What is the initial workup for a patient with hyperbilirubinemia?

Initial Workup for Elevated Bilirubin

The initial workup for hyperbilirubinemia should begin with fractionation of bilirubin into conjugated (direct) and unconjugated (indirect) components, followed by targeted laboratory tests and abdominal ultrasound to determine the underlying cause. 1

Step 1: Bilirubin Fractionation

First, determine whether the hyperbilirubinemia is:

• Unconjugated (indirect): Suggests hemolysis, Gilbert's syndrome, or impaired bilirubin conjugation
• Conjugated (direct): Suggests hepatocellular damage, biliary obstruction, or cholestatic disorders

Step 2: Initial Laboratory Evaluation

For all patients with elevated bilirubin:

• Complete blood count (CBC)
• Liver function tests:
  • ALT (alanine aminotransferase)
  • AST (aspartate aminotransferase)
  • Alkaline phosphatase (ALP)
  • Gamma-glutamyl transferase (GGT)
  • Total and direct bilirubin
  • Albumin
  • Prothrombin time/INR
• Hepatitis panel (HBsAg, hepatitis B surface antibody, hepatitis B core antibody, HCV antibodies) 1

Step 3: Imaging

• Abdominal ultrasound: First-line imaging for all patients with hyperbilirubinemia
  • Evaluates for biliary obstruction with 71-97% specificity
  • Can detect cirrhosis with 65-95% sensitivity 1
  • Assesses for liver masses, biliary dilatation, and gallstones

Step 4: Further Evaluation Based on Bilirubin Type

For Unconjugated Hyperbilirubinemia:

• Evaluate for:
  • Hemolysis (peripheral blood smear, reticulocyte count, haptoglobin, LDH)
  • Gilbert's syndrome (typically mild elevation, exacerbated by fasting)
  • Medication-induced hyperbilirubinemia (medication review) 1

For Conjugated Hyperbilirubinemia:

• If ultrasound shows biliary obstruction:
  • MRI with MRCP (magnetic resonance cholangiopancreatography)
  • Consider ERCP (endoscopic retrograde cholangiopancreatography) for therapeutic intervention
• If no obstruction is identified:
  • Evaluate for viral hepatitis, autoimmune hepatitis, alcoholic liver disease
  • Consider primary sclerosing cholangitis or primary biliary cholangitis 1

Step 5: Additional Testing Based on Clinical Suspicion

• For suspected hepatocellular disease:

  • Alpha-fetoprotein (AFP) if HCC is suspected 1
  • Autoimmune markers (ANA, ASMA, AMA) if autoimmune hepatitis or PBC is suspected
  • Iron studies if hemochromatosis is suspected
  • Ceruloplasmin if Wilson's disease is suspected

• For persistent unexplained hyperbilirubinemia:

  • Consider liver biopsy 1

Common Pitfalls to Avoid

1. Failing to fractionate bilirubin: The distinction between conjugated and unconjugated hyperbilirubinemia is crucial for directing the diagnostic workup.

2. Missing Gilbert's syndrome: A common cause of mild unconjugated hyperbilirubinemia that may be exacerbated by fasting, stress, or illness.

3. Overlooking medication causes: Many drugs can cause hyperbilirubinemia, including certain antiviral medications 2.

4. Inadequate imaging: If ultrasound is negative but clinical suspicion for obstruction remains high, proceed to MRCP rather than assuming a hepatocellular cause.

5. Neglecting to monitor trends: Serial monitoring of bilirubin and other liver tests is essential, particularly for values that are rising or not improving as expected.

6. Delaying workup for significant elevations: Persistent hyperbilirubinemia warrants expeditious evaluation, especially with conjugated hyperbilirubinemia, which often indicates more serious underlying pathology 1.