What labs should be ordered for a patient with hyperbilirubinemia?

Laboratory Evaluation for Hyperbilirubinemia

Initial laboratory testing for hyperbilirubinemia should include fractionated bilirubin levels, complete blood count with differential and peripheral smear, liver function tests (ALT, AST, alkaline phosphatase, γ-glutamyltransferase), albumin, total protein, and prothrombin time/INR. 1

Initial Assessment

• Determine if hyperbilirubinemia is predominantly unconjugated (<20-30% conjugated bilirubin) or predominantly conjugated (>35% conjugated bilirubin) 1
• Measure total and direct (conjugated) bilirubin to differentiate between types of hyperbilirubinemia
• Interpret bilirubin levels according to patient age (especially important in neonates) 2

Laboratory Testing Algorithm

Step 1: Core Laboratory Panel

• Fractionated bilirubin (total and direct/conjugated)
• Complete blood count with differential and peripheral smear
• Liver function tests:
  • ALT (alanine transaminase)
  • AST (aspartate transaminase)
  • Alkaline phosphatase
  • γ-glutamyltransferase (GGT)
• Albumin and total protein
• Prothrombin time/INR 1, 3

Step 2: Additional Testing Based on Bilirubin Pattern

For Predominantly Unconjugated Hyperbilirubinemia:

• Reticulocyte count
• Peripheral blood smear examination
• Glucose-6-phosphate dehydrogenase (G6PD) testing
• Blood type and Coombs' test (especially in neonates) 2

For Predominantly Conjugated Hyperbilirubinemia:

• Urinalysis and urine culture
• Evaluation for sepsis if clinically indicated
• Abdominal ultrasound (first-line imaging) 1, 3

Step 3: Specialized Testing Based on Clinical Suspicion

• For suspected autoimmune liver disease:

  • Anti-mitochondrial antibody (AMA)
  • Anti-nuclear antibody (ANA)
  • Immunoglobulin levels 1

• For suspected biliary obstruction:

  • MRI with MRCP (magnetic resonance cholangiopancreatography) if ultrasound is negative but clinical suspicion remains high 1
  • CT abdomen with contrast for suspected pancreatic or biliary malignancy 1

• For neonates with prolonged jaundice (>3 weeks):

  • Thyroid function tests
  • Galactosemia screening 2

Special Considerations

For Rapidly Rising Bilirubin Levels

If bilirubin is rising rapidly (crossing percentiles) or not explained by history and physical examination:

• Blood type and Coombs' test (if not already obtained)
• Complete blood count and smear
• Direct/conjugated bilirubin measurement
• Consider reticulocyte count and G6PD testing 2

For Severe Hyperbilirubinemia

If bilirubin levels are approaching exchange transfusion levels or not responding to phototherapy:

• Reticulocyte count
• G6PD testing
• Albumin level 2

For Elevated Direct/Conjugated Bilirubin

• Urinalysis and urine culture
• Evaluate for sepsis if clinically indicated 2

Monitoring Recommendations

• For mild elevations (<2× ULN) with no other abnormalities: repeat testing in 2-4 weeks
• For moderate elevations (2-5× ULN): accelerated monitoring and complete diagnostic workup
• For severe elevations (>5× ULN): urgent diagnostic workup and consider hospitalization 1
• Monitor liver enzymes and function tests daily until improvement begins, then every 3-7 days until normalization 1

Common Pitfalls to Avoid

• Do not rely on visual estimation of jaundice alone, as this can lead to errors, particularly in darkly pigmented patients 2
• Do not assume normal aminotransferases rule out significant liver disease 1
• Be aware that overlooking malignancy as a cause of isolated elevated alkaline phosphatase is a significant pitfall 1
• Consider medication-induced bilirubin elevations to avoid delayed diagnosis or inappropriate management 1

By following this structured approach to laboratory evaluation of hyperbilirubinemia, clinicians can efficiently identify the underlying cause and initiate appropriate management to reduce morbidity and mortality associated with liver disease.