What causes elevated uric acid levels?

Causes of Elevated Uric Acid Levels

Elevated uric acid levels are primarily caused by decreased renal excretion (90% of cases), with overproduction of uric acid accounting for only about 10% of cases. 1 Understanding these causes is essential for proper management of hyperuricemia and prevention of associated conditions like gout, kidney stones, and cardiovascular complications.

Primary Causes of Hyperuricemia

Decreased Renal Excretion

• Medications:

  • Thiazide and loop diuretics
  • Low-dose aspirin (though the TFP does not recommend discontinuation for cardiovascular prophylaxis)
  • Niacin
  • Calcineurin inhibitors 1

• Medical Conditions:

  • Chronic kidney disease
  • Hypertension
  • Metabolic syndrome/insulin resistance
  • Obesity (especially abdominal)
  • Lead toxicity

Increased Production

• Dietary Factors:

  • High purine intake (meat, seafood)
  • High fructose consumption 1
  • Alcohol consumption (especially beer)

• Medical Conditions:

  • Tumor lysis syndrome 1
  • Myeloproliferative disorders (leukemia, polycythemia vera)
  • Multiple myeloma
  • Psoriasis 2
  • Genetic disorders affecting purine metabolism

Mechanism of Hyperuricemia

Uric acid is the end product of purine metabolism. Under normal conditions, uric acid is cleared through the kidneys at approximately 500 mg/day 1. The process involves:

1. Production: Purines are metabolized to hypoxanthine, then to xanthine, and finally to uric acid by the enzyme xanthine oxidase 2
2. Excretion: Primarily through the kidneys, with some elimination through the gastrointestinal tract

When this balance is disrupted, hyperuricemia occurs. In the distal tubules and collecting system of the kidney, the pH of urine is approximately 5, and the solubility of uric acid at this pH is about 15 mg/dL. As uric acid concentration increases, crystal formation and deposition becomes more likely 1.

Risk Factors for Hyperuricemia

Modifiable Risk Factors

• Diet:

  • High consumption of meat and seafood 3, 4
  • High fructose intake (especially from sugar-sweetened beverages) 1
  • Alcohol consumption (particularly beer) 3

• Lifestyle:

  • Physical inactivity 4
  • Obesity 3, 4

Non-modifiable Risk Factors

• Demographic:

  • Male sex (men typically have higher uric acid levels than women) 1
  • Increasing age
  • Family history of hyperuricemia

• Medical:

  • Reduced kidney function 5
  • Hypertension 6
  • Metabolic syndrome 6

Clinical Implications

Hyperuricemia is associated with several clinical conditions:

• Gout
• Kidney stones
• Hypertension
• Cardiovascular disease
• Chronic kidney disease progression 5
• Non-alcoholic fatty liver disease 6

Important Caveats

1. Diagnostic Limitations: While being the most important risk factor for gout, serum uric acid levels do not confirm or exclude gout. Many people with hyperuricemia never develop gout, and during acute attacks, serum levels may be normal 1.

2. Uric Acid as a Biomarker: Uric acid may serve as a biomarker for metabolic syndrome and cardiovascular risk, especially in those with obesity 1, 6.

3. Bidirectional Relationship: There appears to be a bidirectional relationship between hyperuricemia and kidney disease, with each potentially worsening the other 5.

4. Screening Recommendations: The American College of Rheumatology recommends screening for uric acid overproduction (by urine uric acid evaluation) in patients with gout clinical disease onset before age 25 or with a history of urolithiasis 1.

Understanding these various causes and risk factors for hyperuricemia is crucial for developing appropriate prevention and treatment strategies, particularly in high-risk individuals.