What is the initial medication treatment for autoimmune hepatitis?

Initial Medication Treatment for Autoimmune Hepatitis

The first-line treatment for autoimmune hepatitis is combination therapy with predniso(lo)ne (starting at 30 mg/day, tapering to 10 mg/day over 4 weeks) plus azathioprine (1-2 mg/kg/day), which should be initiated as early as possible in patients with moderate to severe disease. 1, 2, 3

Standard Induction Regimen

The combination approach is superior to prednisone monotherapy because it produces significantly fewer corticosteroid-related side effects (10% versus 44%) while maintaining equivalent efficacy 1, 2, 3. This difference in side effect profile is clinically meaningful and drives the preference for combination therapy from the outset.

Specific dosing schedule:

• Week 1: Prednisone 30 mg/day + Azathioprine 50 mg/day (US dosing) or 1-2 mg/kg/day (European dosing) 2, 3
• Week 2: Prednisone 20 mg/day + Azathioprine (same dose) 3
• Weeks 3-4: Prednisone 15 mg/day + Azathioprine (same dose) 3
• Maintenance: Prednisone 10 mg/day + Azathioprine (same dose) until remission 2, 3

The European Association for the Study of Liver Diseases (EASL) recommends starting predniso(lo)ne as initial therapy followed by addition of azathioprine after two weeks, particularly when bilirubin levels are below 6 mg/dL (100 μmol/L) 1. However, recent evidence suggests starting both medications simultaneously from the beginning achieves better efficacy 4.

Alternative Regimen for Non-Cirrhotic Patients

Budesonide 9 mg/day plus azathioprine may be considered specifically in treatment-naive, non-cirrhotic patients with early-stage disease who are at high risk for steroid-specific side effects (such as psychosis, poorly controlled diabetes, or severe osteoporosis) 1.

Critical caveat: Budesonide has 90% first-pass hepatic clearance and is absolutely contraindicated in cirrhotic patients or those with peri-hepatic shunting due to high risk of systemic side effects when first-pass metabolism is compromised 1. This is a common pitfall to avoid—always assess for cirrhosis before considering budesonide.

When to Initiate Azathioprine

Azathioprine can be started whenever bilirubin is below 6 mg/dL (100 μmol/L), ideally two weeks after steroid initiation 1. Begin with 50 mg/day and increase based on toxicity and response up to a maintenance dose of 1-2 mg/kg 1.

Before starting azathioprine: Check thiopurine methyltransferase (TPMT) activity in patients with pre-existing cytopenia to exclude homozygote TPMT deficiency 3. If severe cytopenia exists, use prednisone monotherapy instead 3.

Monitoring and Response Assessment

• Assess response at 4-8 weeks after treatment initiation; serum aminotransferases typically improve within 2 weeks 2, 3
• Monitor serum aminotransferase levels monthly because small decrements in prednisone dose can cause marked increases in aminotransferase levels 2
• 80-90% of patients achieve biochemical improvement with transaminases normalizing within 6 months in most responders 1

Treatment target: Complete normalization of both transaminases AND IgG levels should be the goal, as persistent elevations predict relapse after treatment withdrawal, ongoing histological activity, progression to cirrhosis, and poor outcomes 1, 2.

Treatment Duration

Continue treatment for at least 2 years and for at least 12 months after normalization of liver enzymes 2, 3. The average duration of initial treatment is 18-24 months to achieve remission, defined as normal laboratory indices and resolution of liver inflammation on biopsy 2, 3.

Management of Non-Response

If inadequate response occurs despite treatment, first reconsider the diagnosis and re-evaluate medication adherence—this is critical because primary non-response is rare in true AIH 1. Non-response should always trigger diagnostic reconsideration, particularly in young, non-Caucasian patients with acute presentations 1.

For confirmed non-responders:

• Increase doses of prednisolone and azathioprine (up to azathioprine 2 mg/kg/day) 1, 2, 3
• Consider alternative immunosuppressants: tacrolimus or cyclosporine for steroid-refractory cases 2, 3
• Treatment failure warrants high-dose prednisone (60 mg daily) alone or prednisone (30 mg daily) with azathioprine (150 mg daily) for at least 1 month 2

Acute Severe Autoimmune Hepatitis

Patients with acute severe AIH require immediate treatment with high-dose intravenous corticosteroids (≥1 mg/kg) as early as possible 1. Lack of improvement within 7 days mandates listing for emergency liver transplantation 1.

Prevention of Treatment Complications

All patients must receive:

• Calcium and vitamin D supplementation from treatment initiation 2, 3
• DEXA scanning for bone mineral density monitoring at 1-2 year intervals 2, 3
• Vaccination against hepatitis A and B early in susceptible patients 2, 3

Severe complications (osteoporosis, vertebral compression, diabetes, cataracts, hypertension, psychosis) typically develop after 18 months of therapy at prednisone doses >10 mg daily 2.

Long-Term Considerations

Relapse occurs in 50-90% of patients within 12 months of stopping treatment 2, 3, 5. After relapse, long-term maintenance with azathioprine 2 mg/kg/day should be considered, with 87% of adult patients remaining in remission during median follow-up of 67 months 2.