What is the recommended diagnostic and treatment approach for a patient suspected of having autoimmune hepatitis, including the composition of a comprehensive autoimmune hepatitis panel and initial treatment regimen?

Autoimmune Hepatitis Panel Composition and Diagnostic Approach

The comprehensive autoimmune hepatitis panel should include first-line tests (ANA, SMA, serum IgG), followed by second-line antibodies (anti-LKM1, anti-LC1, anti-SLA, atypical pANCA) if initial tests are negative but clinical suspicion remains high. 1

Initial Serological Battery (First-Line Tests)

The diagnostic workup begins with these mandatory tests:

• Antinuclear antibodies (ANA) - Present in 75-95% of AIH type 1 patients; test at ≥1:40 dilution in adults (≥1:80 for definite diagnosis) 1, 2
• Smooth muscle antibodies (SMA) - Found in ~75% of AIH type 1; particularly significant when combined with ANA at high titers 1, 2
• Serum IgG or gamma-globulin levels - Elevated (>1.5× upper limit of normal) in approximately 85% of AIH patients; a central diagnostic element 1, 3

These three tests should be performed simultaneously as the initial screen. 2

Second-Line Autoantibodies (When First-Line Tests Are Negative)

If ANA and SMA are negative but AIH is still suspected, proceed with:

• Anti-liver/kidney microsome type 1 (anti-LKM1) - Defines AIH type 2; present in 70% of type 2 cases; commonly detected when ANA/SMA are absent 1
• Anti-liver cytosol type 1 (anti-LC1) - Found in 30% of AIH type 2 patients 1
• Anti-soluble liver antigen (anti-SLA) - Highly specific for AIH (20-30% of cases); can be the only marker present; associated with more severe disease 1
• Atypical perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) - Detected in 20-96% of AIH type 1; useful when conventional antibodies are negative 1

Critical technical note: Anti-LKM1 requires indirect immunofluorescence on rodent kidney, liver, and stomach sections to avoid confusion with anti-mitochondrial antibodies (AMA). 4, 5

Essential Biochemical Tests

Beyond autoantibodies, the panel must include:

• AST and ALT - Typically elevated 5-20× upper limit of normal; may exceed 400 IU/mL in acute presentations 3
• Alkaline phosphatase (ALP) - Calculate ALP/AST ratio: <1.5 supports AIH, >3 argues against it 3
• Total bilirubin - Markedly elevated in AIH with normal or mildly elevated cholestatic enzymes 1
• Albumin and total protein - To calculate albumin/globulin ratio and assess synthetic function 3

Mandatory Exclusion Tests

Before diagnosing AIH, these must be negative:

• Viral hepatitis markers - HBsAg, anti-HBc, anti-HCV with reflex HCV RNA, HAV IgM, HEV serology 1, 3
• Antimitochondrial antibodies (AMA) - To exclude primary biliary cholangitis, especially if cholestatic pattern present 1
• Ceruloplasmin and 24-hour urinary copper - To exclude Wilson's disease, particularly in patients <40 years 3

A detailed medication history (including over-the-counter drugs and herbals) is essential, as approximately 9% of suspected AIH cases are actually drug-induced liver injury. 3

Diagnostic Scoring Integration

Use the simplified diagnostic scoring system for routine clinical practice: 1, 2

• ANA or SMA ≥1:40 = 1 point; ≥1:80 = 2 points
• Anti-LKM1 ≥1:40 or anti-SLA positive = 2 points
• IgG >upper limit of normal = 1 point; >1.1× upper limit = 2 points
• Liver histology compatible = 1 point; typical = 2 points
• Negative viral markers = 2 points

Score ≥6 = probable AIH; ≥7 = definite AIH 1, 2

For diagnostically challenging cases with atypical features, use the revised original IAIHG scoring system, which assigns additional points for ALP/AST ratio, female gender, and other parameters. 1, 3

Liver Biopsy Requirement

Liver biopsy is essential and should be performed before initiating immunosuppression unless acute liver failure requires immediate treatment. 1, 3, 2

Histological hallmarks include:

• Interface hepatitis (periportal hepatitis) - the defining feature 1, 2
• Plasma cell infiltration in portal tracts - characteristic but not required 1, 3
• Hepatocyte rosettes and emperipolesis - supportive findings 1

Biopsy provides critical information about fibrosis stage (25% have cirrhosis at diagnosis) and helps exclude competing diagnoses. 3, 2

Common Diagnostic Pitfalls to Avoid

• Seronegative AIH occurs in 20% of patients - never exclude AIH based solely on negative standard autoantibodies 1, 3, 2
• 29-39% of acute severe AIH presentations have negative or weakly positive ANA - proceed with second-line antibody testing 3
• EBV and other viral infections can cause transient positive ANA - always exclude viral causes before diagnosing AIH 3
• Drug-induced liver injury can mimic AIH completely - common culprits include nitrofurantoin, minocycline, alpha-methyldopa, hydralazine, and immune checkpoint inhibitors 1, 3
• A single low autoantibody titer should never exclude AIH - clinical context and other features are equally important 2

AIH Classification Based on Autoantibody Pattern

• Type 1 AIH: ANA and/or SMA positive; accounts for ~80% of cases; affects all ages with female predominance 1, 4
• Type 2 AIH: Anti-LKM1 and/or anti-LC1 positive; more common in children; ANA/SMA typically negative 1, 4

The proposed type 3 classification has been abandoned, as anti-SLA can be found in both type 1 and type 2 AIH. 1

Special Consideration: APECED Syndrome

In patients with AIH and multiple endocrine disorders (hypoparathyroidism, adrenal insufficiency, mucocutaneous candidiasis), test for AIRE gene mutations to diagnose autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). 1 This is the only AIH syndrome with Mendelian inheritance requiring genetic counseling. 1