Management of Elevated Liver Enzymes

Grading and Initial Management

• The American Society of Clinical Oncology recommends a systematic approach to managing elevated total bilirubin and AST, with initial workup for underlying causes and treatment tailored to the specific etiology identified, based on the severity of elevation, with Grade 1 defined as AST > ULN to 3.0× ULN and/or total bilirubin > ULN to 1.5× ULN, Grade 2 as AST > 3.0 to ≤ 5.0× ULN and/or total bilirubin > 1.5 to ≤ 3.0× ULN, Grade 3 as AST > 5.0 to 20× ULN and/or total bilirubin > 3.0 to 10× ULN, and Grade 4 as AST > 20× ULN and/or total bilirubin > 10× ULN 1, 2, 3
• The American Gastroenterological Association and the European Society for Medical Oncology support the grading system, emphasizing the importance of prompt intervention for Grade 3-4 elevations to prevent progression to liver failure 1, 2, 4

Etiologic Investigation and Imaging

• The American Society of Clinical Oncology and the European Society for Medical Oncology recommend etiologic investigation, including viral hepatitis serologies, autoimmune markers, iron studies, medication review for hepatotoxic drugs, and alcohol history, as well as abdominal ultrasound as first-line imaging, with consideration of MRCP if biliary obstruction is suspected 1, 2, 5
• The American College of Radiology and the American College of Gastroenterology support the use of abdominal ultrasound as the first-line imaging technique for suspected biliary obstruction, with a sensitivity of 32-100% and specificity of 71-97% 6, 7
• The following table summarizes the recommended imaging techniques:

Treatment and Monitoring

• The American Society of Clinical Oncology recommends continuing monitoring of liver chemistries every 1-2 weeks, evaluating for underlying causes, and considering discontinuing hepatotoxic medications, with no specific treatment required if asymptomatic, and consideration of prednisone 0.5-1 mg/kg/day if no improvement after 3-5 days 1, 3
• The American Gastroenterological Association recommends urgent hepatology consultation, starting methylprednisolone 1-2 mg/kg/day or equivalent, monitoring liver tests daily or every other day, and considering liver biopsy if no improvement or diagnosis unclear, for Grade 3-4 elevations 1, 2, 5
• The American Society of Clinical Oncology recommends immediate hospitalization, permanently discontinuing suspected causative agents, administering methylprednisolone 2 mg/kg/day, and considering transfer to a center with expertise in liver failure, for severe elevations 1, 2
• The American Academy of Pediatrics recommends phototherapy as the primary treatment for severe neonatal hyperbilirubinemia, and exchange transfusion for total serum bilirubin (TSB) levels ≥25 mg/dL (428 μmol/L) or if TSB is at exchange transfusion level per guidelines 8

Special Considerations

• The American Society of Clinical Oncology recommends avoiding infliximab and considering mycophenolate mofetil for steroid-refractory cases of immune checkpoint inhibitor-related hepatitis 1, 3
• The European Respiratory Society recommends antiviral therapy based on specific viral etiology, supportive care, and monitoring for viral hepatitis 4
• The American Association for the Study of Liver Diseases recommends ursodeoxycholic acid (UDCA) at a dose of 15-20 mg/kg/day as the primary treatment for mild elevations in bilirubin in adults 9
• The American Academy of Clinical Toxicology recommends N-acetylcysteine therapy if acetaminophen toxicity is suspected 10

Follow-up and Tapering

• The American Society of Clinical Oncology recommends monitoring liver tests every 3-7 days until normalization for improving cases, tapering steroids over 4-6 weeks once liver tests improve to Grade 1, and considering repeat imaging and follow-up liver tests after discharge for patients with Grade 3-4 elevations 1
• The American Gastroenterological Association recommends repeat testing in 2-4 weeks for mild elevations (<2× ULN) with no other abnormalities, and if persistent, proceed with diagnostic workup 11
• The American Association for the Study of Liver Diseases recommends accelerated monitoring and complete diagnostic workup for moderate elevations (2-5× ULN) 11
• The American College of Emergency Physicians suggests urgent diagnostic workup and consideration of hospitalization if symptoms are present for severe elevations (>5× ULN) 11

Key Recommendations

• The American Gastroenterological Association and the European Society for Medical Oncology emphasize the importance of prompt intervention for Grade 3-4 elevations to prevent progression to liver failure, always performing imaging when bilirubin is elevated, and early discontinuation of potential offending agents 1, 2, 4
• The European Society for Clinical Gastrointestinal Endoscopy recommends considering drug interactions that may potentiate hepatotoxicity 12
• The American Academy of Pediatrics recommends interpreting bilirubin levels according to patient age, especially in neonates, and measuring total and direct (conjugated) bilirubin to differentiate between types of hyperbilirubinemia 8
• The European Association for the Study of the Liver recommends classifying hyperbilirubinemia based on the percentage of conjugated bilirubin, with predominantly unconjugated (<20-30% conjugated bilirubin) and predominantly conjugated (>35% conjugated bilirubin) types 11
• The following table summarizes the classification of hyperbilirubinemia: