What are the EASL (European Association for the Study of the Liver) and AASLD (American Association for the Study of Liver Diseases) guidelines for treating autoimmune hepatitis?

Autoimmune Hepatitis Treatment: EASL and AASLD Guidelines

First-Line Treatment Regimen

Both EASL and AASLD guidelines strongly endorse combination therapy with prednisolone (or prednisone) plus azathioprine as the standard first-line treatment for autoimmune hepatitis, achieving remission in 80-90% of patients. 1, 2

Initial Dosing Strategy

EASL Recommended Approach:

• Start with prednisolone 60 mg/day (1 mg/kg for 60 kg patient) for week 1 1
• Taper weekly: 50 mg (week 2) → 40 mg (week 3) → 30 mg (week 4) → 25 mg (week 5) → 20 mg (week 6) → 15 mg (weeks 7-8) → 12.5 mg (weeks 8-9) → 10 mg (from week 10 onward) 1
• Delay azathioprine introduction by 2 weeks to avoid diagnostic confusion between azathioprine hepatotoxicity and primary non-response 1
• Add azathioprine 50 mg/day starting week 3, increase to 100 mg/day (1-2 mg/kg) by week 5 1

AASLD Recommended Approach:

• Initial prednisolone 30 mg/day, reducing to 10 mg/day over 4 weeks 2
• Azathioprine 1 mg/kg/day, initiated when bilirubin is below 6 mg/dL 2

Alternative High-Dose Strategy

For patients without cirrhosis requiring rapid response:

• Higher initial prednisolone doses up to 1 mg/kg/day combined with azathioprine result in more rapid normalization of transaminases 1, 2
• This approach is particularly effective in patients with severe interface hepatitis 3

Treatment Goals and Monitoring

The therapeutic endpoint is complete normalization of both ALT and IgG levels - not just improvement, but complete normalization. 1, 2

• Persistent elevation of liver enzymes predicts relapse after treatment withdrawal, ongoing histological activity, progression to cirrhosis, and poor outcomes 2
• Follow-up liver biopsy is not routinely required if complete biochemical normalization is achieved 2
• Treatment should be response-guided and individualized based on biochemical markers 1

Maintenance Therapy

Once remission is achieved:

• Reduce prednisolone to 7.5 mg/day when aminotransferases normalize 1
• After 3 months, taper to 5 mg/day 1
• Continue tapering at 3-4 month intervals depending on response 1
• Azathioprine is maintained at 1-2 mg/kg as a steroid-sparing agent 1

Alternative First-Line Option: Budesonide

EASL guidelines acknowledge budesonide as an alternative first-line option for non-cirrhotic patients, particularly those at high risk for steroid side effects. 1

• Budesonide 3 mg three times daily plus azathioprine (1-2 mg/kg/day) 1, 4
• Achieves normalization of aminotransferases more frequently (47% vs 18%) with fewer side effects (28% vs 53%) compared to standard prednisone regimen at 6 months 1, 4
• Critical caveat: Budesonide should NOT be used in cirrhotic patients due to impaired first-pass metabolism leading to systemic side effects 2

Indications for Budesonide:

• Post-menopausal women at risk for osteoporosis 1
• Young females concerned about cosmetic side effects 1
• Patients with pre-existing osteoporosis, brittle diabetes, labile hypertension, or obesity 1
• Emotional instability 1

Second-Line Therapies

When to Consider Second-Line Treatment

Failure of adequate response should prompt reconsideration of diagnosis and evaluation of treatment adherence before escalating therapy. 2

If diagnosis is confirmed and adherence verified:

• Increase azathioprine to 2 mg/kg/day with prednisone 5-10 mg/day 1
• Consider repeat liver biopsy after 12-18 months 1

Mycophenolate Mofetil (MMF)

MMF is the preferred second-line agent, particularly for azathioprine intolerance rather than refractory disease. 1, 2

• Dosing: 1 g daily initially, increase to maintenance of 1.5-2 g daily (range 500 mg to 3 g daily) 1
• Effective in 58% of patients with azathioprine intolerance vs only 23% with refractory disease 1
• Category D in pregnancy - severe cranial, facial, and cardiac abnormalities reported 1
• Side effects similar to azathioprine: anemia, leukopenia, nausea, diarrhea, abdominal pain (3-34% frequency) 1

Calcineurin Inhibitors

For patients requiring high-dose long-term steroids (>20 mg/day) despite optimized conventional therapy:

Tacrolimus:

• Dose: 1-6 mg/day (mean trough level 6 ng/mL) 1
• Achieved normalization in 12/13 patients with refractory AIH or intolerance 1
• Successful in 7/9 patients with severe non-responsive AIH 1

Cyclosporine:

• Dose: 2-3 mg/kg/day 1
• Biochemical response rate >80% in small adult series 1
• More extensive pediatric experience with 84-100% response rates 1

These agents should only be used after consultation with a specialist center. 1

Special Clinical Situations

Acute Severe AIH

EASL recommends treating acute severe AIH with high-dose intravenous corticosteroids (≥1 mg/kg) as early as possible. 2

• If inadequate response, increase to 100 mg prednisolone IV 1
• Consider liver transplant evaluation for fulminant cases 1

AIH-PBC Overlap Syndrome

Combined therapy with ursodeoxycholic acid (UDCA) 13-15 mg/kg/day plus immunosuppressants is recommended. 1, 2

• Diagnosis requires presence of AMA and histological bile duct injury in otherwise classical AIH 1
• Treatment directed at predominant disease component 1

Pregnancy

Azathioprine requires risk-benefit analysis in pregnancy but may be continued if disease control requires it 1

• MMF is absolutely contraindicated (Category D) 1
• Maintain lowest effective steroid dose 1

Critical Pitfalls and Caveats

Azathioprine Safety

• Check TPMT (thiopurine methyltransferase) levels before initiating to exclude homozygote deficiency, especially with pre-existing leukopenia 2
• Azathioprine hepatotoxicity is more common in advanced liver disease 1, 2
• Immediate discontinuation required if intolerance symptoms emerge (nausea, vomiting, fever, arthralgias, rash) 1
• Resolution of intolerance symptoms typically occurs within days 1

Adherence Issues

Non-adherence is a major cause of relapse, particularly in adolescents and young adults. 1

• Cosmetic steroid side effects significantly impact adherence in young patients 1
• Regular monitoring of immunosuppressant drug levels is indicated 1
• Multidisciplinary approach with psychologists and dedicated nurses improves outcomes during transition to adult care 1

Treatment Duration

Treatment is commonly indefinite - relapse occurs in 50-87% after corticosteroid cessation 1

• Attempt steroid withdrawal only after sustained complete biochemical remission 1
• Maintain azathioprine as monotherapy during steroid withdrawal attempts 1

Incomplete Response

Complete response may not be attainable in some patients - the goal becomes lowest achievable biochemical activity with minimum side effects. 1

• Histological control may be necessary to assess treatment effect and disease progression 1
• Children with AIH and sclerosing cholangitis are invariably non-responders to standard therapy 1