Bilirubin metabolism by asogwa innocent kingsley ml 508


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Bilirubin metabolism by asogwa innocent kingsley ml 508

  2. 2. Introduction • Bilirubin is the orange-yellow pigment derived from senescent red blood cells. • It is a toxic waste product in the body. • It is extracted and biotransformed mainly in the liver, and excreted in bile and urine. • It is a bile pigment • Elevations in serum and urine bilirubin levels are normally associated with Jaundice.
  3. 3. Erythrocytes become “old” as they lose their flexibility and become pikilocytes (spherical), increasingly rigid and fragile. Once the cell become fragile, they easily destruct during passage through tight circulation spots, especially in spleen, where the intra-capillary space is about 3 micron as compared to 8 micron of cell size RBCs useful life span is 100 to 120 days,After which they become trapped and fragment in smaller circulatory channels, particularly in those of the spleen. For this reason, the spleen is sometimes called the “red blood cell graveyard.” Dying erythrocytes are engulfed and destroyed by macrophages.
  4. 4. Formation of Bilirubin • Primary site of synthesis:- SPLEEN: The Graveyard of Red Blood Cells • Secondary site of synthesis:- LIVER & BONE MARROW
  5. 5.  An average person produces about 4 mg/kg of bilirubin per day.  The daily bilirubin production from all sources in man averages from 250 to 300 mg. TOTAL BILIRUBIN HEMOGLOBIN FROM SENESCENT RBC’S DESTROYED IN RETICULOENDOTHELIAL CELLS OF LIVER, SPLEEN & BONE MARROW RBC PRECURSORS DESTROYED IN THE BONE MARROW 85% 15% CATABOLISM OF HEME-CONTAINING PROTEINS (MYOGLOBIN, CYTOCHROMES & PEROXIDASES)
  6. 6. Extravascular Pathway for RBC Destruction (Liver, Bone marrow, & Spleen) Hemoglobin Globin Amino acids Amino acid pool Heme Bilirubin Fe2+ Excreted Phagocytosis & Lysis Recycled
  7. 7. Within cells of the RE system, heme degraded to bilirubin in a two-step process . • a. The porphyrin ring is opened and the iron atom is removed by the action of • heme oxygenase to produce the green- colored intermediate biliverdin. • b. Subsequent reduction converts biliverdin to bilirubin, which has a redorange color.
  8. 8. Pathophysiology RBCs Breakdown Hemoglobin Produces & Breakdown Heme Biliverdin Bilirubin Heme Oxygenase Biliverdin Reductase
  9. 9. • The globin is recycled or converted into amino acids, which in turn are recycled or catabolized as required. • Heme is oxidized, with the heme porphyrin ring being opened by the endoplasmic reticulum enzyme, heme oxygenase. • The oxidation occurs on a specific carbon producing equimolar amounts of the biliverdin, iron , and carbon monoxide (CO). This is the only reaction in the body that is known to produce CO. • Most of the CO is excreted through the lungs, with the result that the CO content of expired air is a direct measure of the activity of heme oxygenase in an individual.
  10. 10. III IVI II Oxidation Heme Oxygenase In the first reaction, a bridging methylene group is cleaved by heme oxygenase to form Linear Biliverdin from Cyclic Heme m o l e c u l e . Fe 2+ is released from the ring in this process.
  11. 11. • In the next reaction, a second bridging methylene (between rings III and IV) is reduced by biliverdin reductase, producing bilirubin. I I III III IV IV II II Reduction Biliverdin Reductase
  12. 12. • biliverdin causing a change in the color of the molecule from blue-green (biliverdin) to yellow-red (bilirubin). • The latter catabolic changes in the structure of tetrapyrroles are responsible for the progressive changes in color of a hematoma, or bruise, in which the damaged tissue changes its color from an initial dark blue to a red-yellow and finally to a yellow color before all the pigment is transported out of the affected tissue. • Peripherally arising bilirubin is transported to the liver in association with albumin, where the remaining catabolic reactions take place.
  13. 13. Bilirubin is not very water-soluble, so most of it is carried to the liver bound to albumin.
  14. 14. In cells of the liver, bilirubin undergoes modification to increase its water solubility so that it can be excreted more easily. a.Bilirubin is conjugated to two molecules of glucuronic acid, creating bilirubin diglucuronide. b. Bilirubin diglucuronide is transported out of the hepatocytes into the bile canaliculi and is thus excreted in bile.
  15. 15. In Blood • The bilirubin synthesized in spleen, liver & bone marrow is unconjugated bilirubin. • It is hydrophobic in nature so it is transported to the liver as a complex with the plasma protein, albumin. Unconjugated bilirubin – Lipid soluble – : limits excretion – 1 gm albumin binds 8.5 mg bilirubin – Fatty acids & drugs can displace bilirubin – Indirect positive reaction in van den Bergh test
  16. 16. Role of Blood Proteins in the Metabolism of Bilirubin 1. Albumin Dissolved in Blood
  17. 17. Blood Liver Ligandin (-) charge Ligandin (-) charge Ligandin Prevents bilirubin from going back to plasma
  18. 18. In Endoplasmic Reticulum In the microsomes of the endoplasmic reticulum, unconjugated bilirubin is converted to water soluble mono- or di- conjugates by sequential covalent coupling with glucuronic acid.
  19. 19. Bilirubin is conjugated in a two step process to form bilirubin mono- & di- glucuronide
  20. 20. Conjugation with Glucoronates BILIRUBIN DIGLUCORONIDE
  21. 21. Excretion of Bilirubin
  22. 22. In the Intestine • In the small intestine, conjugated bilirubins are poorly reabsorbed, but are partly hydrolyzed back to unconjugated bilirubin by catalytic action of bacterial ß-glucuronidases. • In the distal ileum and colon, anaerobic flora mediate further catabolism of bile pigments: a) hydrolysis of conjugated bilirubin to unconjugated bilirubin by bacterial β-glucuronidases; b) multistep hydrogenation (reduction) of unconjugated bilirubin to form colorless urobilinogens; and c) oxidation of unconjugated bilirubin to brown colored mesobilifuscins.
  23. 23. • Urobilinogens is a collective term for a group of 3 tetrapyrroles; – Stercobilinogen (6H) – Mesobilinogen (8H)&, – Urobilinogen (12H) • Upto 20 % of urobilinogen produced daily is reabsorbed from the intestine & enters the entero-hepatic circulation. Urobilinogen Structure
  24. 24. • Most of the reabsorbed urobilinogen is taken up by the liver & is re-excreted in the bile. • A small fraction (2 % - 5 %) enters the general circulation & appears in the urine. • In the lower intestinal tract, the 3 urobilinogens spontaneously oxidize to produce the corresponding bile pigments; – Stercobilin – Mesobilin & – Urobilin; which are orange-brown in color and are the major pigments of stool.