by Dr. Miles Nichols and Aaron Mello, CNTP, MNT
Last week I wrote about oxalates, which are substances in plant foods that appear to play a causative role in many health conditions. Oxalates also factor in to gout, a type of arthritis sometimes referred to as “gouty arthritis” that occurs when uric acid accumulates in the body. Uric acid in the form of urate crystals deposit in a joint of the body, most often in the big toe. Much like the oxalate crystals that can form kidney stones, as discussed last week, uric acid crystals are sharp and jagged and can cause intense pain.
Historically, gout was referred to as the “disease of kings,” as one common causative factor is the overconsumption of rich foods. Until fairly recently in our history, only royalty were able to afford and obtain such rich foods and alcohol in sufficient quantities to lead to gout. In contrast, “peasant food” was often bland and rich treats were only an occasional indulgence at best. Today, many people are fortunate enough to eat more rich foods and an estimated 8.3 million people are affected by gout in the United States alone (1). Of course, this is a double-edged sword and for some people, the catch is that eating these type of foods to excess leads to a gout flare.
Gout attacks can be quite painful and prevent people from participating in activities they enjoy, especially if the big toe is affected, as walking can be quite painful. If you, a friend or family member, or a patient of yours is struggling to manage his/her gout, this article is for you! Keep reading to learn more about what factors contribute to gout, how to prevent gout flares, and the treatment options that are most effective to manage gout and prevent future gout attacks.
Uric acid, the primary cause of gout
Accumulation and deposition of uric acid crystals in joints causes gout and the intense pain associated with the disease. Hyperuricemia, or high uric acid levels, have also been linked to hypertension, atherosclerosis, insulin resistance and diabetes. In humans and great apes, uric acid is the end product of purine degradation. In contrast, other mammals have retained uricase, an enzyme that further degrades uric acid into allantoin. The gene which codes for allantoin has been inactivated in hominids due to mutational silencing, leading to significantly higher urate levels in humans than most other mammals (2).
The silencing of this gene is hypothesized to confer a selective advantage in the evolution of homonids because in some chemical environments, urate acts as an antioxidant. But paradoxically, in other situations urate has pro-oxidant properties and hyperuricemia is associated with multiple diseases in humans (3). The details of this paradox are interesting and still being illuminated, but are beyond the scope of this article. We will focus here on reducing uric acid levels to prevent gout attacks.
Demographics and prevalence of gout
Although gout can strike anyone at any age, it primarily affects older men. Multiple studies have found higher levels of serum uric acid levels in men, which presumably helps to explain this gender gap (4). There is a clear increase in the prevalence of gout in both sexes in older age, and rates of gout are increasing in the United States as well as globally (5). Some possible reasons for increased rates of hyperuricemia and gout include several seemingly positive changes like increased prosperity and increased life expectancy. Some other factors are an increased use of hypertensive drugs, and aging of the overall population. In addition, consumption of fructose, especially in the form of high fructose corn syrup (HFCS) has increased dramatically in recent decades (6).
Gout is related to a constellation of metabolic and cardiovascular disorders that are also on the rise. Hyperuricemia is commonly found in patients with metabolic syndrome (7) and obesity, especially visceral adiposity (8). Hyperuricemia is also considered to be an independent risk factor for the development of hypertension and there is also a strong association between serum uric acid levels and cardiovascular mortality (9). In fact, some research has shown that hyperuricemia predisposes to plaque formation and endothelial dysfunction (10). This research indicates that hyperuricemia and gout are not just a matter of annoying pain, but are independent risk factors for serious health conditions. Next, let’s look at gout in more detail.
Purines and gout
Purines are organic compounds that are prevalent throughout the plant and animal kingdom. They are present in human body cells and play and essential role in the synthesis of DNA and RNA. Purines belong to a family of nitrogen-containing molecules that help build genetic material in living organisms. Like anything else, too much of a good thing can lead to trouble, especially in people who are predisposed to high levels of uric acid. As I mentioned in the section above on uric acid, the end result of purine metabolism in humans is uric acid, which in turn contributes to gout attacks. And as we’ll see in the treatment section below, a low purine diet is a key component of preventing gout attacks. Next, I’ll review two other dietary contributing factors that can lead to gout attacks – fructose and alcohol.
Fructose, alcohol and uric acid
Fructose is a type of sugar that is high in fruit, honey, and high fructose corn syrup (HFCS). Dietary fructose is metabolized into purines in the body, especially in people with certain genetic predispositions. This will be discussed in the next section. Even in people without a genetic polymorphism, fructose increases purines and uric acid production by increasing ATP degradation to AMP, which is a precursor of uric acid. Because fructose phosphorylation in the liver uses ATP and phosphorylation prevents regeneration of ADP into ATP, increased levels of AMP are produced (11). This has been demonstrated to increase serum uric acid concentrations within minutes of fructose infusion, which in turn leads to increased urinary uric acid concentrations over time (12). This phenomenon is fructose specific; glucose and other simple sugars do not have the same effect.
A second mechanism of action in uric acid production is that fructose may also increase serum uric acid by increasing insulin resistance and circulating insulin levels (13). Increased fructose consumption has been shown to reduce insulin binding and insulin activity in human, whereas increased glucose intake showed no similar adverse effects (14). Many of these studies have evaluated the role of fructose in gout by looking at soft drink consumption, noting that diet soft drinks do not cause adverse effects either, further confirming the role of fructose specifically.
It’s interesting to note that low fructose diets have been prescribed for more than 100 years to treat gout. William Osler, a 19th century Professor of Medicine at John Hopkins University wrote in 1893 that “The sugar should be reduced to a minimum. The sweeter fruits should not be taken (15).” So in some ways this is not new information, and considerable modern research has now confirmed Dr. Osler’s observations from long ago.
Another factor that contributes to the production of uric acid is alcohol consumption, a relationship which has been observed since ancient times. Alcohol consumption is strongly associated with an increased risk of gout. Beer appears to confer the strongest risk for gout, with liquor and spirits coming in second. Wine appears to be the least likely to cause gout symptoms, but all alcohol increases the risk of gout attacks (16). Ethanol, the type of alcohol in alcoholic beverages, shares the same mechanism of action in raising uric acid levels as fructose described in the above paragraph. The risk posed by fructose is slightly higher than that of alcohol, but alcohol consumption remains a clear risk factor for increased uric acid and gout attacks (17). In the next section we’ll look at genetic polymorphisms that predispose for uric acid formation and gout.
Genetic predispositions for uric acid formation
Several genetic variations have been associated with gout, the majority of which are involved in the renal urate-transport system. This system is involved in processing urate for excretion in the urine. Today, 16 or more genetic variations have been identified that are involved in the pathogenesis of gout. In this section I will focus on the most well-established genetic factors.
GLUT9 is a glucose transporter coded by the SLC2A9 gene. It is found primarily in the proximal tubules of the kidneys that filters uric acid and urate to be removed in urine. Studies have indicated variation in the SLC2A9 gene are the most statistically significant genetic determinant of serum urate (18). The specific causal variant(s) for determining serum uric acid concentrations have not yet be identified.
ABCG2 polymorphisms result in altered uric acid levels and have been replicated in gout cases from several populations. The ABCG2 gene encodes a transporter of the same name, a multifunctional transporter. The ABCG2 transporter is expressed in the brush border membrane of the kidney proximal tubules, where it is involved in the apical secretion of urate (19). ABCG2 is also expressed in epithelial cells of the small intestine and liver, which may indicate a possible role in excretion of urate outside of the kidneys (20). The strongest association between ABCG2 and gout is found in the SNP rs2231142 in exon 5 (21), a polymorphism which has a larger effect on serum urate in men than in women (22).
URAT1 is an essential urate transporter coded by the SLC22A12 gene that is involved in the apical absorption of urate in the proximal tubules (23). Three different polymorphisms in the N-terminus of SLC22A12, -788T>A in the promoter region, C258T in exon 1 and C426T in exon 2, display statistically significant assocations with reduced fractional excretion of uric acid (FEua) in a German population (19). Variations in the SLC22A12 gene were also associated with gout in Mexican (24) and Asian populations (25). SLC22A12 appears to be less significant in populations with European ancestry but the rs12800450 SNP has been identified as associated with a large serum uric acid effect size in African American populations (26).
Many of these polymorphisms express differing prevalence in different ethnic groups and become quite complicated to explain succinctly, so this information has been abbreviated to present here. For more detailed information, this 2013 study called The genetics of hyperuricaemia and gout goes into much more detail.
Oxalates and gout
As I mentioned in the introduction, high oxalate levels are also correlated with an increased risk for gout. Some research shows that people with kidney stones have higher levels of uric acid compared with controls (27). In addition, some treatments to reduce uric acid production and excretion may reduce the incidence of calcium oxalate stone formation (28), although these data are not conclusive. Several studies like the last two which have looked into the oxalate-gout connection did not control for diet, which would influence urinary uric acid excretion.
In contrast, another study which did put participants on a diet which standardized purine intake found that urinary uric acid excretion was not higher in stone formers than in non-stone forming controls (29). In fact, they found similar uric acid excretion in the two groups and one primary conclusion they draw is that diet, and purine intake in particular, is an important variable in controlling urinary acid excretion.
Although details regarding the connection between oxalate levels and gout still need to be investigated further, treatment directed at reducing oxalate levels as described in last week’s post may be appropriate, especially for gout sufferers who also have a history of kidney stones.
Treatment options for gout
Conventional medicine treatments for gout tend to rely heavily on the use of anti-inflammatory drugs like ibuprofen and other non-steroidal anti-inflammatory drugs (NSAIDs) to reduce the pain and inflammation. Although these medications is often effective at relieving pain, they do not help to prevent future gout flare-ups and long-term use of these medications can lead to problems down the road. Another primary treatment option is the use of xanthine oxidase inhibiting drugs like allopurinol, which inhibit the production of purines in the body. Fortunately, your functional medicine practitioner can help you prevent gout attacks by making dietary changes.
The primary dietary changes for treating gout involve reducing intake of substances that contribute to uric acid formation, namely alcohol, fructose, and purines. I’ll go over which foods fall into these categories in more detail in this section. This can be tricky and somewhat frustrating, as many high purine foods are foods that are considered to be quite healthy, especially in the Paleo crowd. But don’t worry, I’ll go over which foods help prevent gout attacks next.
Foods to avoid:
- High purine foods
- Meat, especially red meat and organ meats like liver, kidney and “sweetbreads”
- Seafood and shellfish like anchovies, herring, mackerel, tuna and scallops
- Game meats
- High fructose foods
- Soft drinks, especially those sweetened with high fructose corn syrup
- If eliminating soda is simply not an option, soft drinks sweetened with pure cane sugar contain less fructose
- Stevia-sweetened sodas are a better option
- Agave syrup
- Fruit, especially pears, apples, grapes, pomegranate, mango, banana, and their juices
- Soft drinks, especially those sweetened with high fructose corn syrup
- Alcohol, especially beer and liquor
- Although wine is less likely to trigger gout attacks, it is still best to avoid wine
- Foods high in oxalates
So what should you eat to prevent gout attacks? Here are the main points to remember:
- Drink lots of water!
- Dehydration can contribute to concentration and deposition of uric acid crystals in joints
- Adequate hydration helps the kidneys function properly and eliminate both oxalates and uric acid more effectively
- Eat berries
- Cherries, blueberries and cranberries in particular have been shown to reduce gout attacks (30)
- If you opt for juice like tart cherry juice, make sure it’s unsweetened
- Eat more vegetarian sources of protein
- Rice and beans are a good option
- Quinoa, amaranth, and teff are pseudograins that are high protein and fiber
- Eat bland foods
- People who eat lots of rich foods often benefit from resetting taste receptors by eating an intentionally bland diet for a period of time
- Avoid rich, savory foods and excess spice and seasoning
- Allow your sense of taste to become more sensitive by noticing subtle flavors
- Over time, you will likely become more satisfied with less rich foods
Supplement options for gout
In addition to eating a gout-friendly diet, here are some options to support your health and prevent gout attacks in the future:
- Celery seed extract has been shown to be helpful (31)
- Stinging nettle extract, or Urtica dioica, has been used traditionally for gout (32)
- Omega 3 fish oil may be helpful for gout, as it has shown benefit in reducing inflammation in other forms of arthritis (33)
- This is especially true because gout sufferers usually want to limit seafood
- Folate has also been shown to reduce both serum uric acid levels and hyperuricemia in human trials (34)
Gout is a painful condition that may indicate deeper issues like cardiovascular and metabolic problems. By addressing the dietary factors that contribute to underlying pathology, gout sufferers can improve not only their gout symptoms and prevent future attacks, but also address the underlying biochemical issues contributing to both gout and a whole host of other illnesses.
- Zhu, Yanyan, Bhavik J. Pandya, and Hyon K. Choi. “Prevalence of Gout and Hyperuricemia in the US General Population: The National Health and Nutrition Examination Survey 2007-2008.” Arthritis & Rheumatism 63.10 (2011): 3136-141. Web. doi 10.1002/art.30520.
- Oda, M., Y. Satta, O. Takenaka, and N. Takahata. “Loss of Urate Oxidase Activity in Hominoids and Its Evolutionary Implications.” Molecular Biology and Evolution 19.5 (2002): 640-53. Web.
- So, Alexander, and Bernard Thorens. “Uric Acid Transport and Disease.” Journal of Clinical Investigation 120.6 (2010): 1791-799. Web. doi 10.1172/JCI42344.
- Chang, H. Y., W. H. Pan, W. T. Yeh, and K. S. Tsai. “Hyperuricemia and Gout in Taiwan: Results from the Nutritional and Health Survey in Taiwan (1993-96).” J Rheumatol 28.7 (2001): 1640-646. Web.
- Wallace, K. L., A. A. Riedel, N. Joseph-Ridge, and R. Wortmann. “Increasing Prevalence of Gout and Hyperuricemia over 10 Years among Older Adults in a Managed Care Population.” J Rheumatol 31.8 (2004): 1852-857. Web.
- Bray, G. A., S. J. Nielsen, and B. M. Popkin. “Consumption of High-fructose Corn Syrup in Beverages May Play a Role in the Epidemic of Obesity.” Am J Clin Nutr 79.4 (2004): 537-43. The American Journal of Clinical Nutrition. 01 Apr. 2004. Web. 06 July 2017.
- Reaven, G. “Role of Insulin Resistance in Human Disease (syndrome X): An Expanded Definition.” Annual Review of Medicine 44.1 (1993): 121-31. Web.
- Facchini, Francesco. “Relationship Between Resistance to Insulin-Mediated Glucose Uptake, Urinary Uric Acid Clearance, and Plasma Uric Acid Concentration.” Jama266.21 (1991): 3008-11. Web.
- Alderman, Michael, and Kala J. V. Aiyer. “Uric Acid: Role in Cardiovascular Disease and Effects of Losartan.” Current Medical Research and Opinion 20.3 (2004): 369-79. Web. doi 10.1185/030079904125002982.
- Tavil, Y., M. G. Kaya, S. A. Oktar, N. Sen, K. Okyay, H. U. YazÄ±cÄ±, and A. Cengel. “Uric Acid Level and Its Association with Carotid Intimaâmedia Thickness in Patients with Hypertension.” Atherosclerosis 197.1 (2008): 159-63. Web. doi 10.1016/j.atherosclerosis.2007.03.008.
- Fox, Irving H., Thomas D. Palella, and William N. Kelley. “Hyperuricemia: A Marker for Cell Energy Crisis.” New England Journal of Medicine 317.2 (1987): 111-12. Web. doi 10.1056/NEJM198707093170209.
- Fox, Irving H., and William N. Kelley. “Studies on the Mechanism of Fructose-induced Hyperuricemia in Man.” Metabolism 21.8 (1972): 713-21. Web.
- Wu, T., E. Giovannucci, T. Pischon, S. E. Hankinson, J. Ma, N. Rifai, and E. B. Rimm. “Fructose, Glycemic Load, and Quantity and Quality of Carbohydrate in Relation to Plasma C-peptide Concentrations in US Women.” Am J Clin Nutr 80.4 (2004): 1043-9. Web.
- Beck-Nielsen, H., O. Pedersen, and N. Schwartz SÃ¸rensen. “Effects of Diet on the Cellular Insulin Binding and the Insulin Sensitivity in Young Healthy Subjects.” Diabetologia 15.4 (1978): 289-96. Web.
- Osler W. Gout. The principles and practice of medicine 2nd ed. New York: Appleton, 1893:287–95
- Neogi, Tuhina, Clara Chen, Jingbo Niu, Christine Chaisson, David J. Hunter, and Yuqing Zhang. “Alcohol Quantity and Type on Risk of Recurrent Gout Attacks: An Internet-based Case-crossover Study.” The American Journal of Medicine 127.4 (2014): 311-18. Web. doi 10.1016/j.amjmed.2013.12.019.
- Choi, Hyon K., Karen Atkinson, Elizabeth W. Karlson, Walter Willett, and Gary Curhan. “Alcohol Intake and Risk of Incident Gout in Men: A Prospective Study.” The Lancet363.9417 (2004): 1277-281. Web. doi 10.1016/S0140-6736(04)16000-5.
- Stark, Klaus, Wibke Reinhard, Katharina Neureuther, Silke Wiedmann, Kamil Sedlacek, Andrea Baessler, Marcus Fischer, Stefan Weber, Bernhard Kaess, Jeanette Erdmann, Heribert Schunkert, and Christian Hengstenberg. “Association of Common Polymorphisms in GLUT9 Gene with Gout but Not with Coronary Artery Disease in a Large Case-Control Study.” PLoS ONE 3.4 (2008): n. pag. Web. doi 10.1371/journal.pone.0001948.
- Woodward, O. M., A. Kottgen, J. Coresh, E. Boerwinkle, W. B. Guggino, and M. Kottgen. “Identification of a Urate Transporter, ABCG2, with a Common Functional Polymorphism Causing Gout.” Proceedings of the National Academy of Sciences 106.25 (2009): 10338-0342. Web. doi 10.1073/pnas.0901249106.
- Hosomi, Atsushi, Takeo Nakanishi, Takuya Fujita, and Ikumi Tamai. “Extra-Renal Elimination of Uric Acid via Intestinal Efflux Transporter BCRP/ABCG2.” PLoS ONE 7.2 (2012): n. pag. Web. doi 10.1371/journal.pone.0030456.
- Dehghan, A., A. Kottgen, Q. Yang, S. J. Hwang, and W. L. Kao. “Association of Three Genetic Loci with Uric Acid Concentration and Risk of Gout: A Genome-wide Association Study.” Lancet 372.9654 (2008): 1953-61. Web. doi 10.1016/S0140-6736(08)61343-4.
- Kolz, Melanie, Toby Johnson, Serena Sanna, Alexander Teumer, Veronique Vitart, Markus Perola, Massimo Mangino, Eva Albrecht, Chris Wallace, Martin Farrall, Ã sa Johansson, Dale R. Nyholt, Yurii Aulchenko, Jacques S. Beckmann, Sven Bergmann, Murielle Bochud, Morris Brown, Harry Campbell, John Connell, Anna Dominiczak, Georg Homuth, Claudia Lamina, Mark I. Mccarthy, Thomas Meitinger, Vincent Mooser, Patricia Munroe, Matthias Nauck, John Peden, Holger Prokisch, Perttu Salo, Veikko Salomaa, Nilesh J. Samani, David Schlessinger, Manuela Uda, Uwe VÃ¶lker, GÃ©rard Waeber, Dawn Waterworth, Rui Wang-Sattler, Alan F. Wright, Jerzy Adamski, John B. Whitfield, Ulf Gyllensten, James F. Wilson, Igor Rudan, Peter Pramstaller, Hugh Watkins, Angela Doering, H.-Erich Wichmann, Tim D. Spector, Leena Peltonen, Henry VÃ¶lzke, Ramaiah Nagaraja, Peter Vollenweider, Mark Caulfield, Thomas Illig, and Christian Gieger. “Meta-Analysis of 28,141 Individuals Identifies Common Variants within Five New Loci That Influence Uric Acid Concentrations.” PLoS Genetics 5.6 (2009): n. pag. Web. doi 10.1371/journal.pgen.1000504.
- Enomoto, Atsushi, Hiroaki Kimura, Arthit Chairoungdua, Yasuhiro Shigeta, Promsuk Jutabha, Seok Ho Cha, Makoto Hosoyamada, Michio Takeda, Takashi Sekine, Takashi Igarashi, Hirotaka Matsuo, Yuichi Kikuchi, Takashi Oda, Kimiyoshi Ichida, Tatsuo Hosoya, Kaoru Shimokata, Toshimitsu Niwa, Yoshikatsu Kanai, and Hitoshi Endou. “Molecular Identification of a Renal Urateâanion Exchanger That Regulates Blood Urate Levels.” Nature (2002): n. pag. Web. doi 10.1038/nature742.
- Vazquez-Mellado, J., A. L. Jimenez-Vaca, S. Cuevas-Covarrubias, V. Alvarado-Romano, G. Pozo-Molina, and R. Burgos-Vargas. “Molecular Analysis of the SLC22A12 (URAT1) Gene in Patients with Primary Gout.” Rheumatology 46.2 (2006): 215-19. Web. doi 10.1093/rheumatology/kel205.
- Guan, M., J. Zhang, Y. Chen, W. Liu, N. Kong, and H. Zou. “Highâresolution Melting Analysis for the Rapid Detection of an Intronic Single Nucleotide Polymorphism in SLC22A12 in Male Patients with Primary Gout in China.” Scandinavian Journal of Rheumatology 38.4 (2009): 276-81. Web. doi 10.1080/03009740802572483.
- Tin, Adrienne, Owen M. Woodward, Wen Hong Linda Kao, Ching-Ti Liu, Xiaoning Lu, Michael A. Nalls, Daniel Shriner, Mariam Semmo, Ermeg L. Akylbekova, Sharon B. Wyatt, Shih-Jen Hwang, Qiong Yang, Alan B. Zonderman, Adebowale A. Adeyemo, Cameron Palmer, Yan Meng, Muredach Reilly, Michael G. Shlipak, David Siscovick, Michele K. Evans, Charles N. Rotimi, Michael F. Flessner, Michael KÃ¶ttgen, L. Adrienne Cupples, Caroline S. Fox, and Anna KÃ¶ttgen. “Genome-wide Association Study for Serum Urate Concentrations and Gout among African Americans Identifies Genomic Risk Loci and a Novel URAT1 Loss-of-function Allele.” Human Molecular Genetics 20.20 (2011): 4056-068. Web. doi 10.1093/hmg/ddr307.
- Leonetti, F., B. Dussol, P. Berthezene, X. Thirion, and Y. Berland. “Dietary and Urinary Risk Factors for Stones in Idiopathic Calcium Stone Formers Compared with Healthy Subjects.” Nephrology Dialysis Transplantation 13.3 (1998): 617-22. Web.
- Ettinger, Bruce, Anne Tang, John T. Citron, Barbara Livermore, and Thomas Williams. “Randomized Trial of Allopurinol in the Prevention of Calcium Oxalate Calculi.” New England Journal of Medicine 315.22 (1986): 1386-389. Web. doi 10.1056/NEJM198611273152204.
- Pais, Vernon M., Ross P. Holmes, and Dean G. Assimos. “Effect of Dietary Control of Urinary Uric Acid Excretion in Calcium Oxalate Stone Formers and Non-Stone-Forming Controls.” Journal of Endourology 21.2 (2007): 232-35. Web. doi 10.1089/end.2007.2218.
- Zhang, Yuqing, Tuhina Neogi, Clara Chen, Christine Chaisson, David J. Hunter, and Hyon K. Choi. “Cherry Consumption and Decreased Risk of Recurrent Gout Attacks.” Arthritis & Rheumatism 64.12 (2012): 4004-011. Web. doi 10.1002/art.34677.
- Ashtiyani, S. C., A. Golestanpour, M. Shasmi, S. M. Tabatabaei, and M. Ramazani. “Rhazes’ Prescriptions in Treatment of Gout.” Iran Red Crescent Med J 14.2 (2012): 108-12. Web.
- Hajhashemi, V., and V. Klooshani. “Antinociceptive and Anti-inflammatory Effects of Urtica Dioica Leaf Extract in Animal Models.” Avicenna J Phytomed 3.2 (2013): 193-200. Web.
- Kremer, Joel M., David A. Lawrence, Gayle F. Petrillo, Laura L. Litts, Patrick M. Mullaly, Richard I. Rynes, Ralph P. Stocker, Nourollah Parhami, Neal S. Greenstein, Betsy R. Fuchs, Anupum Mathur, Dwight R. Robinson, Richard I. Sperling, and Jean Bigaouette. “Effects of High-dose Fish Oil on Rheumatoid Arthritis after Stopping Nonsteroidal Antiinflammatory Drugs Clinical and Immune Correlates.” Arthritis & Rheumatism 38.8 (1995): 1107-114. Web.
- Qin, Xianhui, Youbao Li, Mingli He, Genfu Tang, Delu Yin, Min Liang, Binyan Wang, Jing Nie, Yong Huo, Xin Xu, and Fan Fan Hou. “Folic Acid Therapy Reduces Serum Uric Acid in Hypertensive Patients: A Substudy of the China Stroke Primary Prevention Trial (CSPPT).” The American Journal of Clinical Nutrition 105.4 (2017): 882-89. Web. doi 10.3945/ajcn.116.143131.