Causes of Elevated Bilirubin
Elevated bilirubin levels can be categorized into prehepatic, intrahepatic, and posthepatic causes, with each category representing distinct pathophysiological mechanisms affecting bilirubin metabolism. 1
Prehepatic Causes (Unconjugated Hyperbilirubinemia)
- Hemolytic anemias (sickle cell disease, thalassemia, hereditary spherocytosis, G6PD deficiency) lead to increased bilirubin production that overwhelms the liver's conjugation capacity 1
- Large hematoma resorption causes transient elevation in unconjugated bilirubin due to increased red blood cell breakdown 1, 2
- Pathologic hemolysis of any etiology results in excess bilirubin production 3
Intrahepatic Causes
Unconjugated Hyperbilirubinemia
- Gilbert syndrome affects approximately 5% of Americans and is characterized by reduced glucuronosyltransferase activity 1, 4
- Impaired liver uptake of bilirubin from plasma 3
- Defects in UDP-glucuronosyltransferase leading to impaired conjugation 3
Conjugated Hyperbilirubinemia
- Viral hepatitis (hepatitis A, B, C, D, E, and Epstein-Barr virus) disrupts transport of conjugated bilirubin 1
- Alcoholic liver disease impairs hepatocyte function and bilirubin metabolism 1
- Autoimmune hepatitis causes immune-mediated damage to hepatocytes 1
- Cholestatic disorders (primary biliary cholangitis, primary sclerosing cholangitis) 1
- Drug-induced liver injury (acetaminophen, penicillin, oral contraceptives, estrogenic/anabolic steroids, chlorpromazine) 1
- Cirrhosis affects all aspects of bilirubin metabolism 1
Posthepatic Causes (Conjugated Hyperbilirubinemia)
- Gallstone disease (cholelithiasis, acute calculus cholecystitis, choledocholithiasis) causes intrinsic biliary obstruction 1, 2
- Biliary tract infections such as cholangitis cause obstruction and inflammation 1
- Biliary malignancies (cholangiocarcinoma, gallbladder cancer) lead to biliary obstruction 1
- Pancreatic disorders (pancreatitis, pancreatic tumors) cause extrinsic biliary obstruction 1, 2
- Any condition preventing bile from reaching the small bowel through bile ducts 3
Special Populations
- Neonatal hyperbilirubinemia represents a physiological increase in unconjugated bilirubin that may become pathological if high or prolonged 1
- Urgent assessment for liver disease is essential in neonates if conjugated bilirubin exceeds 25 μmol/L 1
Diagnostic Approach
- Initial evaluation should determine whether hyperbilirubinemia is predominantly unconjugated or conjugated 1, 5
- Urine testing for bilirubin indicates conjugated hyperbilirubinemia when positive 2
- The American Gastroenterological Association recommends initial liver function testing (serum bilirubin, ALT, AST, alkaline phosphatase, GGT) when bilirubin is detected in urine 1
- Ultrasound is the most useful initial imaging modality for evaluating conjugated hyperbilirubinemia 1
- Additional testing may include viral hepatitis serologies and advanced imaging (CT, MRI with MRCP) based on clinical suspicion 1
- Interpretation of abnormal liver chemistries must consider the patient's clinical context, including risk factors, medications, alcohol consumption, and signs/symptoms of hepatic disease 1
Clinical Significance
- While typically indicating underlying disease, mild unconjugated hyperbilirubinemia in Gilbert syndrome has been associated with reduced prevalence of cardiovascular diseases, type 2 diabetes mellitus, and related mortality 4
- Persistent hyperbilirubinemia of any etiology warrants expeditious diagnostic evaluation 1