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