What is the diagnosis and treatment for autoimmune hepatitis?

Diagnosis of Autoimmune Hepatitis

The diagnosis of autoimmune hepatitis requires a combination of elevated serum aminotransferases with hypergammaglobulinemia (IgG >1.5 times upper normal limit), positive autoantibodies (ANA, SMA, or anti-LKM1 at titers ≥1:80 in adults), and interface hepatitis on liver biopsy, after excluding viral hepatitis, Wilson disease, drug-induced liver injury, and other chronic liver diseases. 1, 2, 3

Essential Diagnostic Components

Clinical and Laboratory Assessment

Initial laboratory evaluation must include:

• Serum aminotransferases (ALT/AST), alkaline phosphatase, albumin, total or γ-globulin, IgG, and bilirubin 1
• The ALP:AST ratio is typically <1.5 in AIH, distinguishing it from cholestatic diseases 2, 3
• Hypergammaglobulinemia or elevated IgG (≥1.5 times upper normal limit for definite diagnosis; any elevation for probable diagnosis) 1
• Female sex is supportive (gender ratio 3.6:1) 1, 2

Autoantibody Testing

The conventional serological repertoire includes: 1

• Type 1 AIH: ANA and/or SMA positive (96% of North American adults) 1, 2
• Type 2 AIH: Anti-LKM1 and/or anti-LC1 positive (4% of patients) 1, 2
• Significant titers: ≥1:80 in adults for definite diagnosis; ≥1:40 for probable diagnosis 1
• In children, titers of 1:20 for ANA/SMA and 1:10 for anti-LKM1 are clinically relevant 1

Additional autoantibodies for seronegative cases:

• Anti-SLA/LP (high specificity for AIH) 2, 4
• Atypical pANCA, anti-actin 1
• These support probable diagnosis when conventional markers are absent 1

Histological Examination

Liver biopsy is essential for diagnosis and must be performed before treatment initiation (except in acute severe presentations where treatment should not be delayed). 1, 2

Characteristic histological features include: 1

• Interface hepatitis (disruption of limiting plate by lymphoplasmacytic infiltrate) - the histological hallmark 1
• Portal plasma cell infiltration (typical but not required for diagnosis) 1
• Moderate to severe portal inflammation with lobular extension 1, 5
• Periportal hepatocyte rosette formation 6, 5
• Absence of biliary lesions, well-defined granulomas, or prominent steatosis 1

Note: In acute presentations, centrilobular (zone 3) necrosis may be the initial pattern, which can transition to interface hepatitis over time. 1

Diagnostic Scoring Systems

Simplified Scoring System (Preferred for Clinical Use)

This system has ~90% sensitivity and specificity and includes: 2, 7

• Autoantibodies (ANA or SMA ≥1:40, or anti-LKM1 ≥1:40, or anti-SLA positive)
• IgG or γ-globulin levels
• Liver histology (interface hepatitis with lymphocytic/lymphoplasmacytic infiltrates)
• Absence of viral hepatitis

Revised Original Scoring System (For Atypical Cases)

Use this comprehensive system when diagnosis is challenging: 1

• Pretreatment score ≥15: Definite AIH (sensitivity 95%, specificity 97%, diagnostic accuracy 94%) 1
• Pretreatment score 10-14: Probable AIH (sensitivity 100%, specificity 73%) 1
• Posttreatment score ≥12: Probable AIH 1

This system incorporates gender, ALP:AST ratio, serum globulin/IgG levels, autoantibodies, viral markers, drug/alcohol history, histology, concurrent immune diseases, and treatment response. 1, 2

Mandatory Exclusions

Before confirming AIH, you must exclude: 1

• Viral hepatitis: Seronegativity for hepatitis A, B, and C required 1
• Wilson disease: Normal ceruloplasmin, serum copper (especially in patients <40 years) 1
• Alpha-1 antitrypsin deficiency: Normal phenotype 1
• Drug-induced liver injury: No recent use of minocycline, nitrofurantoin, isoniazid, propylthiouracil, methyldopa 1
• Alcohol: Consumption <25 g/day for definite diagnosis 1
• Other autoimmune liver diseases: Primary biliary cholangitis, primary sclerosing cholangitis (check for ductopenia, destructive cholangitis on biopsy) 1, 2
• Nonalcoholic steatohepatitis and hereditary hemochromatosis 1

Special Diagnostic Scenarios

Seronegative AIH

• Occurs in 4% of cases 1
• Test for non-standard autoantibodies (anti-SLA/LP, atypical pANCA, anti-actin) 1, 2
• Diagnosis relies more heavily on histology and exclusion of other diseases 1

Acute Severe Presentation

• Can present with hepatic encephalopathy within 8 weeks of symptom onset 1
• Do not delay treatment waiting for liver biopsy 1
• Diagnosis may require therapeutic trial: rapid response to corticosteroids with relapse upon tapering confirms AIH 7

Asymptomatic Patients

• AIH can be asymptomatic in 34-45% of patients across all ethnic groups and ages 1
• Serum aminotransferases and γ-globulin levels do not predict histologic severity or presence of cirrhosis 1
• Liver biopsy remains essential even in asymptomatic patients 1

Common Diagnostic Pitfalls

Avoid these errors:

• Assuming normal plasma cells on biopsy excludes AIH (plasma cells are typical but not required) 1
• Relying solely on autoantibody titers (low titers don't exclude AIH; high titers alone don't confirm it) 1
• Missing variant syndromes (AIH-PSC, AIH-PBC overlap) - look for ductopenia or destructive cholangitis on biopsy 1
• Failing to check Wilson disease in younger patients (<40 years) 1
• Accepting cholestatic patterns (elevated ALP with ALP:AST ratio >3.0) as AIH 1, 2

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Treatment of Autoimmune Hepatitis

All patients with moderate to severe AIH require immediate immunosuppressive treatment with combination prednisone (or prednisolone) and azathioprine, as untreated disease carries 40% mortality within 6 months and 82% progress to cirrhosis within 5 years. 1, 2, 3

Treatment Indications

Absolute indications for treatment: 2, 3

• Serum AST ≥10-fold upper normal limit
• Serum AST ≥5-fold upper normal limit with γ-globulin ≥2-fold upper normal limit
• Bridging necrosis or multiacinar necrosis on histology
• Symptomatic patients
• Young patients
• Patients with cirrhosis (to prevent decompensation)

Consider treatment in:

• Asymptomatic patients with mild disease (trial basis to assess symptom improvement) 3

Standard Induction Therapy

Combination regimen (preferred): 1, 2

• Prednisone: Start 30 mg daily for 1 week, then taper by 5-10 mg weekly to maintenance dose of 10 mg daily
• Azathioprine: 50 mg daily initially, increase to 1.5-2 mg/kg daily
• This combination reduces corticosteroid-related side effects

Monotherapy (for specific situations):

• Prednisone alone (60 mg daily, tapered to 20 mg daily maintenance) for patients with:
  • Thiopurine methyltransferase deficiency
  • Cytopenia
  • Pregnancy
  • Malignancy
  • Short-term treatment (<6 months planned)

Treatment Goals and Monitoring

The ideal treatment endpoint is complete resolution: 1

• Normal serum AST, ALT, γ-globulin, and IgG levels
• Normal liver histology on repeat biopsy
• Average treatment duration: 18-24 months 1

Critical monitoring points:

• Normalization of laboratory tests before drug withdrawal reduces relapse risk 3-11 fold 1
• Liver biopsy before treatment termination is recommended - 55% of patients with normal labs still have interface hepatitis and will relapse 1
• Do not accept AST/ALT <2 times upper normal as endpoint; normalization is required 1
• Maintain fixed daily doses in adults; dose titrations delay histological improvement 1

Consider treatment termination only after:

• At least 2 years of treatment 1
• Repeatedly normal liver function tests and immunoglobulin levels 1
• Normal liver histology confirmed by biopsy 1

Relapse occurs in 60% of patients after drug withdrawal, even with complete histological resolution. 1

Treatment Outcomes

Response patterns: 1

• Complete response (remission): 80-90% of patients achieve this with standard therapy 2, 3
• Incomplete response: 13% fail to achieve remission after 36 months - consider long-term low-dose prednisone (10 mg daily) or azathioprine monotherapy (2 mg/kg daily) 1
• Drug toxicity: Occurs in 13% - continue tolerated agent in adjusted dose 1
• Treatment failure: Requires second-line therapies

Pediatric Considerations

Treatment in children follows similar principles with modifications: 1

• High-dose prednisone: 1-2 mg/kg daily for up to 2 weeks
• Gradual taper to maintenance: 0.1-0.2 mg/kg daily or 5 mg daily over 6-8 weeks
• 80-90% achieve laboratory remission in 6-12 months 1
• Clinical and laboratory parameters usually sufficient; biopsy less frequently needed for monitoring 1
• Flares treated with temporary increase in corticosteroid dose 1

Long-term Monitoring

Patients require lifelong surveillance: 2

• Regular liver function tests and IgG levels
• Hepatocellular carcinoma screening in cirrhotic patients
• Esophageal varices surveillance in cirrhotic patients (54% develop varices within 2 years of cirrhosis diagnosis; 20% die from hemorrhage) 1, 2
• Dermatological monitoring for non-melanoma skin cancer in patients on long-term immunosuppression 2
• UV-protective measures counseling 2

Prognosis

With treatment: Near-normal life expectancy when diagnosed early and treated appropriately 8

Without treatment: 1, 2, 3

• 40% mortality within 6 months in severe disease
• 82% progress to cirrhosis within 5 years
• 45% mortality in patients with bridging/multiacinar necrosis
• 54% develop esophageal varices within 2 years of cirrhosis
• 20% die from variceal hemorrhage