What are the causes of elevated bilirubin levels?

Causes of Elevated Bilirubin

Elevated bilirubin levels can be categorized into three main phases of bilirubin metabolism: prehepatic, intrahepatic, and posthepatic causes, each with distinct pathophysiological mechanisms. 1

Prehepatic Causes (Predominantly Unconjugated Hyperbilirubinemia)

• Hemolytic anemias: Excessive breakdown of red blood cells leads to increased bilirubin production that can overwhelm the liver's conjugation capacity 1

  • Sickle cell disease
  • Thalassemia
  • Hereditary spherocytosis
  • Glucose-6-phosphate dehydrogenase deficiency

• Large hematoma resorption: Absorption of blood from large hematomas can cause transient elevation in unconjugated bilirubin 1, 2

Intrahepatic Causes

Unconjugated Hyperbilirubinemia

• Gilbert syndrome: A benign hereditary disorder affecting 5% of the American population, characterized by reduced activity of the enzyme glucuronosyltransferase 1, 3

Conjugated Hyperbilirubinemia

• Viral hepatitis: Inflammation disrupts transport of conjugated bilirubin 1

  • Hepatitis A, B, C, D, E
  • Epstein-Barr virus infection

• Alcoholic liver disease: Impairs hepatocyte function and bilirubin metabolism 1

• Autoimmune hepatitis: Immune-mediated damage to hepatocytes affects bilirubin processing 1

• Cholestatic disorders: 1

  • Primary biliary cholangitis
  • Primary sclerosing cholangitis

• Drug-induced liver injury: Multiple medications can cause hyperbilirubinemia 1

  • Acetaminophen
  • Penicillin
  • Oral contraceptives
  • Estrogenic or anabolic steroids
  • Chlorpromazine (Thorazine)

• Cirrhosis: Advanced liver disease affects all aspects of bilirubin metabolism 1

Posthepatic Causes (Predominantly Conjugated Hyperbilirubinemia)

Intrinsic Biliary Obstruction

• Gallstone disease: 1

  • Cholelithiasis
  • Acute calculus cholecystitis
  • Choledocholithiasis

• Biliary tract infection: Cholangitis can cause obstruction and inflammation 1, 2

• Biliary malignancy: 1

  • Cholangiocarcinoma
  • Gallbladder cancer

Extrinsic Biliary Obstruction

• Pancreatic disorders: 1

  • Pancreatitis
  • Pancreatic tumors

• Other malignancies: Diffuse malignancies like lymphoma can compress biliary structures 1

Special Populations

• Neonatal hyperbilirubinemia: Physiological increase in unconjugated bilirubin that may become pathological if high or prolonged 1

  • In neonates with conjugated bilirubin >25 μmol/L, urgent assessment for liver disease is essential 1

• Hepatic encephalopathy: Associated with significantly increased levels of direct (conjugated) bilirubin 4

Diagnostic Approach

• Initial evaluation: Determine whether hyperbilirubinemia is predominantly unconjugated or conjugated, which helps narrow the differential diagnosis 1, 5

• Imaging assessment: Ultrasound is the most useful initial imaging modality for evaluating conjugated hyperbilirubinemia 1

  • High sensitivity (65-95%) for liver parenchymal disease
  • Variable sensitivity (32-100%) but high specificity (71-97%) for biliary obstruction

• Additional testing: Based on clinical suspicion and initial findings 5, 2

  • Liver function tests
  • Complete blood count (to assess for hemolysis)
  • Viral hepatitis serologies
  • Advanced imaging (CT, MRI with MRCP) for suspected biliary obstruction

Clinical Pearls

• Isolated unconjugated hyperbilirubinemia in the absence of hemolysis is virtually always Gilbert syndrome, a benign condition 1, 3

• The presence of conjugated hyperbilirubinemia always indicates pathology and requires thorough investigation 1, 2

• Ultrasound is the first-line imaging modality for evaluating hyperbilirubinemia, particularly for detecting biliary obstruction 1

• Medications are a common and often overlooked cause of hyperbilirubinemia 1