What causes recurrent gout attacks in a patient with normal serum uric acid levels?

Why Patients Have Recurrent Gout Attacks Despite Normal Serum Uric Acid Levels

Serum uric acid levels do not confirm or exclude gout because they behave as a negative acute phase reactant during inflammation, temporarily dropping during acute attacks, and approximately 10% of patients with crystal-proven gout have normal levels during flares. 1, 2

Pathophysiological Mechanism

The key to understanding this paradox lies in the inflammatory response itself:

• During acute gout attacks, serum uric acid temporarily decreases due to increased renal excretion and the acute inflammatory response, causing levels to drop below baseline even in patients with chronic hyperuricemia 2
• Serum uric acid should be measured during intercritical periods (between attacks) rather than during acute flares, as levels are typically higher when inflammation has resolved 2
• The underlying problem is tissue crystal burden, not the serum level at the moment of attack—sustained hyperuricemia over time leads to monosodium urate crystal accumulation in joints, and these pre-existing crystal deposits trigger recurrent attacks regardless of what the serum level shows during the flare 3, 4

Why Recurrent Attacks Continue

The most common cause of recurrent gout attacks is failure to initiate urate-lowering therapy, which perpetuates the cycle of crystal deposition and inflammation 3:

• Without urate-lowering therapy, the intrinsic uric acid pool (tissue crystal deposits) persists, causing progressively frequent and severe attacks that can evolve into chronic inflammatory arthritis 3, 5
• Patients with recurrent flares (≥2 attacks per year) require long-term urate-lowering therapy to prevent progression, regardless of serum uric acid levels measured during acute episodes 3
• The goal is to maintain serum uric acid below 6 mg/dL (360 μmol/L) during intercritical periods to promote dissolution of existing crystals and prevent new crystal formation 5, 4

Contributing Factors in Normouricemic Gout Patients

Certain clinical scenarios are associated with normal serum uric acid during acute attacks 6:

• Post-surgical gout occurs more frequently in normouricemic patients (22.7% vs. 6.0% in hyperuricemic patients) 6
• Hemodialysis initiation is associated with normouricemic acute attacks (9.1% vs. 2.3%) 6
• Preserved renal function is more common in normouricemic patients during attacks (75% vs. 46.6% with renal insufficiency) 6

Critical Clinical Pitfall

The recurrence rate of gout attacks is identical between normouricemic and hyperuricemic patients during acute episodes (24.7% vs. 33.0%, p=0.220), meaning that a normal serum uric acid level during an attack does not predict a lower risk of future attacks 6:

• Female sex, history of urinary stones, presence of tophi, and thiazide use are associated with increased recurrent attacks—not the serum urate status during the acute attack 6
• Careful follow-up and consideration of urate-lowering therapy should be pursued regardless of serum urate levels during an acute attack 6

Diagnostic Approach When Serum Uric Acid is Normal

For patients with recurrent attacks but normal serum uric acid, definitive diagnosis requires monosodium urate crystal identification 1, 7:

• Joint aspiration with polarized light microscopy showing needle-shaped, negatively birefringent crystals provides definitive diagnosis with sensitivity 63-78% and specificity 93-100% 7
• Ultrasound showing the "double contour sign" has 74% sensitivity and 88% specificity for detecting crystal deposition 7
• Dual-energy CT has 85-100% sensitivity and 83-92% specificity for detecting monosodium urate deposits, particularly useful in patients with disease duration >2 years 7

Management Strategy

Initiate urate-lowering therapy in patients with recurrent gout attacks (≥2 per year), regardless of serum uric acid levels measured during acute episodes 1:

• Target serum uric acid <6 mg/dL measured during intercritical periods to dissolve existing crystal deposits 5, 4
• Prophylactic therapy with low-dose colchicine (0.6 mg daily) or low-dose NSAIDs should be continued for at least 8 weeks when initiating urate-lowering therapy to prevent flares 1
• Urate-lowering therapy reduces acute gout attacks after 1 year, but not within the first 6 months, so prophylaxis during this period is essential 1