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JAUNDICE for first mbbs acc to nmc curriculum
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- 2. FATE OF REDBLOOD CELLS Life span in blood stream is 60-120 days Senescent RBCs are phagocytosed and lysed by tissue macrophages which are a part of reticuloendothelial system. Lysis can also occur intravascularly (in blood stream)
- 3. Extravascular Pathway forRBC Destruction (Liver, Bone marrow, & Spleen) Hemoglobin Globin Amino acids Amino acid pool Heme Bilirubin Fe2+ Excreted Phagocytosis & Lysis reused
- 4. Handling of Free(Intravascular) Hemoglobin • Haptoglobin: hemoglobin- haptoglobin complex is readily metabolized in the liver and spleen forming an iron-globin complex and bilirubin. Prevents loss of iron in urine
- 5. DEGRADATION OF HEMETO BILIRUBIN P450 cytochrome In normal adults this results in a daily load of 250-300 mg of bilirubin Normal plasma concentrations are less than 1 mg/dL Hydrophobic – transported by albumin to the liver for further metabolism prior to its excretion “unconjugated” bilirubin
- 6. 1ST Step BILIRUBIN FORMATION RBCs in blood stream Lifespan : 60-120 days. Old RBCs lysis by: 1)Extravascularly phagocytosed in the reticuloendothelial system or 2)intravascularly in blood stream Hemoglobin in Give Split into Globin breakdo wn and form Amino acids Free Iron Transported in the blood by transferrin Stored as a reservoir for erythropoiesis 1st pigment is biliverdin FREE BILIRUBIN into the plasma Bile pigments biliverdin reductase Heme (By heme oxygenize)
- 8. 2ND Step TRANSPORTOF BILIRUBININ PLASMA Formed Bilirubin in spleen immediately combines with plasma proteins (mainly albumin ) give a water soluble compound (hydrophilic) called hemobilirubin/ unconjugated/ indirect bilirubin still called free bilirubin transported to hepatocytes for further metabolism and Conjugation process Significance of bilirubin binding to albumin?!! 1)Increase the solubility of whole molecule. 2)Prevent unconjugated bilirubin freely come into other tissue, causing damage
- 9. Hepatic uptake “1stStep”- Bilirubin(without the albumin)is absorbed through the hepatic cell membrane, mediated by a carrier protein organic anion transport organic anion transport protein 2 (oatp2) . protein 2 (oatp2) .
- 10. Conjugation of bilirubin- -80% of free bilirubin conugate with 2 Uridine diphospho-glucuronic acid (UDPGA) catalyzed by the enzyme glucuronyl transferase in the smooth ER, forming the compound Bilirubin Diglucurnoide (the conjugated form of bilirubin) that is water soluble -20% of the rest bilirubin conjugate with sulphate & other substances.
- 11. Bilirubin throughput: schemaof a hepatocyte Bilirubin throughput: schema of a hepatocyte Sinusoidal surface Canalicular surface Tight junction Liver sinusoid Fenestrated endothelium
- 12. Bilirubin circulatesbound to serum albumin. B B alb Albumin- binding: Keeps bilirubin soluble Prevents tissue deposi- tion. Prevents renal excretion Drugs that displace bilirubin from albumin may precipitate kernicterus: Sulfonamides Coumadin, etc.
- 13. At thesinusoidal surface of hepatocytes, it dissociates from albumin. B B alb
- 14. At thesinusoidal surface of hepatocytes, it dissociates from albumin. B B alb
- 15. . At thesinusoidal surface of hepatocytes, it dissociates from albumin. B B alb
- 16. . At thesinusoidal surface of hepatocytes, it dissociates from albumin. B B alb
- 17. Bilirubin entersthrough the sinusoidal surface, probably by facilitated diffusion. B B Bilirubin uptake is reduced: In neonates In cirrhosis From drug effect: novobiocin In some cases of Gilbert syndrome
- 18. B Inside thehepatocyte, bilirubin binds to cytosolic proteins termed ligandins, which are the same as glutathione-S- transferases (GSTs). GSTs B GST binding inhibits the efflux of bilirubin, thereby increasing its net uptake
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- 20. B Conjugation ofbilirubin with glucuronic acid is catalyzed by UGT1A1(UDP Glucuronyl transferase) which transfers glucuronic acid from UDP-glucuronic acid to bilirubin GSTs UDP UDPGA GA UDP UDP B BGA GA UGT1A1 B Conjugation with glucuronic acid makes bilirubin water-soluble and non-toxic. Glucuronidation is essential for biliary excretion of bilirubin.
- 21. Seceretion of conjugatedbilirubin -“Cholebilirubin” in the bile by liver hepatocytes is by active transport (which needs energy)into bile canaliculi--- it’s a rate limiting step, susceptible to impairment in liver disease -Color of bile is due to bilirubin -Daily load of bilirubin: 250-300 mg in normal adults
- 22. . Conjugated” bilirubin iswater soluble.it is secreted by the hepatocytes into the biliary canaliculi and enters the gut Converted to stercobilinogen (urobilinogen) (colorless) by bacteria in the gut which is excreted in feces-80% and 20% enters entero hepatic circulation ---enters general circulation ----gets filtered in kidney and excreted as urinary urobilinogen or re-excreted by liver.
- 25. HYPERBILIRUBINEMIA Increased plasmaconcentrations of bilirubin (> 2 mg/dL) occurs when there is an imbalance between its production and excretion Recognized clinically as jaundice
- 26. Jaundice It is theyellow discoloration of the skin, sclera, mucous membranes and deep tissues. The usual cause is large quantities of bilirubin in the ECF, either free or conjugated bilirubin. The normal plasma concentration of total bilirubin is 0.3-1.2 mg/dl of blood.
- 28. Prehepatic (hemolytic) jaundice •Results from excess production of bilirubin (beyond the liver’s ability to conjugate it) following hemolysis • Excess RBC lysis is commonly the result of haemolytic anemias. • High plasma concentrations of unconjugated bilirubin cause jaundice.
- 29. Intrahepatic jaundice • Inhepatocellular (or intrahepatic) jaundice, there is dysfunction of the hepatic cells. The liver loses the ability to conjugate bilirubin, but in cases where it also may become cirrhotic, it compresses the intra-hepatic portions of the biliary tree to cause a degree of obstruction- Impaired uptake, conjugation, and secretion of bilirubin • This leads to both unconjugated and conjugated bilirubin in the blood, accompanied by other abnormalities in biochemical markers of liver function
- 30. Posthepatic jaundice •Caused by an obstruction of the biliary tree • Plasma bilirubin is conjugated, and other biliary metabolites, such as bile acids accumulate in the plasma • Characterized by pale colored stools (absence of fecal bilirubin or urobilin), and dark urine (increased conjugated bilirubin) • In a complete obstruction, urobilinogen is absent from the urine
- 32. TYPES OF BILIRUBININ SERUM Direct bilirubin or“Conjugated”-is water soluble and reacts rapidly with reagents. Indirect bilirubin or Unconjugated-is lipid soluble and reacts slowly with reagents. Total bilirubin = Direct bilirubin + Indirect bilirubin Knowing level of each type of bilirubin has diagnostic importance
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- 36. Thank you for yourattention!