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.
You Might Also Like
Explore This IssueAugust 2016
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.
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
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.
- 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 Oct;63(10):3136–3141.
- Campion EW, Glynn RJ, DeLabry LO. Asymptomatic hyperuricemia. Risks and consequences in the Normative Aging Study. Am J Med. 1987 Mar;82(3):421–426.
- Lawrence RC, Felson DT, Helmick CG, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: Part II. Arthritis Rheum. 2008 Jan;58(1):26–35.
- Centers for Disease Control and Prevention.
- Global report on diabetes. World Health Organization. 2016.
- Johnson RJ, Nakagawa T, Sanchez-Lozada LG, et al. Sugar, uric acid, and the etiology of diabetes and obesity. Diabetes. 2013 Oct;62(10):3307–3315.
- Choi HK, Curhan G. Soft drinks, fructose consumption, and the risk of gout in men: Prospective cohort study. BMJ. 2008 Feb;336(7639):309–312.
- Choi HK, Willett W, Curhan G. Fructose-rich beverages and risk of gout in women. JAMA. 2010 Nov 24;304(20):2270–2278.
- Johnson RJ, Andrews P. The Fat Gene: A genetic mutation in prehistoric apes may underlie today’s pandemic of obesity and diabetes. Sci Am. 2015 Oct;313(4):64–69.
- Johnson RJ, Andrews P. Fructose, uricase and the Back-to-Africa hypothesis. Evol Anthropol. 2010 Nov/Dec;19(6):250–257.
- Tapia E, Cristóbal M, García-Arroyo FE, et al. Synergistic effect of uricase blockade plus physiological amounts of fructose-glucose on glomerular hypertension and oxidative stress in rats. Am J Physiol Renal Physiol. 2013 Mar 15;304(6):F727–F736.
- Nakagawa T, Hu H, Zharikov S, et al. A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol. 2006 Mar;290(3):F625–F631.
- Krishnan E, Pandya BJ, Chung L, et al. Hyperuricemia in young adults and risk of insulin resistance, prediabetes, and diabetes: A 15-year follow-up study. Am J Epidemiol. 2012 Jul 15;176(2):108–116.
- Krishnan E, Akhras KS, Sharma H, et al. Relative and attributable diabetes risk associated with hyperuricemia in US veterans with gout. QJM. 2013 Aug;106(8):721–729.
- Yoo TW, Sung KC, Shin HS, et al. Relationship between serum uric acid concentration and insulin resistance and metabolic syndrome. Circ J. 2005 Aug;69(8):928–933.
- Baker JF, Krishnan E, Chen L, et al. Serum uric acid and cardiovascular disease: Recent developments, and where do they leave us? Am J Med. 2005 Aug;118(8):816–826.
- Baker JF, Schumacher HR, Krishnan E. Serum uric acid level and risk for peripheral arterial disease: Analysis of data from the multiple risk factor intervention trial. Angiology. 2007 Aug-Sep;58(4):450–457.
- Brand FN, McGee DL, Kannel WB, et al. Hyperuricemia as a risk factor of coronary heart disease: The Framingham Study. Am J Epidemiol. 1985 Jan;121(1):11–18.
- Grayson PC, Kim SY, LaValley M, et al. Hyperuricemia and incident hypertension: A systematic review and meta-analysis. Arthritis Care Res (Hoboken). 2011 Jan;63(1):102–110.
- Levy GD, Rashid N, Niu F, et al. Effect of urate-lowering therapies on renal disease progression in patients with hyperuricemia. J Rheumatol. 2014 May;41(5):955–962.
- Prasad Sah OS, Qing YX. Associations between hyperuricemia and chronic kidney disease: A review. Nephrourol Mon. 2015 May 23;7(3):e27233.
- El-Bassossy HM, Elberry AA, Azhar A, et al. Ameliorative effect of allopurinol on vascular complications of insulin resistance. J Diabetes Res. 2015;2015:178540.
- El-Bassossy HM, Watson ML. Xanthine oxidase inhibition alleviates the cardiac complications of insulin resistance: Effect on low grade inflammation and the angiotensin system. J Transl Med. 2015 Mar 6;13:82–92.
- Farquharson CA, Butler R, Hill A, et al. Allopurinol improves endothelial dysfunction in chronic heart failure. Circulation. 2002 Jul 9;106(2):221–226.
- Hare JM, Mangal B, Brown J, et al. Impact of oxypurinol in patients with symptomatic heart failure. Results of the OPT-CHF study. J Am Coll Cardiol. 2008 Jun 17;51(24):2301–2309.
- Nakagomi A, Saiki Y, Noma S, et al. Effects of febuxostat and allopurinol on the inflammation and cardiac function in chronic heart failure patients with hyperuricemia. IJC Metab and Endocr. 2015 Sep;8:46–55.
- Fieg DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: A randomized trial. JAMA. 2008 Aug 27;300(8):924–932.
- Akkineni R, Tapp S, Tosteson A, et al. Treatment of asymptomatic hyperuricemia and prevention of vascular disease: A decision analytic approach. J Rheumatol. 2014 Apr;41(4):739–748.
- Liu P, Wang H, Zhang F, et al. The effects of allopurinol on the carotid intima-media thickness in patients with type 2 diabetes and asymptomatic hyperuricemia: A three-year randomized parallel-controlled study. Intern Med. 2015;54(17):2129–2137.
- Liu P, Chen Y, Wang B, et al. Allopurinol treatment improves renal function in patients with type 2 diabetes and asymptomatic hyperuricemia: 3-year randomized parallel-controlled study. Clin Endocrinol (Oxf). 2015 Oct;83(4):475–482.