1. Aino Pynttäri & Margareta Kurkela
Bilirubin metabolism
Aino Pynttäri & Margareta Kurkela

2. Bilirubin End product of heme catabolism
Degradation of red blood cells in spleen/liver
Hemoglobin released and degraded
Globin degraded to amino acids
Heme degraded to bilirubin, iron to the storage pool in bone marrow

3. Heme degradation in spleen
Step 1: Ring opening, removal of iron, biliverdin produced
Heme oxygenase
Step 2: Biliverdin reduced to bilirubin
Biliverdin reductase
Step 3: Transport to the liver in blood
Bound to plasma albumin

5. Bilirubin metabolism in liver
Step 4: Uptake of bilirubin into hepatocytes
Carrier mediated saturable system
Bilirubin can bind to cytosolic proteins which help to keep it soluble (ligandin and protein Y)
Step 5: Conjugation
Glucuronosyltransferase
Two glucuronic acid molecules added to bilirubin making it more soluble

7. Bilirubin secretion
Step 6: Secretetion of conjugated bilirubin to bile
Active transport mechanism, MRP-2 (multidrug resistance protein 2): organic anion transporter
Step 7: Unconjugation in terminal ileum and large intestine
-Bacterial beta-glucuronidases

8. Bilirubin excretion Step 8: Reduction to urobilinogen by fecal flora
Step 9: Reabsorbtion
Small amount of urobilinogens reabsorbed and reexcreted through the liver
Step 10: Oxidation of urobilinogens to urobilins
Fecal flora in the colon
Excreted in the feces

9. Hyperbilirubinemia Blood bilirubin levels exceeds 1 mg/dl Reasons:
Excessive red blood cell degradation
Bilirubin produced more than liver can excrete
Liver damage
Bilirubin accumulates in the blood and diffuses into tissues making them yellow
 Jaundice or icterus

10. Hyperbilirubinemia
Unconjugated bilirubin is hydrophobic and can pass the blood-brain barrier into the central nervous system
Encephalopathy
Water-soluble conjugated bilirubin can appear in urine
Choluric jaundice

11. Hyperbilirubinemia Obstruction of the biliary tree
Conditions with elevated amount of unconjugated bilirubin
Conditions with elevated amount of conjugated bilirubin
Hemolytic anemias
Extensive hemolysis
Neonatal jaundice
Accelerated hemolysis at birth, immature hepatic system
Grigler-Najjar syndrome types I and II
Mutations in glucuronosyltransferase gene
Gilbert syndrome
Toxic hyberbilirubinemia
Toxin induced liver dysfunction
Obstruction of the biliary tree
Blockage of hepatic or common bile ducts
Often due to a gallstone or cancer of the head of the pancreas
Dubin-Johnson syndrome
Mutation in the MRP-2 gene
Rotor syndrome

12. References
Mathews C, Van Holde KE, Appling D, Anthony-Cahill S (2013) Biochemistry. 4th edition. Pearson Canada Inc. Murray R.K, Granner D.K & Rodwell V.W (2006) Harper’s illustrated biochemistry. 27th edition. The McGraw-Hill Copanies, Inc.