What are the diagnostic markers and treatment options for autoimmune hepatitis?

Autoimmune Hepatitis Diagnostic Markers

Primary Serological Markers

The diagnosis of autoimmune hepatitis (AIH) requires testing for antinuclear antibodies (ANA), smooth muscle antibodies (SMA), and anti-liver kidney microsome type 1 (anti-LKM1) as the initial serological battery, combined with elevated serum IgG levels, characteristic liver histology showing interface hepatitis, and exclusion of other liver diseases. 1

Type 1 AIH Markers

• ANA and/or SMA are present in 96% of North American adults with type 1 AIH 1
• ANA detected in 80% of white North American adults at presentation 1
• SMA present in 63% of patients 1
• 49% have ANA, SMA, or anti-LKM1 as isolated findings; 51% have multiple autoantibodies 1
• Diagnostic accuracy improves from 58% to 74% when two autoantibodies are detected concurrently 1

Type 2 AIH Markers

• Anti-LKM1 and/or anti-liver cytosol type 1 (anti-LC1) characterize type 2 AIH 1
• Anti-LKM1 present in 3% of North American adults but more frequent in European patients 1
• Anti-LC1 present in 30% of type 2 AIH cases 1
• These antibodies are commonly detected in the absence of ANA and SMA 1

Additional Diagnostic Markers

Anti-Soluble Liver Antigen (Anti-SLA)

• Anti-SLA has 99% specificity for AIH and should be tested when conventional antibodies are negative 1
• Present in 7-22% of type 1 AIH patients 1
• Can be the sole marker in 14-20% of AIH patients 1
• Associated with more severe disease and higher relapse rates after drug withdrawal 1
• Detectable by ELISA or immunoblot, not by immunofluorescence 2

Atypical Perinuclear Antineutrophil Cytoplasmic Antibodies (pANCA/pANNA)

• Present in 50-92% of type 1 AIH patients 1
• Can be the only serological marker in suspected AIH with negative conventional antibodies 1
• Lacks diagnostic specificity, occurring also in PSC, AIH-PSC overlap, and ulcerative colitis 1

Biochemical Markers

Immunoglobulin G

• Elevated serum IgG or γ-globulin is characteristic but not universal 1
• IgG normal in approximately 10% of European patients and 25-39% of acute presentations in Japanese studies 1
• Levels >2.0 times normal score highest in diagnostic algorithms 1

Aminotransferases and Alkaline Phosphatase

• Elevated AST and ALT are required diagnostic features 1
• Alkaline phosphatase to AST ratio <1.5 supports AIH diagnosis 1, 3
• Ratio >3 argues against AIH 1

Histological Requirements

Liver biopsy is essential for diagnosis and cannot be omitted except in highly typical acute presentations 1

Key Histological Features

• Interface hepatitis is the hallmark finding 1
• Plasma cell infiltration is typical but not required 1
• Portal lymphocytic/lymphoplasmacytic infiltrates extending into lobules 3
• Hepatocyte rosettes may be present 1

Diagnostic Algorithm

Initial Testing Sequence

1. Test ANA and SMA first in adults; assess anti-LKM1 if these are negative 1
2. Test ANA, SMA, and anti-LKM1 simultaneously in all pediatric patients 1
3. Measure serum IgG or γ-globulin levels 1
4. Perform liver biopsy to confirm diagnosis 1

When Conventional Markers Are Negative

• Test for anti-SLA, atypical pANCA, and anti-LC1 1
• Consider tissue transglutaminase antibodies to exclude celiac disease 1
• Consider antimitochondrial antibodies (AMA) to exclude primary biliary cholangitis 1

Diagnostic Scoring Systems

Revised Original IAIHG Score

• Definite diagnosis: pretreatment score >15; probable diagnosis: 10-15 1
• Incorporates female sex, HLA type, ALP:AST ratio, IgG levels, autoantibody titers, AMA status, drug exposure, and alcohol intake 1
• Post-treatment scores: definite >17, probable 12-17 1

Simplified Scoring System

• Applicable when clinical, laboratory, serological, or histological features are atypical or sparse 1, 4
• Includes autoantibodies, IgG levels, liver histology, and absence of viral hepatitis 3

Critical Exclusions Required

Must exclude the following before diagnosing AIH: 1

• Viral hepatitis (hepatitis B, C, E)
• Drug-induced liver injury
• Wilson's disease
• Hereditary hemochromatosis
• Alpha-1 antitrypsin deficiency
• Non-alcoholic fatty liver disease
• Alcoholic liver disease
• Primary biliary cholangitis
• Primary sclerosing cholangitis

Special Considerations

APECED Syndrome

• Test for AIRE gene mutations in patients with AIH plus multiple endocrine disorders 1
• This is the only AIH syndrome with Mendelian inheritance requiring genetic counseling 1
• Associated with antibodies to cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2D6) 1

Testing Methodology

• Indirect immunofluorescence on rodent tissues (liver, kidney, stomach) remains the reference standard 1, 5
• HEp-2 cells used for ANA detection 1
• Initial dilution 1:40 in adults, 1:10 in children 2
• Automated assays may complement but cannot replace immunofluorescence currently 5

Common Pitfalls

• Anti-LKM1 can be confused with AMA if rodent kidney is the sole substrate; use triple tissue substrate 2
• Anti-LKM1 can occur in 5-10% of chronic hepatitis C patients; exclude viral hepatitis first 1
• Normal IgG does not exclude AIH, particularly in acute presentations 1
• Autoantibody titers roughly reflect disease severity but are not established biomarkers for treatment decisions 1