11-1 ). This recommendation could be readily extended to patients with gout or hyperuricemia, perhaps with added benefits against comorbidities such as hypertension, diabetes, and cardiovascular disorders.
Purine-Rich Vegetables and Vegetable Protein
Contrary to popular belief and conventional practice, the consumption of purine-rich vegetables was found not to be associated with the risk of incident gout. Correspondingly, intake of individual purine-rich vegetable items was not associated with the risk of gout, including nuts, legumes, spinach, mushrooms, oatmeal, and cauliflower. Men in the highest quintile of vegetable protein consumption actually had a 27% lower risk of gout compared with the lowest quintile. While these findings may be explained by insufficient amounts or bioavailability of purine content in these food items, other major constituents of these items (fiber or healthy fat) may contribute to lowering insulin resistance and help reduce uric acid levels and eventually the risk of gout.
These findings have important long-term implications for patients with hyperuricemia and gout, as there are virtually no other protein sources for macronutrients, other than vegetables, once animal protein sources such as meat and seafood are reduced or eliminated from gout patients’ diets. Furthermore, these vegetables (especially nuts and legumes) are excellent sources of protein, fiber, vitamins, and minerals. Studies have suggested that nut consumption is associated with several important health benefits, including a lower incidence of CHD, sudden cardiac death, gallstones, and type 2 diabetes. Many kinds of nuts contain healthy fats, and controlled feeding studies have shown that nuts improve blood cholesterol ratios. Legumes or dietary patterns with increased legume consumption have been linked to a lower incidence of CHD, stroke, certain types of cancer, and type 2 diabetes. The recent healthy eating pyramid recommends once- to three-times daily consumption of nuts and legumes (see Fig. 11-1 ), which is also readily applicable to patients with gout or hyperuricemia.
Alcoholic Beverages
Alcohol can induce hyperuricemia, likely through both decreased uric acid excretion and increased production. The former is via conversion of alcohol to lactic acid, which reduces renal uric acid excretion by inhibiting urate anion secretion into the tubule lumen in the renal proximal tubule. The confounding effect of fasting often associated with heavy drinking has also been implicated as the culprit of decreased urinary excretion via inducing acetoacetic and beta-hydroxybutyric acidemia. Additionally, ethanol administration was shown to increase uric acid production by increasing adenosine triphosphate (ATP) degradation to adenosine monophosphate (AMP), a uric acid precursor. This process was later shown to involve acetate conversion to acetyl coenzyme A (CoA) in the metabolism of ethanol. Factors not directly related to uric acid implicated in the pathogenesis of gout include the frequent coexistence in heavy drinkers of other provocative factors, such as trauma and hypothermia of the lower extremities. These factors may explain why alcoholic gouty patients tend to have significantly lower serum urate levels than nonalcoholics during acute attacks of gout.
Prior to the HPFS, several cohort studies attempted to evaluate the association between alcohol intake and gout, but these studies were limited by small sample size and lack of relevant dietary variables. Subsequently, the HPFS showed that increasing alcohol intake was associated with increasing risk of gout in a dose-response relationship. Specifically, as compared with abstinence, daily alcohol consumption of 10 to 14.9 g increased the risk of gout by 32%, 15 to 29.9 g by 49%, 30 to 49.9 g by 96%, and 50 or more g by 153% ( p for trend <.001). Beer consumption showed the strongest independent association with the risk of gout (multivariate risk ratio [RR] per 12-oz serving per day 1.49; 95% CI 1.32-1.70). Consumption of liquor was also significantly associated with gout (multivariate RR per drink or shot per day 1.15; 95% CI 1.04-1.28); however, wine consumption was not associated with an increased risk of gout in this study (multivariate RR per 4-oz serving per day 1.04; 95% CI, 0.88-1.22). Correspondingly, a U.S. national survey study demonstrated corresponding associations between these individual alcoholic beverages and serum urate levels.
These findings confirmed the long-held belief of an association between alcohol intake and the risk of gout. In addition, they suggest that certain nonalcoholic components that vary among these alcoholic beverages may play a role in the incidence of gout. Beer is the only alcoholic beverage acknowledged to have a large purine content, which is predominantly guanosine, a readily absorbable nucleoside. The effect of ingested purine in beer on serum urate may be sufficient to augment the hyperuricemic effect of alcohol itself, producing a greater risk of gout than liquor or wine. There may be other nonalcoholic offending factors, particularly in beer. Wine is known to contain a number of nonalcohol components including antioxidants, vasorelaxants, and stimulants to antiaggregatory mechanisms. Since uric acid is considered an indicator for increased oxidative stress, nonalcoholic components in wine (e.g., polyphenols with antioxidant properties ) may potentially play a role in mitigating the impact of alcohol on serum urate.
The health benefits of moderate drinking likely outweigh the risks, especially among those within the demographics of the peak prevalence of gout (e.g., middle-aged men). More than 60 prospective studies consistently demonstrated that moderate alcohol consumption is associated with a 25% to 40% reduced risk of CHD. Also, a number of prospective studies also suggest a similar degree of protective effect against ischemic stroke, peripheral vascular disease, sudden cardiac death, and death from all cardiovascular causes. The benefits of moderate drinking appear to go beyond the heart. For example, moderate drinking has been linked to a decreased risk of gallstones and type 2 diabetes compared with abstinence. Based on these data, the recent Healthy Eating guideline for the general public allows moderate alcohol consumption (see Fig. 11-1 ), especially if one already drinks alcohol. The key is to keep the consumption in the moderate range (i.e., one to two drinks per day for men, and no more than one drink per day for women ). However, starting drinking is not generally recommended, as similar benefits could be alternatively sought via exercise or healthier eating.
These other health effects of moderate drinking may be considered in advising about alcohol intake to patients with existing gout or at a high risk of developing gout. For example, if you are a middle-aged man with no history of alcoholism who is at moderate to high risk for heart disease and gout, allowing a daily drink of wine may be acceptable, as it could bring associated health benefits perhaps without substantially increasing the risk of gout attacks. This approach may be especially relevant if the patient has low HDL-cholesterol that is not responsive to diet and exercise therapy, because moderate amounts of alcohol raise levels of HDL-cholesterol.
Sugar-Sweetened Sodas and Fructose-Rich Foods
The doubling of the prevalence and incidence of gout over the last few decades in the United States has coincided with a substantial increase in soft drink and fructose consumption. Fructose consumption has also increased dramatically since the introduction of commercially produced high-fructose corn syrup in 1967, while ingestion of naturally occurring fructose consumption has remained relatively stable. Fructose intake can raise serum urate levels by increasing hepatic ATP degradation to AMP, prompting activation of the pathway of purine degradation to uric acid ( Fig. 11-5 ). In contrast, glucose and other simple sugars do not have this effect. Furthermore, fructose intake is associated with serum insulin levels and insulin resistance and could, therefore, indirectly increase serum urate levels and the risk of gout.
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