Hyperuricemia has long been established as the major etiologic factor in gout. In recent years, a large body of evidence has accumulated that suggests that hyperuricemia may play a role in the development and pathogenesis of a number of metabolic, hemodynamic, and systemic pathologic diseases, including metabolic syndrome, hypertension, stroke, and atherosclerosis. A number of epidemiologic studies have linked hyperuricemia with each of these disorders. In some studies, therapies that lower uric acid may prevent or improve certain components of the metabolic syndrome. There is an association between uric acid and the development of systemic lupus erythematosus; the connection between other rheumatic diseases such as rheumatoid arthritis and osteoarthritis is less clear. The mechanism for the role of uric acid in disorders other than gout is not well established but recent investigations point towards systemic inflammation induced by urate, as the major pathophysiological event common to systemic diseases, including atherosclerosis. 1. Introduction More than 150 years ago, Garrod observed that uric acid is elevated in the blood of subjects with gout [1]. However, ultimate proof that uric acid is a causative factor in gout was not forthcoming for another 100 years when it was demonstrated that intra-articular injection of sodium urate produces acute arthritis [2]. Currently, it is well appreciated that chronic hyperuricemia enhances deposition of uric acid in tissues other than the joints, leading ultimately to tophi, nephropathy, and kidney stones. 2. Hyperuricemia Is Not Limited to Gout In recent years there has been a renewed interest in hyperuricemia and its association with a number of clinical disorders other than gout, including hypertension, atherosclerosis, cardiovascular disease, and chronic kidney disease. Indeed, hyperuricemia is commonly part of the cluster of metabolic and hemodynamic abnormalities including abdominal obesity, glucose intolerance, insulin resistance, dyslipidemia, and hypertension all often subsumed under the term “metabolic syndrome” [3, 4]. Not only collectively, but also individually, hypertension, obesity, dyslipidemia, hyperglycemia, and insulin resistance are positively correlated with serum levels of uric acid [5–9]. 3. Hyperuricemia and Metabolic Syndrome and Its Components The association between uric acid and metabolic syndrome is robust throughout human development. Epidemiological studies have demonstrated a close relationship between serum uric acid (SUA) levels and the presence of metabolic syndrome (and
References
[1]
A. Garrod, “Observations on certain pathological conditions of the blood and urine, in gout, rheumatism and Bright’s disease,” Medico-Chirurgical Transactions, vol. 31, pp. 83–97, 1848.
[2]
J. S. Faires and D. Mccarty Jr., “Acute arthritis in man and dog after intrasynovial injection of sodium urate crystals,” The Lancet, vol. 280, no. 7258, pp. 682–685, 1962.
[3]
H. K. Choi and E. S. Ford, “Prevalence of the metabolic syndrome in individuals with hyperuricemia,” The American Journal of Medicine, vol. 120, no. 5, pp. 442–447, 2007.
[4]
G. M. Reaven, “Role of insulin resistance in human disease (syndrome X): an expanded definition,” Annual Review of Medicine, vol. 44, pp. 121–131, 1993.
[5]
S.-D. Lin, D.-H. Tsai, and S.-R. Hsu, “Association between serum uric acid level and components of the metabolic syndrome,” Journal of the Chinese Medical Association, vol. 69, no. 11, pp. 512–516, 2006.
[6]
T. W. Yoo, K. C. Sung, H. S. Shin et al., “Relationship between serum uric acid concentration and insulin resistance and metabolic syndrome,” Circulation Journal, vol. 69, no. 8, pp. 928–933, 2005.
[7]
A. Onat, H. Uyarel, G. Hergenc et al., “Serum uric acid is a determinant of metabolic syndrome in a population-based study,” American Journal of Hypertension, vol. 19, no. 10, pp. 1055–1062, 2006.
[8]
T. Kawada, T. Otsuka, M. Katsumata, and H. Suzuki, “Serum uric acid is significantly related to the components of the metabolic syndrome in Japanese workingmen,” Journal of the Cardiometabolic Syndrome, vol. 2, no. 3, pp. 158–162, 2007.
[9]
V. Bhole, J. W. Choi, S. W. Kim, M. de Vera, and H. Choi, “Serum uric acid levels and the risk of type 2 diabetes: a prospective study,” The American Journal of Medicine, vol. 123, no. 10, pp. 957–961, 2010.
[10]
E. S. Ford, C. Li, S. Cook, and H. K. Choi, “Serum concentrations of uric acid and the metabolic syndrome among US children and adolescents,” Circulation, vol. 115, no. 19, pp. 2526–2532, 2007.
[11]
L. Pacifico, V. Cantisani, C. Anania et al., “Serum uric acid and its association with metabolic syndrome and carotid atherosclerosis in obese children,” European Journal of Endocrinology, vol. 160, no. 1, pp. 45–52, 2009.
[12]
W. Rathmann, E. Funkhouser, A. R. Dyer, and J. M. Roseman, “Relations of hyperuricemia with the various components of the insulin resistance syndrome in young black and white adults: the CARDIA study. Coronary Artery Risk Development in Young Adults,” Annals of Epidemiology, vol. 8, no. 4, pp. 250–261, 1998.
[13]
C. Oyama, T. Takahashi, M. Oyamada et al., “Serum uric acid as an obesity-related indicator in early adolescence,” Tohoku Journal of Experimental Medicine, vol. 209, no. 3, pp. 257–262, 2006.
[14]
D. I. Feig, “Hypertension in adolescents,” Seminars in Nephrology, vol. 25, no. 1, pp. 32–38, 2005.
[15]
D. I. Feig, B. Soletsky, and R. J. Johnson, “Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial,” The Journal of the American Medical Association, vol. 300, no. 8, pp. 924–932, 2008.
[16]
M. Mazzali, J. Hughes, Y.-G. Kim et al., “Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism,” Hypertension, vol. 38, no. 5, pp. 1101–1106, 2001.
[17]
J. H. Magnus, M. K. Doyle, and S. K. Srivastav, “Serum uric acid and self-reported rheumatoid arthritis in a multiethnic adult female population,” Current Medical Research and Opinion, vol. 26, no. 9, pp. 2157–2163, 2010.
[18]
D. Daoussis, V. Panoulas, T. Toms et al., “Uric acid is a strong independent predictor of renal dysfunction in patients with rheumatoid arthritis,” Arthritis Research & Therapy, vol. 11, no. 4, article R116, 2009.
[19]
Z. Yang, Y. Liang, W. Xi, Y. Zhu, C. Li, and R. Zhong, “Association of serum uric acid with lupus nephritis in systemic lupus erythematosus,” Rheumatology International, vol. 31, no. 6, pp. 743–748, 2011.
[20]
Y. Sun, H. Brenner, S. Sauerland, K. P. Günther, W. Puhl, and T. Stürmer, “Serum uric acid and patterns of radiographic osteoarthritis—the Ulm Osteoarthritis Study,” Scandinavian Journal of Rheumatology, vol. 29, no. 6, pp. 380–386, 2000.
[21]
E. Roddy, W. Zhang, and M. Doherty, “Are joints affected by gout also affected by osteoarthritis?” Annals of the Rheumatic Diseases, vol. 66, no. 10, pp. 1374–1377, 2007.
[22]
A. E. Denoble, K. M. Huffman, T. V. Stabler et al., “Uric acid is a danger signal of increasing risk for osteoarthritis through inflammasome activation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 5, pp. 2088–2093, 2011.
[23]
Y. Y. Sautin, T. Nakagawa, S. Zharikov, and R. J. Johnson, “Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress,” American Journal of Physiology, vol. 293, no. 2, pp. C584–C596, 2007.
[24]
N. Kuzkaya, N. Weissmann, D. G. Harrison, and S. Dikalov, “Interactions of peroxynitrite with uric acid in the presence of ascorbate and thiols: implications for uncoupling endothelial nitric oxide synthase,” Biochemical Pharmacology, vol. 70, no. 3, pp. 343–354, 2005.
[25]
R. J. Johnson, C. Rivard, T. Nakagawa, Y. Y. Sautin, and L. G. Sanchez-Lozada, “Uric acid: more to learn, more experiments to do,” American Journal of Hypertension, vol. 22, no. 9, pp. 952–953, 2009.
[26]
C. Schorn, C. Janko, L. Munoz et al., “Sodium and potassium urate crystals differ in their inflammatory potential,” Autoimmunity, vol. 42, no. 4, pp. 314–316, 2009.
[27]
F. Leyva, S. D. Anker, I. F. Godsland et al., “Uric acid in chronic heart failure: a marker of chronic inflammation,” European Heart Journal, vol. 19, no. 12, pp. 1814–1822, 1998.
[28]
P. Olexa, M. Olexová, J. Gonsor？ík, I. Tká？, J. Kisel'ová, and M. Olejníková, “Uric acid—a marker for systemic inflammatory response in patients with congestive heart failure?” Wiener Klinische Wochenschrift, vol. 114, no. 5-6, pp. 211–215, 2002.
[29]
C. Ruggiero, A. Cherubini, A. Ble et al., “Uric acid and inflammatory markers,” European Heart Journal, vol. 27, no. 10, pp. 1174–1181, 2006.
[30]
C. Ruggiero, A. Cherubini, E. Miller III et al., “Usefulness of uric acid to predict changes in C-reactive protein and interleukin-6 in 3-year period in Italians aged 21 to 98 years,” American Journal of Cardiology, vol. 100, no. 1, pp. 115–121, 2007.
[31]
T. Lyngdoh, P. Marques-Vidal, F. Paccaud et al., “Elevated serum uric acid is associated with high circulating inflammatory cytokines in the population-based colaus study,” PLoS ONE, vol. 6, no. 5, Article ID e19901, 2011.
[32]
Z. Zhang, L. Bian, and Y. Choi, “Serum uric acid: a marker of metabolic syndrome and subclinical atherosclerosis in Korean men,” Angiology, vol. 63, no. 6, pp. 420–428, 2012.
[33]
R. Mutluay, S. M. Deger, E. Bahadir, A. O. Durmaz, R. ？itil, and S. Sindel, “Uric acid is an important predictor for hypertensive early atherosclerosis,” Advances in Therapy, vol. 29, no. 3, pp. 276–286, 2012.
[34]
M. Fukui, M. Tanaka, E. Shiraishi et al., “Serum uric acid is associated with microalbuminuria and subclinical atherosclerosis in men with type 2 diabetes mellitus,” Metabolism, vol. 57, no. 5, pp. 625–629, 2008.
[35]
W. Doehner, N. Schoene, M. Rauchhaus et al., “Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: results from 2 placebo-controlled studies,” Circulation, vol. 105, no. 22, pp. 2619–2624, 2002.
[36]
D. Erdogan, H. Gullu, M. Caliskan et al., “Relationship of serum uric acid to measures of endothelial function and atherosclerosis in healthy adults,” International Journal of Clinical Practice, vol. 59, no. 11, pp. 1276–1282, 2005.
[37]
E. Krishnan, B. J. Pandya, L. Chung, and O. Dabbous, “Hyperuricemia and the risk for subclinical coronary atherosclerosis—data from a prospective observational cohort study,” Arthritis Research & Therapy, vol. 13, no. 2, article R66, 2011.
[38]
N. Ishizaka, Y. Ishizaka, E.-I. Toda, H. Hashimoto, R. Nagai, and M. Yamakado, “Higher serum uric acid is associated with increased arterial stiffness in Japanese individuals,” Atherosclerosis, vol. 192, no. 1, pp. 131–137, 2007.
[39]
S. Takayama, R. Kawamoto, T. Kusunoki, M. Abe, and M. Onji, “Uric acid is an independent risk factor for carotid atherosclerosis in a Japanese elderly population without metabolic syndrome,” Cardiovascular Diabetology, vol. 11, article 2, 2012.
[40]
D.-H. Kang, S.-K. Park, I.-K. Lee, and R. J. Johnson, “Uric acid-induced C-reactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells,” Journal of the American Society of Nephrology, vol. 16, no. 12, pp. 3553–3562, 2005.
[41]
G. K. Glantzounis, E. C. Tsimoyiannis, A. M. Kappas, and D. A. Galaris, “Uric acid and oxidative stress,” Current Pharmaceutical Design, vol. 11, no. 32, pp. 4145–4151, 2005.
[42]
A. So and B. Thorens, “Uric acid transport and disease,” The Journal of Clinical Investigation, vol. 120, no. 6, pp. 1791–1799, 2010.
[43]
M. Bagnati, C. Perugini, C. Cau, R. Bordone, E. Albano, and G. Bellomo, “When and why a water-soluble antioxidant becomes pro-oxidant during copper-induced low-density lipoprotein oxidation: a study using uric acid,” Biochemical Journal, vol. 340, no. 1, pp. 143–152, 1999.
[44]
U. M. Khosla, S. Zharikov, J. L. Finch et al., “Hyperuricemia induces endothelial dysfunction,” Kidney International, vol. 67, no. 5, pp. 1739–1742, 2005.
[45]
C. R. White, T. A. Brock, L. Y. Chang, et al., “Superoxide and peroxynitrite in atherosclerosis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 3, pp. 1044–1048, 1994.
[46]
F. C. McGillicuddy, M. L. de La Moya, C. C. Hinkle et al., “Inflammation impairs reverse cholesterol transport in vivo,” Circulation, vol. 119, no. 8, pp. 1135–1145, 2009.
[47]
R. J. Johnson, D.-H. Kang, D. Feig et al., “Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease?” Hypertension, vol. 41, no. 6, pp. 1183–1190, 2003.
[48]
J. Kanellis, S. Watanabe, J. H. Li et al., “Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2,” Hypertension, vol. 41, no. 6, pp. 1287–1293, 2003.
[49]
Q. Li, Z. Yang, B. Lu et al., “Serum uric acid level and its association with metabolic syndrome and carotid atherosclerosis in patients with type 2 diabetes,” Cardiovascular Diabetology, vol. 10, article 72, 2011.
[50]
V. F. Panoulas, H. J. Milionis, K. M. J. Douglas et al., “Association of serum uric acid with cardiovascular disease in rheumatoid arthritis,” Rheumatology, vol. 46, no. 9, pp. 1466–1470, 2007.
[51]
J. M. Sabio, J. A. Vargas-Hitos, J. D. Mediavilla et al., “Correlation of asymptomatic hyperuricaemia and serum uric acid levels with arterial stiffness in women with systemic lupus erythematosus without clinically evident atherosclerotic cardiovascular disease,” Lupus, vol. 19, no. 5, pp. 591–598, 2010.
[52]
M. A. Gonzalez-Gay, C. Gonzalez-Juanatey, T. R. Vazquez-Rodriguez et al., “Asymptomatic hyperuricemia and serum uric acid concentration correlate with subclinical atherosclerosis in psoriatic arthritis patients without clinically evident cardiovascular disease,” Seminars in Arthritis and Rheumatism, vol. 39, no. 3, pp. 157–162, 2009.
[53]
C. K. Kramer, D. von Mühlen, S. K. Jassal, and E. Barrett-Connor, “Serum uric acid levels improve prediction of incident type 2 diabetes in individuals with impaired fasting glucose: the Rancho Bernardo Study,” Diabetes Care, vol. 32, no. 7, pp. 1272–1273, 2009.
[54]
Y. J. Lee, J. H. Lee, Y. H. Shin, J.-K. Kim, H.-R. Lee, and D.-C. Lee, “Gender difference and determinants of C-reactive protein level in Korean adults,” Clinical Chemistry and Laboratory Medicine, vol. 47, no. 7, pp. 863–869, 2009.
[55]
E. Bonora, G. Targher, M. B. Zenere et al., “Relationship of uric acid concentration to cardiovascular risk factors in young men. Role of obesity and central fat distribution. The Verona Young Men Atherosclerosis Risk Factors Study,” International Journal of Obesity and Related Metabolic Disorders, vol. 20, no. 11, pp. 975–980, 1996.
[56]
T. Lyngdoh, P. Marques-Vidal, F. Paccaud et al., “Elevated serum uric acid is associated with high circulating inflammatory cytokines in the population-based colaus study,” PLoS ONE, vol. 6, no. 5, Article ID e19901, 2011.
[57]
B. Kirilmaz, F. Asgun, E. Alioglu et al., “High inflammatory activity related to the number of metabolic syndrome components,” The Journal of Clinical Hypertension, vol. 12, no. 2, pp. 136–144, 2010.
[58]
M. G. Netea, B. J. Kullberg, W. L. Blok, R. T. Netea, and J. W. M. van der Meer, “The role of hyperuricemia in the increased cytokine production after lipopolysaccharide challenge in neutropenic mice,” Blood, vol. 89, no. 2, pp. 577–582, 1997.
[59]
F. S. di Giovine, S. E. Malawista, E. Thornton, and G. W. Duff, “Urate crystals stimulate production of tumor necrosis factor alpha from human blood monocytes and synovial cells. Cytokine mRNA and protein kinetics, and cellular distribution,” The Journal of Clinical Investigation, vol. 87, no. 4, pp. 1375–1381, 1991.
[60]
V. Bordoni, M. de Cal, M. Rassu et al., “Protective effect of urate oxidase on uric acid induced-monocyte apoptosis,” Current Drug Discovery Technologies, vol. 2, no. 1, pp. 29–36, 2005.
[61]
H. Kono, C.-J. Chen, F. Ontiveros, and K. L. Rock, “Uric acid promotes an acute inflammatory response to sterile cell death in mice,” The Journal of Clinical Investigation, vol. 120, no. 6, pp. 1939–1949, 2010.
[62]
F. Martinon, V. Pétrilli, A. Mayor, A. Tardivel, and J. Tschopp, “Gout-associated uric acid crystals activate the NALP3 inflammasome,” Nature, vol. 440, no. 7081, pp. 237–241, 2006.
[63]
H. M. Hoffman, P. Scott, J. L. Mueller et al., “Role of the leucine-rich repeat domain of cryopyrin/NALP3 in monosodium urate crystal-induced inflammation in mice,” Arthritis & Rheumatism, vol. 62, no. 7, pp. 2170–2179, 2010.
[64]
F. Ghaemi-Oskouie and Y. Shi, “The role of uric acid as an endogenous danger signal in immunity and inflammation,” Current Rheumatology Reports, vol. 13, no. 2, pp. 160–166, 2011.
[65]
J. W. Griffith, T. Sun, M. T. McIntosh, and R. Bucala, “Pure hemozoin is inflammatory in vivo and activates the NALP3 inflammasome via release of uric acid,” The Journal of Immunology, vol. 183, no. 8, pp. 5208–5220, 2009.
[66]
Y. Shi, J. E. Evans, and K. L. Rock, “Molecular identification of a danger signal that alerts the immune system to dying cells,” Nature, vol. 425, no. 6957, pp. 516–521, 2003.
[67]
R. Liu-Bryan, P. Scott, A. Sydlaske, D. M. Rose, and R. Terkeltaub, “Innate immunity conferred by toll-like receptors 2 and 4 and myeloid differentiation factor 88 expression is pivotal to monosodium urate monohydrate crystal-induced inflammation,” Arthritis & Rheumatism, vol. 52, no. 9, pp. 2936–2946, 2005.
[68]
C. Conforti-Andreoni, R. Spreafico, H. L. Qian et al., “Uric acid-driven Th17 differentiation requires inflammasome-derived IL-1 and IL-18,” The Journal of Immunology, vol. 187, no. 11, pp. 5842–5850, 2011.
[69]
M. Lozovoy, A. Sim？o, M. S. Hohmann et al., “Inflammatory biomarkers and oxidative stress measurements in patients with systemic lupus erythematosus with or without metabolic syndrome,” Lupus, vol. 20, no. 13, pp. 1356–1364, 2011.
[70]
A. Meneshian and G. B. Bulkley, “The physiology of endothelial xanthine oxidase: from urate catabolism to reperfusion injury to inflammatory signal transduction,” Microcirculation, vol. 9, no. 3, pp. 161–175, 2002.
