What is the diagnostic approach for autoimmune hepatitis?

Diagnostic Approach for Autoimmune Hepatitis

The diagnosis of autoimmune hepatitis requires a systematic combination of serological testing (ANA, SMA, anti-LKM1, and IgG levels), liver biopsy showing interface hepatitis, and rigorous exclusion of competing diagnoses—particularly viral hepatitis, drug-induced liver injury, and Wilson disease. 1, 2, 3

Initial Laboratory Evaluation

Serological Testing Strategy

Begin with ANA and SMA testing in adults; if negative, proceed to anti-LKM1. In pediatric patients, test ANA, SMA, and anti-LKM1 simultaneously. 3

• ANA is present in 80% of North American adults with type 1 AIH 3
• SMA is present in 63% of patients 3
• Diagnostic accuracy improves from 58% to 74% when two autoantibodies are detected concurrently 3
• Anti-LKM1 characterizes type 2 AIH (present in 3% of North American adults but more common in European patients) 3

Additional Autoantibody Testing

Test for anti-SLA when conventional antibodies (ANA, SMA, anti-LKM1) are negative, as it has 99% specificity and can be the sole marker in 14-20% of AIH patients. 3

• Atypical pANCA is present in 50-92% of type 1 AIH and may be the only serological marker when conventional antibodies are negative 3
• Anti-LC1 is present in 30% of type 2 AIH cases 3

Biochemical Parameters

Measure serum IgG or γ-globulin levels, though recognize that IgG can be normal in approximately 10% of European patients and 25-39% of acute presentations. 3

• Predominant aminotransferase elevation is characteristic (bilirubin and aminotransferases range from just above normal to >50 times normal) 2
• Calculate the alkaline phosphatase to AST ratio: a ratio <1.5 supports AIH diagnosis, while >3 argues against it 2, 3
• Hypergammaglobulinemia or IgG ≥1.5 times normal is definite; any degree of elevation is probable 1

Autoantibody Titer Thresholds

For definite diagnosis, require ANA, SMA, or anti-LKM1 titers ≥1:80 in adults and ≥1:20 in children. For probable diagnosis, titers ≥1:40 in adults are acceptable. 1

Liver Biopsy Requirements

Liver biopsy is essential and cannot be omitted except in highly typical acute presentations. 1, 3 Clinical judgment should favor pre-treatment liver tissue examination unless the biopsy is precluded by lack of expertise or the patient requires immediate corticosteroid treatment for acute liver failure. 1

Histological Features to Identify

• Interface hepatitis is the hallmark finding (portal tract expansion with mononuclear infiltrate, disrupted limiting plate, inflammatory extension into acinus) 1, 3
• Portal lymphocytic/lymphoplasmacytic infiltrates extending into lobules 2, 3
• Plasma cell infiltration is typical but not required 1, 3
• Hepatocyte rosettes may be present 3
• Absence of biliary lesions, granulomas, or prominent changes suggesting other diseases 1

Special Histological Considerations in Acute Presentations

In acute severe (fulminant) presentations, look for centrilobular hemorrhagic necrosis with lymphoplasmatic infiltration, lymphoid aggregates, and plasma cell infiltration. 1 Unenhanced CT showing heterogeneous hypoattenuated areas within the liver is present in 65% of these cases. 1

Mandatory Exclusions

You must systematically exclude competing diagnoses before confirming AIH:

Viral Hepatitis

• Test for hepatitis A, B, C, and E markers 1, 2, 3
• Note that anti-LKM1 can occur in 5-10% of chronic hepatitis C patients, making viral exclusion crucial 3

Genetic/Metabolic Diseases

• Wilson disease: Check serum ceruloplasmin, copper, and 24-hour urinary copper 1
• Hereditary hemochromatosis: Measure serum iron, ferritin, and transferrin saturation 1, 3
• Alpha-1 antitrypsin deficiency: Obtain alpha-1 antitrypsin phenotype 1, 3

Drug-Induced Liver Injury

• Obtain detailed medication history, particularly for minocycline, nitrofurantoin, isoniazid, propylthiouracil, and methyldopa 1, 3
• Daily alcohol consumption must be <25 g/day for definite diagnosis and <50 g/day for probable diagnosis 1

Other Autoimmune Liver Diseases

• Test for antimitochondrial antibodies (AMA) to exclude primary biliary cholangitis 1, 3
• Consider imaging or cholangiography if features suggest primary sclerosing cholangitis 3

Other Conditions

• Non-alcoholic fatty liver disease and alcoholic liver disease 1, 3

Diagnostic Scoring Systems

Simplified Scoring System (Preferred for Routine Use)

Use the simplified scoring system when clinical, laboratory, serological, or histological features are typical. It has approximately 90% sensitivity and specificity. 3, 4

Components:

• Autoantibodies (ANA or SMA ≥1:40 = 1 point; ≥1:80 = 2 points; anti-LKM1 ≥1:40 = 2 points; anti-SLA positive = 2 points) 3
• IgG levels (>upper limit of normal = 1 point; >1.1 times upper limit = 2 points) 3
• Liver histology (compatible = 1 point; typical = 2 points) 3
• Absence of viral hepatitis (yes = 2 points) 3

Score ≥6 indicates probable AIH; ≥7 indicates definite AIH 3

Revised Original IAIHG Score (For Atypical Cases)

Use the comprehensive scoring system for diagnostically difficult cases with atypical presentations. 1, 3, 4

Pretreatment score >15 indicates definite diagnosis; 10-15 indicates probable diagnosis. 3 This system incorporates gender, HLA type, ALP:AST ratio, IgG levels, autoantibody titers, AMA status, viral markers, drug exposure, alcohol intake, histology, and concurrent immune diseases. 1, 3

Special Clinical Scenarios

Acute Severe (Fulminant) Presentation

In patients presenting with hepatic encephalopathy within 26 weeks of disease discovery, recognize that conventional diagnostic criteria may not apply. 1

• Serum IgG is normal in 25-39% of these patients 1
• ANA are absent or weakly positive in 29-39% 1
• Liver biopsy must be considered in all acute severe presentations to distinguish from viral, toxic, drug-induced, or Wilson disease 1

APECED Syndrome

In patients with AIH plus multiple endocrine disorders, test for AIRE gene mutations to exclude APECED syndrome, the only AIH syndrome with Mendelian inheritance requiring genetic counseling. 5, 3

Ethnic Variations

African Americans and Alaska Natives present with more severe manifestations, which should lower your threshold for aggressive diagnostic evaluation. 5

Diagnostic Algorithm Summary

1. Measure aminotransferases and calculate ALP:AST ratio 2, 3
2. Test ANA and SMA first in adults; add anti-LKM1 if negative 3
3. Test ANA, SMA, and anti-LKM1 simultaneously in children 3
4. If conventional antibodies negative, test anti-SLA and atypical pANCA 3
5. Measure serum IgG or γ-globulin 2, 3
6. Systematically exclude viral hepatitis, Wilson disease, drug-induced injury, and other competing diagnoses 1, 3
7. Perform liver biopsy to confirm interface hepatitis and assess severity 1, 3
8. Apply simplified scoring system; use comprehensive score if atypical 3, 4

Critical Pitfalls to Avoid

Do not rely on autoantibodies alone—they can be absent in acute presentations and may overlap with other conditions. 1, 3

Do not skip liver biopsy in typical cases—histology distinguishes AIH from mimics and assesses disease severity, which determines treatment urgency. 1, 3

Do not confuse anti-LKM1 with AMA if rodent kidney is the sole substrate for testing. 3

Do not diagnose AIH without excluding Wilson disease in patients under 40, as this is a treatable condition that can mimic AIH. 1

In acute presentations with normal IgG and negative conventional autoantibodies, do not dismiss AIH—proceed with liver biopsy and consider a therapeutic trial if histology is suggestive. 1