BILIRUBIN METABOLISM AND JAUNDICE(0).pptx
- 1. BILIRUBIN METABOLISM AND JAUNDICE DR.HAMISI MKINDI,MD. TO DOWNLOAD CONTACT: [email protected]
- 2. OUTLINE Introduction Metabolism of Bilirubin Excretion of bilirubin Jaundice Definition Pathophysiology of jaundice Lab investigations Imaging in pts with jaundice
- 3. BILIRUBIN METABOLISM • Bilirubin is a tetrapyrrole pigment, a result of a break down of heme (ferroprotoporphyrin IX) • About 250-300mg of Bilirubin is produced everyday, 70-80% of this is from breakdown of Hb • The remaining is from : 1. Premature destruction of erythroid cells from the bone marrow 2. Hemoprotein turnover eg myoglobin, cytochromes The formation of bilirubin occurs in the reticuloendothelial cells, primarily in the liver and the spleen
- 4. Bilirubin metabolism 1. Heme oxygenase (a microsomal enzyme) cleaves the alpha bridge of the porphyrin group and opens up the heme ring forming: • biliverdin, • Iron and • Carbon monoxide
- 5. 2. Biliverdin reductase (a cytosolic enzyme) reduces the central methylene bridge of the biliverdin and converts it to unconjugated bilirubin which in insoluble in water because of the string hydrogen bonds between the water soluble moieties of bilirubin, propionic acid carboxyl group of one dipyrrolic half of the molecule with the Imino and lactam groups of the opposite half
- 6. 3. Since unconjugated bilirubin is insoluble in water, it binds to Albumin and transported into the liver where it is conjugated
- 7. 4. In the liver, the unconjugated bilirubin is taken up by Hepatocytes partly by a process that involves a carrier mediated membrane transport 5. After entering the hepatocytes , it is bound to a number of cytosol protein including glutathione-s-transferase superfamily, this prevents the efflux back into serum and presents the bilirubin for conjugation In the liver……
- 8. In the liver…… 6. In the endoplasmic reticulum, bilirubin is solubilized by conjugation with glucuronic acid which destroys the Hydrogen bonds and yields: • Diglucuronide • Monoglucuronide This is catalyzed by Bilirubin Uridin Diphosphate Glucuronosly Transferase (UDPGT)
- 9. Transport to the small Intestine…. 7. The Diglucuronide and Monoglucuronide are then transported into the canalicular bile by an energy dependent mechanism involving Multi drug resistance Transporter 2
- 10. In the small intestine.. • The conjugated bilirubin in the canalicular bile drains the small intestine (duodenum) • The conjugated bilirubin remains unchanged in the proximal part of the small intestine until it reaches the terminal ileum. • In the terminal ileum: 1. Bilirubin is hydrolyzed by bacterial Beta glucuronidase into unconjugated bilirubin 2. Unconjugated bilirubin is then reduced by normal gut flora to form colorless tetrapyrroles called Urobilinogen
- 11. Excretion • 80-90% is excreted in feces either unchanged or oxidized to orange derivates called urobilins • 10-20% is passively absorbed, enter the portal venous blood and excreted by the liver • A small fraction(less than 3mg/dl) escapes the hepatic uptake, filters across the renal glomerulus and excreted in urine
- 12. JAUNDICE • What is Jaundice? Is a yellow discoloration of the skin or sclera of the eyes caused by an increase bilirubin in the blood which can be by: 1. Increased hemolysis 2. Liver diseases 3. Obstruction of bile outflow
- 16. :Caused by mutations of MDRT-2 protein : caused by defects of storage in the liver
- 20. AST:ALT more than 2 suggestive of Alcoholic hepatitis and less than 1 suggestive of viral hepatitis AST, ALT levels more than 25 times normal are suggestive of hepatocellular injury