Red Blood Cell Destruction kau


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Red Blood Cell Destruction kau

  1. 1. Red blood cell destruction
  2. 2. Recommended Readings <ul><li>Wills’ Biochemical basis of Medicine. Chapter 25 </li></ul><ul><li>Lippincott’s illustrated reviews biochemistry. Chapter 21 </li></ul>
  3. 3. Learning objectives <ul><li>Know the main location and site of haem breakdown </li></ul><ul><li>Outline the pathway for haem degradation </li></ul><ul><li>Compare/contrast types of Plasma Bilirubin & types of Hyperbilirubinemia </li></ul><ul><li>Understand the biochemical basis of different types of jaundice. </li></ul>
  4. 4. Content <ul><li>Main location and site of haem breakdown </li></ul><ul><li>Pathway for haem degradation </li></ul><ul><ul><li>Formation of bilirubin in reticuloendothelial system </li></ul></ul><ul><ul><li>Uptake, conjugation & secretion of bilirubin by liver </li></ul></ul><ul><ul><li>Catabolism of bilirubin in the gut </li></ul></ul><ul><li>Types of Plasma Bilirubin </li></ul><ul><li>Definition & types of Hyperbilirubinemia </li></ul><ul><li>Jaundice </li></ul><ul><ul><li>Definition & </li></ul></ul><ul><ul><li>Types & characteristics of each type </li></ul></ul><ul><ul><li>Physiological Jaundice </li></ul></ul><ul><ul><li>Genetic causes of Jaundice </li></ul></ul>
  5. 5. Degradation of heme <ul><li>Red blood cells are degraded by the cells of the reticuloendothelial system particularly in the liver and spleen after 120 days in the circulation (RBC life span) </li></ul><ul><li>Therefore, The principal sites of heme catabolism are the spleen & the liver </li></ul><ul><li>Bilirubin is the end product of heme catabolism: </li></ul><ul><ul><li>75% from hemoglobin of old RBCs, </li></ul></ul><ul><ul><li>the rest from hemoglobin of immature RBCs & from cytochromes from extra-erythroid tissues </li></ul></ul><ul><li>250-350 mg bilirubin /day is produced in normal adults </li></ul>
  6. 6. <ul><li>Heme catabolism is classified into 3 stages: </li></ul><ul><ul><li>Formation of bilirubin in reticuloendothelial system (RES) </li></ul></ul><ul><ul><li>Uptake, conjugation and secretion of bilirubin by the liver </li></ul></ul><ul><ul><li>Catabolism of bilirubin in the gut </li></ul></ul>Pathway for haem degradation
  7. 7. ( ) Little
  8. 8. CO
  9. 10. <ul><li>Formation of bilirubin in reticuloendothelial system (RES): </li></ul><ul><ul><li>In reticuloendothelial system (RES), hemoglobin is degraded into heme and globin. </li></ul></ul><ul><ul><li>Globin is either degraded to amino acids or reused for synthesis of hemoglobin. </li></ul></ul><ul><ul><li>Heme is converted to biliverdin by the microsomal heme oxygenase (a P450 cytochrom) using NADPH and O 2 . Ferric iron & carbon monoxide are released. Biliverdin is water soluble green pigment </li></ul></ul><ul><ul><li>Biliverdin is converted to bilirubin by biliverdin reductase. Bilirubin is water insoluble yellow pigment </li></ul></ul><ul><ul><li>Bilirubin is transported in blood to the liver carried by plasma albumin (it is termed indirect or unconjugated bilirubin). </li></ul></ul><ul><ul><ul><li>Certain drugs as salicylates & sulfonamides can displace bilirubin from albumin, allowing bilirubin to enter the CNS causing neural damage in infants </li></ul></ul></ul>
  10. 11. <ul><li>Uptake, conjugation and secretion of bilirubin by the liver: </li></ul><ul><ul><li>Uptake of bilirubin: </li></ul></ul><ul><ul><ul><li>Bilirubin leaves albumin & is taken by the hepatocytes </li></ul></ul></ul><ul><ul><ul><li>Hepatic uptake of bilirubin is mediated by a carrier, & may be competitively inhibited by other organic anions </li></ul></ul></ul><ul><ul><li>Synthesis of bilirubin-diglucuronide (Conjugation): </li></ul></ul><ul><ul><ul><li>By UDP glucuronyl transferase enzyme, bilirubin is conjugated with glucuronic acid, to form bilirubin diglucuronide (it is termed direct or conjugated bilirubin & it is water soluble) </li></ul></ul></ul><ul><ul><ul><ul><li>UDP-glucuronate acts as donor for glucuronate group to form bilirubin monoglucuronide then bilirubin diglucuronide </li></ul></ul></ul></ul><ul><ul><li>Conjugated bilirubin is actively secreted by hepatocyte into the biliary canaliculi (with bile) to small intestine </li></ul></ul><ul><ul><ul><li>Secreation is the rate limiting step in bilirubin metabolism </li></ul></ul></ul>
  11. 12. <ul><li>Catabolism of bilirubin in the gut: </li></ul><ul><ul><li>Conjugated bilirubin is converted by bacteria to urobilinogen : </li></ul></ul><ul><ul><ul><li>Conjugated bilirubin is deconjugated and reduced by intestinal bacteria forming urobilinogen. </li></ul></ul></ul><ul><ul><li>Most of urobilinogen is oxidized in colon to a brown pigment, urobilin (stercobilin ) , which is excreted in feces giving feces its color. </li></ul></ul><ul><ul><li>Some urobilinogen (water soluble) is absorbed from gut into portal blood and re-excreted by liver in bile (enterohepatic circulation). </li></ul></ul><ul><ul><li>Traces of this urobilinogen reach the systemic blood & are excreated by kidneys in urine </li></ul></ul>
  12. 14. Plasma Bilirubin <ul><li>Normal plasma bilirubin level is < 1 mg/dL (<17 μ mol/L) </li></ul><ul><li>Plasma bilirubin is present in 2 forms: </li></ul><ul><ul><li>Unconjugated bilirubin (Indirect bilirubin) </li></ul></ul><ul><ul><li>Conjugated bilirubin (Direct bilirubin) </li></ul></ul>
  13. 15. <ul><li>Unconjugated bilirubin (Indirect bilirubin) </li></ul><ul><ul><li>Main bilirubin present in plasma normally </li></ul></ul><ul><ul><li>Water insoluble </li></ul></ul><ul><ul><li>Transported in blood as Bilirubin-albumin complex </li></ul></ul><ul><ul><li>Not excreted in urine </li></ul></ul><ul><ul><li>Increases in blood in cases of: </li></ul></ul><ul><ul><ul><li>Hemolysis </li></ul></ul></ul><ul><ul><ul><li>Liver disease: liver fails to uptake or conjugate it. </li></ul></ul></ul><ul><ul><li>Termed Indirect bilirubin because its estimation by van den Bergh reaction needs addition of methanol to react with the diazo reagent </li></ul></ul>
  14. 16. <ul><li>Conjugated bilirubin (direct bilirubin) </li></ul><ul><ul><li>Bilirubin-diglucuronide which escapes from the liver to the systemic blood </li></ul></ul><ul><ul><li>Water-soluble </li></ul></ul><ul><ul><li>Excreted in urine: Bilirubinuria is due to conjugated bilirubin and is always pathological </li></ul></ul><ul><ul><li>Increases in blood in cases of: </li></ul></ul><ul><ul><ul><li>Liver disease: liver fails to secrete bilirubin </li></ul></ul></ul><ul><ul><ul><li>Obstruction in the biliary system </li></ul></ul></ul><ul><ul><li>Termed direct bilirubin because it reacts directly with the diazo reagent of van den Bergh </li></ul></ul>
  15. 17. Hyperbilirubinemia <ul><li>Increased plasma bilirubin level more than 1mg/dL (17 μ mol/L) </li></ul><ul><li>According to the type of bilirubin increased in plasma, hyperbilirubinemias are classified into 2 types: </li></ul><ul><ul><li>Unconjugated hyperbilirubinemia </li></ul></ul><ul><ul><li>Conjugated hyperbilirubinemia </li></ul></ul><ul><li>According to the underlying defect, hyperbilirubinemias may be: </li></ul><ul><ul><li>Unconjugated , </li></ul></ul><ul><ul><li>Conjugated </li></ul></ul><ul><ul><li>Both </li></ul></ul>
  16. 18. <ul><li>Unconjugated hyperbilirubinemia </li></ul><ul><ul><li>High level of unconjugated bilirubin in blood. </li></ul></ul><ul><ul><li>Unconjugated bilirubin can cross the blood-brain barrier & cause severe brain damage (kernicterus) </li></ul></ul><ul><ul><li>Unconjugated bilirubin is not excreted in urine </li></ul></ul><ul><ul><li>Causes: </li></ul></ul><ul><ul><ul><li>Hemolysis </li></ul></ul></ul><ul><ul><ul><li>Immaturity of the enzyme of bilirubin conjugation in neonates (physiological) </li></ul></ul></ul><ul><ul><ul><li>Genetic defect in the enzyme of bilirubin conjugation </li></ul></ul></ul><ul><ul><ul><ul><ul><li>Gilbert's syndrome </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Crigler-Najjar syndrome </li></ul></ul></ul></ul></ul><ul><ul><ul><li>Most common causes are Hemolysis & Gilbert's syndrome </li></ul></ul></ul>
  17. 19. <ul><li>Conjugated hyperbilirubinemia </li></ul><ul><ul><li>High level of conjugated bilirubin in blood. </li></ul></ul><ul><ul><li>Due to leakage of conjugated bilirubin from hepatocytes or biliary system into blood </li></ul></ul><ul><ul><li>Conjugated bilirubin is water soluble, so it is excreted in urine and darkens urine color to deep orange brown </li></ul></ul><ul><ul><li>Causes: </li></ul></ul><ul><ul><ul><li>Biliarry obstruction </li></ul></ul></ul><ul><ul><ul><li>Decreased hepatic secretion of conjugated bilirubin </li></ul></ul></ul><ul><ul><ul><ul><li>Dubin-Johnson Syndrome </li></ul></ul></ul></ul><ul><ul><ul><li>Unknown cause </li></ul></ul></ul><ul><ul><ul><ul><li>Rotor’s Syndrome. </li></ul></ul></ul></ul><ul><ul><li>Most common cause is biliary obstruction </li></ul></ul>
  18. 20. Jaundice <ul><li>Jaundice is clinically seen as yellow color of skin, nail beds & sclera (due to deposition of bilirubin) when plasma bilirubin concentration exceeds 3 mg/dL (50 μmol/L) due to imbalance between bilirubin production and excretion. </li></ul><ul><li>Types of jaundice are: </li></ul><ul><ul><li>Prehepatic (hemolytic) </li></ul></ul><ul><ul><li>Hepatic </li></ul></ul><ul><ul><li>Posthepatic (obstructive) </li></ul></ul>
  19. 21. <ul><li>Prehepatic (hemolytic) jaundice: </li></ul><ul><li>Due to excess production of unconjugated bilirubin after hemolysis which exceeds the capacity of liver to conjugate it </li></ul><ul><li>Characterized by the following: </li></ul><ul><ul><li>High levels of indirect (unconjugated) bilirubin in plasma i.e., Unconjugated hyperbilirubinemia </li></ul></ul><ul><ul><li>Dark urine caused by high levels of urobilinogen in urine </li></ul></ul><ul><ul><li>Dark stool caused by high levels of Fecal urobilin </li></ul></ul>
  20. 22. <ul><li>Posthepatic (obstructive) jaundice </li></ul><ul><li>Due to biliary obstruction </li></ul><ul><li>Characterized by the following: </li></ul><ul><ul><li>High levels of direct (conjugated) bilirubin in plasma i.e., conjugated hyperbilirubinemia </li></ul></ul><ul><ul><li>Dark urine due to presence of conjugated bilirubin. </li></ul></ul><ul><ul><li>Urine urobilinogen is absent </li></ul></ul><ul><ul><li>Very pale stool (white, clay) due to absence of Fecal urobilin </li></ul></ul>
  21. 23. <ul><li>Hepatic jaundice: </li></ul><ul><ul><li>Due to hepatocyte dysfunction that cause impaired hepatic bilirubin uptake, conjugation, or secretion: </li></ul></ul><ul><ul><ul><li>impaired uptake -> increased unconjugated bilirubin in blood), </li></ul></ul></ul><ul><ul><ul><li>impaired conjugation -> decreased conjugated bilirubin formation in liver-> decreased urobilinogen formation in gut) </li></ul></ul></ul><ul><ul><ul><li>impaired secretion->increased conjugated bilirubin in blood & secretion in urine) </li></ul></ul></ul><ul><ul><li>Characterized by the following: </li></ul></ul><ul><ul><ul><li>High levels of direct (conjugated) & indirect (unconjugated) bilirubin in plasma i.e., conjugated & Unconjugated hyperbilirubinemia </li></ul></ul></ul><ul><ul><ul><li>Dark urine due to the presence of conjugated bilirubin & urobilinogen </li></ul></ul></ul><ul><ul><ul><li>Pale stool due to decreased Fecal urobilin </li></ul></ul></ul>
  22. 24. increased
  23. 25. <ul><li>Neonatal (physiologic) jaundice: </li></ul><ul><ul><li>Transient jaundice, common in neonates (50% of normal babies) particularly in premature infants </li></ul></ul><ul><ul><li>Due to immaturity of the enzymes of bilirubin conjugation leading to unconjugated hyperbilirubinemia </li></ul></ul><ul><ul><li>Unconjugated bilirubin is toxic to the immature brain, it may cause kernicterus if it exceeds 20-25 mg/dl, </li></ul></ul><ul><ul><li>kernicterus may result in mental retardation. </li></ul></ul><ul><ul><li>Treatment: to avoid kernicterus, if plasma bilirubin is too high: </li></ul></ul><ul><ul><ul><li>Phenobarbital: inducer for UDP-glucuronyl transferase </li></ul></ul></ul><ul><ul><ul><li>Phototherapy: converts bilirubin to more soluble derivatives that are easily excreted in bile (detoxifies bilirubin) </li></ul></ul></ul><ul><ul><ul><li>Exchange blood transfusion to remove excess bilirubin </li></ul></ul></ul>
  24. 26. Neonatal jaundice phototherapy
  25. 27. <ul><li>Genetic causes of jaundice : </li></ul><ul><ul><li>Gilbert's syndrome </li></ul></ul><ul><ul><li>Crigler-Najjar syndrome </li></ul></ul><ul><ul><li>Dubin-Johnson syndrome </li></ul></ul><ul><ul><li>Rotor's syndrome </li></ul></ul>
  26. 28. <ul><li>Gilbert's syndrome : </li></ul><ul><ul><li>Affect up to 5% of population </li></ul></ul><ul><ul><li>Due to decreased conjugation of bilirubin & decreased uptake in some cases </li></ul></ul><ul><ul><li>Decreased conjugation of bilirubin is due to moderate deficiency in UDP glucuronyl transferase activity </li></ul></ul><ul><ul><li>Mild intermittent unconjugated hyperbilirubinemia which is noticed after fasting or infection </li></ul></ul><ul><ul><li>Harmless & asymptomatic -> normal lifespan </li></ul></ul>
  27. 29. <ul><li>Crigler-Najjar syndrome: </li></ul><ul><ul><li>Type 1: </li></ul></ul><ul><ul><ul><li>Severe unconjugated hyperbilirubinemia at birth </li></ul></ul></ul><ul><ul><ul><li>Due to absence of conjugating enzymes </li></ul></ul></ul><ul><ul><ul><li>Fatal due to kernicterus </li></ul></ul></ul><ul><ul><ul><li>Partial response to phototherapy, non to Phenobarbital </li></ul></ul></ul><ul><ul><li>Type 2: </li></ul></ul><ul><ul><ul><li>Severe unconjugated hyperbilirubinemia at birth </li></ul></ul></ul><ul><ul><ul><li>Due to partial defect of conjugating enzymes </li></ul></ul></ul><ul><ul><ul><li>Survive to adulthood </li></ul></ul></ul><ul><ul><ul><li>Good response to phototherapy & Phenobarbital </li></ul></ul></ul>
  28. 30. <ul><li>Dubin-Johnson syndrome: </li></ul><ul><ul><li>Due to decreased hepatic secretion of conjugated bilirubin </li></ul></ul><ul><ul><li>Mild intermittent conjugated hyperbilirubinemia </li></ul></ul><ul><ul><li>Bilirubinuria </li></ul></ul><ul><ul><li>Normal lifespan </li></ul></ul><ul><li>Rotor's syndrome: </li></ul><ul><ul><li>Cause is unknown </li></ul></ul><ul><ul><li>Mild intermittent conjugated hyperbilirubinemia </li></ul></ul><ul><ul><li>Bilirubinuria </li></ul></ul><ul><ul><li>Normal lifespan </li></ul></ul>