Download Bilirubin

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
Conditions with elevated amount of
unconjugated bilirubin
Conditions with elevated
amount of conjugated bilirubin
• Hemolytic anemias
• Obstruction of the biliary
tree
– Extensive hemolysis
• Neonatal jaundice
– Accelerated hemolysis at birth,
immature hepatic system
• Grigler-Najjar syndrome types
I and II
– Mutations in
glucuronosyltransferase gene
• Gilbert syndrome
– Mutations in
glucuronosyltransferase gene
• Toxic hyberbilirubinemia
– Toxin induced liver dysfunction
– 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.