What can increase total bilirubin (TBili) levels?

Causes of Elevated Total Bilirubin (TBili) Levels

Total bilirubin levels can be increased by various prehepatic, intrahepatic, and posthepatic causes, with the most common being hemolysis, liver disease, and biliary obstruction. 1

Prehepatic Causes (Increased Bilirubin Production)

• Hemolytic anemias including sickle cell disease, thalassemia, hereditary spherocytosis, and glucose-6-phosphate dehydrogenase deficiency can lead to increased bilirubin production that overwhelms the liver's conjugation capacity 1
• Large hematoma resorption can cause transient elevation in unconjugated bilirubin 1
• Exercise-induced hemolysis can temporarily exceed the liver's conjugation capacity, leading to elevated levels of indirect bilirubin 2
• Dehydration during intense exercise can concentrate blood components, including bilirubin 2

Intrahepatic Causes (Impaired Uptake, Conjugation, or Excretion)

• Gilbert syndrome, affecting approximately 5% of the population, causes reduced activity of glucuronosyltransferase enzyme leading to unconjugated hyperbilirubinemia 1, 3
• Viral hepatitis (A, B, C, D, E, and Epstein-Barr virus) can disrupt transport of conjugated bilirubin 1, 4
• Alcoholic liver disease impairs hepatocyte function and bilirubin metabolism 1
• Autoimmune hepatitis causes immune-mediated damage to hepatocytes, affecting bilirubin processing 1
• Cholestatic disorders such as primary biliary cholangitis and primary sclerosing cholangitis cause conjugated hyperbilirubinemia 1
• Drug-induced liver injury from medications like acetaminophen, penicillin, oral contraceptives, estrogenic or anabolic steroids, and chlorpromazine 1
• Hydroxyurea can cause hepatotoxicity, particularly when used with antiretroviral drugs like didanosine and stavudine 5
• Cirrhosis affects all aspects of bilirubin metabolism, with decreased hepatic clearance and increased production due to portosystemic shunting and splenomegaly-induced hemolysis 1, 6

Posthepatic Causes (Biliary Obstruction)

• Gallstone disease including cholelithiasis, acute calculus cholecystitis, and choledocholithiasis can cause intrinsic biliary obstruction 1, 4
• Biliary tract infection such as cholangitis can cause obstruction and inflammation 1, 4
• Biliary malignancy including cholangiocarcinoma and gallbladder cancer can cause biliary obstruction 1, 4
• Pancreatic disorders such as pancreatitis and pancreatic tumors can cause extrinsic biliary obstruction 1
• Primary sclerosing cholangitis (PSC) can cause episodes of cholangitis with abrupt elevations of total bilirubin due to transient obstruction of strictured bile ducts 7

Special Considerations

• In neonates, physiological hyperbilirubinemia is common but may become pathological if high or prolonged 1, 8
• In patients with PSC, total bilirubin elevations are usually less than 15 mg/dL in cholangitis but may exceed this level with complete bile duct obstruction, which can occur with cholangiocarcinoma 7
• Elevated total bilirubin should be fractionated to determine the percentage derived from direct (conjugated) bilirubin, which helps narrow the differential diagnosis 7, 1
• Laboratory test interference: Hydroxyurea may falsely elevate results of uric acid, urea, or lactic acid assays 5

Diagnostic Approach

• Initial evaluation should determine whether hyperbilirubinemia is predominantly unconjugated or conjugated 1
• Ultrasound is the most useful initial imaging modality for evaluating conjugated hyperbilirubinemia, with high sensitivity for liver parenchymal disease 1, 4
• When elevations in liver tests abruptly occur in PSC patients, evaluation for a dominant stricture by magnetic resonance cholangiography or endoscopic retrograde cholangiography should be considered 7
• If exercise is suspected to be the cause of hyperbilirubinemia, it may be useful to repeat the test after 24-48 hours of rest 2

Remember that persistent hyperbilirubinemia due to any etiology warrants expeditious diagnostic evaluation to identify and address the underlying cause 1.