What are the causes of bilirubin in urine?

Causes of Bilirubin in Urine

The presence of bilirubin in urine is primarily caused by conjugated hyperbilirubinemia, which results from liver parenchymal disease or obstruction of the biliary system. 1

Understanding Bilirubin Metabolism

Bilirubin is predominantly a by-product of the breakdown of hemoglobin's heme component by the reticuloendothelial system. It exists in two forms:

• Unconjugated (indirect) bilirubin: Insoluble form transported to the liver 1
• Conjugated (direct) bilirubin: Soluble form that can be excreted 1

Only conjugated bilirubin appears in urine, as unconjugated bilirubin is bound to albumin and too large to be filtered by the kidneys 1

Causes of Bilirubin in Urine

1. Intrahepatic Causes

• Hepatic inflammation disrupting conjugated bilirubin transport:
  • Viral hepatitis (hepatitis A, B, C, D, E, Epstein-Barr virus) 1
  • Alcohol-induced liver disease 1
  • Autoimmune hepatitis 1
  • Drug-induced liver injury (DILI) from medications such as:
    • Acetaminophen
    • Penicillin
    • Oral contraceptives
    • Estrogenic or anabolic steroids
    • Chlorpromazine (Thorazine) 1
• Cholestatic liver diseases:
  • Primary biliary cholangitis 1
  • Primary sclerosing cholangitis 1
  • Hereditary cholestatic disorders (affecting bile acid transporters, tight junction proteins, etc.) 1

2. Posthepatic (Obstructive) Causes

• Intrinsic biliary obstruction:
  • Cholelithiasis (gallstones) 1
  • Acute calculus cholecystitis 1
  • Choledocholithiasis (stones in bile ducts) 1
  • Cholangitis (bile duct inflammation) 1
  • Cholangiocarcinoma (bile duct cancer) 1
  • Gallbladder cancer 1
• Extrinsic biliary obstruction:
  • Pancreatic tumors causing biliary compression 1
  • Pancreatitis 1
  • Diffuse malignancy (e.g., lymphoma) 1

3. Neonatal Causes

• Neonatal cholestasis (jaundice due to conjugated bilirubin lasting >2-3 weeks after birth):
  • Genetic and metabolic causes account for 25-30% of cases 1
  • Biliary atresia 1
  • Alpha-1-antitrypsin deficiency (particularly ZZ phenotype) 1

Clinical Significance and Evaluation

When bilirubin is detected in urine:

• It indicates the presence of conjugated hyperbilirubinemia 1
• Fractionation of total bilirubin should be performed to determine the percentage derived from direct bilirubin 1
• Elevated alkaline phosphatase (ALP) should be confirmed to be of hepatobiliary origin with gamma-glutamyl transferase (GGT) and/or ALP isoenzyme fractionation 1
• Ultrasound is the most useful initial imaging modality, with a positive predictive value of 98% and sensitivity of 65-95% for liver parenchymal disease 1

Important Considerations

• Isolated unconjugated (indirect) hyperbilirubinemia, as seen in Gilbert's syndrome (affecting 5-10% of the population) or hemolysis, does NOT result in bilirubinuria 1
• Unexpected positive urine bilirubin tests may be clinically significant - in one study, 85% of patients with unexpected positive urine bilirubin had abnormal liver function tests when subsequently tested 2
• Bilirubin in urine may be an early indicator of liver disease before other clinical signs appear 2

Diagnostic Approach

1. Confirm that bilirubin in urine is due to conjugated hyperbilirubinemia by measuring serum total and direct bilirubin 1
2. Evaluate for elevated liver enzymes (AST, ALT) and cholestatic markers (ALP, GGT) 1
3. Perform abdominal ultrasound to assess for biliary obstruction and liver parenchymal disease 1
4. Consider further imaging (MRI, ERCP) if a dominant biliary stricture is suspected 1
5. Evaluate for potential drug-induced causes by reviewing medication history 1

Bilirubin in urine is never normal and always warrants further investigation to determine the underlying cause of conjugated hyperbilirubinemia 1.