What are the causes of increased bilirubin levels?

Causes of Increased Bilirubin

Elevated bilirubin results from disruption at any stage of bilirubin metabolism—from overproduction through hemolysis, impaired hepatic conjugation, intrahepatic dysfunction, or biliary obstruction—with the specific pattern of elevation (unconjugated vs. conjugated) directing the diagnostic approach. 1

Classification by Mechanism

Prehepatic Causes (Unconjugated Hyperbilirubinemia)

Hemolytic disorders cause bilirubin overproduction that overwhelms the liver's conjugation capacity 1, 2:

• Sickle cell disease, thalassemia, hereditary spherocytosis, and glucose-6-phosphate dehydrogenase deficiency 1
• Large hematoma resorption causing transient unconjugated bilirubin elevation 1
• Exercise-induced hemolysis with dehydration concentrating blood components 2

Impaired conjugation from reduced glucuronosyltransferase activity 1:

• Gilbert syndrome affects 5-10% of the population, with unconjugated bilirubin rarely exceeding 4-5 mg/dL and conjugated bilirubin <20-30% of total 1, 3
• Crigler-Najjar syndrome (more severe hereditary conjugation defect) 4

Intrahepatic Causes (Mixed or Conjugated Hyperbilirubinemia)

Hepatocellular injury disrupts bilirubin uptake, conjugation, and excretion 1, 2:

• Viral hepatitis (A, B, C, D, E, Epstein-Barr virus) disrupts conjugated bilirubin transport 1, 2
• Alcoholic liver disease impairs hepatocyte function and bilirubin metabolism 5, 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
• Cirrhosis affects all aspects of bilirubin metabolism 1
• Sepsis and low perfusion states 5

Cholestatic disorders cause conjugated hyperbilirubinemia 1, 2:

• Primary biliary cholangitis and primary sclerosing cholangitis 1, 2
• Dubin-Johnson and Rotor syndromes (hereditary conjugated hyperbilirubinemia) 4, 3

Posthepatic Causes (Conjugated Hyperbilirubinemia)

Biliary obstruction prevents conjugated bilirubin excretion 1, 2:

• Choledocholithiasis (common bile duct stones) is among the most common causes in the United States 5, 1, 2
• Acute calculous cholecystitis 1, 2
• Cholangitis causes obstruction with inflammation 2, 6
• Cholangiocarcinoma and gallbladder cancer 1, 2
• Pancreatic disorders (pancreatitis, pancreatic tumors) cause extrinsic biliary compression 1, 2

Geographic and Demographic Variations

In the United States, the four most common causes are hepatitis, alcoholic liver disease, common bile duct obstruction (gallstone or tumor), and drug toxicity 5. European studies show malignancy as the most common etiology of severe jaundice, followed by sepsis/shock (22-27%), cirrhosis (21%), and CBD stones (13%) 5.

Diagnostic Approach

Initial fractionation determines whether hyperbilirubinemia is predominantly unconjugated (indirect) or conjugated (direct), calculated as Total bilirubin minus Direct bilirubin 1, 2:

• Unconjugated predominance (>70-80% of total) suggests hemolysis or impaired conjugation 1
• Conjugated predominance (>35% of total) indicates hepatocellular disease or biliary obstruction 6

For conjugated hyperbilirubinemia, ultrasound is the mandatory first-line imaging with 98% positive predictive value for cirrhosis and 71-97% specificity for excluding biliary obstruction 6. Additional testing includes viral hepatitis serologies, autoimmune markers, and liver enzymes (ALT, AST, alkaline phosphatase, GGT) 1, 6.

Critical Clinical Pitfalls

Delta bilirubin (albumin-bound conjugated bilirubin with 21-day half-life) is included in "direct" bilirubin measurements, causing prolonged hyperbilirubinemia even after resolution of the underlying cause 6. This explains why direct bilirubin may remain elevated longer than expected clinically.

Neonatal conjugated hyperbilirubinemia >25 μmol/L requires urgent pediatric assessment for possible liver disease 1, 6.