Evaluation and Treatment of Hyperuricemia
Initial Assessment: Distinguish Asymptomatic from Symptomatic Disease
Do not initiate urate-lowering therapy for asymptomatic hyperuricemia, even at levels as high as 9-10 mg/dL, because current evidence shows no benefit in preventing gout, cardiovascular events, or renal disease, while exposing patients to unnecessary medication risks. 1
The American College of Rheumatology conditionally recommends against treatment of asymptomatic hyperuricemia (defined as serum urate >6.8 mg/dL with no prior gout flares or tophi), based on high-certainty evidence showing that 24 patients would need treatment for 3 years to prevent a single gout flare. 1 The FDA labeling for allopurinol explicitly contraindicates its use in asymptomatic hyperuricemia. 1
Diagnostic Evaluation
Essential Laboratory and Clinical Assessment
Measure serum creatinine and calculate eGFR to identify chronic kidney disease, which influences both the cause of hyperuricemia and future treatment decisions. 1, 2
Review all current medications and discontinue non-essential urate-elevating drugs, including thiazide diuretics, loop diuretics, niacin, and calcineurin inhibitors. 1, 2
Obtain 24-hour urine uric acid collection in patients with gout onset before age 25 or history of kidney stones; values >1000 mg/day define overproduction and contraindicate uricosuric agents. 2, 3
Screen for secondary causes: assess for obesity, excessive alcohol intake (especially beer and spirits), consumption of sugar-sweetened beverages with high-fructose corn syrup, purine-rich foods (organ meats, shellfish), and cardiovascular comorbidities (hypertension, heart failure, ischemic heart disease). 1, 2
Perform physical examination specifically looking for subcutaneous tophi, signs of acute or chronic synovitis, and radiographic joint damage. 3
Management of Asymptomatic Hyperuricemia
Non-Pharmacologic Interventions (Primary Strategy)
Weight reduction in overweight or obese individuals. 1
Limit alcohol consumption, particularly beer and spirits, as this is the single most important modifiable risk factor. 1, 2
Avoid sugar-sweetened beverages and high-fructose corn syrup, which increase uric acid synthesis by 1-2 mg/dL within 2 hours per gram of fructose per kilogram body weight. 1, 2
Reduce intake of purine-rich organ meats (liver, kidney) and shellfish. 1, 3
Encourage low-fat dairy products and vegetables, which lower gout risk. 1
Regular physical activity as a preventive measure. 1
Monitoring Strategy for Untreated Patients
Patient education emphasizing that asymptomatic elevation does not warrant medication and teaching recognition of gout symptoms. 1
Periodic cardiovascular risk screening, including blood pressure, lipid profile, and glucose assessment. 1
Do not initiate pharmacologic therapy unless the patient develops symptoms (gout flare, tophi, or urolithiasis). 1
Indications for Initiating Urate-Lowering Therapy
Absolute Indications (Treat Regardless of Serum Urate Level)
One or more subcutaneous tophi identified on physical exam or imaging. 1
Frequent gout flares (≥2 per year). 1
Radiographic joint damage attributable to gout. 1
Chronic tophaceous gouty arthropathy with persistent joint symptoms. 1
Conditional Indications (Consider After First Gout Flare)
Chronic kidney disease stage ≥3 (eGFR <60 mL/min). 1
Serum urate >9 mg/dL after first flare. 1
History of urolithiasis (kidney stones). 1
Young age (<40 years) at first flare with significant comorbidities. 1
Pharmacologic Treatment Protocol
First-Line Agent: Allopurinol
Allopurinol is the preferred first-line agent for all patients, including those with moderate-to-severe chronic kidney disease. 1, 4
Starting Dose
Titration Strategy
Increase by 100 mg every 2-5 weeks based on serum urate measurements. 1, 4
Target <5 mg/dL for severe gout with tophi, chronic arthropathy, or frequent attacks. 1, 3
Maximum dose: 800 mg daily, which can be safely achieved even in renal impairment with appropriate monitoring. 1, 4
Most patients require doses >300 mg daily to reach target; do not stop at 300 mg without checking serum urate. 1
Renal Dosing Adjustments
Creatinine clearance 10-20 mL/min: 200 mg daily maximum. 4
Creatinine clearance <10 mL/min: 100 mg daily maximum; may need to lengthen dosing interval. 4
Creatinine clearance <3 mL/min: extend interval between doses. 4
Mandatory Flare Prophylaxis
Provide colchicine 0.5-1 mg daily for at least 6 months when initiating or escalating urate-lowering therapy to prevent acute flares triggered by rapid uric acid reduction. 1, 3
Reduce colchicine dose in renal impairment and avoid with strong P-glycoprotein/CYP3A4 inhibitors. 1
If colchicine is contraindicated or not tolerated, use low-dose NSAIDs or low-dose glucocorticoids as alternatives. 1
Continue prophylaxis for the full 6 months; stopping prematurely significantly increases breakthrough flare risk. 1
Alternative First-Line Options
Febuxostat is an alternative xanthine oxidase inhibitor when allopurinol is not tolerated or contraindicated. 3
Probenecid may be used if xanthine oxidase inhibitors are unsuitable, but is contraindicated when creatinine clearance <50 mL/min or in patients with history of kidney stones. 1, 3
Second-Line and Refractory Disease
Add a uricosuric agent (probenecid) as combination therapy if eGFR >50 mL/min and target not achieved with allopurinol 800 mg daily. 1
Pegloticase is reserved for refractory tophaceous gout that has failed maximum appropriate doses of xanthine oxidase inhibitor and uricosuric combination therapy. 3
Monitoring Schedule
During dose titration: check serum urate every 2-5 weeks until target is achieved. 1, 3, 4
After target attainment: monitor serum urate every 6 months to assess adherence and maintain control. 1, 3
Monitor renal function periodically, especially in patients with CKD. 1
Critical Pitfalls to Avoid
Undertreatment with fixed 300 mg allopurinol dose: most patients need higher doses to achieve serum urate <6 mg/dL. 1
Treating asymptomatic hyperuricemia: exposes patients to unnecessary medication risks (hypersensitivity reactions, hepatotoxicity, drug interactions) without proven benefit for cardiovascular or renal outcomes. 1, 5
Stopping urate-lowering therapy during acute flares: continue therapy and add anti-inflammatory treatment instead. 1
Inadequate flare prophylaxis: failing to provide colchicine for 6 months is a major cause of treatment failure and non-adherence. 1
Using uricosuric agents in overproducers: increases urinary uric acid excretion and precipitates nephrolithiasis. 2
Relying on single serum urate measurement during acute flare: uric acid behaves as a negative acute-phase reactant and may be falsely normal during acute inflammation. 2
Discontinuing low-dose aspirin (≤325 mg daily): cardiovascular benefits outweigh modest urate-elevating effects. 1, 2
Special Populations
Chronic Kidney Disease
Xanthine oxidase inhibitors are preferred over uricosuric agents in CKD. 3
Start allopurinol at 50 mg daily for CKD stage 4 or worse, then titrate gradually with close monitoring. 1, 4
For acute gout flares in CKD, use low-dose colchicine or glucocorticoids; avoid NSAIDs. 3
Heart Failure
Hyperuricemia confers poor prognosis in heart failure patients, often from loop diuretic use and renal dysfunction. 2, 3
For acute gout with heart failure, consider short course of colchicine; avoid NSAIDs. 3
Tumor Lysis Syndrome
- Rasburicase is recommended for rapid reduction of uric acid in tumor lysis syndrome following chemotherapy, allowing prompt continuation of cancer treatment. 3