EXAMINING THE EVIDENCE: SOY AND GOUT

Globally, in 2017, there were ~41.2 million prevalent cases of gout, with 7.4 million incident cases per year adding up to almost 1.3 million years lived with disability.¹ In the U.S., approximately 3.9% (9.2 million) of Americans have a history of gout, but men (5.2%, 5.9 million) are much more likely to report having this disease than women (2.7%, 3.3 million).²

Gout is the most common form of inflammatory arthritis worldwide. It is caused by deposition of monosodium urate crystals in joints and various other tissues and appears in relation to chronic hyperuricemia.³ Definitions of hyperuricemia vary, but Bardin and Richette⁴ proposed defining hyperuricemia as serum uric acid (SUA) levels above 6mg/dl, based on the increased life-long risk for developing gout that starts at this level. Elevated uric acid levels may also be a risk factor for cardiovascular disease (CVD).⁵

Uric acid is the final enzymatic product in the degradation of purine nucleosides and free bases in humans. It is produced by the conversion of the purine derivative hypoxanthine to xanthine and xanthine to uric acid by xanthine oxidase. Of the 4 purine bases, adenine and hypoxanthine are thought to have much more of an effect on uric acid levels than guanine and xanthine.⁶ More than 90% of gout patients have hyperuricemia; however, 90% of people with hyperuricemia remain asymptomatic.^7,8 

Traditionally, dietary recommendations related to gout have focused on limiting purine intake.⁹ For example, the 2017 position of the British Society for Rheumatology is that high purine foods should be avoided,¹⁰ and the 2014 Japanese Guidelines for the Management of Hyperuricemia and Gout recommend consuming less than 400mg of purines per day.¹¹ However, there is debate about the value of restricting purine intake. According to Beyl and colleagues,¹² the importance of patients with gout maintaining a low-purine diet has been deemphasized in recent years. And after reviewing nutritional recommendations for gout, Nielsen et al.¹³ concluded in 2018 that evidence in support of most of the dietary guidelines related to gout issued by health organizations/authorities are considered to be “moderate or low” or “very low” quality. 

Recent results of a cross-sectional study involving more than 6,000 elderly participants of the PREDIMED-Plus study are relevant to the discussion about purine restriction.¹⁴ Despite consuming purine-rich foods (Table 1), individuals in the highest tertile of total non-soy legume, lentil, and pea consumption had statistically significantly lower SUA levels than those in the lowest tertile, whereas chickpea and dry bean intake was unrelated to uric acid levels. This finding may be because purine bases and metabolites involved in the endogenous synthesis of purines affect SUA levels differently.¹⁵ For this reason, dietary recommendations should not be based solely on the purine content of a food but also on how that food affects plasma urate.⁹ 

Despite age-standardized incidence rates of gout in South Asia, Southeast Asia, and East Asia being lower than in Western Europe and North America (Table 2), there is a common belief among health professionals in Asia that soyfoods increase risk of gout.¹⁶ This perspective conflicts with the position of the British Society for Rheumatology, which recommends the consumption of soybeans be encouraged in overweight patients with gout. Additionally, a meta-analysis by Li et al.¹⁷ found that soyfoods were inversely related to the risk of gout and hyperuricemia. However, these findings were based on only 2 studies, a cross-sectional study from Shanghai¹⁸ and a prospective study from Singapore.¹⁹

The Shanghai study involved 3,978 men aged 40-74. Hyperuricemia was defined as a blood uric acid level >7.0mg/dl. One quarter of this population had hyperuricemia. Dietary information was collected by using a food frequency questionnaire (FFQ). An inverse association between soyfood consumption and hyperuricemia was observed after adjustment for 14 potential confounders (odds ratios for quintiles 1-5: 1.00, 0.90, 0.70, 0.89, and 0.77).¹⁸ During the years 1993-1998, the cohort study from Singapore involved 63,257 adults between the ages of 45 and 74 at the time of recruitment. Habitual diet information was collected via a validated semiquantitative FFQ, and physician-diagnosed gout was self-reported during 2 follow-up interviews up to the year 2010. A total of 2,167 participants developed gout during the follow-up period. The multivariate-adjusted hazard ratio (95% confidence interval) of gout, comparing the fourth soyfood intake quartile with the first quartile, was 0.86 (0.75-0.98; P for trend = 0.018).¹⁹

Observational studies showing that SUA levels of vegetarians (for whom soy is typically a part of the diet) are similar to or lower than the SUA levels of non-vegetarians are of potential relevance to assessing the impact of soy intake on gout risk. These studies have been conducted in Taiwan,^20-24  Hong Kong,²⁵ and the United Kingdom.²⁶ Urinary uric acid levels were also found to be reduced in response to a vegetarian diet, compared to a non-vegetarian diet.^27,28 However, the informative value of this research as it relates to soy is limited because multiple lifestyle and dietary factors impact SUA acid levels (see next article).

In addition to the observational data, 7 intervention trials evaluating the effects of soy or a diet containing soy on uric acid levels were identified (Table 3). These studies varied in design, and all but one were acute studies meaning that changes in SUA levels were determined 1-4 hours after ingestion of a soy product. Breslau et al.²⁹ reported there were no differences in SUA levels between a vegetarian and non-vegetarian diet after 9-12 days of following the respective diets. The exact amount of soy in the vegetarian diet was not indicated, but soymilk and 2 servings of textured vegetable (soy) protein were consumed daily. In contrast, Garell et al.³⁰ found that SUA levels significantly increased by about 10% at 3 hours following ingestion of soy protein isolate; whereas levels decreased in response to casein and lactalbumin. Similar findings were reported by Dalbeth et al.³¹ However, the practical implications of this research are unclear because participants in these studies consumed 80g of each protein. Somewhat parenthetically, some evidence suggests that cow’s milk, as well as several other foods, may have a uricosuric effect.³²

In the study by Brule et al.,³³ SUA levels increased in 1 of 3 participant groups at 2 hours post soy ingestion, whereas there were increases in all 3 groups in response to haddock but no increase was observed in response to liver. Each of the varying protein sources provided 50g protein. The results of one study suggest different soyfoods affect SUA levels differently. In comparison to baseline, whole soybeans, soymilk, and soy powder led to a significant increase in SUA levels of approximately 5-10% at 1 and 2 hours post ingestion, but at 3 hours only the response to soymilk was significant. Furthermore, tofu did not cause an increase.³⁴ However, not only was a non-soy protein control absent from this study, but the test products provided 40g protein, a much larger amount than would typically be consumed at one sitting.

The Japanese study by Yamashita et al.,³⁵ which involved 8 heathy males and 10 males with gout, found that 4 hours post tofu ingestion, SUA levels increased from 5.56 to 5.73mg/dl in the former and increased from 8.10 to 8.12mg/dl in the latter. Assuming the participants weighed 70kg, they consumed approximately 17g soy protein from tofu. The authors concluded that the results suggest tofu is a preferable source of protein for gout patients. Finally, the consumption of soymilk that provided 15.5g protein also had no effect on SUA levels; however, the assessment was done only at 1-hour post-ingestion.

In summary, the limited observational data do not suggest soyfoods increases risk of gout or elevate SUA levels. One longer-term clinical trial shows soyfoods do not increase SUA levels. Several acute intervention studies show modest increases in SUA levels in response to soy protein, but the practical implications of this research are unclear given the large amounts of soy protein consumed (³40g) and when considering that studies intervening 15-17g soy protein showed no effect.

Finally, as noted at the onset, elevated SUA levels may be a risk factor for CVD.⁵ However, elevated SUA levels may impact more than gout and CVD. After extensively reviewing the literature, Kanbaya et al.³⁶ concluded that uric acid is now being viewed “as a potential master conductor in the worldwide symphony of obesity, diabetes, and cardiorenal disease.” Given that the consumption of soyfoods at levels even higher than typically consumed by native Japanese³⁷does not appear to increase SUA levels and that to varying degrees the evidence suggests that soyfoods may help to reduce risk of CVD^38-41 and diabetes,^42,43 it is reasonable to suggest that patients with gout consider adding soyfoods to their diet.

Table 1. Purine content of selected food groups and foods (mg/100g wet weight, edible portion) add more foods

Table 2. Age-standardized incidence rates (per 100,00 population)⁴⁶

Table 3. Acute (3-4 hour) clinical studies examining the effect of soy protein on serum uric acid (SUA) and/or urinary uric acid (UUA) levels

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