How is bilirubin (bili) removed from the body?

How Bilirubin is Eliminated from the Body

Bilirubin is removed from the body through a multi-step process: unconjugated bilirubin is taken up by the liver, conjugated with glucuronic acid to make it water-soluble, then excreted primarily into bile (and subsequently feces), with a smaller fraction secreted into blood for renal excretion in urine. 1, 2, 3

Normal Bilirubin Metabolism and Excretion Pathway

Step 1: Bilirubin Production and Transport to Liver

• Bilirubin forms when red blood cells die and hemoglobin breaks down within macrophages into heme and globins 4
• Unconjugated bilirubin is insoluble and binds to plasma albumin for transport through the bloodstream to the liver 1, 5
• This unconjugated form cannot be excreted in urine due to its water-insoluble nature 1

Step 2: Hepatic Uptake

• Unconjugated bilirubin enters hepatocytes through the sinusoidal membrane, though the exact transporter mechanism remains incompletely defined 2, 5
• Organic anion transporting polypeptides (OATP1B1 and OATP1B3) facilitate uptake of bilirubin conjugates but not unconjugated bilirubin 2, 3
• Unconjugated bilirubin may cross the hepatocyte membrane by diffusion 2

Step 3: Conjugation in the Liver

• Inside hepatocytes, ligandin carries bilirubin to the endoplasmic reticulum 2
• Bilirubin undergoes conjugation with UDP-glucuronic acid via the enzyme bilirubin UDP-glucuronosyltransferase (UGT1A1) 2, 4
• This creates water-soluble mono- and diglucuronides of bilirubin, requiring energy consumption of approximately -22 kCal/mol per molecule 4

Step 4: Biliary Excretion (Primary Route)

• Conjugated bilirubin is transported across the canalicular membrane into bile by multidrug resistance-associated protein 2 (MRP2) 2, 6
• This represents the primary excretion pathway for most conjugated bilirubin 2
• Bilirubin then passes through the biliary tree into the intestine and is eliminated in feces 6

Step 5: Alternative Blood-Urine Route

• A substantial fraction of conjugated bilirubin is secreted by MRP3 at the sinusoidal membrane back into the bloodstream 2, 3
• This creates a liver-blood cycling system where OATP1B1 and OATP1B3 can reuptake these conjugates 3
• Water-soluble conjugated bilirubin in blood can be filtered by the kidneys and excreted in urine 1, 5
• The presence of bilirubin in urine (bilirubinuria) indicates conjugated hyperbilirubinemia from liver disease or biliary obstruction 1

Special Circumstances

Neonatal Bilirubin Elimination

• In newborns with hyperbilirubinemia, phototherapy converts unconjugated bilirubin in skin microcirculation to water-soluble photoisomers (4E,15Z photoisomer, 4Z,15E photoisomer, and lumirubin) that can be excreted without conjugation 7
• Phototherapy using blue-green light (460-490 nm wavelength, optimally 478 nm) at irradiance ≥30 mW/cm²/nm causes immediate photo-isomerization within 120 minutes 7
• Total serum bilirubin decreases within 4-6 hours of phototherapy initiation, with further decline from natural excretion in bile and stools 7

Impaired Excretion States

• When biliary excretion is impaired (cholestasis or obstruction), MRP3 increases regurgitation of conjugated bilirubin into blood 2
• This compensatory mechanism explains why conjugated hyperbilirubinemia and bilirubinuria occur in obstructive jaundice 1
• Delta bilirubin (conjugated bilirubin bound to albumin) has a 21-day half-life, causing prolonged hyperbilirubinemia even after resolution of the underlying cause 1, 8

Clinical Pitfalls to Avoid

• Unconjugated bilirubin cannot appear in urine because it is water-insoluble and albumin-bound; only conjugated bilirubin is renally excreted 1
• In neonates receiving phototherapy, do not subtract direct bilirubin from total bilirubin when using treatment guidelines 8
• The liver-blood cycling of conjugated bilirubin is impaired in cholestatic and parenchymal liver diseases, contributing significantly to jaundice in these disorders 3