What are the potential causes of elevated bilirubin levels?

Potential Causes of Elevated Bilirubin Levels

Elevated bilirubin levels can be classified into predominantly unconjugated (<20-30% conjugated bilirubin) or predominantly conjugated (>35% conjugated bilirubin) hyperbilirubinemia, with specific causes for each type that require targeted diagnostic evaluation. 1

Classification of Hyperbilirubinemia

Predominantly Unconjugated Hyperbilirubinemia (<20-30% conjugated)

• Excess Bilirubin Production

  • Hemolytic disorders (intravascular or extravascular hemolysis)
  • Ineffective erythropoiesis
  • Hematoma resorption

• Impaired Liver Uptake

  • Certain medications (e.g., rifampin)
  • Portosystemic shunts
  • Sepsis

• Impaired Conjugation

  • Gilbert's syndrome (benign condition affecting 5-10% of population) 2
  • Crigler-Najjar syndrome
  • Neonatal jaundice
  • Medications (e.g., simeprevir, paritaprevir) 1

Predominantly Conjugated Hyperbilirubinemia (>35% conjugated)

• Hepatocellular Causes

  • Viral hepatitis
  • Alcoholic liver disease
  • Non-alcoholic fatty liver disease
  • Drug-induced liver injury
  • Cirrhosis
  • Hepatic encephalopathy (significantly increased direct bilirubin) 3

• Biliary Obstruction

  • Choledocholithiasis (gallstones)
  • Malignancy (pancreatic, biliary, or liver cancer)
  • Primary sclerosing cholangitis
  • Primary biliary cholangitis
  • Strictures

• Genetic Disorders

  • Dubin-Johnson syndrome (mutations in ABCC2 gene) 4
  • Rotor syndrome (mutations in SLCO1B1 and SLCO1B3 genes) 4

Diagnostic Approach

Initial Laboratory Evaluation

• Fractionated bilirubin levels (total, direct, indirect)
• Complete blood count with differential and peripheral smear
• Liver function tests (ALT, AST, alkaline phosphatase, γ-glutamyltransferase)
• Albumin, total protein, and prothrombin time/INR 1

Imaging Studies

• Abdominal ultrasound as first-line imaging for suspected biliary obstruction (sensitivity 32-100%, specificity 71-97%) 1
• MRI with MRCP for persistent clinical suspicion despite negative ultrasound 1
• Hepatobiliary scintigraphy for suspected bile leaks 1

Follow-up Recommendations

• For mild elevations (<2× ULN) with no other abnormalities: repeat testing in 2-4 weeks 1
• For moderate elevations (2-5× ULN): accelerated monitoring and complete diagnostic workup 1
• For severe elevations (>5× ULN): urgent diagnostic workup and consideration of hospitalization if symptoms present 1

Common Pitfalls to Avoid

1. Misinterpreting transient increases in bilirubin with certain medications like simeprevir or paritaprevir 1
2. Neglecting medication review when evaluating elevated bilirubin 1
3. Assuming normal aminotransferases rule out significant liver disease 1
4. Overlooking malignancy as a cause of isolated elevated alkaline phosphatase 1
5. Failing to consider benign conditions like Gilbert's syndrome, which affects 5-10% of the population and may be protective against cardiovascular disease 2
6. Not assessing bilirubin in relation to patient history and concurrent biochemical alterations 5

Remember that elevated bilirubin almost always indicates an underlying disease state, and proper classification into unconjugated or conjugated hyperbilirubinemia is essential for directing the diagnostic approach 6.