What is bilirubin?

What is Bilirubin?

Bilirubin is a yellow-orange pigment produced from the breakdown of heme rings during red blood cell metabolism, which exists in both unconjugated and conjugated forms and serves as an important clinical biomarker for liver and biliary function. 1

Bilirubin Formation and Metabolism

Bilirubin metabolism can be divided into three distinct phases:

1. Prehepatic Phase:

   • Bilirubin is formed from the breakdown of heme rings, primarily from hemoglobin in aging red blood cells processed by the reticuloendothelial system
   • Initially produced as unconjugated (indirect) bilirubin, which is insoluble and bound to albumin for transport in blood
   • Excessive production can occur in hemolytic conditions (sickle cell disease, thalassemia, spherocytosis, G6PD deficiency) 1

2. Intrahepatic Phase:

   • Unconjugated bilirubin is taken up by hepatocytes
   • Converted to water-soluble conjugated (direct) bilirubin through the enzyme glucuronosyltransferase
   • Genetic deficiencies in this enzyme cause conditions like Gilbert syndrome (affecting 5% of Americans) 1

3. Posthepatic Phase:

   • Conjugated bilirubin is excreted into bile and transported to the intestine
   • In the gut, it's converted by microbes to urobilinoids and ultimately to stercobilin (the predominant pigment in feces) 2
   • Some is reabsorbed through enterohepatic circulation 3

Types of Bilirubin

• Unconjugated (indirect) bilirubin:

  • Insoluble in water
  • Transported bound to albumin
  • Elevated in hemolysis and impaired conjugation disorders

• Conjugated (direct) bilirubin:

  • Water-soluble
  • Elevated in liver parenchymal disease or biliary obstruction
  • Normally constitutes the majority of measurable bilirubin in adults 1

Clinical Significance

Normal Values and Hyperbilirubinemia

• Hyperbilirubinemia is defined as serum bilirubin >2.5-3 mg/dL 1
• Elevated bilirubin manifests as jaundice (yellowing of skin and sclera)
• The pattern of elevation (unconjugated vs. conjugated) helps determine the underlying cause

Causes of Elevated Bilirubin

1. Predominantly Unconjugated Hyperbilirubinemia:

   • Hemolytic disorders (increased production)
   • Gilbert syndrome (reduced glucuronosyltransferase activity)
   • Neonatal jaundice (physiologic or pathologic) 4

2. Predominantly Conjugated Hyperbilirubinemia:

   • Hepatic inflammation (viral hepatitis, alcoholic liver disease, autoimmune hepatitis)
   • Biliary obstruction (gallstones, tumors, strictures)
   • Genetic disorders (Dubin-Johnson syndrome, Rotor syndrome) 5
   • Medication-induced liver injury (acetaminophen, penicillin, oral contraceptives, steroids) 1

Diagnostic Approach

• Total and direct (conjugated) bilirubin measurements are essential for differential diagnosis
• In neonates with conjugated bilirubin >25 μmol/L, urgent pediatric assessment is required 1, 4
• Ultrasound is the most useful initial imaging modality for evaluating conjugated hyperbilirubinemia, with high positive predictive value (98%) 1

Emerging Research on Bilirubin's Physiological Role

Recent research suggests bilirubin may have additional roles beyond being a waste product:

• Metabolic hormone: Bilirubin may function as a hormone that drives gene transcription by nuclear receptors 6
• Antioxidant properties: Mildly elevated bilirubin levels may protect against oxidative stress-mediated diseases, particularly atherosclerosis 7
• Liver-gut signaling: Bilirubin and its metabolites may play a role in regulating the liver-gut axis 2

Clinical Implications

• Low bilirubin levels ("hypobilirubinemia") may be associated with increased risk of metabolic dysfunction and cardiovascular complications 6
• Mild elevation of unconjugated bilirubin (as in Gilbert syndrome) appears protective against coronary heart disease and peripheral vascular disease 7
• Bilirubin testing is crucial for evaluating liver function, identifying hemolytic conditions, and diagnosing biliary obstruction

Understanding bilirubin metabolism is essential for proper interpretation of liver function tests and diagnosis of various hepatobiliary and hematologic disorders.