Autoimmune Hepatitis Treatment Guidelines
First-Line Treatment
The standard first-line treatment for autoimmune hepatitis is combination therapy with prednisolone (or prednisone) plus azathioprine, which achieves remission in 80-90% of patients and significantly improves survival. 1, 2
Induction Regimen
Start with prednisolone 30 mg/day (or up to 60 mg/day for week 1), tapering to 10 mg/day over 4 weeks, combined with azathioprine 1 mg/kg/day. 3, 1, 2
Delay azathioprine introduction by 2 weeks after starting steroids to avoid diagnostic confusion between azathioprine hepatotoxicity and primary non-response. 1
Azathioprine should only be initiated when bilirubin is below 6 mg/dL. 2
Higher initial prednisolone doses (up to 1 mg/kg/day) may achieve more rapid normalization of transaminases (77% at 6 months), but increase steroid-related side effects. 3
Combination Therapy is Preferred
The combination regimen is strongly preferred over prednisone monotherapy except in patients who are cytopenic (WBC <2.5×10⁹/L or platelets <50×10⁹/L), pregnant, or completely deficient in TPMT activity. 3
Combination therapy reduces corticosteroid-related complications compared to prednisone alone, particularly important in elderly patients. 4
Starting combination therapy from the beginning achieves better efficacy than adding azathioprine after 4 weeks of prednisone monotherapy. 5
Treatment Goals and Monitoring
The therapeutic endpoint is complete normalization of both ALT and IgG levels—not just improvement, but complete normalization. 1, 2
Serum aspartate aminotransferase (AST) and gamma-globulin levels are the most useful indices to monitor during therapy. 4
Persistent elevation of liver enzymes predicts relapse after treatment withdrawal, ongoing histological activity, progression to cirrhosis, and poor outcomes. 1, 2
Liver biopsy to confirm histological remission is valuable in planning further management, though not routinely required if complete biochemical normalization is achieved. 3, 2
Maintenance Therapy
Treatment with azathioprine 1 mg/kg/day and prednisolone 5-10 mg/day should continue for at least 2 years and for at least 12 months after normalization of transaminases. 3
Once remission is achieved, reduce prednisolone to 7.5 mg/day when aminotransferases normalize, and after 3 months, taper to 5 mg/day. 1
Azathioprine is maintained at 1-2 mg/kg as a steroid-sparing agent. 1, 2
The average duration to achieve complete clinical, laboratory, and histological resolution is 22 months (range 1-180 months, median 42 months). 3
Alternative First-Line Option: Budesonide
In non-cirrhotic patients with severe steroid-related side effects (psychosis, poorly controlled diabetes, or osteoporosis), budesonide 9 mg/day (3 mg three times daily) plus azathioprine 1-2 mg/kg/day is an alternative first-line option. 3, 1
Budesonide plus azathioprine achieves normalization of aminotransferases more frequently with fewer side effects compared to standard prednisolone regimen at 6 months. 3, 1
Budesonide should never be used in cirrhotic patients due to risk of systemic side effects from impaired first-pass hepatic metabolism. 2
Second-Line Therapies
For patients who fail to achieve remission after 2 years on standard therapy or develop drug intolerance, mycophenolate mofetil (MMF) is the preferred second-line agent. 1
MMF dosing: start at 1 g daily, increasing to maintenance of 1.5-2 g daily. 1
MMF is effective in 58% of patients with azathioprine intolerance versus only 23% with refractory disease. 1
MMF is absolutely contraindicated in pregnancy due to severe cranial, facial, and cardiac abnormalities. 1
In non-responding patients, higher doses of steroids (including methylprednisolone) combined with 2 mg/kg/day azathioprine may be used, or alternatively tacrolimus. 3
Calcineurin inhibitors (cyclosporine, tacrolimus) are additional salvage options but have serious side effects and variable effectiveness. 3, 6, 7
Special Clinical Situations
Acute Severe/Fulminant AIH
Acute severe AIH should be treated with high-dose intravenous corticosteroids (≥1 mg/kg) as early as possible. 1, 2
In patients with liver failure, bridging necrosis on biopsy, or jaundiced patients whose MELD score does not rapidly improve on treatment, contact a liver transplant center immediately. 3
In one series, only 1 of 12 patients with fulminant AIH improved with corticosteroids; 10 required transplantation. 3
AIH-PBC Overlap Syndrome
AIH-PBC overlap syndrome requires combined therapy with ursodeoxycholic acid (UDCA) 13-15 mg/kg/day plus immunosuppressants (corticosteroids and azathioprine), with treatment directed at the predominant disease component. 3, 1, 2
Pregnancy
Azathioprine requires risk-benefit analysis in pregnancy but may be continued if disease control requires it, as it is primarily a steroid-sparing agent and not essential. 3, 1
Corticosteroids alone induce remission as frequently as combination therapy and can be used as monotherapy during pregnancy. 3
AIH typically subsides during pregnancy due to high estrogen levels strengthening anti-inflammatory pathways. 3
MMF is absolutely contraindicated in pregnancy (Category D). 1
Treatment Dependence
For patients requiring continuous therapy beyond 24 months (age ≥60 years) or 36 months (age ≤40 years) without achieving remission, long-term maintenance therapy adjusted to laboratory evidence of disease activity is justified. 3
Continuous therapy for more than 3 years without achieving complete resolution is associated with progression to cirrhosis (54%) and need for transplantation (15%). 3
Long-term maintenance can be modified by reducing prednisolone by 2.5 mg per month as azathioprine is increased to 2 mg/kg daily, with the goal of withdrawing prednisolone completely if azathioprine alone proves sufficient. 3
Azathioprine 2 mg/kg/day alone can maintain remission in 83% of patients for a median of 67 months after prednisolone withdrawal. 8
Treatment Withdrawal and Relapse
Within 12 months of stopping treatment following biochemical and histological remission, 50-90% of patients relapse. 3
Factors predicting relapse include: raised serum ALT/AST, raised serum globulin/IgG, high serum globulin at presentation, LKM antibody positivity, SLA/LP antibody positivity, and liver biopsy showing any inflammation. 3
Relapse warrants re-treatment with the original regimen followed by long-term maintenance therapy with azathioprine. 6
Critical Pitfalls and Caveats
TPMT Testing
Check TPMT levels before initiating azathioprine to exclude homozygote deficiency, especially in patients with pre-existing leucopenia. 3, 1, 2
About 5% of patients develop severe early azathioprine reactions with fever, arthralgia, rash, and flu-like symptoms requiring immediate discontinuation. 3
Approximately 10-20% develop nausea and anorexia, and about 25% develop side effects requiring withdrawal in 10% of cases. 3
Monitoring for Myelosuppression
With azathioprine 2 mg/kg/day, myelosuppression (WBC <4000 or platelets <150,000) occurs in some patients, and lymphopenia develops in 32 of 56 patients treated for more than 2 years. 8
Regular monitoring of white cell and neutrophil counts is mandatory. 3
Bone Health
Patients should receive calcium and vitamin D supplementation, with DEXA scanning at 1-2 yearly intervals while on steroids, and osteopenia/osteoporosis should be actively treated. 3
Non-Adherence
Non-adherence is a major cause of relapse, particularly in adolescents and young adults; regular monitoring of immunosuppressant drug levels is indicated. 1
Vaccination
Vaccination against hepatitis A and hepatitis B should be performed early in susceptible patients. 3
Failure to Respond
Failure of adequate response should prompt reconsideration of the diagnosis or evaluation of treatment adherence before escalating therapy. 2
- In confirmed cases with adherence but suboptimal response, increase dosage of prednisolone and azathioprine or consider alternative medications. 2