How to differentiate viral hepatitis from ischemic hepatitis based on Liver Function Test (LFT) results?

Differentiating Viral from Ischemic Hepatitis Using LFT Patterns

The ALT/LD ratio is the most reliable LFT-based discriminator: viral hepatitis typically shows an ALT/LD ratio >1.5 (mean 4.65), while ischemic hepatitis shows a ratio <1.5 (mean 0.87), with 94% sensitivity and 84% specificity for this cutoff. 1

Key Biochemical Patterns

Magnitude and Pattern of Aminotransferase Elevation

• Both conditions cause marked aminotransferase elevations (>5× upper limit of normal), but the accompanying enzyme patterns differ significantly 1, 2
• Ischemic hepatitis typically produces extremely high transaminase peaks (often >1,000 IU/mL and frequently exceeding 5,000-8,000 IU/mL) with AST often higher than ALT 2, 3, 4
• Viral hepatitis shows elevated aminotransferases but with proportionally lower lactate dehydrogenase (LD) elevation relative to ALT 1

The Critical ALT/LD Ratio

• Calculate the ALT/LD ratio as your primary discriminator: 1
  • Viral hepatitis: ALT/LD ratio typically >1.5 (mean 4.65)
  • Ischemic hepatitis: ALT/LD ratio typically <1.5 (mean 0.87)
  • Acetaminophen toxicity: ALT/LD ratio intermediate (mean 1.46)
• For a given ALT and AST level, LD is markedly higher in ischemic hepatitis than in viral hepatitis 1

Temporal Pattern of Enzyme Elevation

• Ischemic hepatitis shows a characteristic rapid rise and fall pattern: 4
  • Sudden, massive peak in transaminases (>20× normal)
  • Rapid return toward normal within 3-11 days
  • Short time course distinguishes it from viral hepatitis
• Viral hepatitis demonstrates a more gradual rise and prolonged elevation over weeks 2, 4

Additional Distinguishing LFT Features

Bilirubin Patterns

• Ischemic hepatitis: serum bilirubin usually <3 mg/dL despite massive transaminase elevation 2, 5
• Viral hepatitis: serum bilirubin typically >3 mg/dL (>50 μmol/L) with AST/ALT >400 IU/mL 2

Coagulation Parameters

• Ischemic hepatitis produces deep, marked coagulopathy (INR significantly elevated) that improves rapidly with restoration of perfusion 2, 6
• The coagulopathy in ischemic hepatitis is disproportionately severe relative to bilirubin elevation 2

AST/ALT Ratio

• Ischemic hepatitis may show AST > ALT, though this is not specific 3, 4
• This pattern can also occur in alcoholic hepatitis and Wilson's disease, requiring clinical context 2

Clinical Context Integration

Cardiovascular History

• Ischemic hepatitis requires evidence of cardiovascular compromise: 5, 4
  • Acute fall in cardiac output (documented in only 26% of cases as frank hypotension)
  • Congestive heart failure (left ventricular failure present in 84% of cases)
  • Cardiovascular shock or cardiac tamponade
• The absence of documented hypotension does not exclude ischemic hepatitis - poor hepatic perfusion from low cardiac output is sufficient 5, 4

Viral Serology

• All patients with hepatitic LFT patterns require viral serology testing: 2
  • Anti-HAV IgM for hepatitis A
  • HBsAg and anti-HBc IgM for hepatitis B
  • Anti-HCV and HCV RNA for hepatitis C
  • Anti-HEV IgM and HEV RNA for hepatitis E
• Test for HEV as part of first-line investigation regardless of travel history, as it is now the commonest cause of acute viral hepatitis in many countries 2

Imaging Confirmation

• Abdominal ultrasound with Doppler is essential to verify vascular patency and exclude biliary obstruction 2, 7
• CT with IV contrast can identify ischemic hepatitis by demonstrating hypoenhancement of liver parenchyma and providing hemodynamic information 2

Diagnostic Algorithm

1. Calculate ALT/LD ratio immediately:

   • Ratio >1.5 → strongly suggests viral hepatitis 1
   • Ratio <1.5 → strongly suggests ischemic hepatitis or drug toxicity 1

2. Assess temporal pattern:

   • Rapid peak with return to normal in 3-11 days → ischemic hepatitis 4
   • Gradual rise with prolonged elevation → viral hepatitis 2

3. Evaluate bilirubin-transaminase relationship:

   • Massive transaminases with bilirubin <3 mg/dL → ischemic hepatitis 2, 5
   • Transaminases >400 IU/mL with bilirubin >3 mg/dL → viral hepatitis 2

4. Review cardiovascular status:

   • Evidence of low cardiac output, heart failure, or shock → supports ischemic hepatitis 5, 4
   • Absence of cardiovascular compromise → favors viral or drug-induced hepatitis 2

5. Obtain viral serology and imaging:

   • Negative viral serology + vascular patency confirmed → ischemic hepatitis likely 2, 7
   • Positive viral serology → confirms viral hepatitis 2

Critical Pitfalls to Avoid

• Do not assume normal or mildly elevated bilirubin excludes significant liver injury - ischemic hepatitis characteristically shows this pattern 2, 5
• Do not wait for documented hypotension to diagnose ischemic hepatitis - only 26-30% of cases have recorded hypotensive episodes 5, 4
• Do not overlook drug-induced liver injury (DILI) as a mimic - 13% of presumed DILI cases in elderly patients are actually hepatitis E 2
• Liver biopsy is rarely necessary and should be reserved only for cases where encephalopathy suggests fulminant hepatitis and the diagnosis remains uncertain after biochemical and serological evaluation 6, 4