Causes of Elevated Bilirubin in Adults
Elevated bilirubin in adults can be categorized into prehepatic, intrahepatic, and posthepatic causes, with the most common etiologies in the United States being hepatitis, alcoholic liver disease, common bile duct obstruction by gallstones or tumors, and drug-induced liver injury. 1, 2
Classification by Mechanism
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 causes transient elevation in unconjugated bilirubin 2, 3
Intrahepatic Causes
Unconjugated hyperbilirubinemia:
Conjugated hyperbilirubinemia:
- Viral hepatitis (A, B, C, D, E, Epstein-Barr virus) disrupts transport of conjugated bilirubin 2, 6
- Alcoholic liver disease impairs hepatocyte function and bilirubin metabolism 2, 1
- Autoimmune hepatitis causes immune-mediated damage to hepatocytes 2
- Drug-induced liver injury (acetaminophen, penicillin, oral contraceptives, steroids, chlorpromazine) 1, 2
- Sepsis/shock (identified as a common cause of jaundice in some studies) 1
- Cirrhosis affects all aspects of bilirubin metabolism 1, 2
- Cholestatic disorders (primary biliary cholangitis, primary sclerosing cholangitis) 2
Posthepatic Causes (Conjugated Hyperbilirubinemia)
- Gallstone disease (cholelithiasis, acute calculus cholecystitis, choledocholithiasis) causing intrinsic biliary obstruction 1, 2
- Biliary tract infection (cholangitis) causing obstruction and inflammation 2
- Biliary and pancreatic malignancies (cholangiocarcinoma, gallbladder cancer, pancreatic tumors) causing biliary obstruction 1, 2
- Pancreatitis causing extrinsic biliary compression 2
Epidemiology of Causes
The prevalence of different causes varies by geographic location and clinical setting:
In the United States, the most common causes are: 1
- Hepatitis
- Alcoholic liver disease
- Common bile duct obstruction (gallstones or tumors)
- Drug or herbal toxicity
In European studies, malignancy was identified as the most common cause of severe jaundice 1
A US-based study found the following distribution: 1
- Sepsis (22%)
- Decompensation of pre-existing liver disease (20.5%)
- Alcoholic hepatitis (16%)
- Gallstone disease (14%)
- Gilbert syndrome (5.6%)
- Malignancy (6.2%)
- Hemolysis (2.5%)
Diagnostic Considerations
- Initial evaluation should determine whether hyperbilirubinemia is predominantly unconjugated or conjugated, which guides the differential diagnosis 2, 6
- Presence of urine bilirubin indicates conjugated hyperbilirubinemia 3
- For isolated unconjugated hyperbilirubinemia with normal liver enzymes, consider Gilbert syndrome (affects 5-10% of population) 4
- In Gilbert syndrome, conjugated bilirubin should be less than 20-30% of total bilirubin, in the absence of hemolysis 1
- Persistent isolated elevations in direct bilirubin in patients with underlying liver disease may indicate drug-induced liver injury 1
Clinical Pitfalls and Caveats
- The terms "direct" and "conjugated" hyperbilirubinemia are often incorrectly used interchangeably; direct bilirubin includes both conjugated fraction and delta bilirubin (bound to albumin) 1
- Delta bilirubin has a half-life of approximately 21 days, which explains why direct hyperbilirubinemia may persist longer than expected 1
- In patients with cholestatic liver disease, vitamin K deficiency may cause prolonged INR that could be mistaken for worsening liver function 1
- An isolated elevation of total bilirubin (even when predominantly direct) without elevation of liver enzymes should not be automatically considered drug-induced liver injury 1
- Patients with advanced cirrhosis typically have an altered AST to ALT ratio >1.0 (instead of normal 0.8) and may not manifest the same degree of ALT elevation expected with drug-induced liver injury 1