What causes elevated total bilirubin?

Causes of Elevated Total Bilirubin

Elevated total bilirubin is caused by disruptions in bilirubin metabolism at prehepatic (increased production), intrahepatic (impaired uptake or conjugation), or posthepatic (obstructed excretion) levels, with Gilbert's syndrome being the most common cause of isolated elevation. 1, 2

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 2
• Large hematoma resorption can cause transient elevation in unconjugated bilirubin 2
• Exercise-induced hemolysis can temporarily exceed the liver's conjugation capacity 3

Intrahepatic Causes

Unconjugated Hyperbilirubinemia

• Gilbert's syndrome - a benign hereditary disorder affecting 5% of the population with reduced activity of glucuronosyltransferase enzyme 1, 2
• Crigler-Najjar syndrome - more severe inherited disorder of bilirubin conjugation 4, 5

Conjugated Hyperbilirubinemia

• Viral hepatitis (A, B, C, D, E, Epstein-Barr virus) disrupts transport of conjugated bilirubin 2, 3
• Alcoholic liver disease impairs hepatocyte function and bilirubin metabolism 2, 3
• Autoimmune hepatitis causes immune-mediated damage to hepatocytes 2, 3
• Drug-induced liver injury (acetaminophen, penicillin, oral contraceptives, steroids, chlorpromazine) 2, 3
• Cirrhosis affects all aspects of bilirubin metabolism 2
• Inherited disorders: Dubin-Johnson syndrome (mutations in ABCC2 gene) and Rotor syndrome (mutations in SLCO1B1 and SLCO1B3 genes) 6, 5

Posthepatic Causes (Conjugated Hyperbilirubinemia)

• Gallstone disease (cholelithiasis, acute calculus cholecystitis, choledocholithiasis) causes intrinsic biliary obstruction 2, 3
• Biliary tract infection (cholangitis) causes obstruction and inflammation 2, 3
• Biliary malignancy (cholangiocarcinoma, gallbladder cancer) causes biliary obstruction 2, 3
• Pancreatic disorders (pancreatitis, pancreatic tumors) cause extrinsic biliary obstruction 2, 3
• Primary sclerosing cholangitis can cause episodes of cholangitis with abrupt bilirubin elevations 3

Diagnostic Approach

• Determine whether hyperbilirubinemia is predominantly unconjugated or conjugated to narrow the differential diagnosis 2, 3
• If unconjugated bilirubin predominates and there is no evidence of hemolysis, Gilbert's syndrome is the most likely diagnosis 1
• For conjugated hyperbilirubinemia, ultrasound is the most useful initial imaging modality with high sensitivity for liver parenchymal disease 2, 3
• Additional testing including viral hepatitis serologies and advanced imaging (CT, MRI with MRCP) may be necessary based on clinical suspicion 2

Special Populations

• Neonatal hyperbilirubinemia is a physiological increase in unconjugated bilirubin that may become pathological if high or prolonged 1
• In neonates and infants with conjugated bilirubin >25 μmol/L, urgent assessment for liver disease is essential 1

Clinical Pearls and Pitfalls

• Albumin levels, often measured alongside bilirubin, can be reduced in many clinical situations beyond liver disease (sepsis, inflammatory disorders, nephrotic syndrome, malabsorption) and should not be overinterpreted 1
• Persistent hyperbilirubinemia of any etiology warrants expeditious diagnostic evaluation 2
• Interpretation of abnormal liver chemistries must always consider the clinical context, including risk factors, medications, alcohol consumption, and signs/symptoms of hepatic disease 2
• Mutations in genes responsible for bilirubin transport may increase susceptibility to drug toxicity, even in seemingly benign conditions like Dubin-Johnson and Rotor syndromes 6