When should patients with elevated liver enzymes, such as alanine transaminase (ALT) and aspartate transaminase (AST), be assessed for hepatitis?

Assessment for Hepatitis in Patients with Abnormal Liver Enzymes

All patients with elevated liver enzymes (ALT and AST) should be assessed for hepatitis through serological testing for viral hepatitis markers, autoimmune markers, and other causes of liver disease, with persistent elevations (>6 months) or markedly elevated levels (>5× ULN) warranting more urgent and comprehensive evaluation. 1, 2

Initial Evaluation

Step 1: Risk Assessment

• Evaluate risk factors for viral hepatitis:
  • History of injection drug use
  • Blood transfusion before 1992
  • Hemophilia with clotting factors before 1987
  • Frequent percutaneous exposures
  • Immigration from high-prevalence countries
  • Clinical or biochemical evidence of chronic liver disease 1

Step 2: Initial Laboratory Testing

• For patients with elevated ALT/AST, perform:
  • Complete hepatitis viral panel: HAV-IgM, HBsAg, HBcIgM, HCV antibody
  • Consider HCV RNA testing
  • Autoimmune markers: ANA, SMA, anti-LKM1
  • Metabolic tests: ferritin, transferrin saturation, ceruloplasmin, alpha-1-antitrypsin
  • Complete blood count, albumin, bilirubin, alkaline phosphatase, GGT 1, 2

Step 3: Imaging

• Abdominal ultrasound to assess liver structure and exclude other pathologies 1, 2

When to Pursue Hepatitis Evaluation

Immediate Evaluation Required

• ALT/AST >5× upper limit of normal
• Development of jaundice with elevated transaminases
• Signs of hepatic decompensation (ascites, encephalopathy)
• Elevated bilirubin with elevated transaminases 2

Expedited Evaluation Recommended

• Persistent elevation of ALT/AST for >6 months
• AST/ALT ratio >1 (suggesting advanced fibrosis or cirrhosis)
• AST/ALT ratio >2 (strongly suggesting alcoholic liver disease)
• Presence of risk factors for viral hepatitis 2, 3, 4

Standard Evaluation Indicated

• Any unexplained elevation of liver enzymes, even mild elevations
• Normal ALT/AST does not exclude hepatitis, as up to 20% of patients with chronic HBV may have normal enzymes 5

Special Considerations

Autoimmune Hepatitis

• Up to 20% of autoimmune hepatitis cases are negative for standard autoantibodies (ANA, SMA, LKM1) 1
• Consider testing for additional autoantibodies (SLA, pANCA) in suspected seronegative cases 1

Viral Hepatitis

• HBV and HCV can present with normal enzymes despite active disease
• For suspected HCV, quantitative HCV RNA and genotype testing should be performed 1
• For suspected HBV, testing should include HBeAg, anti-HBe, and HBV DNA quantification 6

Algorithm for Evaluation

1. Mild ALT/AST elevation (<5× ULN) without symptoms:

   • Complete viral hepatitis panel
   • Autoimmune markers
   • Abdominal ultrasound
   • If negative, monitor every 3-6 months for persistence 1

2. Moderate to severe ALT/AST elevation (≥5× ULN) or symptomatic:

   • Complete viral and autoimmune workup as above
   • Expedited imaging
   • Consider early referral to hepatology 2

3. Persistent elevation (>6 months):

   • Non-invasive fibrosis assessment (FIB-4 score, elastography)
   • Consider liver biopsy
   • Referral to hepatology 2

Common Pitfalls to Avoid

• Relying solely on enzyme levels: Normal ALT/AST does not exclude significant liver disease, including chronic hepatitis and cirrhosis 2
• Missing non-viral causes: Remember to assess for autoimmune hepatitis, drug-induced liver injury, Wilson's disease, and hemochromatosis 1
• Incomplete viral testing: Testing for HBV should include HBsAg, HBeAg, anti-HBe, and HBV DNA; HCV testing should include both antibody and RNA 1, 6
• Overlooking AST/ALT ratio: A ratio >1 suggests advanced fibrosis or cirrhosis, warranting more thorough evaluation 3, 4
• Delaying referral: Patients with persistent or significant elevations should be referred to hepatology for comprehensive evaluation and management 2