What is the workup for a patient with elevated Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), and hyperbilirubinemia?

Workup for Abnormal AST, ALT, and Elevated Bilirubin

The workup for abnormal liver enzymes (AST, ALT) and elevated bilirubin should begin with determining the pattern of liver injury (hepatocellular vs. cholestatic), fractionating bilirubin (direct vs. indirect), and conducting a targeted evaluation based on clinical context, with abdominal ultrasound and viral hepatitis screening as first-line tests. 1, 2

Initial Assessment

Pattern Recognition

• Determine if the pattern is:
  • Hepatocellular: Disproportionate elevation of AST/ALT compared to alkaline phosphatase
  • Cholestatic: Disproportionate elevation of alkaline phosphatase compared to AST/ALT
  • Mixed: Elevations in both

Key Laboratory Tests

• Fractionation of bilirubin into direct (conjugated) and indirect (unconjugated) 2
• Complete liver panel: AST, ALT, alkaline phosphatase, GGT, total and direct bilirubin 1
• Confirm hepatic origin of elevated alkaline phosphatase with GGT and/or alkaline phosphatase isoenzyme fractionation 2
• Prothrombin time/INR and albumin (to assess synthetic function) 1
• Complete blood count with platelets 1

Imaging

• Abdominal ultrasound: First-line imaging to differentiate between intrahepatic and extrahepatic cholestasis 2
• Consider CT or MRI depending on clinical scenario if ultrasound is inconclusive 1

Specific Etiologic Workup

For Hepatocellular Pattern (Elevated AST/ALT)

1. Viral hepatitis screening:

   • Hepatitis A IgM (acute presentation)
   • Hepatitis B surface antigen (HBsAg)
   • Hepatitis B core antibody (anti-HBc)
   • Hepatitis C antibody (with reflex RNA testing if positive)
   • Consider HIV testing 2

2. Alcohol-related liver disease:

   • Detailed alcohol consumption history
   • AST/ALT ratio >2 suggests alcoholic liver disease 2

3. Autoimmune hepatitis:

   • ANA, ASMA, immunoglobulin levels 2

4. Metabolic causes:

   • Hereditary hemochromatosis (iron studies, ferritin)
   • Wilson's disease (ceruloplasmin, 24-hour urine copper)
   • Alpha-1 antitrypsin deficiency (alpha-1 antitrypsin levels) 1, 2

5. Non-alcoholic fatty liver disease (NAFLD):

   • Fasting lipid profile
   • Fasting glucose, HbA1c 2

6. Medication/toxin review:

   • Comprehensive medication history including prescription, over-the-counter medications, and supplements 2

For Cholestatic Pattern (Elevated Alkaline Phosphatase and Bilirubin)

1. Primary biliary cholangitis:

   • Anti-mitochondrial antibody 2

2. Primary sclerosing cholangitis:

   • MRCP (magnetic resonance cholangiopancreatography) 2

3. Biliary obstruction:

   • Ultrasound/MRCP/ERCP as indicated 1
   • Note: Choledocholithiasis can occasionally present with markedly elevated transaminases (>1000 IU/L) 3

Monitoring and Management Thresholds

For Mild Elevations (ALT/AST <5× ULN)

• Continue monitoring liver enzymes every 2-5 days
• Investigate potential causes 2

For Significant Elevations

• If ALT increases to >5× ULN:
  • Consider interruption of suspected hepatotoxic medications
  • Expedite diagnostic evaluation 2

Indications for Specialist Referral

• ALT/AST >5× ULN
• ALT/AST >3× ULN with total bilirubin ≥2× ULN
• Persistent elevation >6 months despite interventions
• Development of symptoms such as jaundice, abdominal pain, or fatigue 2

Special Considerations

• Consider liver biopsy when serologic testing and imaging fail to elucidate a diagnosis, to stage a condition, or when multiple diagnoses are possible 4
• In patients with suspected Wilson's disease, the ratio of AST/ALT and alkaline phosphatase/total bilirubin may provide diagnostic clues 5
• Patients with chronic viral hepatitis may have minimal enzyme elevations despite significant liver damage 6

Common Pitfalls to Avoid

• Failing to fractionate bilirubin into direct and indirect components
• Overlooking non-hepatic causes of elevated transaminases (e.g., polymyositis, acute muscle injury, myocardial infarction, hypothyroidism) 6
• Assuming that the degree of enzyme elevation correlates with the severity of liver damage in chronic viral hepatitis 6
• Missing rare causes of hyperbilirubinemia such as hematologic malignancies 7

By following this systematic approach, clinicians can efficiently diagnose the underlying cause of abnormal liver enzymes and hyperbilirubinemia, leading to appropriate management and improved outcomes.