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

AASLD and EASL Autoimmune Hepatitis Treatment Guidelines

First-Line Treatment Recommendations

For adults and children with autoimmune hepatitis without cirrhosis or acute severe presentation, use combination therapy with prednisolone (or prednisone) plus azathioprine as the standard first-line treatment, which achieves remission in 80-90% of patients. 1, 2

Standard Combination Regimen

• Start with prednisolone 30-60 mg/day for week 1, then taper weekly to a maintenance dose of 5-10 mg/day, combined with azathioprine 1-2 mg/kg/day (typically 50-100 mg/day). 2, 3

• Delay azathioprine introduction by 2 weeks after starting steroids to avoid diagnostic confusion between azathioprine hepatotoxicity and primary non-response. 2

• This combination regimen produces significantly fewer corticosteroid-related side effects (10% versus 44%) compared to prednisone monotherapy. 3

• Test for thiopurine methyltransferase (TPMT) activity prior to azathioprine treatment in all patients to exclude homozygote deficiency. 1, 2

Alternative First-Line Option: Budesonide

• Budesonide 9 mg/day (3 mg three times daily) combined with azathioprine 1-2 mg/kg/day can be used as first-line treatment in non-cirrhotic patients, achieving biochemical remission more frequently than standard prednisone regimens (60% versus 28% at 6 months). 1, 2

• Budesonide achieves biochemical remission with an odds ratio of 2.19 (95% CI, 1.30-3.67) compared to prednisone/azathioprine, with fewer steroid-specific side effects. 1

• DO NOT use budesonide in patients with cirrhosis or acute severe AIH due to risk of portal-systemic shunting reducing drug efficacy, promoting systemic steroid side effects, and potential portal vein thrombosis. 1, 2

Prednisone Monotherapy Alternative

• Prednisone alone starting at 60 mg daily, tapered to 40 mg, 30 mg, and maintenance of 20 mg is appropriate for patients with cytopenia, pregnancy, TPMT deficiency, or malignancy. 3

Treatment Goals and Monitoring

The therapeutic endpoint is complete normalization of BOTH serum aminotransferases (ALT/AST) AND immunoglobulin G levels—not just improvement, but complete normalization. 2, 3

• Serum aminotransferase levels should improve within 2 weeks of starting therapy. 3

• Persistent elevation of liver enzymes predicts relapse after treatment withdrawal, ongoing histological activity, progression to cirrhosis, and poor outcomes. 2

• Normalization of laboratory indices before termination of treatment reduces the relative risk of relapse after drug withdrawal by 3-fold to 11-fold. 3

• Liver tissue examination prior to drug withdrawal in individuals with ≥2 years of biochemical remission is preferred but not mandatory in adults and required in children. 1

Maintenance Therapy

• Once remission is achieved, reduce prednisolone to 7.5 mg/day when aminotransferases normalize, and after 3 months, taper to 5 mg/day. 2

• Maintain azathioprine at 1-2 mg/kg as a steroid-sparing agent throughout the maintenance phase. 2

• Continue treatment for at least 2 years before considering withdrawal, as failure to achieve complete normalization leads to almost universal relapse after treatment withdrawal. 3

• Azathioprine monotherapy (median dose 75-100 mg) is equivalent to dual prednisone-azathioprine therapy for maintenance of remission, with 95% maintaining remission versus 80% with dual therapy. 4

Second-Line Therapies for Treatment Failure or Intolerance

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

Mycophenolate Mofetil (MMF)

• Start MMF at 1 g daily initially, increasing to maintenance of 1.5-2 g daily. 2, 3

• MMF is effective in 58% of patients with azathioprine intolerance versus only 23% with refractory disease. 2

• MMF is absolutely contraindicated in pregnancy due to severe cranial, facial, and cardiac abnormalities (Category D). 2, 3

Calcineurin Inhibitors

• Tacrolimus (starting dose 0.075 mg/kg daily) may be more effective for patients with refractory disease not responding to standard therapy. 3

• Cyclosporine (2-5 mg/kg daily) has shown effectiveness in inducing and maintaining remission, particularly in pediatric patients, with normalization of ALT within 6 months and minimal side effects. 3, 5

Special Clinical Situations

Acute Severe AIH

• Patients with acute severe AIH should receive high-dose intravenous prednisolone (≥1 mg/kg) as early as possible. 2, 3

• If no improvement within 7-14 days, evaluate directly for liver transplantation. 1, 3

• Patients with AIH and acute liver failure should be evaluated directly for liver transplantation. 1

AIH-PBC Overlap Syndrome

• Combined therapy with ursodeoxycholic acid (UDCA) 13-15 mg/kg/day plus immunosuppressants is required, with treatment directed at the predominant disease component. 2

Pregnancy Considerations

• Azathioprine can be continued throughout pregnancy with risk-benefit analysis if disease control requires it. 1, 2

• MMF is absolutely contraindicated in pregnancy and must be discontinued. 1, 2

Pediatric Patients

• Treatment regimens in children are similar to adults but with dose adjustments, with early use of azathioprine (1-2 mg/kg daily) or 6-mercaptopurine (1.5 mg/kg daily) recommended to minimize steroid effects on growth. 3

• Response to treatment is excellent in children, with normalization of liver tests in 75-90% after 6-9 months. 3

Critical Pitfalls and Caveats

• Non-adherence is a major cause of relapse, particularly in adolescents and young adults—regular monitoring of immunosuppressant drug levels is indicated. 2

• Cosmetic side effects of corticosteroids occur in 80% of patients after 2 years of treatment, and severe side effects typically develop after 18 months at prednisone doses >10 mg daily. 3

• Liver biopsy may show persistent interface hepatitis in 55% of patients with normal serum enzymes, highlighting the importance of histological assessment before treatment withdrawal. 3

• Azathioprine requires immediate discontinuation if intolerance symptoms emerge. 2

• Elastography may be used to assess stages of hepatic fibrosis noninvasively. 1

• Glucocorticoids can be discontinued after liver transplantation with monitoring for recurrence of AIH. 1