Generic placeholder image

Current Vascular Pharmacology


ISSN (Print): 1570-1611
ISSN (Online): 1875-6212

General Review Article

Uric Acid in Metabolic and Cerebrovascular Disorders: A Review

Author(s): Francesca Cortese*, Pietro Scicchitano, Anna M. Cortese, Giovanni Meliota, Andrea Andriani, Luigi Truncellito, Giacinto Calculli, Paola Giordano and Marco M. Ciccone

Volume 18, Issue 6, 2020

Page: [610 - 618] Pages: 9

DOI: 10.2174/1570161118666191217123930

Price: $65


Background: Several studies showed a close link between metabolic syndrome (MetS), type 2 diabetes (T2DM) and cerebrovascular diseases. There is considerable debate regarding the role of uric acid (UA) as a risk factor in these conditions.

Objective: The aim of this narrative review is to discuss the links between UA, MetS, T2DM and cerebrovascular disease.

Methods: An extensive review has been conducted based on the scientific literature published in English, and indexed in MEDLINE (through PubMed), EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and Google Scholar from January to May 2019. Additional relevant studies published after the initial review were also considered during the period of June 2019-October 2019, during which, this manuscript was written. The Mesh Terms considered were: uric acid, antioxidant, oxidant, metabolic syndrome, diabetes, cerebrovascular diseases, stroke, haemorrhagic stroke, neurocognitive disorders, and their combinations.

Results: The literature review shows a dose-dependent inflammatory action of UA, which occurs with serum concentrations >4 mg/dl (>0.24 mmol/l), representing one of the contributors to the chronic inflammatory process that underlies metabolic and cerebrovascular diseases.

Conclusion: UA, which is associated with arterial hypertension and cardiovascular diseases, represents one of the indicators of oxidative homeostasis. Increasing concentrations represent a status of active inflammation which is observed with metabolic and cerebrovascular diseases.

Keywords: Uric acid, metabolic syndrome, type 2 diabetes, cerebrovascular events, neurocognitive disorders, stroke.

Graphical Abstract
Jabir NR, Firoz CK, Khan MS, et al. Potential linkage between cerebrovascular diseases and metabolic syndrome. Curr Drug Metab 2017; 18(1): 62-8.
[] [PMID: 27515564]
Arenillas JF, Moro MA, Dávalos A. The metabolic syndrome and stroke: potential treatment approaches. Stroke 2007; 38(7): 2196-203.
[] [PMID: 17540972]
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report. Circulation 2002; 106(25): 3143-421.
[] [PMID: 12485966]
Boehme AK, Esenwa C, Elkind MS. Stroke risk factors, genetics, and prevention. Circ Res 2017; 120(3): 472-95.
[] [PMID: 28154098]
Shin JA, Lee JH, Lim SY, et al. Metabolic syndrome as a predictor of type 2 diabetes, and its clinical interpretations and usefulness. J Diabetes Investig 2013; 4(4): 334-43.
[] [PMID: 24843675]
Chen R, Ovbiagele B, Feng W. Diabetes and stroke: epidemiology, pathophysiology, pharmaceuticals and outcomes. Am J Med Sci 2016; 351(4): 380-6.
[] [PMID: 27079344]
Saklayen MG. The global epidemic of the metabolic syndrome. Curr Hypertens Rep 2018; 20(2): 12.
[] [PMID: 29480368]
Williams B, Mancia G, Spiering W, et al. ESC/ESH guidelines for the management of arterial hypertension. Eur Heart J 2018; 39(33): 3021-104.
[] [PMID: 30165516]
El Ridi R, Tallima H. Physiological functions and pathogenic potential of uric acid: A review. J Adv Res 2017; 8(5): 487-93.
[] [PMID: 28748115]
Hediger MA, Johnson RJ, Miyazaki H, Endou H. Molecular physiology of urate transport. Physiology (Bethesda) 2005; 20: 125-33.
[] [PMID: 15772301]
Cortese F, Giordano P, Scicchitano P, et al. Uric acid: from a biological advantage to a potential danger. A focus on cardiovascular effects. Vascul Pharmacol 2019; 120: 106565.
[] [PMID: 31152976]
Kang DH, Chen W. Uric acid and chronic kidney disease: new understanding of an old problem. Semin Nephrol 2011; 31(5): 447-52.
[] [PMID: 22000652]
Perheentupa J, Raivio K. Fructose-induced hyperuricaemia. Lancet 1967; 2(7515): 528-31.
[] [PMID: 4166890]
Lieber CS. Hyperuricemia induced by alcohol. Arthritis Rheum 1965; 8(5): 786-98.
[] [PMID: 5859552]
Neogi T. Clinical practice. N Engl J Med 2011; 364(5): 443-52.
[] [PMID: 21288096]
Khanna D, Fitzgerald JD, Khanna PP, et al. American college of rheumatology guidelines for management of GOUT. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken) 2012; 64(10): 1431-46.
[] [PMID: 23024028]
Chabra I, Singh R. Gouty tophi on the ear: a review. Cutis 2013; 92(4): 190-2.
[PMID: 24195091]
Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the national health and nutrition examination survey 2007-2008. Arthritis Rheum 2011; 63(10): 3136-41.
[] [PMID: 21800283]
Elliot AJ, Cross KW, Fleming DM. Seasonality and trends in the incidence and prevalence of gout in England and Wales 1994-2007. Ann Rheum Dis 2009; 68(11): 1728-33.
[] [PMID: 19029167]
Trifirò G, Morabito P, Cavagna L, et al. Epidemiology of gout and hyperuricaemia in Italy during the years 2005-2009: a nationwide population-based study. Ann Rheum Dis 2013; 72(5): 694-700.
[] [PMID: 22736095]
Sautin YY, Johnson RJ. Uric acid: the oxidant-antioxidant paradox. Nucleosides Nucleotides Nucleic Acids 2008; 27(6): 608-19.
[] [PMID: 18600514]
Gersch C, Palii SP, Imaram W, et al. Reactions of peroxynitrite with uric acid: formation of reactive intermediates, alkylated products and triuret, and in vivo production of triuret under conditions of oxidative stress. Nucleosides Nucleotides Nucleic Acids 2009; 28(2): 118-49.
[] [PMID: 19219741]
Mazzali M, Hughes J, Kim YG, et al. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension 2001; 38(5): 1101-6.
[] [PMID: 11711505]
Khosla UM, Zharikov S, Finch JL, et al. Hyperuricemia induces endothelial dysfunction. Kidney Int 2005; 67(5): 1739-42.
[] [PMID: 15840020]
Gliozzi M, Malara N, Muscoli S, Mollace V. The treatment of hyperuricemia. Int J Cardiol 2016; 213: 23-7.
[] [PMID: 26320372]
Andersson UG, Tracey KJ. HMGB1, a pro-inflammatory cytokine of clinical interest: introduction. J Intern Med 2004; 255(3): 318-9.
[] [PMID: 14871455]
Ramana KV. Aldose Reductase: New insights for an old enzyme. Biomol Concepts 2011; 2(1-2): 103-14.
[] [PMID: 21547010]
Rao GN, Corson MA, Berk BC. Uric acid stimulates vascular smooth muscle cell proliferation by increasing platelet-derived growth factor A-chain expression. J Biol Chem 1991; 266(13): 8604-8.
[PMID: 2022672]
Johnson RJ, Rodriguez-Iturbe B, Kang DH, Feig DI, Herrera-Acosta J. A unifying pathway for essential hypertension. Am J Hypertens 2005; 18(3): 431-40.
[] [PMID: 15797666]
Marsoni S, Damia G. Molecular targeting: new therapeutic strategies to improve tumour apoptosis. Ann Oncol 2004; 15(Suppl. 4): iv229-31.
[] [PMID: 15477312]
Shi Y, Evans JE, Rock KL. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 2003; 425(6957): 516-21.
[] [PMID: 14520412]
Busso N, So A. Mechanisms of inflammation in gout. Arthritis Res Ther 2010; 12(2): 206.
[] [PMID: 20441605]
Joosten LA, Netea MG, Mylona E, et al. Engagement of fatty acids with Toll-like receptor 2 drives interleukin-1β production via the ASC/caspase 1 pathway in monosodium urate monohydrate crystal-induced gouty arthritis. Arthritis Rheum 2010; 62(11): 3237-48.
[] [PMID: 20662061]
Cook S, Hugli O, Egli M, et al. Clustering of cardiovascular risk factors mimicking the human metabolic syndrome X in eNOS null mice. Swiss Med Wkly 2003; 133(25-26): 360-3.
[PMID: 12947532]
Cheung KJ, Tzameli I, Pissios P, et al. Xanthine oxidoreductase is a regulator of adipogenesis and PPARgamma activity. Cell Metab 2007; 5(2): 115-28.
[] [PMID: 17276354]
Kilicarslan A, Yavuz B, Guven GS, et al. Fenofibrate improves endothelial function and decreases thrombin-activatable fibrinolysis inhibitor concentration in metabolic syndrome. Blood Coagul Fibrinolysis 2008; 19(4): 310-4.
[] [PMID: 18469553]
Baldwin W, McRae S, Marek G, et al. Hyperuricemia as a mediator of the proinflammatory endocrine imbalance in the adipose tissue in a murine model of the metabolic syndrome. Diabetes 2011; 60(4): 1258-69.
[] [PMID: 21346177]
Ogino K, Kato M, Furuse Y, et al. Uric acid-lowering treatment with benzbromarone in patients with heart failure: a double-blind placebo-controlled crossover preliminary study. Circ Heart Fail 2010; 3(1): 73-81.
[] [PMID: 19933411]
Takir M, Kostek O, Ozkok A, et al. Lowering uric acid with allopurinol improves insulin resistance and systemic inflammation in asymptomatic hyperuricemia. J Investig Med 2015; 63(8): 924-9.
[] [PMID: 26571421]
Dimitroula HV, Hatzitolios AI, Karvounis HI. The role of uric acid in stroke: the issue remains unresolved. Neurologist 2008; 14(4): 238-42.
[] [PMID: 18617849]
Yu ZF, Bruce-Keller AJ, Goodman Y, Mattson MP. Uric acid protects neurons against excitotoxic and metabolic insults in cell culture, and against focal ischemic brain injury in vivo. J Neurosci Res 1998; 53(5): 613-25.
[<613:AID-JNR11>3.0.CO;2-1] [PMID: 9726432]
Zhang B, Yang N, Lin SP, Zhang F. Suitable concentrations of uric acid can reduce cell death in models of OGD and cerebral ischemia-reperfusion injury. Cell Mol Neurobiol 2017; 37(5): 931-9.
[] [PMID: 27709309]
Takayama S, Kawamoto R, Kusunoki T, Abe M, Onji M. Uric acid is an independent risk factor for carotid atherosclerosis in a Japanese elderly population without metabolic syndrome. Cardiovasc Diabetol 2012; 11: 2.
[] [PMID: 22234039]
Song C, Zhao X. Uric acid promotes oxidative stress and enhances vascular endothelial cell apoptosis in rats with middle cerebral artery occlusion. Biosci Rep 2018; 38(3): BSR20170939.
[] [PMID: 29097484]
Huang TT, Hao DL, Wu BN, Mao LL, Zhang J. Uric acid demonstrates neuroprotective effect on Parkinson’s disease mice through Nrf2-ARE signaling pathway. Biochem Biophys Res Commun 2017; 493(4): 1443-9.
[] [PMID: 28986252]
Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the international diabetes federation task force on epidemiology and prevention; national heart, lung, and blood institute; American heart association; world heart federation; international atherosclerosis society; and international association for the study of obesity. Circulation 2009; 120(16): 1640-5.
[] [PMID: 19805654]
Malik S, Wong ND, Franklin SS, et al. Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease, and all causes in United States adults. Circulation 2004; 110(10): 1245-50.
[] [PMID: 15326067]
Ludwig DS, Peterson KE, Gortmaker SL. Relation between consumption of sugar-sweetened drinks and childhood obesity: a prospective, observational analysis. Lancet 2001; 357(9255): 505-8.
[] [PMID: 11229668]
Johnson RJ, Nakagawa T, Sanchez-Lozada LG, et al. Sugar, uric acid, and the etiology of diabetes and obesity. Diabetes 2013; 62(10): 3307-15.
[] [PMID: 24065788]
Sun HL, Pei D, Lue KH, Chen YL. Uric acid levels can predict metabolic syndrome and hypertension in adolescents: a 10-year longitudinal study. PLoS One 2015; 10(11): e0143786.
[] [PMID: 26618358]
Zurlo A, Veronese N, Giantin V, et al. High serum uric acid levels increase the risk of metabolic syndrome in elderly women: The PROVA study. Nutr Metab Cardiovasc Dis 2016; 26(1): 27-35.
[] [PMID: 26643208]
Choi HK, Ford ES. Prevalence of the metabolic syndrome in individuals with hyperuricemia. Am J Med 2007; 120(5): 442-7.
[] [PMID: 17466656]
Yu TY, Jee JH, Bae JC, et al. Serum uric acid: A strong and independent predictor of metabolic syndrome after adjusting for body composition. Metabolism 2016; 65(4): 432-40.
[] [PMID: 26975535]
Babio N, Martínez-González MA, Estruch R, et al. Associations between serum uric acid concentrations and metabolic syndrome and its components in the PREDIMED study. Nutr Metab Cardiovasc Dis 2015; 25(2): 173-80.
[] [PMID: 25511785]
Yuan H, Yu C, Li X, et al. Serum uric acid levels and risk of metabolic syndrome: a dose-response meta-analysis of prospective studies. J Clin Endocrinol Metab 2015; 100(11): 4198-207.
[] [PMID: 26308292]
Liu Z, Que S, Zhou L, Zheng S. Dose-response relationship of serum uric acid with metabolic syndrome and non-alcoholic fatty liver disease incidence: a meta-analysis of prospective studies. Sci Rep 2015; 5: 14325.
[] [PMID: 26395162]
Niskanen L, Laaksonen DE, Lindström J, et al. Serum uric acid as a harbinger of metabolic outcome in subjects with impaired glucose tolerance: the Finnish diabetes prevention study. Diabetes Care 2006; 29(3): 709-11.
[] [PMID: 16505534]
Kodama S, Saito K, Yachi Y, et al. Association between serum uric acid and development of type 2 diabetes. Diabetes Care 2009; 32(9): 1737-42.
[] [PMID: 19549729]
Krishnan E, Pandya BJ, Chung L, Hariri A, Dabbous O. Hyperuricemia in young adults and risk of insulin resistance, prediabetes, and diabetes: a 15-year follow-up study. Am J Epidemiol 2012; 176(2): 108-16.
[] [PMID: 22753829]
Cicerchi C, Li N, Kratzer J, et al. Uric acid-dependent inhibition of AMP kinase induces hepatic glucose production in diabetes and starvation: evolutionary implications of the uricase loss in hominids. FASEB J 2014; 28(8): 3339-50.
[] [PMID: 24755741]
Choi HK, Ford ES. Haemoglobin A1c, fasting glucose, serum C-peptide and insulin resistance in relation to serum uric acid levels--the third national health and nutrition examination survey. Rheumatology (Oxford) 2008; 47(5): 713-7.
[] [PMID: 18390895]
Rodríguez G, Soriano LC, Choi HK. Impact of diabetes against the future risk of developing gout. Ann Rheum Dis 2010; 69(12): 2090-4.
[] [PMID: 20570836]
Juraschek SP, McAdams-Demarco M, Miller ER, et al. Temporal relationship between uric acid concentration and risk of diabetes in a community-based study population. Am J Epidemiol 2014; 179(6): 684-91.
[] [PMID: 24418684]
Pfister R, Barnes D, Luben R, et al. No evidence for a causal link between uric acid and type 2 diabetes: a Mendelian randomization approach. Diabetologia 2011; 54(10): 2561-9.
[] [PMID: 21717115]
Sluijs I, Holmes MV, van der Schouw YT, et al. A Mendelian randomization study of circulating uric acid and type 2 diabetes. Diabetes 2015; 64(8): 3028-36.
[] [PMID: 25918230]
Lv Q, Meng XF, He FF, et al. High serum uric acid and increased risk of type 2 diabetes: a systemic review and meta-analysis of prospective cohort studies. PLoS One 2013; 8(2): e56864.
[] [PMID: 23437258]
Dunkelgrun M, Welten GM, Goei D, et al. Association between serum uric acid and perioperative and late cardiovascular outcome in patients with suspected or definite coronary artery disease undergoing elective vascular surgery. Am J Cardiol 2008; 102(7): 797-801.
[] [PMID: 18805100]
Kim SY, Guevara JP, Kim KM, Choi HK, Heitjan DF, Albert DA. Hyperuricemia and risk of stroke: a systematic review and meta-analysis. Arthritis Rheum 2009; 61(7): 885-92.
[] [PMID: 19565556]
Zhong C, Zhong X, Xu T, Xu T, Zhang Y. Sex-specific relationship between serum uric acid and risk of stroke: a dose-response meta-analysis of prospective studies. J Am Heart Assoc 2017; 6(4): e005042.
[] [PMID: 28356280]
Ryu WS, Kim CK, Kim BJ, Lee SH. Serum uric acid levels and cerebral microbleeds in patients with acute ischemic stroke. PLoS One 2013; 8(1)e55210
[] [PMID: 23372838]
Wang Z, Lin Y, Liu Y, et al. Serum uric acid levels and outcomes after acute ischemic stroke. Mol Neurobiol 2016; 53(3): 1753-9.
[] [PMID: 25744569]
Yu X, Shi J, Jiang C, et al. Association study of serum uric acid levels with clinical outcome and hemorrhagic transformation in stroke patients with rt-PA intravenous thrombolysis. Zhonghua Yi Xue Za Zhi 2015; 95(29): 2351-4.
[PMID: 26711068]
Song Q, Wang Y, Cheng Y, Liu J, Wei C, Liu M. Serum uric acid and risk of hemorrhagic transformation in patients with acute ischemic stroke. J Mol Neurosci 2020; 70(1): 94-101.
[] [PMID: 31486972]
Chamorro A, Amaro S, Castellanos M, et al. Safety and efficacy of uric acid in patients with acute stroke (URICO-ICTUS): a randomized, double-blind phase 2b/3 trial. Lancet Neurol 2014; 13(5): 453-60.
[] [PMID: 24703208]
Cervellati C, Romani A, Seripa D, et al. Oxidative balance, homocysteine, and uric acid levels in older patients with late onset alzheimer’s disease or vascular dementia. J Neurol Sci 2014; 337(1-2): 156-61.
[] [PMID: 24321755]
Tana C, Ticinesi A, Prati B, Nouvenne A, Meschi T. Uric acid and cognitive function in older individuals. Nutrients 2018; 10(8): E975.
[] [PMID: 30060474]
Tuven B, Soysal P, Unutmaz G, Kaya D, Isik AT. Uric acid may be protective against cognitive impairment in older adults, but only in those without cardiovascular risk factors. Exp Gerontol 2017; 89: 15-9.
[] [PMID: 28062372]
Latourte A, Bardin T, Richette P. Uric acid and cognitive decline: a double-edge sword? Curr Opin Rheumatol 2018; 30(2): 183-7.
[] [PMID: 29389776]
Daskalopoulou SS, Tzovaras V, Mikhailidis DP, Elisaf M. Effect on serum uric acid levels of drugs prescribed for indications other than treating hyperuricaemia. Curr Pharm Des 2005; 11(32): 4161-75.
[] [PMID: 16375738]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy