What causes an increase in total bilirubin?

Causes of Total Bilirubin Elevation

Total bilirubin elevations can be classified into predominantly unconjugated (<20-30% conjugated) or predominantly conjugated (>35% conjugated) hyperbilirubinemia, with specific underlying causes for each type. 1

Classification of Hyperbilirubinemia

Predominantly Unconjugated Hyperbilirubinemia (<20-30% conjugated)

• Increased bilirubin production

  • Hemolytic disorders (intravascular or extravascular hemolysis)
  • Ineffective erythropoiesis
  • Blood transfusions and hematoma resorption

• Impaired hepatic uptake or conjugation

  • Gilbert's syndrome (affects 5-10% of population) 2
  • Crigler-Najjar syndrome (types I and II)
  • Drug-induced impairment (e.g., rifampicin) 3
  • Neonatal hyperbilirubinemia

Predominantly Conjugated Hyperbilirubinemia (>35% conjugated)

• Hepatocellular disorders

  • Viral hepatitis
  • Alcoholic/non-alcoholic fatty liver disease
  • Drug-induced liver injury
  • Cirrhosis

• Biliary obstruction

  • Choledocholithiasis
  • Biliary strictures
  • Pancreatic or biliary malignancy
  • Primary biliary cholangitis

• Genetic disorders

  • Dubin-Johnson syndrome
  • Rotor syndrome (deficiency in OATP1B proteins) 4

Medication-Related Causes

Medications are common causes of bilirubin elevation:

• Direct hepatotoxicity: Medications can cause direct liver injury with pattern of:

  • Hepatocellular (elevated ALT/AST)
  • Cholestatic (elevated ALP/GGT)
  • Mixed pattern

• Specific drug examples:

  • Rifampicin can cause hepatotoxicity with elevations in serum bilirubin, alkaline phosphatase, and transaminases 3
  • Hy's law pattern (ALT >3× ULN and bilirubin >2× ULN) suggests high risk of severe drug-induced liver injury 1

Special Clinical Scenarios

• Post-surgical hyperbilirubinemia: After extracorporeal circulation surgery, hyperbilirubinemia occurs in approximately 25% of patients, with 80% showing increases in both conjugated and unconjugated bilirubin 5

• Primary biliary cirrhosis with hemolysis: Patients with primary biliary cirrhosis may develop concurrent hemolytic anemia, causing disproportionate elevation of bilirubin compared to other liver enzymes 6

• Liver-blood cycling impairment: In cholestatic and parenchymal liver diseases, impaired cycling of conjugated bilirubin between liver and blood contributes to jaundice 4

Diagnostic Approach

For patients with elevated total bilirubin:

1. Fractionation of bilirubin (direct/indirect) to determine predominant type 1

2. Initial laboratory testing should include:

   • 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

3. Imaging studies based on clinical suspicion:

   • Abdominal ultrasound as first-line for suspected biliary obstruction (sensitivity 32-100%, specificity 71-97%) 1
   • MRI with MRCP for persistent clinical suspicion despite negative ultrasound 1
   • CT abdomen with contrast for suspected pancreatic or biliary malignancy 1

Monitoring 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

• Overlooking hemolysis as a cause of unconjugated hyperbilirubinemia
• Assuming normal aminotransferases rule out significant liver disease 1
• Misinterpreting transient increases in bilirubin with certain medications 1
• Neglecting to confirm hepatobiliary origin of elevated alkaline phosphatase 1
• Failing to consider medication-induced bilirubin elevations 1