man preparing to exercise in order to help reduce Gout and Hyperuricemia

Gout and Hyperuricemia

Gout and Hyperuricemia

Last Section Update: 11/2011

Contributor(s): Debra Gordon, MS

1 Overview

Summary and Quick Facts for Gout and Hyperuricemia

  • Gout is one of the oldest known and most common forms of arthritis; it is a crystal deposition disease in which crystals of monosodium urate form in joints and other tissues.
  • This protocol provides information concerning risk factors for gout as well as diseases associated with gout and elevated uric acid. It also describes emerging therapeutics, lifestyle and dietary changes, and integrative interventions.
  • Treatments for acute gout attacks typically manage pain and inflammation, and include NSAIDS, corticosteroids and colchicine. Lifestyle can also have a significant influence on the development of hyperuricemia and gout.

Gout is a form of arthritis in which excess uric acid forms crystals in joints and other tissues causing painful inflammation. Vitamin C, cherries, and other integrative interventions have been shown to decrease uric acid levels and the frequency of gout attacks.

Risk Factors for Gout

Several risk factors promote a high uric acid level and gout attacks:

  • Increasing age and being male
  • Intake of high-purine foods, including red meat, fish and shellfish
  • Alcoholic beverage intake, specifically beer and spirits

Diseases Associated with Gout/High Uric Acid

Along with gout, elevated blood levels of uric acid have been associated with other diseases:

  • Hypertension
  • Heart disease
  • Heart failure
  • Stroke
  • Metabolic syndrome and type 2 diabetes
  • Kidney stones or other kidney disease

Diagnosis and Conventional Medical Treatments

Blood tests can determine whether a patient is hyperuricemic (above 7 mg/dL in males and 6 mg/dL in females), but the most definitive feature in the diagnosis of gout is the identification of monosodium urate crystals in joint fluid or aspirates of tophi. Once gout has been diagnosed, conventional medical treatments include:

  • Drugs for acute attacks (non-steroidal anti-inflammatory drugs [NSAIDs], corticosteroids, colchicine)
  • Drugs to reduce hyperuricemia (xanthine oxidase inhibitors like allopurinol to decrease production of uric acid, uricosuric drugs to increase excretion of uric acid)

Emerging Therapeutics

Most mammals are able to convert uric acid to allantoin with the enzyme uricase and then easily excrete it through the kidneys. Humans and primates do not have this enzyme, but recently injectable drugs have been made available that will break down uric acid into allantoin in the blood.

  • Rasburicase (Elitek) and pegloticase (Krystexxa), which is approved by the Food and Drug Administration to lower uric acid levels in patients with gout

Lifestyle and Dietary Changes

  • Exercise daily and reduce weight as excess adiposity is associated with increased uric acid levels
  • Limit red meat intake (beef, pork, lamb); consume low-fat dairy products since they are inversely associated with gout risk; and consume vegetable protein, nuts, and legumes as they are not associated with gout risk.
  • Reduce alcohol intake and limit intake of sugar-sweetened beverages

Integrative Interventions

  • Vitamin C: Significantly reduces uric acid by inhibiting the enzyme xanthine oxidase.
  • Cherries: A traditional gout treatment rich in polyphenol antioxidants, cherries have been shown to reduce the number of acute gout attacks.
  • Coffee: Contains both caffeine and polyphenol antioxidants that may have independent roles in the reduction of gout risk.
  • Fiber: There is a significant association between higher fiber intake and lower risk of gout and hyperuricemia.
  • Folate: A dietary folate intake of at least 51.5 mcg/day showed a 70% reduction in gout risk compared to those who consumed less than this amount.

2 Introduction

Gout is one of the oldest known and most common forms of arthritis; it is a crystal deposition disease in which crystals of monosodium urate form in joints and other tissues. Gout attacks cause a characteristic painful inflammation of one or more joints of the extremities, or nodules in soft tissues called tophi. An acute attack of gout, although brief and usually subsiding spontaneously, can be temporarily debilitating, and predisposes an individual to subsequent attacks.

Once a disease of only the affluent (who could afford the purine-rich foods and drink linked to gout risk), this "disease of kings" has rapidly become a disease of everyman. The prevalence of gout among US adults, according to the National Health and Nutrition Examination Survey (2007‒2008) is estimated at 3.9% (8.3 million people), favoring men over women by almost 3:1.1 This represents a significant 44% increase in gout frequency from previous estimates just a decade earlier.2

The primary risk factor for gout is elevated levels of a metabolic byproduct called uric acid in the blood; this condition is known as hyperuricemia. Hyperuricemia is estimated to affect over 21% of the US population, and doubles in frequency between ages 20 and 80 years.1

Hyperuricemia increases the risk of not only gout, but other diseases as well, including hypertension, kidney disease, and metabolic syndrome. Even during the asymptomatic periods between gout attacks, the body is exposed to periods of low-grade, chronic inflammation. The propensity for excessive blood uric acid and gout is also increased by other disease states; therefore, a gout or hyperuricemic patient should consider Life Extension's recommendations and protocols for inflammation, cardiovascular disease, hypertension, kidney health, and weight loss as well.

3 Uric Acid Metabolism

Uric acid is the final product of purine metabolism in humans. Purines are components of nucleosides, the building blocks of DNA and RNA. Purine nucleosides (adenosine and guanine) are used in the creation of other metabolically important factors as well, such as adenosine triphosphate (ATP; the energy-carrying molecule), S-adenosyl methionine (SAMe; the methyl donor), and nicotine adenine dinucleotide (NADH; an important cofactor in energy production and antioxidation). Given the importance of purine-containing molecules for survival, vertebrates, including humans, have developed robust systems for synthesizing sufficient purine nucleosides for their metabolism using readily available materials (such as glucose, glycine, and glutamine), as well as recycling purine nucleosides from throughout the body or from the diet.

In mammals, excess purine nucleosides are removed from the body by breakdown in the liver and excretion from the kidneys. For most mammals, the purines are first converted into the intermediate uric acid, which is then metabolized by the enzyme uricase into the compound allantoin. Allantoin is a very soluble compound that can easily travel through the bloodstream, become filtered by the kidneys, and be excreted from the body. In contrast to other mammals, humans and other primates lack a functional uricase enzyme, and can only break purines down into uric acid.

The levels of uric acid in the blood depend on two factors. The first is the rate of uric acid synthesis in the liver. Since uric acid results from purine degradation, its levels are influenced by both the amount of purines synthesized in the body, as well as the amounts of purines absorbed from the diet.3 The second determinant of blood uric acid levels is the rate of uric acid excretion from the kidneys. Excretion has the greatest effect on blood uric acid levels, with about 90% of hyperuricemia cases attributed to impaired renal excretion.4 Impaired excretion is most often due to abnormalities in the kidney urate transporter (called URAT1) or organic ion transporter (OAT), both of which control the movement of uric acid out of proximal kidney tubules and into urine.5

One of the most intriguing aspects of uric acid is that although it appears to be a "waste product" of purine metabolism, only about 10% of the uric acid that enters a normal human kidney is excreted from the body.3 In other words, rather than eliminating uric acid, a healthy kidney returns up to 90% of it to the bloodstream. The reason for this is likely due to the role or uric acid as one of the most important antioxidants in body fluids, responsible for the neutralization of over 50% of the free radicals in the blood stream.6

The ability of humans and primates to preserve blood levels of uric acid (due to slow kidney filtration and lack of a uricase enzyme) was probably advantageous to our evolution, by increasing antioxidant capacity of the blood.7

Humans and primates are one of the few mammals that cannot produce their own vitamin C, and may have evolved the ability to preserve uric acid to compensate for this.8 For example, blood uric acid levels in humans are normally about six times that of vitamin C, and about 10 times the levels in other mammals.9 Like vitamin C, uric acid has a principle role in protecting high-oxygen tissues (like the brain) from damage, and low blood uric acid levels have been associated with the progression or increased risk of several neurological disorders, including amyotrophic lateral sclerosis,10 multiple sclerosis,11 and Huntington's,12 Parkinson's,13 and Alzheimer's diseases.14

4 Hyperuricemia and the Development of Gout

Uric acid is a metabolic "waste product" with poor solubility in body fluids, yet its potential role as a primary antioxidant in body fluids suggests it should be kept at sufficient levels in the blood. Clearly, these diametric properties of uric acid define a range for normal blood uric acid levels. Commonly, the upper limit of this range is taken as 8.6 mg/dL in men and 7.1 mg/dL in women, (although some laboratories and research groups use different limits).15-17 Uric acid levels above this limit are considered as hyperuricemia.

Hyperuricemia is a primary risk factor for the development of gout, although it is likely that many hyperuricemic individuals will not develop symptoms.7 While the risk of a gout attack increases with blood uric acid, the annual occurrence of inflammatory gout is fairly low; persons with blood uric acid levels between 7 and 8.9 mg/dL have a 0.5‒3% change of developing the disease, which rises to 4.5% at levels over 9 mg/dL.18

Hyperuricemia without symptoms (asymptomatic hyperuricemia) is also a risk factor for other diseases. Although patients with asymptomatic hyperuricemia may never experience the symptoms of a gout attack, ultrasound studies have revealed that up to one-third may have urate deposits and evidence of inflammation in their joints and surrounding soft tissues.19

As local serum uric acid concentrations rise above their limit of solubility, monosodium urate can begin to precipitate out of the blood, forming needle-like crystals preferentially in cartilage and fibrous tissues. Here, the crystals may reside for years without causing problems.20 Urate crystals within tissues have two fates; they can re-dissolve in body fluids and reenter circulation, or may be "shed" from the tissue. Shed monosodium urate crystals can enter nearby joint spaces or bursa (the fluid-filled sacs that provide cushioning between tendons and bones around a joint), where they are quickly engulfed by immune cells. This activates a localized inflammatory response, leading to the characteristic arthritis of gout.21

Gout is commonly divided into distinct "phases" of recurrent attacks of acute gout interspersed with symptom free periods, with cumulative crystal deposition gradually contributing to a chronic condition (chronic tophaceous gout).

An attack of acute gout usually appears as a sudden inflammatory arthritis of a single joint in the lower extremities, most often the metatarsophalangeal joint of the big toe (the "ball" of the foot). At this joint, gout is called podagra. Other joints that are frequently affected include the mid-foot, ankle, knee, wrists and finger joints. The skin may be red and shiny above the affected area. Attacks often begin in the early morning and reach a peak within 6 to 24 hours. The pain is severe, and patients often cannot wear socks or touch bedsheets during flare-ups.22 Even without treatment, the attacks typically subside spontaneously within several days to two weeks. Acute gout attacks can also be accompanied by high fever and leukocytosis (elevated white blood cell count).20

Gout attacks can be triggered by a variety of factors, many of which reduce the solubility of urate in the blood; these include infection, trauma to the joint, rapid weight loss, dehydration, acidosis, and lower body temperature (which explains the timing of gout attacks and why they most frequently occur in the extremities).22

Following resolution of an acute attack, a patient can enter an "intercritical period," or a period without symptoms. Although the patient may be asymptomatic, monosodium urate crystals and low-grade inflammation can persist in the joint during this period.23 Once an initial acute gout attack has occurred, further attacks are likely to follow. Recurrent attacks of acute gout often lead to chronic tophaceous gout, in which monosodium urate deposits (tophi) form in the soft tissues, usually along the rim of the ear, over the elbow joint, and in the joints of the fingers and toes. Tophi reduce the growth and viability of bone cells (osteoblasts)24 and if left untreated, tophaceous gout can lead to significant joint erosion and loss of function.22

The Role of Hyperuricemia in Other Conditions

Although hyperuricemia is most often associated with gout, elevated blood levels of uric acid have also been associated with other diseases. Hyperuricemia and gout are both risk factors for kidney or bladder stones (urolithiasis). Both conditions increase the risk of forming not only uric acid stones, but also the more common calcium oxalate stones. The presence of calcium oxalate stones is 10‒30 times higher in gout patients than those without gout.25 Deposits of monosodium urate crystals in kidney tissues can result in kidney damage (nephropathy), either acutely by formation of crystals within the tubules of the kidney, or through a chronic inflammatory response to urate deposits in other tissues of the kidney.26 Prior to the development of uric acid lowering treatments, kidney disease occurred in up to 40% of gout patients; renal failure was the usual cause of death in 18‒25% of these patients.7

Hyperuricemia is a risk factor for cardiovascular diseases in high risk groups, and has been associated with small increases in the risk of coronary events,27 heart failure,28 and stroke.29 It is often seen in patients with hypertension; high blood pressure has long been thought to contribute to elevated blood uric acid, possibly due to reduced blood flow to the kidneys and lower urate excretion.30 However, recent experimental and epidemiological data suggest that the opposite may be true: a comprehensive review of 18 observational studies revealed that for each 1 mg/dL increase in blood uric acid, in risk of hypertension increased by 13%.31 This effect was more pronounced in women and young adults. Lowering of uric acid levels in hyperuricemic, hypertensive adolescents reduced their blood pressure as well.32 Ironically, the increased risk of cardiovascular diseases associated with hyperuricemia may be due to increases in oxidative stress: xanthine oxidase, the enzyme that synthesizes uric acid, also produces free radicals in the process.6

Hyperuricemia is an integral part of metabolic syndrome,20 and epidemiological studies have demonstrated that elevated uric acid levels substantially increase metabolic syndrome risk (and vice versa).33,34 Data from the Multiple Risk Factor Intervention Trial (MRFIT) showed hyperuricemia was associated with increased risk of type 2 diabetes, and that male patients with gout had a 41% increased risk for the disease.35

5 Risk Factors for Gout

Hyperuricemia is the primary risk factor for gout, and is required, although not sufficient, for the progression of the disease. The risk of gout increases with age and is more common in men; increased risk is also associated with other medical conditions including hypertension, obesity, renal insufficiency, early menopause (hormone therapy can reduce this risk), hypercholesterolemia, and surgery. Some medications increase gout risk (which is reversible upon discontinuation), particularly loop and thiazide diuretics, but also anti-tuberculous drugs, cyclosporin, and levodopa.20,36-38 Aspirin has a dual effect on uric acid levels; low doses inhibit excretion and increase blood levels, while very high doses (>3,000 mg/day) reduce levels.20 At 75 mg/day in elderly patients, the increase in blood uric acid is about 6%.39

Uric acid levels are very sensitive to dietary influences. High-purine foods, particularly red meat, fish, and shellfish, have long been known to increase hyperuricemia and gout risk. Data from the Health Professionals Follow-up Study, which followed over 47,000 health professionals for 12 years, revealed that individuals with the highest intakes of beef, pork, or lamb (>1.9 servings/day) and seafood (>0.6 servings/day) increased their risk of gout by 77% and 53%, respectively.40 There were no associations between total protein intake, total animal protein (including dairy protein, poultry, and eggs) intake, or purine-rich vegetable intake and the incidence of gout.

Alcoholic beverages increase blood uric acid and gout risk.41,42 In one study, individuals who consumed one beer or one serving of spirits per day had 1.75 and 1.22 times the incidence of gout, respectively, than individuals who consumed less than one drink a month. Drinking over two beers/day increased gout risk by 2.5-fold.42 Wine does not appear to affect gout risk. Alcohol metabolism to acetate accelerates the breakdown of purine-containing nucleotides (like ATP) and raises blood uric acid.43 Alcohol can also lower body temperature in the extremities which may precipitate an acute attack independent of blood uric acid concentration (gout attacks can occur in alcoholics at lower blood urate levels than in non-alcoholics).44 Beer, despite having less alcohol per serving than the other beverages, is more hyperuricemic due to its high purine content.45

Fructose has been positively associated with both gout and hyperuricemia risk in some studies, but has had no significant effect in others. In the third National Health and Nutritional Examination Survey (NHANES III), 14,761 individuals over 20 years old who consumed one or more sweetened soft drinks per day had levels of blood uric acid that averaged 0.5 mg/dL higher than non-drinkers.46 By comparison, persons who consumed an equivalent amount of orange juice had blood uric acid levels that averaged only about 0.15 mg/dL higher than non-juice drinkers. An analysis of more recent NHANES data, however, failed to find any significant association between total fructose consumption and hyperuricemia risk. These results, in addition to the conflicting results of several metabolic studies of fructose in human volunteers, suggest the relationship between fructose and hyperuricemia may be sensitive to factors aside from just the amount of ingested sugar.16

6 Diagnosis of Gout

Gout usually presents with characteristic inflamed, painful joints in the extremities, but these symptoms are also common to other conditions, particularly pseudogout (a related condition caused by the accumulation of calcium pyrophosphate crystals in the joint) or septic arthritis (caused by joint infection). Blood tests can determine whether the patient is hyperuricemic (typically a serum concentration above 7 mg/dL in males and above 6 mg/dL in females). While hyperuricemia is the most important risk factor for gout its diagnostic power may be limited; as some hyperuricemic patients may never develop the disease, and blood urate levels may be normal during an acute attack (in one study, 14% of patients had blood uric acid levels of <6 mg/dL during their gout attacks).17

The European League Against Rheumatism (EULAR) recently published guidelines for gout diagnostic criteria, based on accumulated studies of gout diagnoses. According to their analysis, the most definitive feature in the diagnosis of gout is the identification of monosodium urate crystals in synovial (joint) fluid or aspirates of tophi.15 This involves the insertion of a fine needle into the joint or tophus and withdrawing a fluid sample, which is subsequently examined under a microscope.47 The presence of large needle-shaped crystals confirms the presence of monosodium urate, and can be used to differentiate gout from pseudogout or septic arthritis.

The presence of urate crystals in the joints of asymptomatic patients can be used to identify intercritical periods in patients with recurrent gout, or can be used to screen patients who may benefit from urate-lowering therapy prior to their first acute gout attack. Screening of the joints of the extremities using ultrasound is being explored as a non-invasive method to improve the detection of urate crystals in asymptomatic patients. In a pilot study, ultrasound correctly identified urate crystals in the joints of asymptomatic, hyperuricemic volunteers with an accuracy of 81%.48

7 Conventional Treatment of Gout

Treatments for acute gout attacks typically manage pain and inflammation, and include NSAIDS, corticosteroids, and colchicine. While treatments for acute gout are typically short term, there are risks of significant gastrointestinal side effects for NSAIDs and colchicine in some individuals. Moreover, though colchicine is approved by the Food and Drug Administration (FDA) to treat acute gout flares, it has a low therapeutic index, meaning the dose required to exert a beneficial effect is near that which is potentially toxic. Aspiration of affected joints to relieve pressure, and injection of long-acting steroids are commonly used treatments in practice, although they have not been investigated in controlled trials.49

After the initial attack has subsided, patients are usually encouraged to adopt lifestyle changes that may reduce hyperuricemia and gout risk (such as lower purine diets, weight loss, or exercise). Many will be placed on longer-term uric acid-reduction therapy. Recall that uric acid levels are controlled by the rate of uric acid production and the rate of uric acid excretion; current therapies address either of these two aspects.

Xanthine oxidase inhibitors reduce the activity of xanthine oxidase, the final step in uric acid synthesis. This has the effect of lowering uric acid production. Allopurinol (Zyloprim) has a long history of usage as a xanthine oxidase inhibitor; recently febuxostat (Uloric) has been approved for treatment of hyperuricemia in the United States. Febuxostat exhibits greater uric acid-lowering effects than allopurinol, although the incidence of gout flares is similar between the two drugs.50

Uricosuric drugs increase the excretion of uric acid from the kidneys, primarily by reducing the absorption of uric acid from the kidneys back into the blood. Probenecid (Benemid) and sulfinpyrazone (Anturane) are two examples. These drugs tend to increase urinary uric acid levels, which can cause kidney stones.

The tophi of chronic gout, if severe enough to cause joint dysfunction or deformity, can also be treated by surgical removal.51,52

Innovative New Drugs for the Management of Chronic Gout

As mentioned earlier in this protocol, in most mammals uric acid is converted into the more soluble compound allantoin by an enzyme called uricase. This conversion allows for the urinary excretion of allantoin, thereby reducing uric acid blood levels. However, humans are unable to facilitate this conversion due to an evolutionary loss of the uricase enzyme.

Recently, scientists have recreated the mammalian uricase enzyme in the laboratory and generated injectable medications that deliver the recombinant enzyme it into the blood. Once in the blood stream, the recombinant uricase enzyme breaks down uric acid into allantoin, which is then easily excreted through the human kidneys.

By injecting this enzyme otherwise not present in higher primates, the rate of uric acid excretion can be expedited.

Two such medications are available—rasburicase (Elitek), and a chemically modified version of this same drug, called pegloticase (Krystexxa). Pegloticase is FDA approved to lower uric acid levels in patients with chronic gout.53

In two concurrent randomized, double-blind, placebo-controlled trials, pegloticase, administered at a dose of 8 mg either every two weeks or every four weeks, efficiently lowered uric acid levels.54 The participants in these studies consisted of patients with chronic gout, which had not been relieved by allopurinol, and blood uric acid levels above 8.0 mg/dL at baseline. Reduction of uric acid levels to <= 6.0 mg/dL was the primary endpoint, and was achieved in 38% of patients receiving biweekly injections, and in 49% of those receiving monthly injections.

However, pegloticase may cause some side effects. In the studies mentioned previously, between a quarter and a half of subjects experienced an injection site reaction, of which 6.5% were considered to be anaphylaxis. This means that physicians may opt to administer corticosteroids before pegloticase in order to suppress the immune system in hopes of avoiding an inflammatory response. The long-term effects of corticosteroids in combination with pegloticase have not been studied as of yet, so the side effects in gout patients remain unknown.55

Many physicians may not be aware of the availability of pegloticase for lowering uric acid levels in gout patients due to its recent FDA approval. Individuals with chronic gout that has not improved after the use of conventional gout medications should consider asking their healthcare professional if pegloticase is right for them.

8 Dietary Approaches to Control Hyperuricemia and Reduce Gout Risk

Lifestyle can have a significant influence on the development of hyperuricemia and gout. Accumulated data from several large epidemiological studies suggest several possible modifications for significant reductions in gout risk56:

Exercise daily and reduce weight. Increased adiposity is associated with increased uric acid levels and gout risk.

Limit red meat intake. Beef, pork, and lamb are high-purine foods that can significantly increase gout risk.

Adjust fish intake to individual needs. Carefully balance the benefits of omega-3 fatty acids with the increased gout risk; or consider taking an omega-3 supplement. High quality fish oil supplements are highly purified and the purine content in these oils is either undetectable, or present in trace amounts that pose no risk of raising gout levels.

Drink skim milk or consume other low-fat dairy products. Dairy consumption is inversely associated with gout risk.

Consume vegetable protein, nuts, and legumes. Nuts and legumes are good sources of non-uricemic protein; legumes and vegetables (even those high in purines) are not associated with gout risk.

Reduce alcohol intake. Moderate alcohol consumption has cardiovascular benefits, but beer and spirits significantly increase gout risk. Red wine, on the other hand, appears not to increase gout risk.

Limit intake of sugar-sweetened beverages. Fructose in these beverages might increase hyperuricemia and gout risk. Although fruits also contain fructose, it is usually present at lower levels and most have health benefits that justify their consumption.

9 Nutrients

In addition to these diet and lifestyle changes, several individual dietary factors may reduce hyperuricemia or gout risk.

Vitamin C

Vitamin C is an essential water-soluble antioxidant vitamin in humans, which has been shown in laboratory tests to exert a uric acid-lowering effect by inhibiting the enzyme xanthine oxidase.57 In a comprehensive review of 13 randomized controlled trials of vitamin C supplementation in a total of 556 adults with normal kidney function, an average reduction in blood uric acid of 0.35 mg/dL was observed for an average dose of 500 mg/day for a median duration of 30 days.58 The most significant reductions were observed in persons with higher initial baseline uric acid concentrations (patients with a blood uric acid level of >4.85 mg/dL saw a 0.78 mg/dL reduction). In a large study (184 healthy subjects), vitamin C also increased the glomerular filtration rate (the rate at which blood is filtered in the kidney and a measurement of kidney function) when compared to the control group.59 Future trials are necessary to determine whether vitamin C intervention can prevent the incidence and recurrence of gout. Plasma levels of vitamin C are also inversely associated with blood pressure,60,61 which may be an independent risk factor for gout.


Cherries are a traditional gout treatment rich in polyphenol antioxidants,62,63 and a small set of clinical cases in the 1950's documented decreased duration and severity of gout attacks in three people on cherry-supplemented diets.64 Two more recent investigations have demonstrated a potential role of cherries in the management of gout, although they present conflicting mechanisms for this action. After a single dose of 280 grams of cherries, blood urate levels in 10 healthy women dropped by 14% after five hours, while urinary urate levels increased.62 C-reactive protein (CRP), a marker of inflammation, also decreased slightly. A second study of 100 patients with recurrent gout taking 15 mL/day of cherry juice concentrate for 4‒6 months also revealed decreases in markers of inflammation, as well as a >50% reduction in the number of acute gout attacks for 92% of treated patients.65 However, uric acid levels were not lowered in this group, and averaged 7.8 mg/dL. Although it appears that cherries may reduce the frequency of gout attacks, the mechanism for this action clearly does not depend solely on lowering blood uric acid levels.


More than 50% of Americans drink coffee, and the average per capita intake is two cups per day.66 Coffee contains both caffeine and polyphenolic antioxidants that may have independent roles in the reduction of gout risk. The relationship between coffee consumption and the risk of gout has been examined in two large observational studies. In the Nurse's Health Study, 89,433 women were tracked over 26 years for their consumption of coffee—those who consumed more coffee had a lower risk of gout.56 The largest reductions in risk were observed in women who consumed over four cups of caffeinated coffee per day (-63%), although modest consumption of decaffeinated coffee (>1 cup/day) reduced gout risk by 23%. In the same population, tea had no effect. A similar study of 45,869 men for 12 years demonstrated a similar effect for both caffeinated and decaffeinated coffees, which was significant at coffee intakes over four cups a day (-40% risk).67

Much of the protective effect of coffee against acute gout can be attributed to caffeine in the above studies; caffeine (1,3,7- trimethyl-xanthine) is a competitive inhibitor of xanthine oxidase.68 The protective effect of decaffeinated coffee suggests other compounds may also important. For example, some evidence suggests iron overload may contribute to the development of gout, and chlorogenic acids from coffee have been shown to reduce iron absorption.69 Conventional coffee, due to the roasting process, contains very little chlorogenic acids. However, recent innovations have led to the availability of a green coffee extract high in chlorogenic acids, which can be taken in the form of a supplement. Green coffee extract supplements are a superior source of chlorogenic acids and other healthful coffee compounds as compared to conventionally roasted coffee beans used to make coffee beverages.70,71


An analysis of fiber intake data in 9,384 adults without cancer, diabetes, or heart disease from the National Health and Nutrition Examination Survey (NHANES) 1999‒2004 revealed a significant association between higher fiber intake and lower hyperuricemia risk. The study, which used a higher blood uric acid limit for the definition of hyperuricemia (8.4 mg/dL for men and 7.4 mg/dL for women), demonstrated a 55% reduction in hyperuricemia risk between the highest fiber consumption (9.5 grams fiber/1,000 kcal of total food intake, or 19 grams fiber/day for the average 2,000 kcal diet) and the lowest (<4.6 grams/1,000kcal, less than 9.2 grams fiber/day).16 A smaller case-controlled study of 92 gout patients and 92 gout-free controls demonstrated a statistically significant reduction in the risk of gout among people with the highest intake of total- and soluble fiber.72 While these mechanisms for this reduction is unknown, dietary fiber may inhibit purine or adenine absorption in the digestive system.73 Fiber has also been shown to reduce other independent risk factors for gout, including hypertension74,75 and high cholesterol.76


A small case-controlled study of 92 gout patients and 92 gout-free controls demonstrated a statistically significant reduction in the risk of gout among persons who consumed over 51.5 mcg/day of folate from food sources (a 70% reduction compared to those who consumed less than this value).72 No significant effects on gout risk were observed for vitamins A, E, or the other B vitamins in this study.

Chinese Herbs

Several Chinese medicinal plants have been tested for xanthine oxidase inhibitory activity. The most active was the methanol extract of Chinese cinnamon (Cinnamomum cassia), followed by Chrysanthemum indicum and Lycopus europaeus. Among water extracts, the strongest inhibition was observed with Polygonum cuspidatum, which is an excellent source of the polyphenol resveratrol. These herbs have been used in China to suppress gout.77 Extracts from two traditional Chinese anti-gout treatments (Paederia scandens and Smilax china) both decreased blood uric acid concentration in rats with experimentally-induced hyperuricemia.78,79

Terminalia bellerica (T. bellerica), native to parts of Asia, is an important medicinal plant in traditional Ayurvedic medicine. The dried fruit of T. bellerica is the part used in medicine, and is considered to have a wide range of benefits including cholesterol- and blood sugar-lowering effects; protecting the heart, kidney, and liver; and combatting inflammation and oxidative stress.80,81

T. bellerica is a source of many bioactive compounds, notably tannins and related constituents, that contribute to its usefulness in gout and arthritis. Specifically, T. bellerica is believed to inhibit the enzyme xanthine oxidase, which may account for its ability to lower uric acid in both animals and humans. In fact, in a laboratory trial, T. bellerica was found to exert the same degree of xanthine oxidase inhibition as the gout drug allopurinol.81-83

A six-month, double-blind, placebo-controlled clinical trial was completed by 88 individuals with elevated uric acid. This trial compared 500 mg twice daily of a T. bellerica fruit extract, standardized to 15% tannins, to 250 mg of the same extract, placebo, and 40 mg of the uric acid-lowering medication febuxostat. The higher dosage of T. bellerica reduced uric acid concentrations by over 27%, while the low dose was roughly half as effective; and uric acid increased in the placebo group. While all subjects in the febuxostat group reached the target uric acid concentration of ≤ 6 mg/dL, nearly 89% in the high dosage and 12% in the low-dosage T. bellerica group did so as well. No adverse effects were observed in any subjects receiving T. bellerica.82


Flavonoids may lower blood uric acid through their ability to inhibit the enzyme xanthine oxidase; olive leaf constituents, milk thistle constituents, apigenin, myricetin, luteolin, and genistein have all shown this ability in laboratory experiments; apigenin had an inhibitory activity comparable to the synthetic xanthine oxidase inhibitor allopurinol.84-87 In fructose-induced hyperuricemic rodents, quercetin, rutin, kaempferol, myricetin, and puerarin all significantly reduced blood uric acid to levels equivalent to healthy control animals.88,89 Grape seed procyanidins were found to have uric acid-lowering effects in rats with hyperuricemia. The procyanidin-treated animals exhibited normal growth compared to animals treated with allopurinol, which exhibited some retarded growth.90

Anti-inflammatory Nutrients: A Potential Role in Chronic Gout?

While hyperuricemia and urate crystal formation are requirements for an acute gout attack and a contributing factor for chronic gout, inflammation is clearly central to the disease. Several labs have investigated the chemical cascades that mediate this process. Under certain conditions, cells of the innate immune system (the macrophages or "big-eaters") that reside within tissues recognize the presence of urate crystals. Through a process that is still not fully elucidated, these cells are stimulated to produce pro-inflammatory cytokines (particularly IL-1β), which recruit inflammatory white blood cells (neutrophils) to the site of crystal deposition.91,92 The circumstances surrounding the cessation of inflammation in acute gout are equally puzzling. Data suggest a yet-unidentified gout promoting "factor" that must be present with the urate crystals in order for an acute attack to occur.93

Although it seems a reasonable assumption that anti-inflammatory nutrients may have a role in mitigating gout attacks, research in this specific area is lacking. The quick progression and resolution of acute gout may make it less amenable to nutrient "interventions" (many of which have only been tested for their long-term effects on inflammation). However, the intercritical periods between attacks have been associated with sustained low-level inflammation,94 a situation more readily addressed by dietary modification. Nutrients that have been shown to attenuate joint inflammation and reduce pro-inflammatory cytokines (including IL-1β), such as curcumin,95,96 omega-3 fatty acids,97 and resveratrol98 may be especially suited for this purpose. Experimental diets high in the omega-3 fatty acid EPA and the healthy omega-6 fatty acid GLA were shown to reduce urate crystal-induced inflammation in a rat model.99 Omega-3 supplements may be more suitable for hyperuricemic patients who are limiting fish intake.56


  • Nov: Comprehensive update & review

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