What are the management options for Azothioprine (Imuran)-induced transaminitis?

Management of Azathioprine-Induced Transaminitis

Mild derangement of liver blood tests due to azathioprine is common and may not require alteration of therapy, but abnormal liver tests should prompt careful evaluation and increased frequency of monitoring, with dose reduction or drug withdrawal needed for more significant elevations. 1

Understanding Azathioprine Hepatotoxicity

Azathioprine can cause liver injury through two main patterns:

1. Acute idiosyncratic drug-induced liver injury (DILI)

   • Cholestatic pattern (elevated bilirubin and alkaline phosphatase)
   • Hepatocellular pattern (elevated transaminases)

2. Nodular regenerative hyperplasia

   • Can lead to portal hypertension even with minimal liver function abnormalities

Management Algorithm for Azathioprine-Induced Transaminitis

Step 1: Assess Severity of Liver Injury

• Mild elevation: Continue monitoring with increased frequency
• Moderate elevation: Consider dose reduction
• Severe elevation or symptoms: Withdraw azathioprine

Step 2: Management Options Based on Severity

For Mild Transaminitis:

• Increase monitoring frequency of liver function tests (LFTs)
• Continue current dose if patient is asymptomatic
• Re-evaluate in 2-4 weeks

For Moderate Transaminitis:

• Reduce azathioprine dose
• Monitor LFTs every 1-2 weeks until stabilization
• Consider splitting daily dose to reduce peak drug levels

For Severe Transaminitis or Symptomatic Patients:

• Immediately withdraw azathioprine
• Monitor LFTs until normalization
• Consider liver biopsy if abnormalities persist
• Evaluate for alternative immunosuppressants

Step 3: Additional Considerations

If Azathioprine Must Be Continued Despite Mild-Moderate Transaminitis:

• Split the daily dose to reduce peak drug levels
• Administer after food to improve tolerance
• Monitor LFTs more frequently (every 1-2 weeks)
• Consider measuring 6-thioguanine nucleotide levels if available

Important Caveats and Pitfalls

1. Delayed Hepatotoxicity Risk: Azathioprine can cause liver injury at any time during treatment, even after years of stable therapy 2, 3. Regular monitoring should continue throughout treatment.

2. Portal Hypertension Risk: Patients may develop portal hypertension with minimal liver function abnormalities 4. Watch for signs like splenomegaly or thrombocytopenia.

3. Hypersensitivity Reactions: Nausea with fever, myalgia, or arthralgia suggests hypersensitivity rather than simple transaminitis and requires immediate drug withdrawal 1.

4. TPMT Testing: Consider thiopurine methyltransferase (TPMT) testing in patients with hepatotoxicity, as enzyme deficiency can lead to increased drug metabolites and toxicity 1.

5. Monitoring Requirements: Regular LFTs are essential for early detection of hepatotoxicity. The British Association of Dermatologists recommends:

   • Weekly for first month
   • Biweekly for second month
   • Monthly thereafter
   • More frequent monitoring if abnormalities develop 1

Evidence Quality and Considerations

The British Association of Dermatologists' guidelines provide the strongest evidence for managing azathioprine hepatotoxicity (Level 2++ evidence) 1. These guidelines recognize that mild LFT derangements are common and often don't require therapy alteration, but emphasize the importance of careful evaluation and increased monitoring frequency when abnormalities are detected.

Case reports demonstrate that severe hepatotoxicity can occur even after prolonged stable treatment 2, 3, highlighting the importance of continued vigilance throughout therapy.

Human morbidity and mortality risks are minimized by early detection and appropriate management of hepatotoxicity, with prompt withdrawal of the medication in severe cases being essential to prevent progression to irreversible liver damage.