Elevated Bilirubin Workup
Initial Step: Fractionate the Bilirubin
The first step in evaluating elevated bilirubin is to fractionate total bilirubin into direct (conjugated) and indirect (unconjugated) components to determine the underlying mechanism and guide subsequent workup. 1, 2
This single test immediately narrows your differential diagnosis and determines whether you're dealing with a prehepatic, intrahepatic, or posthepatic process 3.
Laboratory Panel to Order Immediately
Alongside fractionated bilirubin, obtain the following tests simultaneously 1, 2:
- Complete blood count with differential and peripheral smear - to evaluate for hemolysis 1
- Reticulocyte count - elevated in hemolytic processes 1
- Liver function tests: ALT, AST, alkaline phosphatase, GGT 1, 2
- Albumin and prothrombin time/INR - to assess synthetic liver function 1, 2
- Haptoglobin and LDH - if hemolysis is suspected based on CBC findings 1
Decision Algorithm Based on Bilirubin Fractionation
If Conjugated Bilirubin <20-30% of Total (Unconjugated Hyperbilirubinemia)
Gilbert syndrome is the most likely diagnosis in asymptomatic adults with isolated mild unconjugated hyperbilirubinemia (total bilirubin rarely exceeding 4-5 mg/dL) and normal liver tests. 1, 4
Workup for Unconjugated Hyperbilirubinemia:
Review medications - protease inhibitors, rifampin, and probenecid can cause unconjugated hyperbilirubinemia 1
Evaluate for hemolysis if reticulocyte count is elevated 1:
Gilbert syndrome requires no treatment - provide full reassurance and no further monitoring if liver tests are otherwise normal 1
Genetic testing for UDP-glucuronosyltransferase mutations may confirm Gilbert syndrome definitively but is not necessary for clinical management 1
If Direct Bilirubin >35% of Total (Conjugated Hyperbilirubinemia)
Obtain abdominal ultrasound within 24-48 hours to exclude biliary obstruction - this is mandatory. 1, 3
Why Ultrasound First:
- 98% positive predictive value for liver parenchymal disease 1
- 65-95% sensitivity for detecting biliary obstruction 1
- 71-97% specificity for excluding mechanical obstruction 3, 1
- Non-invasive, low cost, and evaluates for gallstones, cholecystitis, choledocholithiasis, and focal liver lesions 1
Additional Laboratory Tests for Conjugated Hyperbilirubinemia:
- Verify elevated alkaline phosphatase is of hepatic origin by checking GGT or alkaline phosphatase isoenzymes 1
- Check INR and consider vitamin K deficiency before attributing prolonged INR to liver dysfunction - fat-soluble vitamin deficiencies are common in cholestatic disease and correctable with supplementation 1
- Evaluate for common hepatic diseases with serologic tests (hepatitis panel, autoimmune markers) 1
When to Escalate Beyond Ultrasound
If ultrasound shows biliary dilation OR clinical suspicion remains high despite negative ultrasound, proceed immediately to MRI with MRCP. 1
- MRI with MRCP has 90.7% accuracy for determining biliary obstruction etiology 1
- Superior for evaluating cholangitis, primary sclerosing cholangitis, primary biliary cirrhosis, and malignant biliary strictures 1, 3
- Critical pitfall: Do not rely on ultrasound alone for distal common bile duct obstruction - overlying bowel gas frequently obscures the distal CBD, causing false-negative results 1
CT abdomen/pelvis with IV contrast is appropriate when malignancy staging or surgical planning is needed, with 95% sensitivity and 93.35% specificity for malignant biliary strictures 1
Clinical Red Flags Requiring Urgent Action
- Fever, right upper quadrant pain, and jaundice (Charcot's triad) with elevated WBC and CRP suggests cholangitis - requires urgent intervention 1
- Total bilirubin ≥25 mg/dL or ≥20 mg/dL in a sick infant - immediate hospital admission and consideration for exchange transfusion 1
- Jaundice in the first 24 hours of life - requires immediate measurement of total and direct/conjugated bilirubin 1
- Jaundice persisting ≥3 weeks in infants - measure total and direct/conjugated bilirubin to identify cholestasis 1
Monitoring Strategy
- For mild isolated elevations with normal physical examination and intact hepatic function: close clinical follow-up with serial liver chemistry testing 1
- Repeat blood tests within 1-2 weeks for Grade 1 elevations (ALT or AST >ULN to 3× ULN with normal bilirubin) 1
- Monitor 2-3 times weekly for higher grade elevations or if bilirubin continues to rise 1
- Persistent hyperbilirubinemia ≥6 months warrants expeditious and complete diagnostic evaluation, including possible liver biopsy 1
Critical Pitfalls to Avoid
- Never rely on visual estimation of jaundice - always obtain objective bilirubin measurements, especially in darkly pigmented patients 1
- Do not subtract direct (conjugated) bilirubin from total bilirubin when making treatment decisions - this leads to inaccurate assessments 1
- Direct bilirubin is not synonymous with conjugated bilirubin - direct bilirubin includes both conjugated bilirubin and delta bilirubin, which has a 21-day half-life and causes persistent hyperbilirubinemia even after the underlying cause resolves 1
- Do not order contrast-enhanced ultrasound (CEUS) or Doppler ultrasound - there is no evidence supporting their use in initial evaluation of hyperbilirubinemia 3, 1
- Avoid overinterpreting isolated mild unconjugated hyperbilirubinemia as indicative of significant liver disease when Gilbert syndrome is likely 1