What liver function tests are recommended for patients on azathioprine (Imuran)?

Liver Function Testing for Patients on Azathioprine

Regular monitoring of liver function tests (LFTs) is required for all patients on azathioprine therapy, with testing recommended weekly for the first 4 weeks of treatment, then monthly until maintenance dose is achieved, followed by monitoring at least every 3 months for the duration of therapy. 1

Pre-Treatment Baseline Testing

• Baseline liver function tests should include transaminases (ALT, AST), alkaline phosphatase, and bilirubin before starting azathioprine 1, 2
• Thiopurine methyltransferase (TPMT) activity testing should be performed prior to initiating therapy to guide dosing and identify patients at high risk for toxicity 1, 2
• Consider hepatitis B (HBsAg and anti-HBc) and hepatitis C screening prior to treatment, especially important as immunosuppression can cause flares in viral hepatitis 1
• Complete blood count (CBC) with differential should also be performed as baseline 1, 2

Monitoring Schedule

Initial Phase

• Weekly monitoring of LFTs for the first 4 weeks of therapy or until maintenance dose is achieved 1, 2
• Return to weekly monitoring following any dose increase 1, 2
• More frequent monitoring is advised in patients with:
  • Hepatic or renal impairment 1
  • Elderly patients 1
  • Those treated with high doses of azathioprine 1

Maintenance Phase

• Once stable on a fixed dose, reduce monitoring to a minimum of once every 3 months for the duration of therapy 1
• Long-term monitoring is essential as some forms of liver injury may develop after several years of treatment 1

Specific Parameters to Monitor

• Transaminases (ALT, AST) - these give a day-to-day account of hepatocellular injury 3, 4
• Alkaline phosphatase - estimates impedance of bile flow 1, 4
• Bilirubin - considered the best test of overall liver function 4
• Complete blood count - to monitor for myelosuppression, which can occur alongside hepatotoxicity 1
• Macrocytosis - a common finding that can be used to assess patient compliance 1

Patterns of Azathioprine-Induced Hepatotoxicity

• Hepatotoxicity can present in different patterns:
  • Mixed pattern (most common - 50% of cases) 5
  • Cholestatic pattern (37.5% of cases) 5
  • Hepatocellular pattern (12.5% of cases) 5
• Hepatotoxicity typically occurs within the first few months of treatment but can occur after prolonged use (even after 22 months of treatment) 6, 7
• The incidence of hepatotoxicity in patients receiving azathioprine is relatively uncommon (2.7% in one study) 5

Patient Instructions

• Patients should report immediately any evidence of:
  • Jaundice (yellowing of skin or eyes) 1, 3
  • Unexpected bruising or bleeding 1
  • Infection symptoms 1
  • Severe abdominal pain or vomiting (which may indicate pancreatitis) 3

Management of Abnormal LFTs

• If liver test abnormalities persist despite azathioprine withdrawal or dose reduction, consider alternative causes of hepatitis, particularly those related to immunosuppression such as Epstein-Barr virus infection 1
• Most patients recover fully after drug withdrawal, with a median recovery time of 41.3 days in one study 5
• Severe cholestasis can occur but is generally reversible after interruption of azathioprine 3, 5
• Rare but life-threatening hepatic veno-occlusive disease has been described - if clinically suspected, azathioprine should be permanently withdrawn 3

Special Considerations

• Patients with preexisting liver disease require more cautious monitoring and potentially lower dosing 1, 3
• Drug metabolism may be impaired in patients with hepatic dysfunction, and the azathioprine dosage should be reduced if hepatic toxicity occurs 1
• Patients with low or absent TPMT activity are at increased risk for severe adverse effects 3