What causes elevated bilirubin levels?

Causes of Elevated Bilirubin

Elevated bilirubin results from three main pathophysiologic mechanisms: increased production (prehepatic), impaired hepatic processing (intrahepatic), or obstructed excretion (posthepatic), with the pattern of elevation—unconjugated versus conjugated—directing the diagnostic approach. 1

Prehepatic Causes (Increased Bilirubin Production)

Hemolytic processes overwhelm the liver's conjugation capacity, causing unconjugated hyperbilirubinemia:

• Hemolytic anemias including sickle cell disease, thalassemia, hereditary spherocytosis, and glucose-6-phosphate dehydrogenase (G6PD) deficiency increase bilirubin production beyond hepatic processing capacity 1
• Large hematoma resorption causes transient unconjugated bilirubin elevation as red blood cells break down 1
• Hemolysis appears to augment bilirubin neurotoxicity risk, particularly in neonates, through mechanisms beyond simply raising serum levels 2

Intrahepatic Causes (Impaired Hepatic Processing)

Defective Conjugation

• Gilbert syndrome affects 5-10% of the population with reduced glucuronosyltransferase activity, causing benign unconjugated hyperbilirubinemia that rarely exceeds 4-5 mg/dL 1, 3
• Crigler-Najjar syndrome represents severe glucuronosyltransferase deficiency, increasing bilirubin encephalopathy risk 3, 4

Hepatocellular Injury

• Viral hepatitis (A, B, C, D, E, Epstein-Barr virus) disrupts conjugated bilirubin transport and typically presents with transaminases >400 IU/mL 1
• Alcoholic liver disease impairs hepatocyte function and all aspects of bilirubin metabolism 1
• Autoimmune hepatitis causes immune-mediated hepatocyte damage affecting bilirubin processing 1
• Drug-induced liver injury from acetaminophen, penicillin, oral contraceptives, anabolic steroids, and chlorpromazine can cause hyperbilirubinemia, with cholestatic patterns presenting 2-12 weeks (up to one year) after drug initiation 1, 5
• Cirrhosis affects all bilirubin metabolism stages in advanced disease 1

Cholestatic Disorders

• Primary biliary cholangitis and primary sclerosing cholangitis cause conjugated hyperbilirubinemia through intrahepatic bile duct damage 1

Posthepatic Causes (Obstructed Excretion)

Biliary obstruction prevents conjugated bilirubin excretion into the intestine:

• Gallstone disease including cholelithiasis, acute calculus cholecystitis, and choledocholithiasis causes intrinsic biliary obstruction 1
• Cholangitis produces obstruction and inflammation 1
• Biliary malignancy (cholangiocarcinoma, gallbladder cancer) obstructs bile flow 1
• Pancreatic disorders including pancreatitis and pancreatic tumors cause extrinsic biliary compression 1

Defective Hepatocyte Transport

• Dubin-Johnson syndrome impairs bilirubin excretion into bile, causing conjugated hyperbilirubinemia 3, 4
• Rotor syndrome affects conjugated bilirubin re-uptake 3, 4

Critical Diagnostic Framework

The initial step is determining whether hyperbilirubinemia is predominantly unconjugated (>70-80% of total) or conjugated (>35% of total), which fundamentally narrows the differential diagnosis. 1, 6, 5

For Unconjugated Hyperbilirubinemia

• Obtain complete blood count with reticulocyte count, peripheral smear, LDH, and haptoglobin to differentiate hemolysis from Gilbert syndrome 6
• If hemolysis is excluded and conjugated bilirubin is <20-30% of total, Gilbert syndrome is confirmed 1, 6

For Conjugated Hyperbilirubinemia

• Ultrasound is the mandatory first-line imaging with 98% positive predictive value for liver parenchymal disease and 71-97% specificity for excluding biliary obstruction 5
• Measure hepatocellular enzymes (ALT, AST) and cholestatic enzymes (alkaline phosphatase, GGT) to distinguish hepatocellular from cholestatic patterns 5
• Obtain viral hepatitis serologies, autoimmune markers, and detailed medication/toxin history based on initial findings 1, 5

Special Population Considerations

• Neonatal conjugated hyperbilirubinemia >25 μmol/L requires urgent pediatric assessment for possible liver disease 1, 5
• Hemolysis in neonates lowers the bilirubin threshold for neurotoxicity, particularly in direct antiglobulin test (DAT)-positive isoimmune hemolytic disease 2

Common Pitfalls to Avoid

• Never assume Gilbert syndrome without confirming unconjugated fraction predominates (>70-80%) and excluding hemolysis with appropriate laboratory testing 6
• Recognize that "direct bilirubin" includes both conjugated bilirubin and delta bilirubin (albumin-bound with 21-day half-life), which can cause prolonged hyperbilirubinemia even after the underlying cause resolves 5
• Do not delay evaluation of bilirubinuria—most cases represent true pathology requiring diagnosis, and many patients with significant liver disease remain asymptomatic until advanced stages 5
• For suspected drug-induced cholestatic injury, immediate discontinuation is critical as continued exposure risks progression to vanishing bile duct syndrome causing irreversible biliary fibrosis 5