What is the management approach for a patient with autoimmune hepatitis?

Management of Autoimmune Hepatitis

First-Line Treatment: Combination Immunosuppression

All patients with active autoimmune hepatitis should receive combination therapy with prednisolone plus azathioprine as first-line treatment, which achieves remission in 80-90% of patients and significantly improves survival. 1, 2

Standard Induction Regimen

• Start prednisolone 30 mg/day combined with azathioprine 1-2 mg/kg/day (typically 50 mg/day initially in the US). 2, 3
• Taper prednisolone over 4 weeks to a maintenance dose of 10 mg/day, then further reduce to 7.5 mg/day once aminotransferases normalize, and after 3 months taper to 5 mg/day. 2, 3
• Maintain azathioprine at 1-2 mg/kg/day as a steroid-sparing agent throughout treatment. 2
• Some guidelines recommend delaying azathioprine introduction by 2 weeks to avoid diagnostic confusion between azathioprine hepatotoxicity and primary non-response. 2

Absolute Indications for Treatment

Immediate immunosuppressive therapy is mandatory for patients meeting any of these criteria (untreated mortality is 60% at 6 months): 1

• AST/ALT >10-fold upper limit of normal (ULN), OR
• AST/ALT ≥5-fold ULN with serum globulin ≥2-fold ULN, OR
• Liver biopsy showing bridging necrosis or multilobular necrosis (82% progression to cirrhosis if untreated). 1

Additional Treatment Indications

Treatment should also be initiated for: 4, 1

• Symptomatic patients (trial basis to assess improvement) 4
• Patients with established cirrhosis on biopsy (adverse prognostic feature) 4, 1
• Younger patients to prevent cirrhosis development over decades 4, 1
• Asymptomatic patients with moderate disease (untreated 10-year survival 67% versus 98% with treatment) 1

Pre-Treatment Requirements

Mandatory Testing

• Check thiopurine methyltransferase (TPMT) levels before starting azathioprine to exclude homozygote deficiency. 1, 2
• Do NOT start azathioprine if white blood cell count <2.5 × 10⁹/L or platelets <50 × 10⁹/L. 1
• Screen for hepatitis B (HBsAg, anti-HBc, anti-HBs) to identify patients requiring monitoring for reactivation. 2

Vaccinations

• Vaccinate against hepatitis A and B in susceptible patients prior to immunosuppression if possible. 4, 2, 3

Treatment Monitoring and Goals

Therapeutic Endpoint

• Complete normalization of both ALT and IgG levels is the therapeutic endpoint, not just improvement. 1, 2
• Persistent elevation of liver enzymes predicts relapse after treatment withdrawal. 1
• Patients with normalized labs before drug withdrawal have a 3-11 fold lower relapse risk compared to those who don't achieve this endpoint. 1

Monitoring Schedule

• Assess treatment response at 4-8 weeks after initiation; serum aminotransferases typically improve within 2 weeks. 3
• Monitor serum aminotransferase levels monthly, as small decrements in prednisone dose can cause marked increases in aminotransferases. 3
• Clinical and laboratory improvement occurs within 2-4 weeks in most patients, with biochemical remission typically achieved within 6-12 months. 1

Treatment Duration

• Continue treatment for at least 2 years and for at least 12 months after normalization of transaminases. 4, 3
• Average treatment duration is 18-24 months before considering withdrawal. 1, 3
• Histological resolution lags behind biochemical improvement by 3-8 months. 1
• Liver biopsy to confirm histological remission is valuable in planning further management before treatment withdrawal. 4

Bone Protection (Mandatory)

• All patients should receive calcium and vitamin D supplementation. 4, 3
• Perform bone DEXA scanning at 1-2 yearly intervals while on steroids and actively treat osteopenia and osteoporosis. 4, 3

Alternative First-Line Therapy

Budesonide-Based Regimen (Non-Cirrhotic Patients Only)

• For non-cirrhotic patients at high risk for steroid side effects, use budesonide 3 mg three times daily plus azathioprine (1-2 mg/kg/day). 4, 2
• This regimen achieves normalization of aminotransferases more frequently with fewer side effects at 6 months compared to prednisolone. 2
• Do NOT use budesonide in cirrhotic patients (contraindicated due to altered first-pass metabolism). 4

Management of Treatment Failure or Intolerance

Non-Response to Standard Therapy

For patients failing to achieve remission after 2 years on prednisolone plus azathioprine: 4

• Increase azathioprine to 2 mg/kg/day while continuing prednisolone (5-10 mg/day), with repeat biopsy after 12-18 months. 4
• Alternatively, consider higher doses of steroids (including methylprednisolone) combined with 2 mg/kg/day azathioprine, or tacrolimus, but expert advice should be sought. 4

Second-Line Agents

• Mycophenolate mofetil (MMF) is the preferred second-line agent, particularly for azathioprine intolerance rather than refractory disease. 2
• MMF dosing: Start at 1 g daily, maintain at 1.5-2 g daily. 2
• For prednisolone intolerance in non-cirrhotic patients, use budesonide as described above. 4
• For azathioprine intolerance, use prednisolone alone in higher doses (initial dose 60 mg/day based on controlled trials, reducing over 4 weeks to 20 mg/day), though side effects are common. 4
• Alternative: Prednisolone 10-20 mg/day plus mycophenolate. 4

Other Salvage Options

• Calcineurin inhibitors (tacrolimus, cyclosporine), sirolimus, and rituximab have rescued refractory patients but experiences are limited. 5, 6, 7

Acute Severe Autoimmune Hepatitis

Emergency Management

• Acute severe AIH or fulminant hepatic failure requires high-dose intravenous corticosteroids as early as possible. 1
• Contact a liver transplant center immediately for patients with liver failure, bridging necrosis on biopsy, or jaundiced patients whose MELD score does not rapidly improve on treatment. 4, 1
• Liver transplantation is the treatment of choice for managing decompensated disease. 5, 6

Relapse Management

Relapse Rates and Risk Factors

• 50-90% of patients relapse within 12 months of stopping treatment following biochemical and histological remission. 4, 3
• Risk factors for relapse include: raised serum ALT or AST at withdrawal, raised serum globulin/IgG, liver biopsy with any inflammation or portal tract plasma cells. 4

Treatment After Relapse

• After relapse, re-treat with combination prednisone and azathioprine therapy. 3
• For patients who have relapsed more than once, consider long-term maintenance with azathioprine 2 mg/kg/day or low-dose prednisone. 3
• 87% of adult patients remain in remission during long-term maintenance therapy (median observation 67 months). 3

Special Populations

Pregnancy

• Azathioprine requires risk-benefit analysis but may be continued if disease control requires it. 1, 2
• MMF is absolutely contraindicated in pregnancy. 1, 2

Children

• Children with AIH require treatment indications similar to adults. 1
• Use high-dose prednisone for up to 2 weeks, then gradual decrease to maintenance. 1
• 80-90% achieve laboratory remission in 6-12 months. 1

Type 2 AIH

• Type 2 AIH primarily occurs in children under 14 years or young adults, with acute onset in 31-40% of cases and up to 25% presenting as acute liver failure. 2
• Despite these differences, the same first-line treatment regimen applies to both type 1 and type 2 AIH. 2

AIH-PBC Overlap Syndrome

• Requires combined therapy with ursodeoxycholic acid (UDCA) plus immunosuppressants. 1
• UDCA dosing: 13-15 mg/kg/day. 1

Critical Pitfalls to Avoid

• Do NOT stop treatment too early: 50-90% of patients relapse within 12 months if treatment is discontinued prematurely. 2
• Do NOT accept partial biochemical response: persistent ALT elevation predicts poor outcomes including progressive fibrosis and liver-related death. 4, 2
• Do NOT treat patients with serious pre-existing comorbid conditions (vertebral compression, psychosis, brittle diabetes, uncontrolled hypertension) or previous prednisone intolerance unless disease is severe and progressive. 1
• Do NOT use budesonide in cirrhotic patients. 4
• Severe corticosteroid complications (osteoporosis, vertebral compression, diabetes, cataracts, hypertension, psychosis) typically develop after 18 months of therapy at prednisone doses >10 mg daily. 3

Lifelong Monitoring

• Lifelong clinical and biochemical monitoring is mandatory, whether actively treated or not. 4
• Patients should be under the supervision of a hepatologist or gastroenterologist with an interest in liver disease, ideally monitored in a designated liver clinic. 4