What is the recommended work‑up for suspected autoimmune hepatitis?

Testing for Autoimmune Hepatitis

The diagnostic work-up for suspected autoimmune hepatitis requires a systematic approach combining specific autoantibody testing, immunoglobulin G measurement, liver function tests, exclusion of alternative diagnoses, and mandatory liver biopsy for definitive diagnosis. 1

Initial Laboratory Assessment

Liver Function Tests:

• Measure serum AST, ALT, alkaline phosphatase (ALP), and total bilirubin to identify the characteristic hepatitic pattern with markedly elevated aminotransferases (ranging from just above normal to >50 times the upper limit of normal) and normal or only mildly elevated cholestatic enzymes 1
• Calculate the ALP/AST (or ALT) ratio, as a ratio <1.5 favors AIH diagnosis and contributes to diagnostic scoring 2, 3

Immunoglobulin Assessment:

• Measure serum IgG or gamma-globulin levels, which are elevated (>1.5 times upper normal limit) in approximately 85% of AIH patients 1
• Note that IgG may be normal in 10-25% of cases, particularly in acute presentations, so normal IgG does not exclude AIH 1, 4

Autoantibody Testing Protocol

First-Line Screening (Type 1 AIH):

• Test for antinuclear antibody (ANA) and smooth muscle antibody (SMA) using indirect immunofluorescence on rodent tissue sections, with significant titers being ≥1:40 in adults and ≥1:20 in children 1, 4
• ANA typically shows a homogeneous pattern in 2/3 of cases 1, 5
• SMA with vascular/glomerular/tubular (VGT) pattern is most specific for AIH 5

Second-Line Testing (Type 2 AIH):

• Test for anti-liver kidney microsomal type 1 (anti-LKM1) and anti-liver cytosol type 1 (anti-LC1) antibodies, which characterize Type 2 AIH and are found in 5-10% of adult patients 1
• Significant titers for anti-LKM1 in children are ≥1:10 4

Additional Autoantibodies:

• Test for anti-soluble liver antigen (anti-SLA) using ELISA or immunoblot (not detectable by immunofluorescence), as this is the only antibody specific for AIH and is associated with more severe disease 1, 4, 5
• Consider testing for atypical perinuclear anti-neutrophil cytoplasmic antibodies (pANCA), especially when other autoantibodies are negative, but rule out sclerosing cholangitis and inflammatory bowel disease if positive 1, 2, 5

Exclusion of Alternative Diagnoses

Viral Hepatitis:

• Test for hepatitis A, B, C, D, and E markers to exclude viral causes, as negative viral markers are essential for diagnosis and add points to diagnostic scoring 1

Drug-Induced Liver Injury:

• Obtain detailed medication history including recent use of nitrofurantoin, minocycline, alpha-methyldopa, hydralazine, and herbal/dietary supplements, as drug-induced hepatitis can mimic AIH with positive autoantibodies 1, 3
• Note that latency periods vary from 1-8 weeks to 3-12 months after drug exposure 3

Other Liver Diseases:

• Assess alcohol intake (consumption <25 g/day supports AIH diagnosis) 1, 3
• Test for antimitochondrial antibody (AMA) if cholestatic pattern is present (ALP/AST ratio >1.5) to exclude primary biliary cholangitis overlap 2, 3
• Perform hepatobiliary imaging (ultrasound and/or cross-sectional imaging) to rule out biliary obstruction, cholecystitis, and hepatic vein thrombosis 1
• Consider testing for Wilson's disease (ceruloplasmin), hereditary hemochromatosis (iron studies), and alpha-1 antitrypsin deficiency in appropriate clinical contexts 1

Liver Biopsy - Mandatory for Diagnosis

Liver biopsy is essential and cannot be omitted, as AIH cannot be definitively diagnosed without compatible histological findings. 1, 4

Key Histological Features:

• Interface hepatitis (moderate to severe) with lymphoplasmacytic infiltrates extending from portal tracts into hepatic lobules 1
• Clusters of plasma cells, which are characteristic but not pathognomonic 1
• Hepatocyte rosetting (emperipolesis) 1, 2
• Absence of biliary lesions, granulomas, or prominent changes suggesting alternative diagnoses 1

Timing:

• Perform liver biopsy before initiating treatment to confirm diagnosis, assess disease severity and stage (including presence of cirrhosis), and exclude other entities 1, 4, 6

Diagnostic Scoring Systems

Simplified Diagnostic 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 1, 2, 4
• IgG: >upper limit of normal = 1 point; >1.1× upper limit of normal = 2 points 1, 2, 4
• Liver histology: compatible = 1 point; typical = 2 points 1, 2, 4
• Absence of viral hepatitis = 2 points 2, 4
• Interpretation: ≥6 points = probable AIH; ≥7 points = definite AIH 1, 2, 4

Revised Original Diagnostic Scoring System (More Comprehensive):

• Includes additional parameters: gender, ALP/AST ratio, drug history, alcohol intake, HLA typing, and treatment response 2
• Pre-treatment score >15 = definite AIH; 10-15 = probable AIH 2

Special Considerations for Children

• All children diagnosed with AIH should undergo magnetic resonance cholangiopancreatography (MRCP) to exclude autoimmune sclerosing cholangitis, as approximately 50% of children have cirrhosis at presentation 1
• Lower autoantibody titers (≥1:20 for ANA/SMA, ≥1:10 for anti-LKM1) are clinically significant in children 4

Common Diagnostic Pitfalls to Avoid

• Do not diagnose AIH based on autoantibodies alone, as seronegative AIH exists in up to 5% of cases, and autoantibodies can be present in other liver diseases 4, 3
• Do not assume normal IgG excludes AIH, as 10-39% of patients (especially those with acute presentations) may have normal IgG levels 1, 4
• Do not skip liver biopsy, even if laboratory features appear typical, as histology is mandatory for definitive diagnosis and to exclude alternative diagnoses 1, 4
• Do not overlook drug-induced liver injury, which can present identically to AIH with positive autoantibodies and elevated IgG 1, 3
• Do not miss overlap syndromes: if cholestatic features develop, perform cholangiography to exclude AIH-PSC overlap 3

Monitoring After Diagnosis

• Biochemical remission is defined as normalization of both transaminases and IgG levels 4
• Combined ALT and IgG measurements provide the best non-invasive monitoring of disease activity 4
• Patients with cirrhosis require liver ultrasound every six months for hepatocellular carcinoma screening 1