What additional blood work is recommended for high bilirubin levels?

Essential Blood Work for Elevated Bilirubin

When bilirubin is elevated, you must immediately obtain fractionated bilirubin (direct and indirect), complete liver function tests (ALT, AST, ALP, GGT), albumin, PT/INR, and a complete blood count with peripheral smear. 1

Initial Core Laboratory Panel

The following tests should be ordered together as your initial workup:

Liver Function Assessment

• ALT, AST, ALP, GGT, and total bilirubin - These differentiate hepatocellular injury from cholestatic patterns and are essential for initial evaluation 2
• Fractionated bilirubin (direct and indirect) - This single test determines whether you're dealing with conjugated versus unconjugated hyperbilirubinemia, fundamentally changing your diagnostic approach 1, 3
• Albumin and total protein - These assess synthetic liver function, though albumin should not be overinterpreted as it decreases in sepsis and malnutrition 1

Coagulation and Hematologic Studies

• PT/INR - Critical for evaluating liver synthetic capacity and identifying potential liver failure 1
• Complete blood count with peripheral smear - Essential if unconjugated hyperbilirubinemia is present to evaluate for hemolysis 1, 3
• Reticulocyte count, haptoglobin, and LDH - Add these specifically when unconjugated hyperbilirubinemia suggests hemolysis 1

Algorithmic Approach Based on Bilirubin Fractionation

If Predominantly Unconjugated (Indirect) Hyperbilirubinemia:

• Evaluate for Gilbert syndrome - Consider this benign condition, though levels rarely exceed 3 mg/dL (occasionally up to 6 mg/dL) 1, 4
• Assess for hemolysis with reticulocyte count, haptoglobin, LDH, and peripheral smear 1, 3
• Screen for G6PD deficiency if ethnicity or clinical picture suggests it 1

If Predominantly Conjugated (Direct) Hyperbilirubinemia:

• Order abdominal ultrasound immediately as your initial imaging study to evaluate for biliary obstruction (specificity 71-97%) 2, 1
• The pattern of liver enzyme elevation guides further workup - hepatocellular (elevated ALT/AST) versus cholestatic (elevated ALP/GGT) 2, 3

Additional Testing for Severe or Persistent Elevation

When bilirubin remains elevated or clinical concern is high:

• CK (creatine kinase) and INR should be added for closer monitoring 2
• Viral hepatitis serologies (HAV-IgM, HBsAg, HBc-IgM, HCV antibody) when hepatocellular pattern is present 2
• Autoimmune antibody assays if chronic liver disease is suspected 3
• GDLH testing can be considered as an emerging biomarker of drug-induced liver injury 2

Critical Timing Considerations

Repeat blood tests within 2-5 days for mild elevations, but within 2-3 days if there are significant ALT elevations concurrent with hyperbilirubinemia 2. The combination of elevated aminotransferases with bilirubin >2x upper limit of normal (Hy's Law pattern) signals potential severe liver injury requiring urgent evaluation 2.

Key Clinical Pitfalls to Avoid

• Never subtract direct bilirubin from total bilirubin when making clinical decisions - always use the actual measured values 1
• Do not delay imaging in conjugated hyperbilirubinemia, as early identification of biliary obstruction is critical 1
• Standard hemolysis tests have poor sensitivity and specificity - interpret them in clinical context 1
• In Gilbert syndrome, direct bilirubin should guide decisions when total bilirubin fluctuates significantly 2
• Albumin is not a reliable marker of acute liver disease severity as it decreases in many conditions including sepsis 1