What is the main cause of hyperuricemia (elevated uric acid levels)?

Main Causes of Hyperuricemia (Elevated Uric Acid Levels)

The main cause of hyperuricemia is impaired renal excretion of uric acid, which accounts for approximately 90% of cases, while overproduction of uric acid accounts for the remaining 10% of cases. 1

Pathophysiology of Hyperuricemia

Hyperuricemia results from an imbalance between uric acid production and elimination. Understanding this balance is crucial for proper management:

Reduced Excretion (Primary Cause)

• Renal underexcretion: Most common cause (90% of cases)
• Contributing factors:
  • Medications: Thiazide and loop diuretics, low-dose aspirin, calcineurin inhibitors 2
  • Chronic kidney disease
  • Genetic polymorphisms affecting renal transporters of urate 2
  • Obesity and insulin resistance (reduce uric acid excretion) 1
  • Dehydration

Overproduction (Secondary Cause)

• Purine metabolism disorders: Accounts for approximately 10% of cases
• Contributing factors:
  • High cell turnover conditions (leukemia, polycythemia, psoriasis)
  • Tumor lysis syndrome 1
  • Genetic disorders (e.g., Lesch-Nyhan syndrome, HGPRT deficiency) 3
  • De novo synthesis of purines associated with triglyceride synthesis in the liver 4

Risk Factors and Modifiable Contributors

Dietary Factors

• High intake of purine-rich foods (meat, seafood) with relative risk of 1.51 for seafood 1
• Alcohol consumption, especially beer (relative risk of 1.49 per serving/day) 1
• High fructose intake from sugar-sweetened beverages 2

Metabolic Factors

• Obesity and metabolic syndrome 4, 5
• Higher waist circumference associated with insulin resistance and leptin production 4
• Weight gain (increases uric acid levels) 1

Medications

• Thiazide and loop diuretics
• Niacin
• Calcineurin inhibitors
• Low-dose aspirin (modest effect) 2

Clinical Evaluation

For patients with hyperuricemia, especially those with early onset or family history, evaluation should include:

• Assessment for renal uric acid excretion in patients with:

  • Family history of young-onset gout
  • Onset of gout under age 25
  • History of renal calculi 2

• 24-hour urine collection to assess:

  • Uric acid/creatinine ratio
  • Categorization as overexcreters, normoexcreters, or underexcreters 2

Biochemical Considerations

Uric acid is the end product of purine nucleic acid catabolism and has antioxidant properties. Its solubility is highly pH-dependent:

• Solubility of ~15 mg/dL at pH 5.0
• Solubility of ~200 mg/dL at pH 7.0 1

This pH dependency explains why acidic urine increases the risk of uric acid kidney stones.

Conclusion

While hyperuricemia can lead to conditions such as gout, kidney stones, and is associated with metabolic syndrome and cardiovascular disease, the predominant underlying mechanism is impaired renal excretion of uric acid in approximately 90% of cases, with overproduction accounting for only about 10% of cases.