Aino Pynttäri & Margareta Kurkela Bilirubin metabolism Aino Pynttäri & Margareta Kurkela

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

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

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

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

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

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

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

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

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.