What are the causes of elevated bilirubin levels?

Causes of Elevated Bilirubin Levels

Elevated bilirubin levels can be classified into three main categories: prehepatic (hemolytic), hepatocellular, and post-hepatic (obstructive), each with distinct underlying pathologies and bilirubin profiles. 1

Classification Based on Bilirubin Type

Predominantly Unconjugated Hyperbilirubinemia (<20-30% conjugated)

• Gilbert syndrome: Most common cause of mild unconjugated hyperbilirubinemia in young adults with normal liver function tests 1, 2
• Hemolytic disorders:
  • ABO incompatibility (particularly in newborns) 3
  • Autoimmune hemolytic anemia 4
  • Spherocytosis and other red cell membrane disorders
  • Sickle cell disease
  • Thalassemias
• Crigler-Najjar syndrome: Severe genetic deficiency of glucuronyl transferase
• Ineffective erythropoiesis
• Drugs that inhibit bilirubin conjugation

Predominantly Conjugated Hyperbilirubinemia (>35% conjugated)

• Hepatocellular causes:

  • Viral hepatitis
  • Alcoholic liver disease
  • Non-alcoholic fatty liver disease
  • Drug-induced liver injury (DILI) 1
  • Autoimmune hepatitis
  • Primary biliary cirrhosis 4

• Obstructive/Cholestatic causes:

  • Gallstones
  • Biliary strictures
  • Pancreatic cancer
  • Cholangiocarcinoma
  • Primary sclerosing cholangitis
  • Dubin-Johnson syndrome
  • Rotor syndrome

Diagnostic Approach

Laboratory Evaluation

• Fractionated bilirubin (direct vs. indirect) is essential to determine the type of hyperbilirubinemia 1
• Complete blood count to assess for hemolysis
• Liver enzymes (ALT, AST, ALP, GGT) to evaluate liver function 1
• Albumin and prothrombin time/INR to assess synthetic liver function
• Autoimmune markers (ANA, ASMA, AMA) when autoimmune liver disease is suspected 1

Imaging Studies

• Abdominal ultrasound is the first-line imaging technique for suspected biliary obstruction (sensitivity 32-100%, specificity 71-97%) 1
• MRCP or CT with contrast may be necessary if bile ducts are dilated 1

Special Considerations

Gilbert Syndrome

• Affects 5-10% of the population 2
• Characterized by mild unconjugated hyperbilirubinemia
• Benign condition with no long-term health consequences
• Bilirubin levels may fluctuate with fasting, illness, or stress 1
• Recent evidence suggests potential protective effects against cardiovascular diseases and type 2 diabetes 2, 5

Drug-Induced Liver Injury (DILI)

• Can cause isolated hyperbilirubinemia without affecting other liver enzymes 1
• Typically shows a direct bilirubin fraction >35% of total bilirubin 1
• Medication history review is crucial for diagnosis

Severe Hyperbilirubinemia

• Significantly elevated total bilirubin (>3× ULN) with AST/ALT >5× ULN may indicate severe hepatitis requiring hospitalization 1
• In neonates, severe hyperbilirubinemia (e.g., >20 mg/dL) may require exchange transfusion to prevent kernicterus 3

Clinical Pearls

• Isolated mild elevation of unconjugated bilirubin in young adults with normal liver function tests is most likely Gilbert syndrome 1
• Abdominal ultrasound is indicated when bilirubin levels are significantly elevated (>3 mg/dL) to rule out biliary obstruction 1
• When evaluating hyperbilirubinemia, always consider potential comorbid conditions (e.g., hemolytic anemia in a patient with known liver disease) 4
• Mildly elevated bilirubin may have protective effects against oxidative stress-mediated diseases, particularly atherosclerotic conditions 5, 6

Monitoring and Follow-up

• For patients with severe hepatitis, liver enzymes and function tests should be checked daily until improvement begins 1
• For milder cases, monitoring every 3-7 days until normalization is recommended 1
• Poor prognostic indicators include development of hepatic encephalopathy, INR >1.5, and failure to improve with initial therapy 1