What are the implications and management of hyperuricemia?

What Happens If You Have Elevated Blood Uric Acid

Elevated blood uric acid (hyperuricemia) can lead to gout, kidney disease, cardiovascular complications, and metabolic disorders, but treatment is only recommended when you have symptomatic disease—not for asymptomatic hyperuricemia alone. 1, 2

Clinical Consequences of Hyperuricemia

Gout Development

• Uric acid becomes supersaturated and precipitates as monosodium urate crystals when levels exceed 6.8 mg/dL (404 µmol/L), causing gout attacks. 1
• Gout manifests initially as acute, episodic arthritis but can progress to chronic arthritis affecting multiple joints. 1
• Tophi (crystal deposits) develop in joints, periarticular tissues, bursae, bone, ears, and skin in chronic disease. 1
• Patients who maintain uric acid levels below 6.0 mg/dL have approximately 5% risk of acute gout attacks at one year, compared to 10-15% risk in those with levels at or above 6.0 mg/dL. 1

Kidney Complications

• Approximately 70% of uric acid is excreted by the kidneys, making renal function critical for uric acid homeostasis. 3, 4
• Hyperuricemia increases the risk of new chronic kidney disease diagnoses—4% versus 2% at year 1 and 9% versus 5% at year 3 in high versus low uric acid groups. 1
• Uric acid kidney stones occur, typically with acidic urine pH. 1
• Chronic interstitial nephropathy from crystal deposition in the renal medulla can occur in severe disease, though this is uncommon. 1
• Hyperuricemia is both a consequence of declining kidney function and a risk factor for progression of kidney disease. 3, 4

Cardiovascular and Metabolic Associations

• Hyperuricemia is independently associated with hypertension, coronary heart disease, heart failure, stroke, peripheral arterial disease, and cardiovascular mortality. 1, 5
• Strong associations exist with metabolic syndrome, type 2 diabetes, obesity, and hyperlipidemia. 1, 5
• The renin-angiotensin system appears to play an important role in hypertension and renal damage from hyperuricemia. 3
• Treatment with allopurinol has shown blood pressure reduction in some studies of juvenile essential hypertension with hyperuricemia. 3

When Treatment Is Indicated

Absolute Indications for Urate-Lowering Therapy

• Recurrent gout flares, tophi, urate arthropathy, or renal stones. 6
• Chronic tophaceous gouty arthropathy detected on physical examination. 1

Strong Indications for Early Treatment

• Age less than 40 years at gout presentation. 6
• Serum uric acid greater than 8.0 mg/dL. 6
• Comorbidities including renal impairment, hypertension, ischemic heart disease, or heart failure. 6

When NOT to Treat

• Asymptomatic hyperuricemia alone is NOT an indication for urate-lowering therapy due to insufficient evidence of benefit. 1, 7
• No direct evidence supports treating elevated uric acid in the absence of gout or kidney stones. 1

Management Approach When Treatment Is Warranted

Initial Evaluation

• Screen for chronic kidney disease by calculating estimated glomerular filtration rate (eGFR) at diagnosis and monitor regularly. 1
• Screen for associated comorbidities: coronary heart disease, heart failure, stroke, peripheral arterial disease, diabetes, obesity, hyperlipidemia, and hypertension. 1, 6
• For gout onset before age 25 or history of urolithiasis, obtain 24-hour urine uric acid to screen for overproduction. 2, 6
• Review and eliminate non-essential medications that elevate uric acid: thiazide and loop diuretics, niacin, and calcineurin inhibitors. 2

Lifestyle Modifications (First-Line for All Patients)

• Limit purine-rich meats and seafood, high-fructose corn syrup sweetened beverages. 2
• Avoid alcohol, especially beer. 2
• Encourage low-fat or non-fat dairy products, vegetables, coffee, and cherries. 2, 6
• Weight loss if overweight or obese, with regular physical activity. 6

Pharmacologic Urate-Lowering Therapy

• Target serum uric acid below 6 mg/dL for all patients, maintained lifelong. 2, 6
• For severe disease with tophi, target below 5 mg/dL until complete crystal dissolution. 6

First-Line Agent

• Start allopurinol 100 mg daily, increase by 100 mg every 2-4 weeks until target achieved. 2, 6, 8
• Allopurinol inhibits xanthine oxidase, blocking conversion of hypoxanthine to xanthine and xanthine to uric acid. 8
• Adjust dose based on creatinine clearance in renal impairment. 6
• Allopurinol reduces both serum and urinary uric acid within 2-3 days, with full effects in one week or more. 8

Second-Line Options

• If allopurinol fails to reach target, switch to febuxostat or add uricosuric agent (probenecid, sulphinpyrazone). 6
• Benzbromarone can be used in mild-to-moderate renal impairment but carries hepatotoxicity risk. 6

Flare Prophylaxis During Treatment Initiation

• All patients starting urate-lowering therapy require prophylaxis for the first 6 months. 6
• Colchicine 0.5-1 mg daily is first choice. 6
• Low-dose NSAIDs are an alternative if colchicine is contraindicated or not tolerated. 6

Monitoring Strategy

• Check serum uric acid every 2-4 weeks during dose titration. 6
• Once stable at target, monitor regularly to ensure target is maintained. 6
• Continue urate-lowering therapy indefinitely as this is lifelong treatment. 6

Specialist Referral Indications

• Consider rheumatology referral for unclear etiology of hyperuricemia, refractory gout symptoms, difficulty reaching target uric acid, or multiple serious adverse events from urate-lowering therapy. 2

Critical Pitfalls to Avoid

• Do not treat asymptomatic hyperuricemia—there is insufficient evidence for benefit and potential for harm from unnecessary medication. 1, 7
• Do not start urate-lowering therapy during an acute gout attack; address the acute attack first. 2
• Do not fail to provide flare prophylaxis when initiating urate-lowering therapy, as mobilization of tissue urate deposits can trigger attacks. 6
• Do not use salicylates as they nullify the effect of uricosuric drugs, though they do not compromise allopurinol action. 8