Does hyperuricemia (elevated uric acid levels) or fluctuations in uric acid levels cause gout?

Hyperuricemia and Fluctuations in Uric Acid Levels in Gout Development

Both hyperuricemia and fluctuations in uric acid levels contribute to gout development, with sustained hyperuricemia being the primary risk factor, while rapid fluctuations can trigger acute gout attacks. 1

Hyperuricemia as the Primary Risk Factor

• Hyperuricemia is a major risk factor for gout development, with higher serum uric acid (SUA) levels associated with increased risk of developing gout 1
• The theoretical saturation point for monosodium urate (MSU) crystal formation is approximately 6.8 mg/dL (404 μmol/L), above which precipitation of crystals may begin 1
• Longitudinal studies show that individuals with SUA levels above 6 mg/dL have significantly higher risk of developing gout - men with SUA >6 mg/dL have 4.5 times higher risk, while women have nearly 17 times higher risk compared to those with lower levels 1
• The risk increases proportionally with rising SUA levels, with each level increase (in categories of <6-, 7-, 8-, 9-, and 10+ mg/dL) associated with a 2.33-fold higher risk of developing gout 1

Fluctuations in Uric Acid and Acute Attacks

• While sustained hyperuricemia leads to crystal deposition over time, fluctuations in uric acid levels can trigger acute gout attacks 1
• SUA levels often decrease during acute gout attacks, with studies showing lower levels (sometimes within normal range) during flares compared to intercritical periods 1
• This phenomenon occurs because SUA behaves as a negative acute phase reactant, being temporarily lowered during episodes of acute inflammation and stress 1
• Increased renal excretion of uric acid during acute episodes is suggested as the mechanism for this temporary reduction 1
• Rapid changes in SUA levels, whether increasing or decreasing, can trigger crystal shedding from deposits and initiate inflammatory responses 2

The Relationship Between Hyperuricemia and Gout

• Despite the strong association, many people with hyperuricemia never develop gout - only about 22% of asymptomatic patients with SUA levels above 9 mg/dL develop gout over a 5-year period 1
• The specificity of hyperuricemia for diagnosing gout is relatively low (53-61%), meaning many people with high SUA levels don't have gout 1
• Conversely, some patients with MSU crystal-proven gout may have normal SUA levels at the time of investigation 1
• Approximately 15-25% of people with asymptomatic hyperuricemia have asymptomatic MSU crystal deposition, supporting the concept of a continuum from asymptomatic hyperuricemia to symptomatic gout 1

Clinical Implications

• SUA has limited diagnostic value during acute gout attacks due to its fluctuation, and should preferably be measured between attacks 1
• Long-term treatment aims to reduce SUA levels below 6 mg/dL to prevent new crystal formation and promote dissolution of existing crystals 3, 4
• Patients who achieve SUA levels below 6 mg/dL have significantly lower risk of acute gout attacks (approximately 5%) compared to those with higher levels (10-15%) 1
• Environmental factors that can trigger fluctuations in uric acid levels include dietary changes (high purine foods, alcohol), medication changes, dehydration, and physiologic stress 2

Pitfalls and Caveats

• Diagnosis of gout should not be made on the presence of hyperuricemia alone 1
• SUA levels may be normal during an acute gout attack, potentially leading to misdiagnosis if relied upon exclusively 1
• Different diagnostic thresholds for hyperuricemia should be used for men and women, as men typically have higher baseline SUA levels 1
• The gold standard for gout diagnosis remains identification of MSU crystals in synovial fluid, not SUA measurement 1
• When initiating urate-lowering therapy, prophylaxis against acute flares is recommended as rapid changes in SUA can trigger attacks 1