What is the treatment for autoimmune hepatitis?

Treatment of Autoimmune Hepatitis

Start combination therapy with prednisone 30 mg/day (tapering to 10 mg/day over 4 weeks) plus azathioprine 1-2 mg/kg/day as first-line treatment, continuing for at least 2 years and at least 12 months after complete normalization of both aminotransferases AND IgG levels. 1, 2

First-Line Treatment Regimen

Standard Combination Therapy (Preferred)

• Prednisone plus azathioprine from treatment initiation produces significantly fewer corticosteroid-related side effects compared to prednisone monotherapy (10% versus 44%) while maintaining equivalent efficacy. 1, 3
• The specific dosing schedule is: 1, 2
  • Week 1: Prednisone 30 mg/day + Azathioprine 50 mg/day (US) or 1-2 mg/kg/day (Europe)
  • Week 2: Prednisone 20 mg/day + Azathioprine (same dose)
  • Weeks 3-4: Prednisone 15 mg/day + Azathioprine (same dose)
  • Maintenance: Prednisone 10 mg/day + Azathioprine (same dose)

Alternative Approach: Delayed Azathioprine

• European guidelines support starting prednisone first, then adding azathioprine after 2 weeks, particularly when bilirubin is below 6 mg/dL (100 μmol/L). 4, 2
• This approach may be safer in patients with severe hyperbilirubinemia, though starting combination therapy from day one achieves better efficacy in the induction phase. 5

Special Consideration: Budesonide for Non-Cirrhotic Patients

• Budesonide 9 mg/day plus azathioprine may be used specifically in treatment-naive, non-cirrhotic patients with early-stage disease who face high risk of steroid side effects (psychosis, poorly controlled diabetes, severe osteoporosis). 4, 2
• Critical caveat: Budesonide has 90% first-pass hepatic clearance and is absolutely contraindicated in cirrhotic patients or those with portosystemic shunting due to loss of hepatic metabolism and risk of systemic steroid toxicity. 4

Treatment Goals and Monitoring

Target Endpoints

• Complete normalization of BOTH serum aminotransferases AND IgG levels must be the treatment goal, as persistent elevations predict relapse, ongoing histological activity, progression to cirrhosis, and poor outcomes. 4, 2
• 80-90% of patients achieve biochemical improvement, with transaminases normalizing within 6 months in most responders. 4, 2

Monitoring Schedule

• Assess treatment response at 4-8 weeks after initiation; serum aminotransferases typically improve within 2 weeks. 1, 3
• Monitor serum aminotransferase levels monthly, as small decrements in prednisone dose can trigger marked increases in aminotransferases. 3
• Normal liver tests are achieved in 66-91% of treated patients within 2 years, with average duration to normalization being 19 months. 4

Treatment Duration

• Continue treatment for at least 2 years and for at least 12 months after complete normalization of liver enzymes. 4, 1, 2
• Histological resolution may lag biochemical resolution by 3-8 months, making the expected total treatment duration 22-27 months to achieve both biochemical and histological remission. 4

Management of Special Situations

Pre-Treatment Considerations for Azathioprine

• For patients with cytopenia, measure thiopurine methyltransferase (TPMT) activity before starting azathioprine to exclude homozygote TPMT deficiency. 1
• Use prednisone monotherapy in patients with severe pre-treatment cytopenia. 1

Acute Severe Autoimmune Hepatitis

• Treat immediately with high-dose intravenous corticosteroids (≥1 mg/kg) as early as possible. 4, 2
• If no improvement occurs within 7 days, list for emergency liver transplantation. 4
• Patients with liver failure and lack of improvement in bilirubin and MELD score should be referred early to transplant centers, as this phenotype has high mortality without transplantation. 4

Non-Response or Treatment Failure

• Non-response should always trigger careful reconsideration of the diagnosis and re-evaluation of treatment adherence. 4
• For confirmed non-responders after excluding diagnostic error and non-adherence, increase to high-dose therapy: prednisone 60 mg daily alone OR prednisone 30 mg daily plus azathioprine 150 mg daily for at least 1 month. 4
• Then taper by 10 mg prednisone and 50 mg azathioprine monthly until reaching conventional maintenance doses. 4
• Alternative second-line agents for steroid-refractory cases include: 4, 1
  • Tacrolimus: Starting dose 0.075 mg/kg daily (range 0.5-1 mg daily), adjusted to maintenance of 1-3 mg twice daily targeting trough level 0.6-1.0 ng/mL
  • Cyclosporine: 2-5 mg/kg daily targeting trough levels 100-300 ng/mL
  • Mycophenolate mofetil: 2 g daily (1 g twice daily), particularly beneficial in azathioprine-intolerant rather than azathioprine-failure patients

Long-Term Management and Relapse

Expected Relapse Rates

• Relapse occurs in 50-90% of patients within 12 months of stopping treatment, even after achieving complete biochemical and histological remission. 4, 1, 2
• Only 20-28% achieve sustained remission off therapy. 4

Management After Relapse

• After relapse, institute long-term maintenance with azathioprine 2 mg/kg/day, which maintains remission in 87% of adult patients during median follow-up of 67 months. 1, 3, 2
• For patients who relapse repeatedly, use combination prednisone and azathioprine therapy, low-dose prednisone alone, or azathioprine monotherapy for indefinite maintenance. 3

Prevention of Treatment Complications

Mandatory Prophylaxis

• All patients must receive calcium and vitamin D supplementation from treatment initiation. 1, 3, 2
• Monitor bone mineral density with DEXA scanning at 1-2 year intervals. 1, 3, 2
• Vaccinate against hepatitis A and B early in susceptible patients. 1, 2

Steroid-Related Complications

• Severe complications (osteoporosis, vertebral compression, diabetes, cataracts, hypertension, psychosis) typically develop after 18 months of therapy at prednisone doses >10 mg daily. 3
• This risk profile strongly supports the use of combination therapy over prednisone monotherapy to minimize cumulative steroid exposure. 4, 1