What is the appropriate initial laboratory and imaging work‑up for a suspected case of autoimmune hepatitis?

Autoimmune Hepatitis Diagnostic Workup

The initial workup for suspected autoimmune hepatitis requires a comprehensive liver panel (AST, ALT, alkaline phosphatase, bilirubin, albumin), serum IgG level, a complete autoantibody panel (ANA, SMA, anti-LKM1, anti-SLA/LP), viral hepatitis serologies (HAV, HBV, HCV), and a liver biopsy—which is mandatory for definitive diagnosis. 1, 2

Initial Laboratory Testing

Liver Function Tests

• Measure serum aminotransferases (AST and ALT), which are typically elevated from just above normal to more than 50-fold the upper limit of normal 2, 3
• Calculate the alkaline phosphatase to AST (or ALT) ratio, which should be <1.5 in autoimmune hepatitis; ratios ≥1.5 suggest cholestatic disease and should prompt evaluation for overlap syndromes 2, 3
• Check serum bilirubin and albumin to assess synthetic function and disease severity 3

Immunoglobulin Assessment

• Measure serum IgG (or gamma-globulin) levels, which are elevated >1.5 times the upper limit of normal in approximately 85% of patients with autoimmune hepatitis 2, 3
• Do not exclude autoimmune hepatitis if IgG is normal—10-39% of patients, particularly those with acute presentations, have normal IgG levels 2

Autoantibody Panel (Mandatory)

• Screen for antinuclear antibodies (ANA) and smooth muscle antibodies (SMA) by indirect immunofluorescence on rodent tissue sections; titers ≥1:40 in adults (≥1:20 in children) are significant 1, 2
• Test for anti-liver kidney microsomal type 1 (anti-LKM1) to identify Type 2 autoimmune hepatitis, which accounts for 5-10% of adult cases 2, 3
• Measure anti-soluble liver antigen (anti-SLA/LP) by ELISA or immunoblot, as this is the only truly specific antibody for autoimmune hepatitis and indicates more severe disease 2
• Consider atypical perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) when conventional autoantibodies are negative, but exclude primary sclerosing cholangitis and inflammatory bowel disease if positive 2

Exclusion of Alternative Diagnoses

Viral Hepatitis Serologies (Mandatory)

• Test for hepatitis A, B, C, D, and E viruses—negative viral markers are required for diagnosis and contribute points to diagnostic scoring 1, 2

Drug-Induced Liver Injury

• Obtain a detailed medication history including nitrofurantoin, minocycline, α-methyldopa, hydralazine, isoniazid, propylthiouracil, and herbal/dietary supplements, as drug-induced hepatitis can mimic autoimmune hepatitis with positive autoantibodies 1, 2

Hereditary Liver Diseases

• Measure serum ceruloplasmin to exclude Wilson disease, particularly in patients under age 40 1
• Check alpha-1 antitrypsin phenotype to rule out alpha-1 antitrypsin deficiency 1
• Assess serum iron, ferritin, and transferrin saturation to exclude hereditary hemochromatosis 1

Alcohol History

• Document daily alcohol consumption—intake <25 g/day supports the diagnosis of autoimmune hepatitis 1, 2

Imaging Studies

• Perform hepatobiliary ultrasound to exclude biliary obstruction, cholecystitis, hepatic vein thrombosis, and assess for cirrhosis 2
• Consider magnetic resonance cholangiopancreatography (MRCP) if the alkaline phosphatase to AST ratio is ≥1.5 or if there are histologic features suggesting overlap with primary sclerosing cholangitis 4
• In acute severe presentations, unenhanced CT of the liver may show heterogeneous hypoattenuated areas in 65% of cases, helping distinguish autoimmune hepatitis from other causes of acute liver failure 1

Liver Biopsy (Mandatory)

Liver biopsy is essential and cannot be omitted—it confirms the diagnosis, assesses disease severity and stage (including cirrhosis), and excludes alternative diagnoses 1, 2

Timing

• Perform biopsy before initiating immunosuppressive therapy unless the patient has acute liver failure requiring immediate treatment 1, 2

Key Histologic Features to Identify

• Interface hepatitis (lymphoplasmacytic infiltrates extending from portal tracts into hepatic lobules) is the histologic hallmark 1, 2
• Portal plasma cell infiltration is characteristic but neither pathognomonic nor required for diagnosis 1
• Hepatocyte rosetting (emperipolesis) supports the diagnosis 2, 4
• Absence of biliary lesions, granulomas, or steatosis helps exclude overlap syndromes, primary biliary cholangitis, sarcoidosis, and nonalcoholic fatty liver disease 1

Histologic Findings That Suggest Alternative Diagnoses

• Ductopenia or destructive cholangitis indicates overlap with primary sclerosing cholangitis or primary biliary cholangitis 1
• Steatosis or iron overload suggests nonalcoholic fatty liver disease, Wilson disease, or hemochromatosis 1
• Centrilobular hemorrhagic necrosis is typical of acute severe (fulminant) autoimmune hepatitis 1

Diagnostic Scoring

Simplified Scoring System (Recommended for Clinical Practice)

• Autoantibodies: ANA or SMA ≥1:40 = 1 point; ≥1:80 = 2 points; anti-LKM1 ≥1:40 = 2 points; anti-SLA positive = 2 points 2, 4
• IgG: >upper limit of normal = 1 point; >1.1 × upper limit of normal = 2 points 2, 4
• Histology: compatible = 1 point; typical = 2 points 2, 4
• Viral hepatitis exclusion: 2 points 2, 4
• Interpretation: ≥6 points = probable autoimmune hepatitis; ≥7 points = definite autoimmune hepatitis 2, 4

Common Pitfalls to Avoid

• Do not rely solely on autoantibody positivity—up to 5% of autoimmune hepatitis patients are seronegative 2
• Do not exclude autoimmune hepatitis based on normal IgG—25-39% of patients with acute presentations have normal IgG levels 1, 2
• Do not skip liver biopsy—serum aminotransferase and gamma-globulin levels do not predict histologic severity or the presence of cirrhosis 1
• Do not overlook drug-induced hepatitis—many medications can trigger autoimmune-like features with positive autoantibodies and elevated IgG 1, 2
• In acute severe presentations, do not delay biopsy if feasible—centrilobular hemorrhagic necrosis with lymphoplasmacytic infiltration distinguishes autoimmune hepatitis from viral or toxic acute liver failure 1

Post-Diagnosis Surveillance

• In patients with established cirrhosis, perform liver ultrasound every 6 months for hepatocellular carcinoma surveillance 1, 2