What is the appropriate workup for indirect hyperbilirubinemia?

Workup of Indirect Hyperbilirubinemia

The appropriate workup for indirect 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 as the initial laboratory evaluation. 1

Initial Classification and Assessment

First, confirm that the hyperbilirubinemia is predominantly unconjugated by determining the percentage of conjugated bilirubin:

• Predominantly unconjugated: <20-30% conjugated bilirubin
• Predominantly conjugated: >35% conjugated bilirubin 1

Laboratory Evaluation

1. First-line tests:

   • Fractionated bilirubin levels
   • Complete blood count with differential and peripheral smear (to evaluate for hemolysis)
   • Liver function tests (ALT, AST, alkaline phosphatase, γ-glutamyltransferase)
   • Albumin and total protein
   • Prothrombin time/INR 1

2. Second-line tests (based on clinical suspicion):

   • Reticulocyte count (to assess for hemolysis)
   • Direct Coombs test (for immune-mediated hemolysis)
   • Glucose-6-phosphate dehydrogenase (G6PD) level (especially in neonates with severe hyperbilirubinemia) 2
   • Thyroid function tests (TSH, free T4)
   • Genetic testing for inherited disorders of bilirubin metabolism (Gilbert syndrome, Crigler-Najjar syndrome)

Imaging Studies

• Abdominal ultrasound is recommended as the first-line imaging technique to exclude biliary obstruction, with a specificity of 71-97% 1
• If clinical suspicion persists despite negative ultrasound:
  • MRI with MRCP (magnetic resonance cholangiopancreatography) 1
  • CT abdomen with contrast (if malignancy is suspected) 1

Specific Etiologies to Consider

Common causes of indirect hyperbilirubinemia:

1. Hemolytic disorders:

   • Evaluate peripheral blood smear for red cell morphology
   • Check reticulocyte count and haptoglobin
   • Consider G6PD deficiency testing, particularly in neonates 2

2. Impaired bilirubin conjugation:

   • Gilbert syndrome (most common genetic cause)
   • Crigler-Najjar syndrome
   • Drug-induced impairment of conjugation 3

3. Medication-related causes:

   • Review all medications, particularly antivirals which can cause isolated increases in indirect bilirubin 3
   • Consider medication discontinuation and monitoring liver tests every 2-5 days initially 1

Monitoring and Follow-up

• For mild elevations (<2× ULN) with no other abnormalities, repeat testing in 2-4 weeks
• For moderate elevations (2-5× ULN), accelerate monitoring and complete diagnostic workup
• For severe elevations (>5× ULN), urgent diagnostic workup and consideration of hospitalization if symptoms are present 1

Common Pitfalls to Avoid

1. Overlooking medication-induced causes: Many antivirals can cause indirect hyperbilirubinemia without liver injury 3

2. Assuming normal aminotransferases rule out significant liver disease: Indirect hyperbilirubinemia can occur with normal liver enzymes 1

3. Missing underlying hemolytic disorders: Always evaluate for hemolysis in cases of indirect hyperbilirubinemia, especially in neonates 2

4. Neglecting genetic causes: Gilbert syndrome is common (affecting up to 10% of the population) and can be exacerbated by fasting, stress, or illness 4

5. Failing to consider long-term complications: In neonates, severe indirect hyperbilirubinemia (>25 mg/dL) can lead to neurodevelopmental disorders and hearing loss even in term infants without hemolysis 5

By following this systematic approach to the workup of indirect hyperbilirubinemia, clinicians can effectively identify the underlying cause and implement appropriate management strategies to prevent potential complications.