What laboratory tests are used to evaluate hyperbilirubinemia (elevated bilirubin levels)?

Laboratory Tests for Hyperbilirubinemia Evaluation

The initial laboratory evaluation for hyperbilirubinemia should include fractionated bilirubin (total, direct/conjugated, and indirect/unconjugated), complete blood count, liver enzymes (ALT, AST, ALP, GGT), coagulation studies (PT/INR), albumin, and total protein. 1

Primary Laboratory Tests

Essential First-Line Tests

• Fractionated bilirubin
  • Total bilirubin
  • Direct (conjugated) bilirubin
  • Indirect (unconjugated) bilirubin
  • Delta bilirubin (when available)
• Liver function tests
  • Alanine aminotransferase (ALT)
  • Aspartate aminotransferase (AST)
  • Alkaline phosphatase (ALP)
  • Gamma-glutamyl transferase (GGT)
• Complete blood count (CBC)
  • Hemoglobin/hematocrit
  • White blood cell count with differential
  • Platelet count
• Synthetic liver function
  • Prothrombin time (PT)/International Normalized Ratio (INR)
  • Albumin
  • Total protein
• Urinalysis (to detect bilirubin in urine)

Interpretation of Bilirubin Results

Classification Based on Fractionation

• Predominantly unconjugated hyperbilirubinemia: Direct bilirubin <20-30% of total bilirubin 1
  • Suggests hemolysis, Gilbert's syndrome, or other disorders of bilirubin conjugation
• Predominantly conjugated hyperbilirubinemia: Direct bilirubin >35% of total bilirubin 1
  • Suggests hepatocellular damage, cholestasis, or biliary obstruction

Secondary Laboratory Tests Based on Initial Findings

For Suspected Hemolytic Causes

• Hemolysis workup 1, 2
  • Reticulocyte count
  • Lactate dehydrogenase (LDH)
  • Haptoglobin
  • Peripheral blood smear
  • Direct antiglobulin test (DAT/Coombs' test)
  • Glucose-6-phosphate dehydrogenase (G6PD) screening

For Suspected Hepatocellular Disease

• Viral hepatitis serologies
  • Hepatitis A, B, and C
• Autoimmune markers
  • Anti-nuclear antibody (ANA)
  • Anti-smooth muscle antibody (ASMA)
  • Anti-mitochondrial antibody (AMA)
• Ceruloplasmin (for Wilson's disease)
• Alpha-1 antitrypsin levels and phenotype
• Iron studies (ferritin, transferrin saturation)

For Suspected Drug-Induced Liver Injury

• Detailed medication history 3, 1
• More frequent monitoring of liver tests (2-3 times weekly) 3

Imaging Studies

• Abdominal ultrasound: First-line imaging with 71-97% specificity for biliary obstruction 1, 4, 5

  • Evaluates biliary dilation, gallstones, liver parenchyma, and masses

• Additional imaging based on ultrasound findings:

  • If dilated bile ducts: Magnetic resonance cholangiopancreatography (MRCP) or CT with contrast
  • If normal bile ducts but persistent abnormalities: Consider liver biopsy

Monitoring Recommendations

• For mild elevations: Repeat tests within 1-2 weeks 3
• For moderate to severe elevations: Repeat tests within 2-5 days 3
• For suspected drug-induced injury: Monitor 2-3 times weekly initially 3

Special Considerations

• Gilbert's syndrome: Present in 5-10% of the population, characterized by mild unconjugated hyperbilirubinemia 1
• Drug-induced liver injury: Typically shows direct bilirubin >35% of total bilirubin 1
• Persistent hyperbilirubinemia: Warrants more expeditious and complete evaluation 3

Common Pitfalls to Avoid

1. Terminology confusion: "Direct" and "conjugated" bilirubin are often incorrectly used interchangeably, which can lead to misdiagnosis 1

2. Visual estimation of jaundice: Can lead to errors, particularly in darkly pigmented individuals 3

3. Failure to fractionate bilirubin: Total bilirubin alone is insufficient; fractionation is essential for proper diagnosis 1, 4

4. Overlooking hemolysis: Increased hemolysis in severe hyperbilirubinemia appears to augment the risk of bilirubin neurotoxicity 2

5. Delayed evaluation: Persistent hyperbilirubinemia of any etiology warrants expeditious diagnostic evaluation 3

By following this systematic approach to laboratory evaluation of hyperbilirubinemia, clinicians can efficiently identify the underlying cause and implement appropriate management strategies to reduce morbidity and mortality associated with this condition.