Approach to Autoimmune Hepatitis

Diagnosis and Initial Assessment

Autoimmune hepatitis (AIH) requires a systematic diagnostic approach combining clinical, serological, and histological criteria before initiating treatment. 1

Essential Diagnostic Workup

Obtain comprehensive history focusing on medication exposure, alcohol intake (<25 g/day supports diagnosis), viral hepatitis exposure, and family history of autoimmune diseases 1
Perform complete "non-invasive" liver screen to exclude viral hepatitis (HBV, HCV) and metabolic liver diseases 1
Measure serum autoantibodies including ANA, SMA, or LKM-1 (titers >1:80 strongly support diagnosis) and quantify IgG and globulin levels (>2-fold elevation is highly suggestive) 1
Liver biopsy is essential for diagnosis and provides critical prognostic information; it should be performed unless active contraindications exist 1
Apply the revised IAIHG scoring system when diagnosis is uncertain (definite AIH: pre-treatment score >15; probable AIH: 10-15) 1

Key Histological Features to Identify

Interface hepatitis (scores +3 points) 1
Predominantly lymphoplasmacytic infiltrate (+1 point) 1
Rosetting of liver cells (+1 point) 1
Bridging necrosis or multilobular necrosis (indicates severe disease requiring treatment) 1

Treatment Indications

Absolute Indications for Immediate Treatment

Patients with severe disease manifestations require immediate immunosuppressive therapy based on mortality data showing 60% death at 6 months if untreated. 1

Serum AST/ALT >10-fold upper limit of normal (ULN) 1
Serum AST/ALT ≥5-fold ULN with serum globulin ≥2-fold ULN 1
Histological findings of bridging necrosis or multilobular necrosis (82% progress to cirrhosis if untreated) 1
Incapacitating symptoms (fatigue, arthralgia) regardless of laboratory severity 1

Patients Who Should NOT Be Treated

Inactive cirrhosis without biochemical activity (excellent immediate survival without treatment) 1
Minimal or no disease activity on biopsy 1
Serious comorbidities including vertebral compression, psychosis, brittle diabetes, or uncontrolled hypertension unless disease is severe and progressive 1
Severe pretreatment cytopenia (WBC <2.5×10⁹/L or platelets <50×10⁹/L) precludes azathioprine 1

Uncertain Indications (Favor Treatment in Most Cases)

Asymptomatic patients with mild disease should generally receive treatment, especially if young, as untreated patients have lower 10-year survival (67% vs 98%, P<0.01) despite only 12% spontaneous improvement rate 1
Patients with established cirrhosis on biopsy should be treated due to adverse prognosis 1

First-Line Treatment Regimen

The standard first-line treatment is prednisolone plus azathioprine, achieving remission in 80-90% of patients with significantly improved survival. 2, 3

Standard Dosing Protocol

Prednisolone 30 mg/day initially, reducing to 10 mg/day over 4 weeks 1, 2
Azathioprine 1 mg/kg/day (start at 50 mg/day, increase to maintenance 1-2 mg/kg/day) 2, 3
Delay azathioprine initiation by 2 weeks after starting steroids when bilirubin >6 mg/dL to avoid diagnostic confusion with azathioprine hepatotoxicity 2, 3
Higher initial prednisolone doses (up to 1 mg/kg/day) may be used for more rapid transaminase normalization, but use caution in elderly patients 1, 2

Critical Pre-Treatment Safety Measure

Check TPMT (thiopurine methyltransferase) levels before starting azathioprine to exclude homozygote deficiency, especially if pre-existing leucopenia exists 1, 4

Alternative First-Line Option: Budesonide

Budesonide 3 mg three times daily plus azathioprine is an alternative for non-cirrhotic patients at high risk for steroid side effects, achieving better normalization with fewer side effects at 6 months 3, 5
Never use budesonide in cirrhotic patients due to impaired first-pass metabolism causing systemic side effects 2, 4

Treatment Goals and Monitoring

The therapeutic endpoint is complete normalization of serum AST, ALT, and IgG levels—not just improvement, but complete normalization. 1, 2, 3

Why Complete Normalization Matters

Persistent elevation of liver enzymes predicts relapse after treatment withdrawal, ongoing histological activity, progression to cirrhosis, and poor outcomes 2, 3
Patients with normalized labs before drug withdrawal have 3-11 fold lower relapse risk compared to those who don't achieve this endpoint 1
Interface hepatitis persists in 55% of patients with normal serum AST and globulin during therapy, and these patients typically relapse after cessation 1

Timeline for Response

Clinical and laboratory improvement occurs within 2-4 weeks in most patients 1, 3
Biochemical remission is typically achieved within 6-12 months 1, 3
Histological resolution lags behind biochemical improvement by 3-8 months 1
Average treatment duration is 18-24 months before considering withdrawal 1

Monitoring Strategy

Maintain fixed daily maintenance doses until treatment goal achieved; dose titrations delay histological improvement 1
Perform liver biopsy before treatment withdrawal to ensure complete histological resolution, as this is the only method to confirm optimal endpoint 1
Consider repeat biopsy after 12-18 months if liver enzymes normalize but remain borderline or if clinical response is suboptimal 1

Management of Incomplete Response or Treatment Failure

Incomplete Response (13% of patients after 36 months)

When patients improve but don't achieve complete remission, escalate therapy rather than accept suboptimal control. 1

Gradually decrease prednisone by 2.5 mg/month to lowest stable dose (10 mg daily) while monitoring AST/ALT 1
Increase azathioprine to 2 mg/kg/day combined with 5-10 mg/day prednisolone 1
Reassess diagnosis and treatment adherence before escalating therapy 2

Second-Line Therapies

Mycophenolate mofetil (MMF) is the preferred second-line agent, particularly for azathioprine intolerance rather than refractory disease. 3

MMF dosing: 1 g daily initially, increasing to maintenance of 1.5-2 g daily 3, 4
MMF efficacy: 58% in azathioprine-intolerant patients vs only 23% in refractory disease 3
MMF is absolutely contraindicated in pregnancy (Category D) due to severe cranial, facial, and cardiac abnormalities 3, 4

Tacrolimus is more effective for truly refractory disease not responding to standard therapy. 3, 4

Tacrolimus starting dose: 0.075 mg/kg daily 4
Consider tacrolimus or cyclosporin when azathioprine escalation fails, but seek expert advice 1

Drug Toxicity (13% of patients)

Continue the tolerated agent (prednisone or azathioprine) in adjusted dose to prevent disease worsening 1
Azathioprine hepatotoxicity is dose-dependent and associated with high 6-methylmercaptopurine metabolite levels; more common in advanced liver disease 1, 4

Maintenance and Withdrawal Strategy

Achieving Maintenance Phase

Once remission achieved, reduce prednisolone to 7.5 mg/day when aminotransferases normalize 3
After 3 months at 7.5 mg/day, taper to 5 mg/day 3
Maintain azathioprine at 1-2 mg/kg as steroid-sparing agent 3
Continue treatment for at least 2 years before considering withdrawal 4

Withdrawal Criteria

Complete biochemical normalization for at least 12 months 1
Histological remission confirmed on liver biopsy (Ishak necroinflammatory grade ≤3 optimal) 1
Absence of portal tract plasma cells associated with lower relapse risk 1

Expected Relapse Rate

60% of patients relapse after drug withdrawal despite disappearance of inflammatory features 1
Relapse is almost universal if complete normalization of liver enzymes and IgG not achieved before withdrawal 4

Special Clinical Situations

Acute Severe AIH or Fulminant Hepatic Failure

Treat acute severe AIH with high-dose intravenous corticosteroids (≥1 mg/kg) as early as possible. 2, 3

Contact liver transplant center immediately for patients with liver failure, bridging necrosis, or jaundice with MELD score not rapidly improving 1
Transplant referral strongly recommended for fulminant hepatic failure presentation 1
Consider transplant evaluation when MELD score >15 or Child-Pugh score >10 1

AIH-PBC Overlap Syndrome

Combined therapy with ursodeoxycholic acid (UDCA) plus immunosuppressants is required for overlap syndromes. 1, 3

UDCA dosing: 13-15 mg/kg/day plus standard immunosuppression 3
Suspect overlap when serum alkaline phosphatase is elevated and doesn't normalize rapidly with immunosuppression 1
Expect transaminase improvement but not alkaline phosphatase with treatment; Mayo risk score remains stable 1

Pregnancy Considerations

Azathioprine requires risk-benefit analysis but may be continued if disease control requires it 3
MMF is absolutely contraindicated in pregnancy 3, 4

Children

Treatment indications similar to adults but disease typically more severe at presentation with >50% having cirrhosis at diagnosis 1
High-dose prednisone (1-2 mg/kg daily) for up to 2 weeks, then gradual decrease to maintenance (0.1-0.2 mg/kg daily or 5 mg daily) over 6-8 weeks 1
80-90% achieve laboratory remission in 6-12 months 1

Critical Pitfalls to Avoid

Never accept biochemical endpoint of <2× ULN as treatment goal; relapse is universal with this approach 1
Never use budesonide in cirrhotic patients due to systemic side effects from impaired metabolism 2, 4
Never start azathioprine with severe cytopenia (WBC <2.5×10⁹/L or platelets <50×10⁹/L) 1
Never withdraw treatment without liver biopsy confirmation of histological remission 1
Never ignore non-adherence as a major cause of relapse, particularly in adolescents and young adults 3
Never delay transplant referral in patients with decompensation (ascites, encephalopathy, hepatorenal syndrome, variceal bleeding) 1

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