What is the role of azathioprine in treating autoimmune hepatitis?

Azathioprine in Autoimmune Hepatitis

Azathioprine combined with prednisolone at 1-2 mg/kg/day is the preferred first-line treatment for autoimmune hepatitis, achieving remission in 80-90% of patients with significantly fewer steroid-related side effects (10%) compared to prednisolone monotherapy (44%). 1, 2

Standard Dosing and Initiation Strategy

The recommended approach combines prednisolone starting at 30-60 mg/day with azathioprine at 50 mg/day (USA) or 1-2 mg/kg/day (Europe). 1 A pragmatic strategy involves delaying azathioprine introduction by approximately 2 weeks after starting prednisolone to avoid diagnostic confusion between azathioprine-induced hepatotoxicity and primary non-response. 3, 2

The prednisolone dose should be tapered gradually:

• Reduce to 10 mg/day over 2-3 months as transaminases fall 3
• Once aminotransferases normalize, reduce to 7.5 mg/day, then to 5 mg/day after 3 months 1, 2
• Continue azathioprine at 1-2 mg/kg as a steroid-sparing agent throughout 2

Patient Selection: Who Benefits Most from Azathioprine

Combination therapy with azathioprine is particularly advantageous for patients at high risk of steroid complications: 1, 2

• Postmenopausal women (osteoporosis risk)
• Patients with pre-existing osteoporosis, brittle diabetes, or labile hypertension
• Young female patients concerned about weight gain and cosmetic side effects
• Individuals with emotional instability
• Obese patients

Contraindications and Cautions

Azathioprine should be avoided or used with extreme caution in: 3, 1

• Patients with complete TPMT deficiency (homozygous deficiency affects 0.3% of European/African ancestry patients) 4
• Cytopenic patients (white blood cell count <2.5 × 10⁹/L or platelet count <50 × 10⁹/L) 3
• Pregnancy (requires individual risk-benefit analysis, though not absolutely contraindicated) 2
• Patients with malignancy 3

Critical pitfall: Azathioprine monotherapy is ineffective in autoimmune hepatitis and should never be used alone. 3

Pre-Treatment Testing: TPMT Assessment

TPMT testing before initiating azathioprine is recommended, particularly in patients with pre-existing cytopenia. 1, 2 However, the evidence reveals important nuances:

• Approximately 10% of patients have intermediate TPMT activity (heterozygous deficiency), and 0.3% have complete deficiency (homozygous) 4
• TPMT activity does not reliably predict azathioprine intolerance—most patients with side effects have normal or near-normal TPMT activity 3
• Among East Asian patients, NUDT15 deficiency is more relevant (2% homozygous, 21% heterozygous) 4

The primary value of TPMT testing is to identify the rare homozygous deficient patients who require alternative therapy or significant dose reduction to avoid severe myelosuppression. 3, 4

Side Effects and Monitoring

Approximately 25% of patients develop azathioprine side effects, requiring drug withdrawal in about 10% of cases. 3 Side effects are more common in patients with cirrhosis. 3

Common adverse effects include: 3, 1

• Nausea and anorexia (10-20% of patients)
• Severe early hypersensitivity reaction (5%): fever, arthralgia, rash, influenza-like symptoms
• Bone marrow suppression (most serious): manifests as decreased white cell and neutrophil counts
• Rare: cholestatic hepatitis, veno-occlusive disease, pancreatitis

Regular monitoring of complete blood counts is mandatory to detect marrow depression early. 3

Treatment Response and Goals

The therapeutic endpoint is complete normalization of both ALT and IgG levels—not just improvement, but complete normalization. 2 This typically requires:

• 6-12 months for biochemical remission
• 24-36 months for histological remission 3

Persistent elevation of liver enzymes predicts relapse after treatment withdrawal, ongoing histological activity, progression to cirrhosis, and poor outcomes. 2

When Azathioprine Fails or Cannot Be Tolerated

If azathioprine causes intolerable side effects, mycophenolate mofetil (MMF) is the preferred second-line agent. 2 Recent high-quality evidence challenges azathioprine's primacy:

• A 2024 randomized controlled trial showed MMF achieved biochemical remission in 56.4% versus 29.0% with azathioprine at 24 weeks (p=0.022) 5
• MMF had zero serious adverse events versus 12.9% with azathioprine (p=0.034) 5
• A 2022 long-term prospective study demonstrated MMF had lower non-response rates and higher complete biochemical response at 12 months (86% vs 71.8%) 6

However, current guidelines still recommend azathioprine as first-line based on decades of established efficacy and safety data. 3, 1 The newer MMF data may prompt guideline revisions but represents emerging rather than established standard of care.

Special Populations

In pregnancy: Azathioprine requires individual risk-benefit analysis but may be continued if disease control requires it, as studies in AIH and inflammatory bowel disease show no increased fetal risk. 3, 2 In contrast, MMF is absolutely contraindicated (Category D) due to severe cranial, facial, and cardiac abnormalities. 2

In cirrhotic patients: Azathioprine side effects are more common, and hepatotoxicity risk is increased. 3 Consider delaying azathioprine introduction or using alternative agents.

Maintenance and Long-Term Strategy

After achieving remission, azathioprine at 2 mg/kg daily can be used as a steroid-sparing maintenance strategy, allowing prednisolone withdrawal or reduction to minimal doses. 1 For patients who relapse multiply, indefinite azathioprine therapy is indicated. 7, 8