Treating Asymptomatic Hyperuricemia Could Lower Risk of Developing Chronic Conditions

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When uric acid becomes elevated in the human body, a variety of problems can develop, most notably gout—a painful, inflammatory arthritis caused by uric acid crystal deposition in joints. Chronically elevated uric acid can also lead to painful kidney stones. The majority of patients found to have hyperuricemia, however, never go on to develop gout or nephrolithiasis, and unless tested, they would never know. Therefore, asymptomatic hyperuricemia is not considered a disease, and treatment has not been indicated. In the early 1980s, uric acid was removed from routine metabolic chemistry blood panels because of this.

Evidence is growing that chronically elevated serum uric acid can contribute to a variety of health problems, including type II diabetes, hypertension, vascular disease and chronic kidney disease. Treatment of hyperuricemia may therefore—at least theoretically—result in beneficial risk reduction for these diseases.

Pathophysiology, Diet & Evolution

In humans, uric acid is the end product of purine catabolism. Two-thirds of uric acid is derived endogenously from normal cell breakdown and one-third from dietary intake. Hyperuricemia is defined as a serum level >7.0 mg/dL. Uric acid elevation early in life (primary hyperuricemia) in most patients is due to decreased renal urate clearance and a smaller percentage from overproduction. The prevalence of hyperuricemia in adult men is 20–25% and much less (4–6%) in premenopausal women (thought to be due to estrogen-induced increased renal urate clearance).¹ The prevalence of gout in these patients is only around 4%. The risk of developing gout depends on the duration and level of hyperuricemia. Levels >9.0 pose a significant risk.²

Hyperuricemia tends to begin around puberty, but clinical manifestations, if they do occur, take on average 20 years to develop.

Since the 1960s, the prevalence of both hyperuricemia and gout has more than doubled.³ During this same period, the incidence of type II diabetes, metabolic syndrome and obesity has similarly increased.⁴ These increases are likely related to lifestyle and dietary factors, including inactivity, obesity, sugars (particularly fructose) and purine-rich fatty food.⁵

The intake of added sugars to the Western diet, particularly table sugar and high-fructose corn syrup, has greatly increased in the past hundred years. Metabolic syndrome is characterized by hyperglycemia, dyslipidemia and hypertension and its clinical consequence of insulin resistance. Fructose is a major component of added sugars, and its consumption has been directly linked to hyperuricemia and metabolic syndrome.⁶ Increased dietary intake of such sugars can lead to fat production and obesity.

In humans, there is a two- to threefold increased risk for hyperuricemia and gout in men and women who consume two or more beverages sweetened by high-fructose corn syrup per day.^7,8 Fructose, unlike other sugars, produces uric acid when it is broken down inside cells, leading to elevated serum levels. Modern dietary habits, therefore, likely explain the surge in gout cases and possibly uric acid-related metabolic syndrome.

Uricase (urate oxidase) is an enzyme that catalyzes the oxidation of uric acid to 5-hydroxyisourate, which is then further metabolized and excreted as waste, mostly by the kidneys. Uricase is produced by virtually all organisms from bacteria to mammals. For reasons that until recently remained unknown, humans and modern great apes (i.e., gorillas, orangutans, chimpanzees and bonobos) are the only mammals that do not make uricase. In these species, the uricase gene is present, but inactive. As a result, humans and higher primates have higher serum urate levels than other mammals.

In 2010, Richard Johnson and Peter Andrews proposed a hypothesis that the uricase gene mutation was an evolutionary product of a need for northern migrating apes of 15 million years ago to survive harsh winters.^9,10 With fructose-laden fruit as a major dietary component, the primates could benefit from increased available blood sugar and fat from increased insulin resistance. This “thrift gene” would give the brain access to glucose, enabling proper function during times when foraging for food would be most essential. The mutation would survive through the evolution of humans.

The Research

With modern dietary habits and the abundance of available food, the “thrift gene” would lead to pathologic consequences. When uricase is inhibited, rats respond to a fructose challenge by increasing blood pressure and liver fat.¹¹

In 2006, an elegant study showed that lowering serum uric acid with allopurinol was able to prevent metabolic syndrome in rats fed a fructose-rich diet.¹²

Hyperuricemia itself may cause metabolic syndrome. A 2012 study followed young adults 18–30 years old for 15 years.¹³ They showed that hyperuricemia was an independent risk factor for diabetes and pre-diabetes. Several other studies have shown a relationship between hyperuricemia, type II diabetes and insulin resistance.^14,15 The mechanism of this relationship is still not clear. Elevated serum insulin levels, as in type II diabetes, cause a decrease in renal uric acid excretion. Insulin requires nitric oxide for glucose uptake in cells. Elevated uric acid levels can then lead to further insulin resistance by directly blocking nitric oxide bioavailability.

Hyperuricemia has for many years been linked to cardiovascular diseases, such as hypertension, coronary artery disease, peripheral vascular disease and stroke.^16-18 In 2011, a meta-analysis showed that for every 1 mg/dL increase in serum uric acid there is a 13% increased risk for hypertension.¹⁹

A growing number of studies are demonstrating that hyperuricemia is an independent risk factor for progression of chronic kidney disease.^20,21

Evidence is growing that chronically elevated serum uric acid can contribute to a variety of health problems, including type II diabetes, hypertension, vascular disease & chronic kidney disease.

There is a paucity of human studies attempting to demonstrate the benefits of treating asymptomatic hyperuricemia. Animal studies have shown the benefit of xanthine oxidase inhibition preventing vascular complications of insulin resistance.^22,23 Several studies have shown the benefits of allopurinol, febuxostat and oxipurinol (the active metabolite of allopurinol) in myocardial function.^24-26

In 2008, a double-blind, placebo-controlled, crossover study demonstrated that allopurinol successfully lowered blood pressure in hypertensive adolescents, suggesting that allopurinol could be as effective as most conventional antihypertensive drugs.²⁷ A model designed to simulate the effects of uric acid lowering with allopurinol predicted that a significant reduction of vascular events, such as stroke and myocardial infarction, could be achieved in men with serum urate levels >7.0 mg/dL and women with levels >5.0 mg/dL.²⁸ A randomized, open, parallel-controlled study in patients with type II diabetes and asymptomatic hyperuricemia showed that allopurinol improved insulin resistance, reduced serum levels of high-sensitivity C-reactive protein and reduced carotid intima-media thickness, suggesting a delay in development of atherosclerosis.²⁹ Kidney function was also significantly improved in this group.³⁰

A retrospective study following 111,992 patients with a serum uric acid level >7.0 mg/dL over nine years showed that urate-lowering therapy treated patients who achieved a serum uric acid level <6.0 mg/dL had 37% reduction in renal disease progression.²⁰

Drug Therapies

So should we be treating asymptomatic hyperuricemia?

We do not routinely monitor uric acid levels in patients with at-risk diseases who do not have gout. Should we be testing more frequently?

Allopurinol is an inexpensive and relatively safe medication. Two synthetic uricase products are available for clinical use: Pegloticase (Kreystexxa) is now marketed for treatment refractory gout and rasburicase (Elitek) for prevention and treatment of tumor lysis syndrome, but because of the relatively high rates of side effects, these are not practical for use in most patients with hyperuricemia.

More than 30 studies can be found on ClincalTrials.gov—recruiting, active or completed—where uric acid lowering with allopurinol or febuxostat is being tested for effects on insulin resistance, hypertension, kidney disease, heart failure, left ventricular hypertrophy and vascular disease. Perhaps, we will soon have answers as to how to survive the evolutionary advantage that has failed us in the modern world.

Martin Garber, DO, is a rheumatologist in a three-doctor private practice rheumatology group serving the communities of Ann Arbor and Southeastern Michigan. He performs inpatient consults at St. Joseph Mercy Hospital in Ann Arbor and participates in the hospital’s internal medicine resident teaching program.

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