Causes of Elevated Bilirubin
Elevated bilirubin results from three main pathophysiologic categories: prehepatic (increased production), intrahepatic (impaired hepatic processing), or posthepatic (biliary obstruction), and the first critical step is determining whether the elevation is predominantly unconjugated or conjugated. 1
Algorithmic Approach to Classification
The pattern of bilirubin elevation directs your differential diagnosis:
Unconjugated (Indirect) Hyperbilirubinemia
When indirect bilirubin comprises >70-80% of total bilirubin, consider:
Prehepatic causes:
- Hemolytic anemias including sickle cell disease, thalassemia, hereditary spherocytosis, and G6PD deficiency overwhelm the liver's conjugation capacity 1, 2
- Large hematoma resorption causes transient unconjugated elevation 1, 3
- Exercise-induced hemolysis temporarily exceeds conjugation capacity 2, 3
Intrahepatic causes:
- Gilbert syndrome (5-10% of population) results from reduced glucuronosyltransferase activity, with total bilirubin rarely exceeding 4-5 mg/dL and conjugated bilirubin <20-30% of total 1, 4
- Fasting, illness, or stress exacerbate Gilbert syndrome 3
Conjugated (Direct) Hyperbilirubinemia
When direct bilirubin is elevated, the pathology lies in hepatic excretion or biliary obstruction:
Intrahepatic causes:
- Viral hepatitis (A, B, C, D, E, EBV) disrupts conjugated bilirubin transport, typically with AST/ALT >400 IU/mL 1, 2
- Alcoholic liver disease impairs hepatocyte function and bilirubin metabolism 1, 2
- Drug-induced liver injury from acetaminophen, penicillin, oral contraceptives, anabolic steroids, chlorpromazine 1, 2
- Autoimmune hepatitis causes immune-mediated hepatocyte damage 1, 2
- Cholestatic disorders including primary biliary cholangitis and primary sclerosing cholangitis 1, 2
- Cirrhosis affects all aspects of bilirubin metabolism 1
Posthepatic causes:
- Gallstone disease (cholelithiasis, acute cholecystitis, choledocholithiasis) causes intrinsic biliary obstruction 1, 2
- Cholangitis produces obstruction and inflammation 2
- Biliary malignancy (cholangiocarcinoma, gallbladder cancer) obstructs bile flow 1, 2
- Pancreatic disorders (pancreatitis, pancreatic tumors) cause extrinsic biliary compression 1, 2
Critical Diagnostic Steps
Initial laboratory evaluation:
- Fractionate total bilirubin into direct and indirect components to narrow the differential 1, 2, 3
- Obtain liver function tests (ALT, AST, alkaline phosphatase, GGT) when bilirubin is detected 1
- Check complete blood count to evaluate for hemolysis 5
Imaging approach:
- Ultrasound is the initial imaging modality of choice for conjugated hyperbilirubinemia, with high sensitivity for liver parenchymal disease and high specificity for biliary obstruction 1, 2
- Advanced imaging (CT, MRI with MRCP) may be necessary based on initial findings 1
Critical Pitfalls to Avoid
Distinguish "direct" from "conjugated" bilirubin: Direct bilirubin includes both conjugated bilirubin and delta bilirubin, which can persist in serum after resolution of acute hepatobiliary injury 1
Context matters for interpretation: Always assess risk factors, medications, alcohol consumption, and clinical signs of hepatic disease rather than interpreting laboratory values in isolation 1
Neonatal considerations: In neonates, conjugated bilirubin >25 μmol/L requires urgent assessment for liver disease 1
Primary sclerosing cholangitis patients: Abrupt bilirubin elevations warrant evaluation for dominant stricture by MRCP or ERCP 2
Exercise-related elevation: If suspected, repeat testing after 24-48 hours of rest 2
Wilson disease presentation: Consider when bilirubin >10 mg/dL (mainly indirect) with Coombs-negative hemolysis and altered copper metabolism 1