What is the differential diagnosis for hyperbilirubinemia?

Differential Diagnosis for Hyperbilirubinemia (Total Bilirubin 1.6 mg/dL)

The first step is to fractionate the bilirubin to determine if this is unconjugated or conjugated hyperbilirubinemia, as this fundamentally divides the differential diagnosis into distinct pathophysiologic categories. 1, 2

Initial Diagnostic Approach

Order fractionated bilirubin immediately to calculate the percentage of conjugated (direct) bilirubin relative to total bilirubin, as this determines the entire diagnostic pathway. 2, 3

If Unconjugated Hyperbilirubinemia (Conjugated <20-30% of Total)

Gilbert syndrome is by far the most common cause of isolated mild unconjugated hyperbilirubinemia in asymptomatic adults, affecting approximately 5% of the population. 1, 2 Total bilirubin in Gilbert syndrome rarely exceeds 4-5 mg/dL and typically fluctuates with illness or fasting. 2

Additional causes to consider for unconjugated hyperbilirubinemia include:

• Hemolytic disorders: Check complete blood count with peripheral smear, reticulocyte count, haptoglobin, and LDH to evaluate for hemolysis. 2, 3 Consider G6PD deficiency testing, particularly in African American patients (11-13% prevalence), Mediterranean, or Asian descent patients. 1, 2

• Medication-induced: Review all medications, as many drugs can cause unconjugated hyperbilirubinemia through various mechanisms. 1, 2

• Hematoma resorption: Large hematomas can overwhelm hepatic conjugation capacity. 4

• Rare inherited disorders: Crigler-Najjar syndrome types 1 and 2 present with much higher bilirubin levels and are typically diagnosed in childhood. 5

If Conjugated Hyperbilirubinemia (Direct Bilirubin >35% of Total)

Conjugated hyperbilirubinemia indicates either hepatocellular injury or cholestatic disease and requires more extensive evaluation. 1, 2

Intrahepatic causes include:

• Viral hepatitis: Check hepatitis A, B, C serologies as part of initial workup. 1, 4

• Alcoholic liver disease: Obtain detailed alcohol history; alcohol commonly causes conjugated hyperbilirubinemia. 1

• Drug-induced liver injury: Common culprits include acetaminophen, penicillin, oral contraceptives, anabolic steroids, and chlorpromazine. 1

• Autoimmune hepatitis: Consider checking autoimmune antibody assays if other causes excluded. 1, 3

• Primary biliary cholangitis or primary sclerosing cholangitis: These cause intrahepatic cholestasis with elevated conjugated bilirubin. 1

Posthepatic (obstructive) causes include:

• Choledocholithiasis: Most common benign cause of posthepatic jaundice. 4

• Cholangitis: Biliary tract infection causing obstruction. 4

• Pancreatic disease: Pancreatitis or pancreatic malignancy can cause extrinsic biliary compression. 1, 6

• Cholangiocarcinoma or gallbladder cancer: Intrinsic biliary malignancies. 1

• Lymphoma or other malignancies: Can cause extrinsic biliary compression. 1

Essential Additional Laboratory Tests

Order the following tests concurrently with fractionated bilirubin: 1, 2, 3

• ALT, AST (hepatocellular injury markers)
• Alkaline phosphatase and GGT (cholestatic markers; GGT confirms hepatic origin of elevated alkaline phosphatase) 1, 2
• Albumin and prothrombin time/INR (synthetic liver function) 1, 2
• Complete blood count with differential and peripheral smear (hemolysis evaluation) 2

Imaging Strategy

If conjugated hyperbilirubinemia is present, obtain abdominal ultrasound as first-line imaging to evaluate for biliary obstruction and liver parenchymal disease, with 98% positive predictive value for liver parenchymal disease and 65-95% sensitivity for biliary obstruction. 1, 2 Ultrasound is the least invasive and least expensive imaging modality. 3

Critical Pitfalls to Avoid

• Do not overinterpret isolated mild unconjugated hyperbilirubinemia as significant liver disease—Gilbert syndrome is benign and requires only reassurance. 1, 2

• Remember that direct bilirubin is not synonymous with conjugated bilirubin—it includes delta bilirubin, which has a 21-day half-life and can cause persistent hyperbilirubinemia even after the underlying cause resolves. 2

• In cholestatic disease, check vitamin K status before interpreting elevated INR, as fat-soluble vitamin deficiencies are common and can mimic synthetic liver dysfunction. 2

• Do not obtain venous sample to "confirm" an elevated capillary bilirubin—this delays treatment without providing useful information. 1

Follow-Up Strategy

For mild isolated elevations with normal physical examination and intact hepatic function, perform close clinical follow-up with serial liver chemistry testing. 2 If bilirubin remains persistently elevated for ≥6 months or continues rising, expedite complete diagnostic evaluation including possible liver biopsy. 2