How should I manage a woman with acute severe hepatitis, markedly elevated alanine aminotransferase, significant hyperbilirubinemia, coagulopathy (elevated INR), iron‑deficiency anemia, and a negative antinuclear antibody?

Management of Acute Severe Hepatitis with Negative ANA in a Woman

You must strongly consider autoimmune hepatitis (AIH) despite the negative ANA, because 29-39% of patients with acute severe AIH present with negative or weakly positive ANA, and this patient's clinical picture—marked transaminase elevation, significant hyperbilirubinemia, and coagulopathy—fits the acute severe AIH phenotype. 1

Immediate Diagnostic Workup

Exclude competing diagnoses urgently before attributing this to AIH:

• Check viral hepatitis serologies immediately: HBsAg, anti-HBc IgM, anti-HCV with reflex HCV RNA, anti-HAV IgM, and anti-HEV IgM/IgG with HEV RNA, as viral hepatitis commonly causes this presentation and can mimic AIH 1
• Obtain detailed medication history: Review all prescription drugs, over-the-counter medications, and herbal supplements against the LiverTox® database, as drug-induced liver injury (DILI) causes 8-11% of cases and can present with autoantibodies 1, 2
• Rule out ischemic hepatitis: Verify vascular patency with abdominal ultrasound Doppler and assess cardiac function with echocardiography, as ischemic hepatitis typically shows AST/ALT >1,000 IU/mL with rapid improvement 1
• Exclude Wilson's disease: Check serum ceruloplasmin and 24-hour urinary copper, especially given the coagulopathy; Wilson's presents with AST/ALT ratio >2.2, ALP/bilirubin ratio <4, and Coombs-negative hemolysis 1, 2

Critical Consideration: EBV and False-Positive Serology

Test for Epstein-Barr virus (EBV) immediately, as EBV infection can cause:

• Elevated liver enzymes, positive ANA, fever, and fatigue that mimic AIH 3
• False-positive anti-HAV IgM and autoantibodies (ANA, anti-SLA) 3
• Spontaneous resolution without immunosuppression within 1 month 3

If EBV VCA IgM is positive, do NOT start corticosteroids—provide supportive care and recheck autoantibodies at 4 weeks, as they typically become negative once EBV resolves 3

Expanded Autoantibody Panel for Seronegative AIH

Since ANA is negative, obtain additional autoantibodies:

• Anti-smooth muscle antibody (SMA): Present in 63% of ANA-negative AIH patients 4
• Anti-liver kidney microsome type 1 (anti-LKM1): Defines type 2 AIH 1
• Anti-soluble liver antigen (anti-SLA): Disease-specific for AIH, present in 20-30% of patients 2
• Perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA): Can be positive when standard antibodies are negative 1
• Quantitative IgG level: 25-39% of acute severe AIH patients have normal IgG, but elevated IgG >1.5× ULN strongly supports AIH 1, 2

Imaging to Support AIH Diagnosis

Order non-contrast abdominal CT scan, as 65% of AIH patients with acute liver failure show heterogeneous hypo-attenuated regions on CT, compared to only 2.2% of viral hepatitis patients—this finding helps differentiate AIH from viral causes 1

Liver Biopsy Considerations

Liver biopsy is essential but timing depends on coagulopathy severity:

• If INR 1.5-2.0 without encephalopathy (acute severe AIH definition): Correct coagulopathy with fresh frozen plasma or vitamin K, then perform transjugular liver biopsy if percutaneous approach is contraindicated 1
• If INR ≥2.0 or encephalopathy present (acute liver failure): This is a medical emergency requiring immediate hepatology consultation and liver transplant evaluation; biopsy may need to be deferred 1
• Histologic features supporting AIH: Interface hepatitis, lymphoplasmacytic infiltration, hepatocyte rosettes, and emperipolesis—but acute presentations may show zone 3 necrosis and acute hepatitis patterns rather than typical chronic features 1, 4

Iron-Deficiency Anemia Context

The iron-deficiency anemia is likely unrelated to the acute hepatitis but requires separate evaluation:

• Check for gastrointestinal blood loss (stool guaiac, consider endoscopy if indicated) 5
• Assess for menstrual blood loss in this woman 5
• Note that severe anemia can occur with AIH due to hypersplenism and portal hypertension, but this typically causes pancytopenia rather than isolated iron deficiency 5

Treatment Decision Algorithm

If Viral Hepatitis and DILI Are Excluded:

Start corticosteroid therapy immediately if:

• Bilirubin >3 mg/dL AND transaminases markedly elevated (ALT/AST >400 IU/mL) 1
• INR 1.5-2.0 without encephalopathy (acute severe AIH) 1
• Histology shows interface hepatitis or acute hepatitis with lymphoplasmacytic infiltration 1

Initiation regimen:

• Intravenous methylprednisolone 40-60 mg daily for 3 days, then transition to oral prednisone 40-60 mg daily 5
• Do NOT add azathioprine initially given the coagulopathy and need to assess bone marrow function first 5
• Monitor liver enzymes every 2-4 weeks initially 2

If EBV Is Positive:

Provide supportive care only:

• Hydration and symptom management 3
• Monitor liver enzymes every 2-4 weeks until complete normalization 3
• Recheck autoantibodies at 4 weeks—they should become negative 3
• Do NOT start corticosteroids, as EBV hepatitis resolves spontaneously 3

Common Diagnostic Pitfalls to Avoid

• Do not exclude AIH based on negative ANA alone—29-39% of acute severe AIH patients are ANA-negative, and 20% of all AIH patients are seronegative for standard antibodies 1, 2
• Do not assume stable drug use excludes DILI—patients may have taken the causative drug for months to years before presentation, and latency periods vary from 1 week to 12 months 2
• Do not miss EBV—it can cause false-positive HAV IgM and autoantibodies that resolve spontaneously, and treating EBV hepatitis with corticosteroids is harmful 3
• Do not delay hepatology referral—acute severe AIH with INR ≥2.0 or encephalopathy requires immediate transplant center evaluation 1

Monitoring for Treatment Response

If corticosteroids are started:

• Expect ALT/AST to decline within 2 weeks 2
• Recheck liver panel at 2 weeks, then every 2-4 weeks until normalization 2
• If no improvement by 4 weeks, reconsider the diagnosis and evaluate for DILI or other causes 2
• Monitor for relapse: 13 of 24 ANA-negative AIH patients relapsed after initial normalization, so long-term follow-up is essential 4