Medical Care
Asymptomatic hyperuricemia
Most patients with asymptomatic hyperuricemia never develop gout or stones. Pharmacologic treatment for asymptomatic hyperuricemia carries some risk, is not considered beneficial or cost-effective, and generally is not recommended. However, these patients can be advised on lifestyle changes such as changes in diet, reduction in alcohol intake, and exercise, which may lower uric acid levels. [35] The exception to this is in an oncologic setting, in which patients receiving cytolytic treatment may receive prophylaxis against acute uric acid nephropathy.
In addition to avoiding foods that are high in purines, dietary measures may include ensuring adequate magnestium and zinc intake, as higher intake is associated with decreased hyperuricemia risk. [14, 15] Use of probiotics (eg, Bifidobacteria,Lactobacilli) may promote purine and uric acid catabolism by the gut microbiota. [36, 37]
Symptomatic hyperuricemia
The clinical scenarios under which hyperuricemia can be symptomatic are gout, uric acid stones, or uric acid nephropathy.
Acute gouty arthritis
The initial goal in acute gouty arthritis is to provide symptomatic relief from pain. Indomethacin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are the drugs of choice. NSAIDs are prescribed for approximately a 7- to 10-day course or until 3-4 days after all signs of inflammation have resolved. Use NSAIDs with caution or avoid them in patients in edematous states, such as heart failure, and in patients with peptic ulcer disease or kidney insufficiency.
Colchicine, which inhibits neutrophil activation, is effective but is currently used less frequently because of its adverse effects. Traditionally, colchicine is administered as a 0.6-mg dose every hour until improvement occurs, adverse gastrointestinal effects occur, or a total of 10 doses is reached and no relief is noted. The adverse gastrointestinal effects include abdominal pain, diarrhea, and nausea, which occur in most patients started on colchicine. Although colchicine can be administered intravenously, this is usually avoided because of its potential for serious toxicity.
Use intra-articular glucocorticoids in patients with contraindications to NSAID or colchicine use. Occasionally, intra-articular glucocorticoids may be used in patients with gouty arthritis refractory to NSAIDs or colchicine.
Chronic gout therapy
After the symptoms of acute gout subside, patients enter the intercritical period during which a decision must be made regarding the need for treatment with a urate-lowering medication. One important point to consider is that abrupt lowering of urate levels can precipitate an attack of acute gout during the intercritical period. Thus, these patients should receive prophylactic colchicine coverage irrespective of which urate-lowering medication is used.
The choice of urate-lowering medications is uricosuric drugs (which promote uric acid excretion) or xanthine oxidase inhibitors (which inhibit uric acid production).
Probenecid, which is a uricosuric drug, inhibits the tubular reabsorption of filtered and secreted urate, thereby increasing urate excretion. The ideal candidates for probenecid therapy are those with a 24-hour urine uric acid excretion of less than 800 mg, no history of nephrolithiasis, and good kidney function (creatinine clearance >80 mL/min). The starting dose for probenecid is 250 mg twice a day, which can be increased gradually to a maximum daily dose of 3 g/d. Some degree of gastrointestinal irritation is experienced by approximately 2% of patients.
Allopurinol is the most widely used antihyperuricemic agent. The major metabolite of allopurinol is oxypurinol, and both allopurinol and oxypurinol are competitive inhibitors of the enzyme xanthine oxidase.
The ideal candidates for allopurinol treatment are as follows:
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Uric acid overproducers (24-h urinary uric acid excretion >800 mg on general diet or >600 mg on a purine-restricted diet)
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Patients with kidney insufficiency, nephrolithiasis, or tophaceous gout
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Patients at risk for developing uric acid nephropathy
Although allopurinol can be used in almost any hyperuricemic state, the above-mentioned conditions are more specific indications for allopurinol use. The usual maintenance dose for adults is 200-300 mg/d. The long half-life of oxypurinol makes once-daily dosing possible. Very importantly, adjust the dose in persons with chronic kidney disease because a higher incidence of adverse effects is observed if the dose is not adjusted.
Allopurinol is well tolerated by most patients, but hypersensitivity reactions may develop, which can be severe or fatal. Because a skin rash may progress to a severe hypersensitivity reaction, patients who develop a skin rash should discontinue allopurinol. Hepatotoxicity, bone marrow depression, and interstitial nephritis are rare but serious adverse effects of allopurinol.
Febuxostat is an orally administered xanthine oxidase inhibitor that was approved by the US Food and Drug Administration (FDA) in 2009 for the long-term treatment of hyperuricemia in patients with gout. In the CONFIRMS trial, a 6-month study that compared febuxostat and allopurinol in 2269 subjects with gout and serum urate levels ≥8.0 mg/dL, febuxostat 80 mg daily proved superior to allopurinol in lowering uric acid levels in patients with normal renal function, and febuxostat 40 mg daily was equivalent to allopurinol in such patients. In patients with mild-to-moderate renal impairment, febuxostat at any dose was superior to allopurinol in lowering uric acid levels. [38]
Overall, febuxostat was as safe as allopurinol in the CONFIRMS trial. [38] However, previous studies have identified cardiovascular events with febuxostat, and large ongoing trials are comparing the cardiovascular safety of febuxostat versus allopurinol. [39]
Lesinurad (Zurampic) is the first selective uric acid reabsorption inhibitor (SURI) approved by the FDA. It acts by inhibiting the urate transporter, URAT1, which is responsible for the majority of the renal reabsorption of uric acid. It also inhibits organic anion transporter 4 (OAT4), a uric acid transporter associated with diuretic-induced hyperuricemia.
Lesinurad must be coadministered with a xanthine oxidase inhibitor and is indicated for hyperuricemia associated with gout in patients who have not achieved target serum uric acid levels with a xanthine oxidase inhibitor alone. It is not approved for asymptomatic hyperuricemia and it is contraindicated for increased uric acid levels caused by tumor lysis syndrome or Lesch-Nyhan syndrome.
Monotherapy or higher than recommended doses are associated with an increased serum creatinine level. Kidney function should be assessed before initiating therapy and periodically thereafter. More frequent monitoring is required for an estimated creatinine clearance (CrCl) below 60 mL/min. Do not initiate therapy if the CrCl is below 45 mL/min and discontinue if CrCl decreases persistently to below 45 mL/min.
Approval was based on three randomized, placebo-controlled studies involving 1537 participants for up to 12 months. Serum uric acid levels were lower in participants treated with lesinurad plus allopurinol or febuxostat than in those who received placebo in combination with a xanthine oxidase inhibitor. [40]
Pegloticase (Krystexxa) is a recombinant, pegylated, uric acid–specific enzyme that catalyzes the oxidation of uric acid to allantoin. It is approved for use in adults with chronic gout that is refractory to conventional therapy. It is administered by intravenous infusion.
Uric acid nephrolithiasis
Allopurinol is the mainstay of drug therapy in patients with hyperuricemia who develop uric acid stones. Patients with calcium stones who are hyperuricosuric may also benefit from allopurinol because urate crystals in the urine may act as a nidus for other stones to form.
Potassium citrate and occasionally sodium bicarbonate or acetazolamide may be required to alkalinize the urine and to increase the solubility of uric acid.
Adequate hydration is recommended to maintain a high urine output of at least 2 L daily, unless otherwise contraindicated for other medical conditions where volume overload may be a concern.
Uric acid nephropathy
Over the years, efforts to prevent uric acid nephropathy, especially in the oncological setting, have resulted in a decrease in mortality from uric acid nephropathy. Intravenous hydration with saline and the administration of furosemide or mannitol (to dilute the urine) are necessary to prevent further precipitation of uric acid. Alkalinizing the urine with sodium bicarbonate or acetazolamide may be necessary to further enhance uric acid elimination.
Rasburicase (Elitek), a recombinant urate oxidase, is approved for use in preventing complications of hyperuricemia during the tumor lysis syndrome in both adults and children. It facilitates the conversion of urate to a more soluble product, allantoin. Although rasburicase treatment has become the standard of care for patients at high risk of tumor lysis syndrome, debate continues on whether the profound and rapid lowering of plasma uric acid levels produced by rasburicase has a significant effect on patient outcomes (eg, need for renal replacement therapy and mortality). [41]
Higher doses than usual of rasburicase (600-900 mg/d) are administered to decrease uric acid production prior to chemotherapy in patients with leukemias and lymphomas; allopurinol and hydration are continued for several days. If acute kidney injury develops despite these measures, then early hemodialysis is indicated to reduce the total body burden of uric acid, thereby facilitating recovery of kidney function.
Consultations
Consultations with the following specialists may be indicated:
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A rheumatologist, for patients with acute or chronic gouty arthritis
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A nephrologist, for patients with acute urate nephropathy or chronic kidney disease
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A urologist, for patients who present with symptomatic uric acid nephrolithiasis
Diet
The use of a low-purine diet may significantly lower serum uric acid levels. This diet principally consists of sugars, starches, and fats, with protein supplied by eggs and cheese. The following foods should be avoided:
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Meats
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Poultry
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Fish
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Seafood
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Organ meats
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Alcohol
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Beans
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Peas
High consumption of dairy products has been associated with a lower risk of hyperuricemia. [42]
Activity
No limitation exists on activity for patients with hyperuricemia, although strenuous exercise may raise serum uric acid levels.
Prevention
Dietary measures that may help prevent hyperuricemia include the following:
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Avoidance or restricted consumption of high-purine foods (eg, organ meats, sardines)
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Avoidance of excess ingestion of alcoholic drinks, particularly beer
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Avoidance of soft drinks and other beverages or foods sweetened with high-fructose corn syrup
A review of data from the National Health and Nutrition Examination Survey (NHANES) found that in women, higher folate intake was associated with lower risk of hyperuricemia. In men, both higher folate and higher vitamin B12 intake were associated with lower risk. [43]
Long-Term Monitoring
For patients with symptomatic hyperuricemia, provide regular follow-up evaluations with serum uric acid level determinations. For patients with gout, attempt to maintain uric acid levels below 6 mg/dL.
For patients with a history of uric acid nephrolithiasis, provide follow-up determinations of 24-hour urine excretion of uric acid to ensure that therapy has helped lower the excretion into the reference range.
