What are the causes of increased bilirubin levels?

Causes of Elevated Bilirubin Levels

Elevated bilirubin levels can be categorized into three main pathophysiological mechanisms: prehepatic (increased production), intrahepatic (impaired processing), and posthepatic (obstructed excretion) causes, each requiring specific diagnostic approaches and management strategies. 1

Prehepatic Causes (Increased Bilirubin Production)

• 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 1
• Exercise-induced hemolysis can temporarily exceed the liver's conjugation capacity 2
• Dehydration during intense exercise can concentrate blood components, including bilirubin 2

Intrahepatic Causes (Impaired Bilirubin Processing)

• Gilbert syndrome affects approximately 5% of the American population, characterized by reduced glucuronosyltransferase activity leading to unconjugated hyperbilirubinemia 1, 3
• Viral hepatitis (A, B, C, D, E, Epstein-Barr virus) disrupts transport of conjugated bilirubin 1, 2
• Alcoholic liver disease impairs hepatocyte function and bilirubin metabolism 1, 2
• Autoimmune hepatitis causes immune-mediated damage to hepatocytes 1, 2
• Cholestatic disorders (primary biliary cholangitis, primary sclerosing cholangitis) cause conjugated hyperbilirubinemia 1, 2
• Drug-induced liver injury from medications like acetaminophen, penicillin, oral contraceptives, estrogenic or anabolic steroids, and chlorpromazine 1, 2
• Cirrhosis affects all aspects of bilirubin metabolism 1
• Dubin-Johnson syndrome (mutations in ABCC2 gene) and Rotor syndrome (mutations in SLCO1B1 and SLCO1B3 genes) are inherited conditions causing conjugated hyperbilirubinemia 4

Posthepatic Causes (Obstructed Bilirubin Excretion)

• Gallstone disease (cholelithiasis, acute calculus cholecystitis, choledocholithiasis) causes intrinsic biliary obstruction 1, 2
• Biliary tract infections such as cholangitis cause obstruction and inflammation 1, 2
• Biliary malignancies (cholangiocarcinoma, gallbladder cancer) cause biliary obstruction 1, 2
• Pancreatic disorders (pancreatitis, pancreatic tumors) cause extrinsic biliary compression 1, 2
• Primary sclerosing cholangitis can cause episodes of cholangitis with abrupt elevations of total bilirubin due to transient obstruction of strictured bile ducts 2

Special Populations

• Neonatal hyperbilirubinemia is a physiological increase in unconjugated bilirubin that may become pathological if high or prolonged 1
• Hepatic encephalopathy is associated with significantly increased glucuronidated (direct) bilirubin levels 5

Diagnostic Approach

• Initial evaluation should determine whether hyperbilirubinemia is predominantly unconjugated or conjugated, which helps narrow the differential diagnosis 1, 2
• Presence of bilirubin in urine indicates conjugated hyperbilirubinemia, typically caused by parenchymal liver disease or biliary obstruction 6
• Ultrasound is the most useful initial imaging modality for evaluating conjugated hyperbilirubinemia, with high sensitivity for liver parenchymal disease and high specificity for biliary obstruction 1, 2, 6
• Additional testing, including viral hepatitis serologies and advanced imaging (CT, MRI with MRCP), may be necessary based on clinical suspicion 1, 6
• In Gilbert's syndrome, conjugated bilirubin is less than 20-30% of total bilirubin 1
• For suspected exercise-induced hyperbilirubinemia, repeat testing after 24-48 hours of rest may be useful 2

Clinical Significance

• While traditionally viewed as potentially toxic, mild elevations in bilirubin (particularly in Gilbert syndrome) have been associated with reduced prevalence of chronic diseases including cardiovascular diseases, type 2 diabetes, and cancer 3, 7
• Elevated direct bilirubin is significantly increased in hepatic encephalopathy, while decreased in conditions like uremia, nephrotic syndrome, and preeclampsia 5
• Mutations in genes responsible for bilirubin transport may increase susceptibility to drug toxicity 4

Common Pitfalls and Caveats

• It is important to distinguish between "direct" and "conjugated" hyperbilirubinemia, as direct bilirubin includes both conjugated bilirubin and delta bilirubin 1
• Persistent hyperbilirubinemia due to any etiology warrants expeditious diagnostic evaluation 1
• Interpretation of abnormal liver chemistries must always consider the clinical context, including risk factors, medications, alcohol consumption, and signs/symptoms of hepatic disease 1
• In neonates and infants, conjugated bilirubin >25 μmol/L requires urgent pediatric assessment for possible liver disease 1, 6