Journal of Obesity and Metabolic Research

REVIEW ARTICLE
Year
: 2015  |  Volume : 2  |  Issue : 4  |  Page : 228--233

Hyperuricemia: A risk factor beyond gout


Sujeet Raina1, Rashmi Kaul Raina2, Sunil K Raina3,  
1 Department of Medicine, Dr. Rajendra Prasad Government Medical College, Tanda, Kangra, Himachal Pradesh, India
2 Department of Pathology, Dr. Rajendra Prasad Government Medical College, Tanda, Kangra, Himachal Pradesh, India
3 Department of Community Medicine, Dr. Rajendra Prasad Government Medical College, Tanda, Kangra, Himachal Pradesh, India

Correspondence Address:
Sujeet Raina
C-15, Type-V Quarters, Dr. Rajendra Prasad Government Medical College Campus, Tanda, Kangra - 176 001, Himachal Pradesh
India

Abstract

A global epidemiological transition in the prevalence of noncommunicable diseases is taking place due to the emergence of behavioral and metabolic risk factors. A renewed interest in the role of serum uric acid as a risk factor has been generated and a crossover from rheumatology to composite of cardiovascular disorders is taking place. Hyperuricemia (HU) is defined as serum urate level > 6.8 mg/dl that is, the limit of urate solubility at physiological temperature and pH. The prevalence of HU and its complications have increased globally in the past decades. It is an indicator of a widespread transition in lifestyle. The positive association between serum uric acid and hypertension, coronary artery disease, stroke, heart failure, renal failure, and preeclampsia has been recognized. Evidence suggests that elevated serum uric acid is strongly associated with and predictive of insulin resistance and metabolic syndrome. The role of HU in the pathogenesis of cardiovascular and renal diseases involves effects on the endothelial function, oxidative metabolism, and platelet aggregation. Among the constellation of established atherosclerotic cardiovascular risk factors HU has an additive or synergistic impact on the outcomes. As an independent risk factor for cardiovascular and related diseases, the role of HU has been extensively debated for many years. Besides being a biomarker and risk factor, HU is also emerging a target for the prevention of atherosclerotic cardiovascular diseases. In most of the patients, with asymptomatic HU, treatment is not advocated to reduce cardiovascular risk. Currently, no guidelines and recommendations have been updated in the pharmacological management of asymptomatic HU. It will be particularly important to design large, long-term studies that would determine the effects of urate-lowering therapy on cardiovascular disease.



How to cite this article:
Raina S, Raina RK, Raina SK. Hyperuricemia: A risk factor beyond gout.J Obes Metab Res 2015;2:228-233


How to cite this URL:
Raina S, Raina RK, Raina SK. Hyperuricemia: A risk factor beyond gout. J Obes Metab Res [serial online] 2015 [cited 2019 Aug 22 ];2:228-233
Available from: http://www.jomrjournal.org/text.asp?2015/2/4/228/170903


Full Text

 Introduction



Medicine is ever evolving with the rapid expansion of knowledge-based on evidence, availability of newer diagnostic and therapeutic options, and confronting debatable and emerging issues. Epidemiological transition in the prevalence of diseases is taking place worldwide and with regional variations. The shift is driven by nutritional, demographic, socioeconomic, industrialization, urbanization, and associated lifestyle changes. In low- and middle-income countries, communicable diseases continue to be a major cause of death, but noncommunicable diseases related to inactivity and obesity are also on the rise and projected to increase substantially over the next two decades.[1] The prevalence of hyperuricemia (HU) and its irrefutable complications have increased globally in the past decades.[2] Our ability to understand and manage gout continues to advance.[3] Beyond gout, however, little progress has been achieved in other aspects of HU and its prognostic importance. First, the role of uric acid as an emerging risk factor for cardiovascular diseases, stroke and chronic kidney disease (CKD) (independent of urate crystal deposition) has been extensively debated for many years with different views. Evidence from various longitudinal population-based cohort studies has found elevated serum uric acid as predictive of increased mortality in patients with coronary artery disease, heart failure, stroke, and renal failure.[4] HU, as a pro-oxidant, causes endothelial dysfunction with the subsequent effects on smooth muscle proliferation, oxidative metabolism, and platelet aggregation. Second, guidelines have not been updated in the pharmacological management of asymptomatic HU due to the paucity of prospective, randomized, controlled clinical trials in this area.[5] Is asymptomatic HU a benign condition? Is HU a biomarker predictive of an outcome or an emerging risk factor for cardiovascular and related diseases? Has the time arrived when uric acid should be taken seriously?

 Definition



There is no consensus on the definition of HU.[6] On the physiochemical basis, HU is defined as serum urate level >6.8 mg/dl. This is the limit of urate solubility at physiological temperature and pH.[5],[7] Thus, a value >6.8 mg/dl indicates supersaturation of the body fluids.

 Epidemiology



The prevalence of HU and gout has risen globally. Especially over the last few decades, this is promoted by an increased prevalence of comorbidities such as hypertension, obesity, metabolic syndrome, type 2 diabetes mellitus, CKD and an aging population. Other factors in the rising prevalence of gout include certain dietary trends like the use of high fructose corn syrup sweetened beverages and widespread prescriptions of thiazide and loop diuretics for cardiovascular diseases.[2] HU is fairly common with prevalence between 2.6% and 47.2% in various populations.[8]

 Hyperuricemia and Controversial Associations



What is irrefutable is that persistent HU leads to gout, urate nephropathy, uric acid nephropathy and urolithiasis. What is known is that HU with or without gout is also associated with cardiovascular diseases, hypertension, atherosclerosis, metabolic syndrome and CKD. But what is controversial is that HU is an independent risk factor for cardiovascular diseases, stroke, and chronic renal failure! HU can be considered as an emerging risk factor for composite cardiovascular disorders and not just a biomarker because of the role it plays in the pathogenesis of these diseases [Figure 1].{Figure 1}

 Hyperuricemia and Systemic Inflammation



HU in the absence of gout, obesity, and metabolic syndrome has been linked to systemic inflammation.[9] Markers of systemic inflammation in the form of raised leukocyte count, C-reactive protein and inflammatory cytokines such as interleukin-6 (IL-6), IL-1ra, IL-18, tumor necrosis factor-α have accompanied HU.[10] In addition, serum monocyte chemoattractant protein-1 and CD14-positive monocytes were found elevated in patients with elevated serum urate levels compared with normouricemic controls. The chemokine ligand 2 levels were elevated in patients with gout as well as asymptomatic HU.[11] Uric acid has antioxidant properties in the extracellular environment. The proinflammatory effect of uric acid is derived from its intracellular effects on the vascular cells or adipocytes where it induces its pro-oxidative effects through activation of NADPH oxidase system and stimulating mitochondrial oxidative stress [Figure 2].[12]{Figure 2}

 Hyperuricemia and Atherosclerosis



HU causes atherosclerosis not only in macrovascular beds like coronaries and the carotids but also in the microvessels of renal vascular bed.[13] Coronary artery calcification is highly predictive of histopathological atherosclerosis and is a surrogate marker for subclinical atherosclerosis. Data from the participants in the coronary artery risk development in young adults study proved that HU is associated with coronary artery calcification and is an independent risk factor for subclinical atherosclerosis in young adults.[14]

 Hyperuricemia and Metabolic Syndrome



Persistent obesity and sedentary lifestyle begin with a constellation of metabolic abnormalities; dysglycemia, dyslipidemia, hypertension and procoagulant state, known as the metabolic syndrome. Emmerson has reviewed evidence supporting inclusion of HU as an intrinsic component of metabolic syndrome.[15] HU was proposed to be a marker of insulin resistance.[16] In addition, HU promotes insulin resistance thus HU and insulin resistance share a bidirectional causal effect. Hyperinsulinemia reduces the renal excretion of uric acid and reflects the defect in insulin action on the renal tubular reabsorption of uric acid.[17]

 Hyperuricemia and Hypertension



HU is associated with an increased risk for incident hypertension, independent of traditional hypertension risk factors.[18],[19] This risk appears more pronounced in younger individuals and women.[20] Animal models data of pharmacologically induced HU have linked uric acid as a predictor of hypertension, which can be ameliorated by uric acid-lowering drugs. Early hypertension is completely reversible with urate reduction but prolonged HU results in irreversible sodium-sensitive hypertension that become uric acid-independent. The early hypertension is mediated by increased renal renin activity and reduction of circulating plasma nitric oxide leading to a phenotype of excessive vasoconstriction that can be reversed by reduction of uric acid or renin-angiotensin system blockade. The later irreversible hypertension is secondary to altered intrarenal vascular architecture and vascular smooth muscle cell proliferation.[21],[22] In our study, association of hypertension and metabolic syndrome, the mean serum uric acid levels in hypertensive patients with metabolic syndrome were significantly higher when compared with patients without metabolic syndrome.[23] A recent publication shows that the incidence of new-onset hypertension in the allopurinol group has shown a declining trend in raised blood pressure as compared to that in the conventional treatment group.[24]

 Hyperuricemia and Cardiovascular Diseases



Epidemiological evidences have supported established risk factors for coronary artery disease. Known risk factors such as gender, age, obesity, diabetes, and hypertension have been included in myocardial infarction risk estimation algorithms. Gout, an inflammatory joint disease was found to have a 60% increased risk for carotid artery disease in Framingham study.[25] Gout has been found to be an independent risk factor for myocardial infarction in young patients and those without cardiovascular risk factors.[26] High serum urate as a true independent risk factor for coronary artery disease is debatable. HU is not an independent risk factor, but it is an integral part of the cluster of risk factors associated with metabolic syndrome, which is the breeding ground for future cardiovascular diseases and diabetes.[27],[28],[29] However, other investigators came with positive associations and found HU significantly and independently associated with cardiovascular mortality and the association was more pronounced in women.[30],[31] HU is also associated with poor outcome in patients with acute and chronic heart failure. HU in heart failure may be due to the upregulation of the xanthine oxidase. It is a key enzyme in the generation of oxygen free radicals. Therefore, it may induce proinflammatory activation, impaired oxidative metabolism, and vascular endothelial dysfunction by inducing antiproliferative effect and impairing nitric oxide production, and exercise intolerance.[32],[33] In an Indian study, it was observed that serum uric acid levels are higher in patients of acute myocardial infarction as compared to normal healthy persons and correlate with Killip class; patients in higher Killip class had higher serum uric acid levels [Figure 3].[34]{Figure 3}

 Hyperuricemia and Stroke



The beneficial potential antioxidant effect of uric acid as neuroprotective is possibly being taken over by the pro-oxidant neurotoxic effect of HU. HU may modestly increase the risks of both stroke incidence and mortality. A systematic review and meta-analysis of 16 prospective cohort studies found that the elevated serum uric acid level in adults is associated with a modest, but statistically significant increased risk of stroke incidence and mortality.[35] A Taiwanese population cohort study has established serum uric acid level as an independent risk factor for ischemic stroke.[36] HU is associated with hypertension, systemic inflammation, endothelial dysfunction, and vascular smooth muscle proliferation are the possible pathogenic mechanism for these observations. Uric acid as pro-oxidant increases oxygen radicals in circulation, which promote lipid oxidation leading to atherogenesis and thrombogenesis.[37]

 Hyperuricemia and Vitamin D



Parathyroid hormone (PTH) has a significant biologic influence on serum uric acid and HU has been observed in hyperparathyroid milieu.[38] Through negative feedback, Vitamin D deficiency or insufficiency activates parathyroid to induce the release of PTH.[39] Vitamin D insufficiency was associated with an increased risk of having elevated serum uric acid in postmenopausal Chinese women and not in premenopausal women.[40] Elevated PTH levels are thought to reduce renal urate excretion, although the exact mechanism remains unclear.[41]

 Hyperuricemia and Fructose



HU and increasing dietary exposure to sweetened foods and beverages containing high fructose corn syrup in the general population and especially pediatric age groups universally have shown secular trends.[42] Fructose raises uric acid levels rapidly via activation of the fructokinase pathway in hepatocytes. Fructokinase consumes adenosine triphosphate leading to an increased load of intracellular purines requiring metabolism and disposal through xanthine oxidase-mediated metabolism ending in uric acid.[43] Decreased renal uric acid excretion also contributes to fructose-induced HU.[44] Human studies show that fructose loading leads to increased serum uric acid levels acutely and that chronic increase in fructose consumption leads to chronically increased serum uric acid level and increases in blood pressure.[45] However, there are studies that argue against fructose as a risk for gout. The systematic review and meta-analysis of controlled feeding trials in nondiabetic and diabetic population did not support that increasing effect of isocaloric fructose intake was associated with an increase in uric acid levels.[46]

 Hyperuricemia and Chronic Kidney Disease



HU is not only the effect of chronic renal failure but also a cause of progressive nephropathy. HU causes the slow decline of kidney function which is independent of urate crystal deposition. Individuals with HU are at an increased risk of new-onset CKD than those without HU.[47] Urate-lowering therapy has a beneficial effect on protecting renal function and slowing down the progression of renal dysfunction in CKD patients with HU.[48],[49] HU induces inflammasomes which cause renal inflammation without urinary obstruction. Urate crystals are taken up by intracellular lysosomes followed by a lysosomal rupture with mitochondrial reactive oxygen species production, which activates the NLRP3 inflammasome. Thus, management of urate-induced inflammasome may offer alternative therapies.[50]

 Hyperuricemia and Diabetic Complications



In type 1 diabetes, serum, uric acid independently predicted the development of vascular complications, both retinopathy and nephropathy and coronary artery calcification.[51] HU is associated with increased insulin resistance and onset and progression of microvascular as well as macrovascular complications of diabetes including diabetic foot.[52]

 Asymptomatic Hyperuricemia



Asymptomatic HU is defined as a patient who has serum uric acid levels more than 6.8 mg/dl and do not have manifestations of gout that is, arthritis, tophi, and uric acid nephrolithiasis.[53] Substantial gaps still exist in the pharmacologic management of asymptomatic HU due to a paucity of prospective, randomized, controlled human research trials in this area. In addition inconvenience due to lifelong therapy, cost and side effects of drugs tilt the balance in risk-benefit ratio and justify the present status. Asymptomatic HU is not an indication for urate-lowering therapy at present. However, therapy is indicated in patients receiving chemotherapy or radiotherapy, with history of renal stone, strong family history of gout, urolithiasis, uric acid nephropathy, and high levels of serum uric acid (13 mg/dl in men and 10 mg/dl in women).[54] Asymptomatic HU with metabolic syndrome requires lifestyle advice, address other factors such as hypertension, dyslipidemia, obesity, and diabetes. Losartan, fenofibrate, and sulfinpyrazone may be considered in metabolic syndrome. A new battlefront has been opened by the radiological evidences demonstrating morphostructural changes in intra and extraarticular structures in asymptomatic individuals with HU. Taking together these findings with the pathophysiological role in cardiorenal metabolic disorders the concept of asymptomatic HU needs a reappraisal.[55] A Japanese guideline recommends treatment in a patient with asymptomatic HU at 8 mg/dl if cardiovascular risk factors are present and 9 mg/dl if not present.[56]

 Conclusions



The prevalence of HU is increasing. Chronic HU has achieved a new clinical meaning as a cardiometabolic disease.[57] HU is just not a biomarker for cardiovascular diseases, but an emerging risk factor, thereby adding to the overall burden of cardiovascular disease risk factors. Increasing evidence suggests a causal role for uric acid in hypertension.[58] Though a causal role between HU and cardiovascular events has not been unequivocally established and requires long-term incidence studies and randomized control trials, but serum uric acid levels provides useful prognostic information. It would be particularly important to design large, long-term studies that determine the effect of urate-lowering therapy on cardiovascular disease.[19],[31] Clinical evidence suggests a relationship of uric acid level with CKD and trials using urate-lowering therapy provide some promising evidence that lowering uric acid levels may retard the progression of CKD [Figure 4].[58]{Figure 4}

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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