The prevalence of gout has increased substantially in recent years, and most individuals with the disease are not getting the recommended treatment.1 Additionally, there is increasing evidence linking hyperuricemia with the promotion of hypertension, cardiovascular disease, insulin resistance, inflammation, adipogenesis, lipogenesis, and liver disease.1
Michael Pillinger, MD, professor of medicine at New York University School of Medicine, spoke with Rheumatology Advisor about his team’s recent review of gout and metabolic syndrome.1 “In most patients, gout exists within a matrix of multiple comorbidities, many of which comprise metabolic syndrome. If we can show gout contributes to metabolic syndrome, both gout — which is eminently treatable but almost universally undertreated — and metabolic syndrome may be positively impacted.”
Pathophysiology of Gout
Uric acid is mainly synthesized in the liver, intestines, and vascular endothelium from exogenous (mostly animal protein) and endogenous purines and is mainly found in its salt form, urate.2 Fructose also increases intracellular uric acid production. Its consumption has increased substantially over the last few decades, primarily due to the increased use of corn syrup as a commercial sweetener.1
Serum urate levels also depend on the degree of excretion by the kidneys, and low excretion is the main factor contributing to high urate levels.3
Hyperuricemia increases the risk of gout from monosodium urate crystal formation, which can occur spontaneously at a concentration of 6.8 mg/dL.4 Hyperuricemia may also increase the risk of urolithiasis in the form of uric acid precipitation in the renal collecting system. Urate and uric acid solubility decrease with increasing pH.4
Epidemiologic studies have recently shown that there is a higher prevalence of metabolic syndrome in individuals with hyperuricemia and gout compared with controls.5,6
In a cross-sectional study of 21,544 individuals who underwent work-related health examinations, the odds of developing metabolic syndrome were approximately 5 times higher for those with serum urate levels ≥9 mg/dL compared with those with serum urate levels <7 mg/dL.5
Ford et al performed a cross-sectional analysis of 1370 children and adolescents using data from the National Health and Nutrition Examination Surveys (NHANES) from 1999 to 2002 to determine the association between serum urate and metabolic syndrome.7 The prevalence of metabolic syndrome was <1%, 3.7%, 10.3%, and 21.1% in the lowest to highest quartiles of serum urate. The risk of metabolic syndrome was approximately 15 times higher for the highest quartile of urate compared with the lowest 2 quartiles.
Additionally, NHANES showed the prevalence of gout and metabolic syndrome increasing steadily and at similar rates when comparing data from 1988-1994 to 1999-2006.1
Rheumatology Advisor discussed the epidemiologic connection between gout and metabolic syndrome with Rashad Barsoum, MD, FRCP, FRCPE, emeritus professor of medicine at Cairo University. “Despite strong evidence of the association of hyperuricemia with the metabolic syndrome, it is still debatable whether it is a surrogate marker or a confounding risk factor, but the statistical association does not imply causality,” he said.
Elevated levels of serum urate may promote increases in blood pressure through changes produced in the vascular endothelium and kidney.1
Kang et al found that urate in a dose-dependent manner inhibited endothelial nitric oxide production. The effect was inhibited by probenecid, a urate transport blocker.8 In a different study, the same group showed that urate dose dependently promoted vascular smooth muscle proliferation and cell migration.9 Taken together, the studies suggest hyperuricemia may lead to a vascular state that is hypertrophied, with an inability of the vessels to relax.
Urate may also affect blood pressure by influencing kidney function.1 Hyperuricemia can cause acute renal failure through supersaturation in kidney tubules with crystal formation and obstruction.10 However, can elevated uric acid affect kidney function at concentrations below crystal formation? Or more importantly, can lowering high serum urate lower blood pressure?
Since hyperuricemia is commonly encountered in patients with new-onset essential hypertension, a small randomized controlled crossover trial was performed on adolescents to determine if lowering serum urate improved hypertension.11 Patients had newly diagnosed, untreated, stage 1 essential hypertension with serum urate levels ≥6 mg/dL. Allopurinol or placebo 200 mg was administered twice daily for 4 weeks with a 2-week washout period. Compared with placebo, allopurinol significantly reduced mean casual and ambulatory systolic and diastolic blood pressures with 20 of 30 (66.7%) in the allopurinol group achieving normalized blood pressure.
Since cardiovascular disease continues to be the leading cause of death in the United States,12 finding additional treatments is a high priority.
It may be difficult, however, to determine whether it is the hyperuricemia or comorbidities that elevate the risk of cardiovascular events. In a prospective study, Wu et al13 evaluated 2142 patients without comorbidities over a mean follow-up of 57 months and found that hyperuricemia independently predicted the risk of new coronary artery disease events (adjusted hazard ratio [HR]: 1.71; 95% CI: 1.26-2.34). The authors concluded, “asymptomatic hyperuricemia is a valuable biomarker for predicting the development of incident coronary artery disease events.”
Additional confirmation comes from a recent review of hyperuricemia, gout, and cardiovascular disease in which the authors state, “Accruing evidence from prospective studies suggests that gout is an independent risk factor for developing cardiovascular disease and for higher cardiovascular mortality.”14
The critical question is whether treating gout or asymptomatic hyperuricemia protect patients from cardiovascular death. In a prospective, case-matched, cohort study of more than 40,000 patients, Chen et al15 compared those with gout on urate-lowering therapy (ULT) with patients with gout not on ULT. The investigators found a lower risk of cardiovascular disease (adjusted HR: 0.29; 95% CI: 0.11-0.80) and all-cause mortality (adjusted HR: 0.47; 95% CI: 0.29-0.79) in those on ULT. Chen et al16 also retrospectively compared patients with hyperuricemia on ULT vs those not on ULT and found a lower risk of all-cause death (adjusted HR: 0.60; 95% CI: 0.41-0.88) and a nonsignificant lower risk of cardiovascular death for those on ULT.
De Abajo et al17 compared 3171 cases of nonfatal acute myocardial infarction (AMI) with 18,525 controls and found a lower use of allopurinol among cases (odds ratio [OR]: 0.52; 95% CI: 0.33-0.83). The protective effect was only found at doses ≥300 mg and longer durations (>180 days). Allopurinol use was also associated with a reduced risk of recurrence for those with a previous AMI (OR: 0.16; 95% CI: 0.04-0.76).
Patients with gout are at increased risk for insulin resistance.18 A meta-analysis of prospective cohort studies with no evidence of heterogeneity found hyperuricemia to be an independent risk factor for incident type 2 diabetes.19 The authors stated that the evidence strongly supported hyperuricemia as a causal factor in the development of type 2 diabetes.
Multiple physiologic mechanisms may play a role in the association between hyperuricemia and the development of type 2 diabetes. Hyperuricemia induces endothelial dysfunction,20 reduces nitric oxide21 (important in stimulating glucose uptake), and is associated with oxidative stress.22
However, can lowering serum urate improve insulin sensitivity? In a recent small study, Takir et al23 compared the effect of allopurinol 300 mg daily for 3 months vs observation only in patients with hyperuricemia but without diabetes. After 3 months, patients taking allopurinol showed reductions in serum urate, fasting blood glucose, fasting insulin, insulin resistance (measured by homeostatic model assessment of insulin resistance), and serum high-sensitivity C-reactive protein. The number of patients with impaired fasting glucose after 3 months compared with baseline was reduced (20% vs 75%; P <.001).
The Question of Treatment
Although limited evidence is available, an important question is whether patients with metabolic syndrome and asymptomatic hyperuricemia should be treated with ULT. Current American College of Rheumatology guidelines (2012) cite insufficient evidence for a determination, while Japanese guidelines recommend treatment for serum urate levels >9 mg/dL, irrespective of the presence of metabolic syndrome.1
Drs Pillinger and Barsoum agree that more evidence is needed, particularly from large randomized trials.
Dr Pillinger may treat patients with asymptomatic hyperuricemia in certain situations. “In patients with renal insufficiency, several small studies suggest a nephroprotective effect. Also, I consider using ULT in some high-risk patients in whom urate is approaching 10 mg/dL. In both cases, the current state of the data makes this decision more art than science.”
Dr Barsoum felt that it would be premature recommend ULT for patients with metabolic syndrome and asymptomatic hyperuricemia. “Asymptomatic hyperuricemia is common, may be harmless, and may even be useful (as a powerful scavenger of peroxynitrite). It is common practice to attribute vague musculoskeletal symptoms to a high blood uric acid level without good evidence of a causal relationship. We should use caution in making treatment decisions until we have enough evidence from reliable RCTs [randomized controlled trials].”
A large percentage of individuals with gout are not receiving adequate urate lowering. Effectively treating gout may improve and prevent some comorbidities, though the evidence is limited.1 Whether patients with asymptomatic hyperuricemia should be similarly treated with urate lowering, and under what circumstances, remains a pressing research topic.
- Thottam GE, Krasnokutsky S, Pillinger MH. Gout and metabolic syndrome: a tangled web. Curr Rheumatol Rep. 2017;19(10):60.
- El Ridi R, Tallima H. Physiological functions and pathogenic potential of uric acid: a review. J Adv Res. 2017;8(5):487-493.
- Choi HK, Mount DB, Reginato AM; American College of Physicians; American Physiological Society. Pathogenesis of gout. Ann Intern Med. 2005;143(7):499-516.
- Gustafsson D, Unwin R. The pathophysiology of hyperuricaemia and its possible relationship to cardiovascular disease, morbidity and mortality. BMC Nephrol. 2013;14:164.
- Wei CY, Sun CC, Wei JC, et al. Association between hyperuricemia and metabolic syndrome: an epidemiological study of a labor force population in Taiwan. Biomed Res Int. 2015;2015:369179.
- Yoo HG, Lee SI, Chae HJ, et al. Prevalence of insulin resistance and metabolic syndrome in patients with gouty arthritis. Rheumatol Int. 2011;31(4):485-491.
- Ford ES, Li C, Cook S, Choi HK. Serum concentrations of uric acid and the metabolic syndrome among US children and adolescents. Circulation. 2007;115(19):2526-2532.
- Kang DH, Park SK, Lee IK, Johnson RJ. Uric acid-induced C-reactive protein expression: implication on cell proliferation and nitric oxide production of human vascular cells. J Am Soc Nephrol. 2005;16(12):3553-3562.
- Kang DH, Han L, Ouyang X, et al. Uric acid causes vascular smooth muscle cell proliferation by entering cells via a functional urate transporter. Am J Nephrol. 2005;25(5):425-433.
- Ejaz AA, Mu W, Kang DH, et al. Could uric acid have a role in acute renal failure? Clin J Am Soc Nephrol. 2007;2(1):16-21.
- Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial. JAMA. 2008;300(8):924-932.
- Centers for Disease Control and Prevention. Heart disease facts. https://www.cdc.gov/heartdisease/facts.htm. Updated November 28, 2018. Accessed January 30, 2018.
- Wu J, Lei G, Wang X, et al. Asymptomatic hyperuricemia and coronary artery disease in elderly patients without comorbidities. Oncotarget. 2017;8(46):80688-80699.
- Abeles AM. Hyperuricemia, gout, and cardiovascular disease: an update. Curr Rheumatol Rep. 2015;17(3):13.
- Chen JH, Lan JL, Cheng CF, et al. Effect of urate-lowering therapy on the risk of cardiovascular disease and all-cause mortality in patients with gout: a case-matched cohort study. J Rheumatol. 2015;42(9):1694-1701.
- Chen JH, Lan JL, Cheng CF, et al. Effect of urate-lowering therapy on all-cause and cardiovascular mortality in hyperuricemic patients without gout: a case-matched cohort study. PLoS One. 2015;10(12):e0145193.
- de Abajo FJ, Gil MJ, Rodríguez A, et al. Allopurinol use and risk of non-fatal acute myocardial infarction. Heart. 2015;101(9):679-685.
- Rathmann W, Funkhouser E, Dyer AR, Rothman JM. Relations of hyperuricemia with the various components of the insulin resistance syndrome in young black and white adults: the CARDIA study. Ann Epidemiol. 1998;8(4):250-61.
- 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.
- Khosla UM, Zharikov S, Finch JL, et al. Hyperuricemia induces endothelial dysfunction. Kidney Int. 2005;67(5):1739-1742.
- Johnson RJ, Kang DH, Feig D, et al. Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension. 2003;41(6):1183-1190.
- Sautin YY, Nakagawa T, Zharikov S, Johnson RJ. Adverse effects of the classic antioxidant uric acid in adipocytes: NADPH oxidase-mediated oxidative/nitrosative stress. Am J Physiol Cell Physiol. 2007;293(2):C584-C596.
- 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):924-929.