What is the management for Autoimmune Hepatitis (AIH) type 1 and 2?

Management of Autoimmune Hepatitis Type 1 and Type 2

First-Line Treatment: Combination Therapy is Standard

All patients with active AIH type 1 or type 2 should receive combination therapy with prednisolone (or prednisone) plus azathioprine as first-line treatment, achieving remission in 80-90% of patients. 1

Induction Regimen

• Start prednisolone at 60 mg/day for week 1, then taper weekly to maintenance dose 1
• Delay azathioprine introduction by 2 weeks to avoid diagnostic confusion between azathioprine hepatotoxicity and primary non-response 1
• Once aminotransferases normalize, reduce prednisolone to 7.5 mg/day, then after 3 months taper to 5 mg/day 1
• Maintain azathioprine at 1-2 mg/kg/day as steroid-sparing agent 1

Critical Pre-Treatment Testing

• Check TPMT levels before initiating azathioprine to exclude homozygote deficiency 1
• Vaccinate against hepatitis A and B in susceptible patients prior to immunosuppression if possible 2
• Screen for HBV (HBsAg, anti-HBc, anti-HBs) to identify patients requiring monitoring for reactivation 2

Treatment Goals: Complete Normalization Required

The therapeutic endpoint is complete normalization of both ALT and IgG levels, not just improvement. 1 This distinction is critical because persistent elevation of liver enzymes predicts relapse after treatment withdrawal, ongoing histological activity, progression to cirrhosis, and poor outcomes 1.

Who Must Be Treated

Absolute indications for treatment (based on controlled trials demonstrating survival benefit): 2

• AST >5 times normal
• Serum globulins >2 times normal
• Liver biopsy showing confluent necrosis or bridging necrosis
• Symptomatic patients
• Patients with established cirrhosis on biopsy
• Younger patients to prevent cirrhosis development

Patients with mild interface hepatitis (Ishak score 4-6) who are asymptomatic and older may be monitored every 3 months with ALT and IgG, with repeat liver biopsy after 2-3 years if liver tests remain abnormal 2

Alternative First-Line Option: Budesonide

For non-cirrhotic patients at high risk for steroid side effects, budesonide 3 mg three times daily plus azathioprine (1-2 mg/kg/day) is an alternative first-line option that achieves normalization of aminotransferases more frequently with fewer side effects at 6 months 1. However, budesonide is contraindicated in cirrhotic patients due to loss of first-pass hepatic metabolism with portosystemic shunting and safety concerns 3.

Type 2 AIH: Special Considerations

Type 2 AIH (anti-LKM1 or anti-LC1 positive) differs from type 1 in several important ways: 2

• Primarily occurs in children under 14 years or young adults
• Acute onset in 31-40% of cases
• Up to 25% present as acute liver failure
• Relatively more cases are unresponsive to treatment
• IgG may be normal or even low (unlike type 1)

Despite these differences, the same first-line treatment regimen applies to both type 1 and type 2 AIH. 2

Second-Line Therapies

Mycophenolate mofetil (MMF) is the preferred second-line agent, particularly for azathioprine intolerance rather than refractory disease 1:

• Start at 1 g daily, increase to maintenance of 1.5-2 g daily
• Effective in 58% of patients with azathioprine intolerance vs only 23% with refractory disease
• Absolutely contraindicated in pregnancy due to severe cranial, facial, and cardiac abnormalities 1

Alternative second-line options include cyclosporine, tacrolimus, or increasing azathioprine to 2 mg/kg/day while continuing prednisolone 5-10 mg/day 2.

Acute Severe and Fulminant AIH

Acute severe AIH should be treated with high-dose intravenous corticosteroids (≥1 mg/kg) as early as possible, with immediate liver transplant evaluation for fulminant cases 1, 4.

Diagnostic Challenges in Fulminant Presentations

• ANA is absent or weakly positive in 29-39% of fulminant AIH cases 4
• Serum IgG levels are normal in 25-39% of patients 4
• Do not delay treatment waiting for "classical" serological findings to appear 4
• A short (≤2 weeks) prednisolone trial is appropriate when diagnosis is uncertain but AIH is suspected 4

Evidence Controversy on Corticosteroids in Fulminant AIH

There is conflicting evidence regarding corticosteroid efficacy in fulminant AIH. One retrospective study found corticosteroids of little benefit in severe/fulminant forms, potentially favoring septic complications 5. However, current guidelines from EASL and AASLD recommend immediate immunosuppressive therapy once other causes are excluded 4. Given the high mortality without treatment and the potential for response, immediate high-dose corticosteroids should be initiated while simultaneously evaluating for transplantation. 4

Monitoring During Treatment

Regular monitoring must include: 2

• Liver enzymes (ALT, AST) and IgG levels
• Complete blood count (for azathioprine bone marrow suppression)
• HBsAg and HBV DNA at 1-3 month intervals in HBsAg-negative/anti-HBc-positive patients on conventional therapy 2
• Bone density assessment and calcium/vitamin D supplementation (1,000-1,200 mg calcium daily, 400-800 IU vitamin D daily) for patients on glucocorticoids 2

Special Populations

Pregnancy

• Azathioprine requires risk-benefit analysis but may be continued if disease control requires it 1
• MMF is absolutely contraindicated (category D) 1

Pediatric Patients

• Same treatment principles apply as adults 2
• Non-adherence is a major cause of relapse in adolescents and young adults; regular monitoring of immunosuppressant drug levels is indicated 1

Elderly Patients

• Treatment should be considered even in older patients with active disease 2
• Asymptomatic older patients with mild disease may be monitored closely 2

Common Pitfalls to Avoid

1. Stopping treatment too early: 50-90% of patients relapse within 12 months of stopping treatment 2
2. Accepting partial biochemical response: Persistent ALT elevation predicts poor outcomes 1
3. Missing autoantibody-negative AIH: 19-34% of AIH patients lack ANA, SMA, or anti-LKM1 at diagnosis 2
4. Using azathioprine monotherapy for induction: Associated with high mortality (24-36%) 2
5. Prescribing budesonide to cirrhotic patients: Loss of first-pass effect and safety concerns 3
6. Failing to check TPMT before azathioprine: Risk of severe bone marrow toxicity 1