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Bilirubin Metabolism: Pre-Hepatic
Bilirubin is formed in macrophages of the reticuloendothelial system. The initial substrate is predominantly hemaglobin.
Heme group  biliverdin  bilirubin
Bilirubin is insoluble in water and so must be carried by albumin within plasma.
Bilirubin circulates in the blood before uptake by the liver.
Pre-hepatic jaundice = if bilirubin is not taken up by the liver or if it is produced in excess, unconjugated bilirubin is deposited in extra-hepatic tissues.

Bilirubin Metabolism: Hepatic
Bilirubin is taken up into hepatocytes and bound to intracellular proteins.
Bilirubin + UDP glucuronic acid = bilirubin diglucuronide > bilirubin monoglucuronide > UDP
The glucuronide conjugated form of bilirubin is water soluble and is excreted into bile. Excretion occurs into the bile canaliculus by carrier-mediated transport.
Hepatic jaundice = disorders of bilirubin uptake or conjugation

Bilirubin Metabolism: Post-Hepatic
Glucuronide-conjugated bilirubin in bile may be degraded to urobilinogen or partially reabsorbed into plasma.
Urobilinogen pathway:
may be reabsorbed by the gut and returned to the liver
converted to urobilin
reabsorbed into plasma for excretion by kidneys
Conjugated bilirubin pathway:
May be acted upon by bacterial enzymes within the gut to form the bile pigment stercobilinogen. Stercobilinogen may be reabsorbed into plasma for recycling to the liver or for excretion by the kidney, or, it may be oxidized to stercobilin.
Obstructive jaundice = failure of bilirubin to reach the gut, resulting in a reduction in pigment within the stool

DDX: Unconjugated Hyperbilirubinemia
Increased Bilirubin Production
Extravascular hemolysis
Extravasation of blood into tissues
Intravascular hemolysis
Errors in production of red blood cells
Impaired Hepatic Bilirubin Uptake
Portosystemic shunts
Drug inhibition: rifampin, probenecid
Impaired Bilirubin Conjugation
Gilbert’s disease
Crigler-Najarr syndrome
Neonatal jaundice (this is physiologic)
Liver diseases (chronic hepatitis, cirrhosis, Wilson’s)...

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