How is autoimmune hepatitis diagnosed in a young to middle‑aged woman with fatigue, anorexia, right‑upper‑quadrant discomfort, jaundice, pruritus, or asymptomatic elevated aminotransferases?

Diagnosis of Autoimmune Hepatitis

Autoimmune hepatitis is diagnosed by integrating three essential components: (1) exclusion of competing etiologies, (2) characteristic laboratory findings (elevated aminotransferases and IgG with positive autoantibodies), and (3) compatible liver histology showing interface hepatitis with plasma cell infiltration. 1

Initial Diagnostic Workup

Mandatory Exclusions

Before diagnosing AIH, you must systematically exclude:

• Viral hepatitis: Test HBsAg, anti-HBc, anti-HCV with reflex HCV RNA, HAV IgM, and HEV serology 1, 2
• Drug-induced liver injury: Obtain detailed medication history including over-the-counter drugs, herbals, and supplements—particularly nitrofurantoin, minocycline, alpha-methyldopa, hydralazine, and immune checkpoint inhibitors (DILI mimics AIH in 9% of cases) 1, 2
• Wilson disease: Check ceruloplasmin and 24-hour urinary copper, especially in patients under age 40 1, 2
• Metabolic liver disease: Assess for alpha-1-antitrypsin deficiency (phenotype), hemochromatosis (iron studies), and non-alcoholic fatty liver disease 1
• Alcohol: Document consumption <25 g/day for definite AIH, <50 g/day for probable AIH 1

Core Laboratory Assessment

Biochemical pattern 1, 2:

• AST/ALT typically elevated 5-20× upper limit of normal (may exceed 400 IU/mL in acute presentations)
• Predominantly hepatocellular pattern with normal or mildly elevated alkaline phosphatase
• Key ratio: ALP/AST ratio <1.5 supports AIH; ratio >3 argues against it and suggests cholestatic disease

Immunologic markers 1, 2:

• IgG or gamma-globulin >1.5× upper limit of normal in ~85% of patients (definite AIH)
• Any elevation above normal supports probable AIH
• Selective IgG elevation (without IgA/IgM increase) is particularly suggestive

Autoantibody Testing

First-line screening 1, 3, 2:

• Antinuclear antibody (ANA) and smooth muscle antibody (SMA) by indirect immunofluorescence
• Use rodent substrate (kidney, liver, stomach) at initial dilution 1:40 in adults, 1:10 in children
• Diagnostic titers: ≥1:80 for definite AIH, ≥1:40 for probable AIH in adults 1

Type classification 3, 4:

• Type 1 AIH (75% of cases): ANA and/or SMA positive
• Type 2 AIH: Anti-LKM1 and/or anti-LC1 positive

Additional testing if ANA/SMA negative 1, 2:

• Anti-soluble liver antigen (anti-SLA): disease-specific, present in 20-30% of AIH patients
• Perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA)
• Important: 20% of AIH patients are seronegative for standard autoantibodies 1, 2

Liver Biopsy—Mandatory for Diagnosis

Histological hallmarks 1, 5, 6:

• Interface hepatitis (moderate to severe periportal inflammation)
• Plasma cell-predominant portal infiltrate
• Hepatocyte rosette formation
• Emperipolesis (lymphocyte penetration into hepatocytes)
• Absence of bile duct injury, granulomas, or features suggesting alternative diagnosis

Timing 2:

• Perform pre-treatment biopsy before initiating immunosuppression
• Exception: acute liver failure requiring immediate treatment

Prognostic information 1:

• Assess fibrosis stage (25-33% have cirrhosis at presentation)
• Patients with cirrhosis require HCC surveillance with ultrasound every 6 months

Diagnostic Scoring Systems

Simplified IAIHG Criteria (Preferred for Clinical Use) 1, 7

Parameter	Points
ANA or SMA ≥1:40	+1
ANA or SMA ≥1:80	+2
Anti-LKM ≥1:40	+2
Anti-SLA positive	+2
IgG >1.0× ULN or gamma-globulin >1.0× ULN	+1
IgG >1.1× ULN or gamma-globulin >1.1× ULN	+2
Liver histology: compatible	+1
Liver histology: typical	+2
Absence of viral hepatitis	+2

Interpretation 1, 7:

• ≥7 points = definite AIH
• ≥6 points = probable AIH

Revised Original IAIHG Score (For Complex Cases) 1, 8

Pre-treatment score 1:

• ≥15 points = definite AIH (sensitivity 95%, specificity 97%)
• 10-14 points = probable AIH (sensitivity 100%, specificity 73%)

Post-treatment score 1:

• ≥17 points = definite AIH
• 12-16 points = probable AIH

Special Diagnostic Challenges

Acute Presentation

• 25-39% may have normal or weakly positive autoantibodies 2
• IgG may be normal in acute-onset disease 1
• Histology may show centrilobular necrosis without chronic changes 1, 5
• Consider therapeutic trial: prednisone 60 mg/day with rapid taper—response with relapse upon withdrawal confirms AIH 8

Seronegative AIH

• Occurs in 20% of patients 1, 2
• Test anti-SLA and p-ANCA if ANA/SMA/anti-LKM1 negative
• Diagnosis relies heavily on histology and exclusion of alternatives
• Consider therapeutic trial if clinical suspicion remains high

Overlap Syndromes

If cholestatic pattern present (elevated ALP) 1:

• Test anti-mitochondrial antibody (AMA) for AIH-PBC overlap
• Perform MRCP or ERCP to exclude AIH-PSC overlap
• Pediatric consideration: 50% of children with AIH have autoimmune sclerosing cholangitis—all children require cholangiography 1, 3

Common Diagnostic Pitfalls

1. EBV infection mimics AIH: Can cause elevated transaminases, positive ANA, fever, rash, fatigue—but resolves spontaneously without immunosuppression 2

2. Drug-induced liver injury: Patients may have taken causative drugs for months to years before presentation; latency period varies 1 week to 12 months 1

3. Assuming remission based on symptoms: 34-45% of AIH patients are asymptomatic despite active disease 2

4. Confusing anti-LKM1 with AMA: Use rodent kidney substrate to distinguish these patterns 4

5. Treating without biopsy: Histology is essential—treating viral hepatitis or alcoholic liver disease with corticosteroids worsens outcomes 2