What is the treatment for autoimmune hepatitis?

Treatment of Autoimmune Hepatitis

First-line treatment for autoimmune hepatitis is combination therapy with prednisone (30 mg/day initially, tapering to 10 mg/day over 4 weeks) plus azathioprine (1-2 mg/kg/day, typically 50 mg/day), which achieves remission in 80-90% of patients and produces significantly fewer corticosteroid-related side effects (10% versus 44%) compared to prednisone monotherapy. 1, 2

Initial Treatment Strategy

Standard Combination Regimen:

• Start prednisone 30 mg/day plus azathioprine 50 mg/day (US dosing) or 1-2 mg/kg/day (European dosing) for week 1 1, 2
• Taper prednisone to 10 mg/day over 4 weeks while maintaining azathioprine at the same dose 1, 2
• Initiate azathioprine when bilirubin is below 6 mg/dL, ideally two weeks after starting steroids 2
• Consider measuring thiopurine methyltransferase (TPMT) before azathioprine initiation to exclude homozygote deficiency, especially in patients with pre-existing leucopenia 2, 3

Alternative Monotherapy Option:

• Prednisone alone starting at 60 mg daily, then tapered to 40 mg, 30 mg, and maintenance of 20 mg until endpoint 2
• This approach is appropriate for patients with cytopenia, pregnancy, TPMT deficiency, or malignancy 2

Budesonide Alternative:

• Budesonide 9 mg/day with azathioprine may be considered as first-line therapy 2
• Critical caveat: Do NOT use budesonide in patients with cirrhosis or acute severe AIH due to risk of systemic side effects from impaired first-pass metabolism 2, 3

Treatment Monitoring and Goals

Early Assessment:

• Serum aminotransferase levels should improve within 2 weeks of starting therapy 1, 2
• Assess treatment response at 4-8 weeks after initiation 1
• Monitor serum aminotransferase levels monthly, as small decrements in prednisone dose can trigger marked increases in aminotransferase levels 1

Treatment Endpoint:

• The goal is complete normalization of liver enzymes (AST, ALT) and IgG levels—not just improvement 1, 2, 3
• Biochemical remission achieved within 6 months is associated with lower frequency of progression to cirrhosis 1
• Liver biopsy assessment prior to termination of treatment is recommended to ensure full resolution, as 55% of patients with normal serum enzymes may still have persistent interface hepatitis 2
• Normalization of laboratory indices before termination reduces the relative risk of relapse by 3-fold to 11-fold 2

Treatment Duration:

• Continue treatment for at least 2 years and for at least 12 months after normalization of liver enzymes 1, 3
• Average duration of initial treatment is 18-24 months 1
• Failure to achieve complete normalization of liver enzymes and IgG leads to almost universal relapse after treatment withdrawal 2, 3

Management of Treatment Failure or Intolerance

For Incomplete Response:

• Consider long-term low-dose corticosteroid therapy with gradual decrease to 10 mg daily 2
• Long-term azathioprine 2 mg/kg daily can stabilize liver enzymes in corticosteroid-intolerant individuals 2
• Treatment failure warrants high doses of prednisone alone (60 mg daily) or prednisone (30 mg daily) in conjunction with azathioprine (150 mg daily), continued for at least 1 month 1

Second-Line Agents (Ranked by Indication):

1. Mycophenolate Mofetil (MMF) - First choice for azathioprine intolerance:

   • Initial dose: 1 g daily, increased to maintenance level of 1.5-2 g daily 2, 3
   • Beneficial in 45% of problematic patients overall, but 58% effective for azathioprine intolerance versus only 23% for refractory disease 4
   • Important caveat: Children with autoimmune hepatitis and sclerosing cholangitis are invariably non-responders to MMF 4

2. Tacrolimus - More effective for refractory disease:

   • Starting dose: 0.075 mg/kg daily (range 0.5-1 mg daily) 4, 2, 3
   • Adjust to maintenance level of 1 mg daily to 3 mg twice daily to achieve trough level of 0.6-1.0 ng/mL 4
   • Improvement by any measure achieved in 98% of patients receiving tacrolimus as salvage therapy 4

3. Cyclosporine - Alternative calcineurin inhibitor:

   • Dose: 2-5 mg/kg daily 4, 2
   • Target trough levels: 100-300 ng/mL 4
   • Effective to some degree in 93% of patients across 10 reports involving 133 patients 4
   • Particularly effective in pediatric patients 2

Concerns with Calcineurin Inhibitors:

• Possible paradoxical autoimmune effects due to impaired negative selection and apoptosis of autoreactive lymphocytes 4
• Unable to consistently prevent or treat recurrent autoimmune hepatitis after liver transplantation 4
• Expensive with long-term treatment requirements and toxicities including neurotoxicity 4
• Have not generated strong endorsement by AASLD or BSG 4

Management of Relapse

Post-Treatment Relapse:

• Relapse occurs in 50-90% of patients within 12 months of stopping treatment 1
• After relapse, consider long-term maintenance with azathioprine 2 mg/kg/day 1
• For patients who have relapsed more than once, treat with combination prednisone and azathioprine therapy, low-dose prednisone, or azathioprine only 1
• 87% of adult patients remain in remission during a median observation interval of 67 months on maintenance therapy 1

Special Populations

Acute Severe AIH:

• High-dose intravenous corticosteroids (≥1 mg/kg) should be administered as early as possible 2
• If no improvement within 7 days, evaluate for liver transplantation 2

Children:

• Treatment regimens are similar to adults but with dose adjustments 2
• Early use of azathioprine (1-2 mg/kg daily) or 6-mercaptopurine (1.5 mg/kg daily) is recommended to minimize steroid effects on growth 2
• Response to treatment is excellent, with normalization of liver tests in 75-90% after 6-9 months 2

Overlap Syndromes (AIH/PSC):

• Manage with prednisolone and azathioprine with or without UDCA 4
• Falls are usually seen in serum transaminases but not in serum alkaline phosphatase level 4
• Long-term outlook may be worse than AIH without overlap, emphasizing the importance of proactive diagnosis and treatment 4

Prevention of Treatment Complications

Bone Health:

• All patients should receive calcium and vitamin D supplementation 1
• Monitor bone mineral density with DEXA scanning at 1-2 year intervals 1

Vaccination:

• Perform vaccination against hepatitis A and B early in susceptible patients 1

Timing of Severe Complications:

• Severe complications (osteoporosis, vertebral compression, diabetes, cataracts, hypertension, psychosis) typically develop after 18 months of therapy at prednisone doses >10 mg daily 1, 2
• Cosmetic side effects of corticosteroids occur in 80% of patients after 2 years of treatment 2

Liver Transplantation Indications

Urgent Referral:

• Decompensation at presentation with severe disease showing no or very slow response to treatment 4
• Fulminant hepatic failure 4
• Clinical liver decompensation (ascites, hepatic encephalopathy, hepatorenal syndrome) 4
• Hepatocellular carcinoma 4
• MELD score >15 or Child-Pugh score >10 4

Consider Referral/Discussion:

• Signs of impending liver decompensation: variceal bleed, ultrasound showing small 'fibrotic' liver, falling serum albumin, development of even mild ascites or ankle edema 4