Supplements Update on the Diagnosis and Treatment of Gout
Epidemiology of Hyperuricemia and Gout
Up to 76% of patients with gout have the metabolic syndrome.46,47 Hyperuricemia is related to the individual components of the metabolic syndrome in complex ways. Hypertension itself can induce hyperuricemia, possibly because the decreased renal blood flow increases urate reabsorption.48 Conversely, experimentally induced hyperuricemia (>~2 mg/dL) in rats causes hypertension and vascular injury, which can then be reversed by lowering urate levels with the xanthine oxidase inhibitor allopurinol.49 Hyperuricemia in childhood was found to be associated with hypertension that persists into adulthood.50 According to one theory, the loss of uricase (which breaks down uric acid) during the evolution of African hominids may have conserved sodium and increased blood pressure in response to an upright posture.51 Alternatively, urate, an effective antioxidant, may have been retained to replace the antioxidant properties of vitamin C, which hominids lost the ability to synthesize at about the same time.52
Hyperuricemia is probably associated with glucose intolerance via multiple mechanisms, but the central one may be the enhancing effect of insulin resistance on renal urate absorption.47 Increased body mass index is also directly correlated with hyperuricemia, and leptin may be a contributory factor.53 Higher adiposity and weight gain are strong risk factors for gout, whereas weight loss is protective.5,6,54 Dyslipidemia may induce hyperuricemia through its negative effect on renal function.55
Hyperuricemia has long been suspected to be a cardiovascular risk factor. Although the Framingham Heart Study found no independent association between hyperuricemia and increased risk of coronary artery disease, several subsequent studies have found one.56-59 A recent review concluded that SU is a moderate, independent cardiovascular risk factor, and appears to be a stronger risk factor in individuals already at high risk for cardiovascular disease than in healthy individuals. The authors therefore proposed a trial of urate-lowering therapy in high-risk patients to determine whether this improves cardiovascular outcomes.60
Hyperuricemia was a poor prognostic factor in patients with congestive heart failure, and allopurinol treatment may improve outcomes.61,62 In a clinical trial, the angiotensin receptor blocker losartan (which has uricosuric properties) was shown to improve cardiovascular outcomes, and it was estimated that 29% of the treatment effect was because of lowering SU.63 Despite all these data, it is still not completely clear if there is an independent association between hyperuricemia and cardiovascular risk in adults, or if hyperuricemia is merely a marker for those at risk.
Gout and Diet: New Insights
Gout and diet were explored in a prospective study of 47 150 men in the Health Professionals Follow-up Study between 1986 and 1998.16 The adjusted risk of gout was approximately 40% to 50% greater in those with a diet highest in red meat or seafood compared with those with the diet lowest in these foods (Figure 1). Despite popular belief, the risk of gout was not correlated with consumption of purine-rich vegetables nor total protein intake. Interestingly, high consumption of low-fat dairy products was associated with decreased gout risk, possibly because casein and other milk proteins have uricosuric properties. However, it is thought that reducing dietary purines in patients with gout leads to only modest reductions in serum uric acid levels.64 Alcohol consumption increases gout risk in dose-dependent fashion. Beer increases the risk more than liquor (possibly because beer has a higher purine content), whereas wine does not increase risk (Figure 2).17 Similar associations between hyperuricemia and diet were found in the Third National Health and Nutritional Examination Survey (NHANES).65,66
Problems With Gout Treatment
Pharmacologic treatment of hyperuricemia with urate-lowering drugs has led to a dramatic reduction in long-term gouty arthritis and tophaceous gout.67 However, gout is often mismanaged by both physicians and patients alike. Fewer than 10% of patients with gout are referred to rheumatologists, who may have more experience with managing this disease than primary care physicians.68 Adherence to gout medications, such as allopurinol, is spotty at best, possibly because patients are not adequately taught how to take them. (For example, allopurinol should not be taken intermittently.)69
In up to 50% of patients, allopurinol is prescribed for asymptomatic hyperuricemia instead of an approved indication (eg, frequent and debilitating gout attacks, tophi, chronic erosive arthritis, urate nephrolithiasis). The drug should be used cautiously and in reduced dosages in patients with impaired renal function.70 More than 50% of cases of allopurinol hypersensitivity syndrome (eg, rash, fever, eosinophilia, hepatitis, renal failure) had been inappropriately treated for asymptomatic hyperuricemia in one study.71
Medication errors are often observed in the setting of associated comorbid illnesses and polypharmacy.72 Hospitalized patients with acute gout are often treated with colchicine or nonsteroidal anti-inflammatory drugs, even in the setting of renal failure, which greatly increases the toxicity of these drugs.73 Quality-control indicators have recently been developed, which pertain to the use of urate-lowering medications and anti-inflammatory drugs in patients with gout.74
The apparent rise in the prevalence and incidence of gout over the past several decades may be caused by growing populations with risk factors for this disease, such as advanced age, high intake of purine-rich animal protein, metabolic syndrome, diuretic use, organ transplant, and end-stage renal disease. Polyarticular gout can mimic osteoarthritis (especially in elderly women) or rheumatoid arthritis. Hyperuricemia may be an independent cardiovascular risk factor, but treating asymptomatic hyperuricemia cannot be recommended until clinical trials demonstrate that lowering serum uric acid reduces cardiovascular risk. Physicians and patients should be taught how to manage gout properly to minimize the adverse effects of medications.
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