Can Drug-Induced Liver Injury (DILI) cause a rise in uric acid levels?

Drug-Induced Liver Injury (DILI) and Uric Acid Levels

Drug-induced liver injury (DILI) can cause elevated uric acid levels through disruption of normal hepatic metabolism and excretion pathways.

Pathophysiological Mechanism

DILI can lead to hyperuricemia through several mechanisms:

1. Impaired Hepatic Metabolism:

   • When liver function is compromised due to DILI, the liver's ability to metabolize purines (precursors to uric acid) is reduced 1
   • This leads to increased purine breakdown and subsequent uric acid production

2. Reduced Renal Excretion:

   • Hepatic dysfunction can affect renal function through hepatorenal syndrome
   • This reduces the kidney's ability to excrete uric acid, leading to accumulation 1

3. Metabolic Derangements:

   • DILI can cause metabolic alterations that affect purine metabolism
   • Severe DILI may lead to cell death (hepatocellular necrosis), releasing intracellular purines into circulation 1

Clinical Presentation and Assessment

When evaluating a patient with suspected DILI and elevated uric acid:

• Liver Function Tests:

  • Monitor ALT, AST, ALP, and bilirubin levels
  • ALT ≥3× ULN with total bilirubin ≥2× ULN is particularly concerning (Hy's Law) 1

• Uric Acid Monitoring:

  • Check baseline and follow-up uric acid levels
  • Assess for symptoms of hyperuricemia (joint pain, gout)

• Pattern Recognition:

  • Hepatocellular injury (R value ≥5) is more commonly associated with metabolic derangements including hyperuricemia 1
  • Cholestatic patterns (R value ≤2) may have different effects on uric acid metabolism 1

Management Approach

1. Immediate Drug Discontinuation:

   • Withdraw the suspected causative agent
   • This is the most important intervention for DILI management 1

2. Liver Function Monitoring:

   • For patients with normal baseline ALT:

     • Monitor more frequently if ALT ≥3× ULN
     • Consider drug interruption when ALT ≥8× ULN 1

   • For patients with elevated baseline ALT:

     • Monitor if ALT >2× baseline
     • Consider drug interruption at higher thresholds based on baseline 1

3. Uric Acid Management:

   • Hyperuricemia typically resolves with improvement of liver function
   • Consider uric acid-lowering therapy only for symptomatic hyperuricemia
   • Ensure adequate hydration to promote uric acid excretion

Special Considerations

• Pre-existing Liver Disease:

  • Patients with underlying liver conditions are at higher risk for both DILI and hyperuricemia 1
  • Lower thresholds for drug discontinuation may be appropriate

• Gilbert's Syndrome:

  • Present in up to 10% of the population
  • May affect bilirubin levels but does not typically affect uric acid metabolism 1

• Monitoring Frequency:

  • For suspected hepatocellular DILI: Repeat tests within 2-5 days
  • For suspected cholestatic DILI: Repeat tests within 7-10 days 2

Potential Treatments

• N-acetylcysteine: May be beneficial in selected cases of DILI with hepatocellular pattern

• Ursodeoxycholic acid (UDCA):

  • Some evidence suggests benefit in treatment and prevention of DILI 3, 4
  • May help normalize liver function and subsequently improve uric acid metabolism

• Corticosteroids:

  • May be considered in severe DILI cases with autoimmune features
  • Combined steroid/UDCA therapy has shown promise in severe DILI 4

Conclusion

DILI can cause elevated uric acid levels through disruption of normal hepatic metabolism and excretion. Management should focus on identifying and discontinuing the offending agent, monitoring liver function, and addressing hyperuricemia if symptomatic. Resolution of hyperuricemia typically follows improvement in liver function.