How should I evaluate and manage a patient with elevated serum uric acid (hyperuricemia)?

Evaluation and Management of Elevated Serum Uric Acid

Do not treat asymptomatic hyperuricemia with urate-lowering therapy unless the patient has symptomatic gout, tophi, recurrent gout flares (≥2 attacks/year), CKD stage 2 or worse, or past urolithiasis. 1, 2

Initial Evaluation

Determine if Hyperuricemia is Symptomatic or Asymptomatic

• Symptomatic hyperuricemia includes patients with gout attacks, tophi on physical exam, urate arthropathy, or renal stones 1, 3
• Asymptomatic hyperuricemia is elevated serum uric acid without any of these manifestations 2, 4
• The evidence does not support treating asymptomatic hyperuricemia to prevent cardiovascular disease or CKD progression 1, 2, 4

Assess for Secondary Causes

• Review all medications and eliminate non-essential drugs that elevate uric acid: thiazide and loop diuretics, niacin, and calcineurin inhibitors 1, 5
• Screen for comorbidities: obesity, hypertension, hyperlipidemia, diabetes, CKD, coronary heart disease, heart failure 5, 6
• For patients with gout onset before age 25 or history of urolithiasis, obtain 24-hour urine uric acid collection to screen for uric acid overproduction 3, 5, 6

Evaluate Renal Function

• Calculate eGFR to determine allopurinol dosing requirements 6, 7
• CKD stage 2 or worse is itself an indication for urate-lowering therapy in patients with established gout 1

Management Strategy for Symptomatic Hyperuricemia

Indications for Pharmacologic Urate-Lowering Therapy (ULT)

Start ULT if any of the following are present: 1, 3

• Tophi detected on physical exam or imaging
• Frequent gout attacks (≥2 attacks per year)
• CKD stage 2 or worse
• Past urolithiasis
• Chronic tophaceous gouty arthropathy

Target Serum Uric Acid Levels

• Minimum target: <6 mg/dL for all patients on ULT, maintained lifelong 1, 3, 5, 6
• More aggressive target: <5 mg/dL for patients with severe disease, tophi, or chronic tophaceous gout until complete crystal dissolution 3, 6
• Avoid targeting levels <3 mg/dL for long-term therapy 5

First-Line Pharmacologic Treatment

Allopurinol is the first-line agent: 3, 5, 6

• Start at 100 mg daily 3, 5, 6, 7
• Titrate upward by 100 mg increments every 2-4 weeks until target serum uric acid is achieved 3, 5, 6
• Adjust dose based on creatinine clearance in renal impairment: 7
  • CrCl 10-20 mL/min: maximum 200 mg daily
  • CrCl <10 mL/min: maximum 100 mg daily
  • CrCl <3 mL/min: may need to lengthen interval between doses

Second-Line Options

If allopurinol fails to reach target or is not tolerated: 3, 5, 6

• Switch to febuxostat (another xanthine oxidase inhibitor)
• Add or switch to a uricosuric agent (probenecid or sulphinpyrazone) if CrCl >50 mL/min 1, 5
• Benzbromarone can be used in mild-to-moderate renal impairment but carries hepatotoxicity risk 3

Mandatory Flare Prophylaxis During ULT Initiation

All patients starting ULT require prophylaxis for at least 6 months: 3, 6

• First choice: Colchicine 0.5-1 mg daily 3, 6
• Alternative: Low-dose NSAIDs if colchicine is contraindicated or not tolerated 3, 6
• In CKD, low-dose colchicine or intra-articular/oral glucocorticoids are preferable to NSAIDs 1
• Avoid concomitant use of colchicine with potent CYP3A4 inhibitors (macrolide antibiotics, diltiazem, verapamil, azole antifungals, cyclosporine, ritonavir/nirmatrelvir) 1

Acute Gout Attack Management

For acute flares while on or initiating ULT: 6

• NSAIDs at full anti-inflammatory doses (avoid in CKD) 6
• Colchicine 1.2 mg followed by 0.6 mg one hour later for acute flares 1
• Corticosteroids (oral or intra-articular) when NSAIDs and colchicine are contraindicated 6

Non-Pharmacologic Management

Dietary and Lifestyle Modifications

Implement the following for all patients with hyperuricemia and gout: 1, 3, 5, 6

• Avoid: Alcohol (especially beer and spirits), sugar-sweetened beverages, high-fructose corn syrup, purine-rich meats (red meat, organ meats), and seafood 1, 3, 5, 6
• Encourage: Low-fat dairy products, coffee, cherries, weight loss if overweight/obese, regular physical activity 3, 5, 6
• Maintain: Fluid intake sufficient to yield at least 2 liters daily urinary output 6, 7

Medication Adjustments for Comorbidities

• For hypertension: Consider losartan or calcium channel blockers instead of diuretics 5
• For hyperlipidemia: Consider statins or fenofibrate 5

Monitoring Strategy

• Check serum uric acid every 2-4 weeks during dose titration 3, 5, 6
• Once target is achieved, monitor regularly to ensure target is maintained 1, 3, 5
• Continue ULT indefinitely—this is lifelong therapy 1, 3, 5, 6
• After tophi and all gout symptoms resolve, continue all measures to maintain serum uric acid <6 mg/dL indefinitely 1

When to Refer to Specialist

Consider rheumatology referral for: 1, 5, 6

• Unclear etiology of hyperuricemia
• Refractory signs or symptoms despite appropriate therapy
• Difficulty reaching target serum uric acid, particularly with renal impairment
• Multiple or serious adverse events from ULT

Management of Asymptomatic Hyperuricemia

Do not initiate urate-lowering therapy for asymptomatic hyperuricemia to delay CKD progression or prevent cardiovascular disease. 1, 2, 4

• The evidence does not support routine pharmacotherapy for asymptomatic hyperuricemia 2, 4, 8
• Allopurinol can trigger severe, sometimes fatal, hypersensitivity reactions, and its potential benefits must be weighed against this risk 2
• Focus on lifestyle modifications and treating underlying comorbidities 5