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Heme Degradation and Jaundice
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- 2. In the human body approx. 100 – 200 million RBCs are broken down every hour. Degradation of Hb begins in ER of reticuloendothelial cells (RE) of the liver, spleen, bone marrow and skin. Hb is degraded to: Globins → AAs → metabolism Heme → bilirubin Fe2+ → transported with transferrin and used in the next heme biosynthesis Not only Hb but other hemoproteins also contain heme groups which are degraded by the same pathway. Hemoglobin degradation
- 3. Breakdown of Hemoglobin Heme globin Biliverdin Biliverdin Amino acids Reutilized O2, NADPH+H+ NADP+,O2 NADPH+H+ NADP+ Heme oxygenase Bilirubin reductase Fe+++ Hemoglobin
- 5. I II III IV Fe2+ NADPHC O2O O2 Heme Oxygenase O
- 8. 250-300mg of bilirubin per day Bilirubin is much less soluble in aqueous media than biliverdin. Potent anti-oxidant properties The further metabolism (fate) & excretion of bilirubin occurs in liver & intestine. It can be divided into following process…… Uptake of bilirubin by liver cells Conjugation of bilirubin in liver Secretion of conj. Bilirubin into bile Excretion of bilirubin (in feces & urine) Fate of Bilirubin
- 9. Role of Blood Proteins in the Metabolism of Bilirubin 1. Albumin Dissolved in Blood
- 10. Bilirubin transported to the liver by plasma albumin. In liver bilirubin binds to intracellular protein. Uptake of bilirubin by liver cells
- 11. Blood Liver Ligandin (-) charge Ligandin (-) charge Ligandin Prevents bilirubin from going back to plasma
- 12. Hepatocytes convert sparingly soluble bilirubin to a more soluble form. This done by conjugation of two molecules of glucuronate. Conjugation of bilirubin in liver Bilirubin UDP-Glucuronate UDP Bilirubin glucuronyl transferase Bilirubin monoglucuronide UDP-Glucuronate UDP Bilirubin glucuronyl transferase Bilirubin diglucuronide
- 13. Two molecules of glucuronic acid are attached sequentially to bilirubin by UDP glucuronyl transferase (UGT) The product, bilirubin diglucuronide is excreted in the bile
- 14. Most conjugated bilirubin formed in the liver secretes into bile by an active transport process. It is a rate limiting step for the hepatic bilirubin metabolism. Unconjugated bilirubin is not secreted into bile. Secretion of bilirubin into bile
- 15. Following secretion conj bilirubin passes through hepatic & bile duct into intestinal lumen. By bacterial enzyme β-glucuronidase bilirubin diglucuronidase is hydrolyzed. Bilirubin is reduced by the fecal flora to colorless urobilinogen. Upto 20 % of urobilinogen produced daily is reabsorbed from the intestine & enters the entero-hepatic circulation. 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 as oxidized yellow pigment, urobilin. The remaining urobilinogen is reduced to stercobilinogen, Which is excreted as oxidized brown pigment, stercobilin. Excretion of bilirubin into bile
- 20. The normal conc of serum bilirubin is… Total bilirubin 0.1 to 1.0 mg/dl Conjugated (direct) 0.1 to 0.4 mg/dl Unconjugated (indirect) 0.2 to 0.7 mg/dl Serum Bilirubin
- 21. Any conditions that interfere with bilirubin metabolism may cause a rise in its serum conc. If bilirubin in the blood exceeds 3mg/dl, that condition is called hyperbilirubinaemia. Disorders of heme catabolism
- 22. Hyperbilirubinaemia It may be due to …… Production of bilirubin Hepatic uptake Hepatic conjugation Excretion of bilirubin into bile These leads to accumulation of bilirubin in the blood, this will leads to diffusion into the tissue. The skin & sclera appear yellowish due to deposition of bilirubin. This condition is called jaundice or icterus.
- 24. Classification of Hyperbilirubinaemia Hyperbilirubinaemia may be…… Acquired Inherited Acquired Hyperbilirubinaemia, examples… Hemolytic or prehepatic jaundice Hepatocellular or Hepatic jaundice Obstructive or posthepatic jaundice Neonatal or physiological jaundice. Inherited Hyperbilirubinaemia, examples… Gilbert’s syndrome Crigler Najjar syndrome Dubin Johnson syndrome Rotor syndrome
- 25. Classification of Jaundice Hemolytic or prehepatic jaundice Hepatocellular or Hepatic jaundice Obstructive or posthepatic jaundice Neonatal or physiological jaundice.
- 26. In this there is breakdown of hemoglobin to bilirubin takes place. The rate of bilirubin formation is more than the ability of liver cell to conjugate bilirubin. So, the levels of unconjugated bilirubin . Excess hemolysis may be due to…… Sickle hemoglobin (Sickle cell anaemia) Deficiency of G6-P dehydrogenase. Incompatible blood transfusion. Hemolytic or pre-hepatic Jaundice
- 27. Since the excess bilirubin is unconjugated, it is not excretable in the urine. The urine color is normal. As more than normal amounts of bilirubin are excreted into the intestine, resulting in amount of urobilinogen in urine and faeces. Biochemical picture in hemolytic jundice…. serum unconjugated bilirubin amount of urobilinogen in urine and faeces Absence of bilirubin in the urine. Hemolytic or pre-hepatic Jaundice
- 29. In this kind of jaundice, there is some disorder of the liver cells or bile passages within the liver. Hepatic cells damage impairs conjugation of bilirubin and results in serum unconjugated bilirubin. Patients with jaundice due to hepatocellular damage commonly have obstruction of the biliary tree within the liver that results in the serum conjugated bilirubin. The causes of hepatocellular damage are…. Infection (viral hepatitis) Toxic chemicals (alcohol, chloroform,CCl4 etc) Drugs Cirrhosis. Hepatocellular or Hepatic jaundice
- 30. Biochemical picture in hepatic jaundice…. serum unconjugated & conjugated bilirubin amount of urobilinogen in urine and faeces Presence of bilirubin in the urine. level of the SGPT (ALT). Hepatocellular or Hepatic jaundice
- 32. This occurs when there is an obstruction to the flow of conjugated bilirubin from liver cells to intestine. The condition is also called cholestasis. This obstruction may be intrahepatic or extrahepatic. Extrahepatic cholestasis occurs due to… Blockage to the common bile duct by gallstone. Carcinoma of the head of pancreas. Carcinoma of duct itself. Biochemical picture in obstructive jaundice…. serum conjugated bilirubin Absence of urobilinogen in urine and faeces. Presence of bilirubin and bile salts in the urine. level of the SGPT (ALP). Obstructive or posthepatic jaundice
- 34. PRE-HEPATIC HEPATIC POST HEPATIC cause Excessive breakdown of RBC’s, Malaria, HS Gilbert Syndrome Infective Liver Damage Bile Duct Obstruction Sr. Bilirubin unconjugated Both conj +unconj conjugated Urine bilirubin Absent Bilirubinemia + Deep yellow urine As in hepatic jaundice (++) Urine urobilinogen Increases Because of increased stercobilinogen Decreases Because of decreased stercobilinogen Absent(-) Fecal stercobilinogen (20-250mg/day) Markedly increased Dark brown stool Reduced Pale coloured stool Absent clay colored stool Vonden burg Indirect+ biphasic Direct+
- 35. Mild jaundice in the first few days after birth is common & physiological It results from hemolysis & immature liver enzyme system for conjugation of bilirubin. Liver is deficient in enzyme UDP-glucuronyl transferase. Enzyme deficiency is more serious with increasing degree of prematurity. unconjugated bilirubin capable of crossing BBB when its conc in plasma exceed 20-25mg/dl. This results in… Hyperbilirubinaemic toxic encephalopathy / kernicterus Which cause mental retardation. Neonatal or physiological jaundice
- 36. If bilirubin levels are judged to be too high, then phototherapy with UV light is used to convert it to a water soluble, non-toxic form. If necessary, exchange blood transfusion is used to remove excess bilirubin Phenobarbital is oftentimes administered to Mom prior to an induced labor of a premature infant – crosses the placenta and induces the synthesis of UDP glucuronyl transferase Jaundice within the first 24 hrs of life or which takes longer then 10 days to resolve is usually pathological and needs to be further investigated
- 37. Phototherapy •During phototherapy, (the treatment of choice for jaundice), babies are placed under blue lights that convert the bilirubin into compounds that can be eliminated from the body. Phototherapy is usually not needed unless the bilirubin levels rise very quickly or go above 16-20 mg/dl in healthy, full term babies.
- 38. Gilbert’s Syndrome Crigler-Najjar (Type I) Crigler-Najjar (Type II) Dubin-Johnson Rotor’s Syndrome Inherited Disorders of Bilirubin Metabolism
- 39. Isolated increased serum bilirubin Ruling out of hemolysis, subsequent fractionation of the bilirubin Possibility of the following syndromes: • Dublin-Johnson • Rotor Possibility of following syndromes based on the bilirubin conc. : • Gilbert’s - <3 mg/dl • Crigler-Najjar (Type I) - >25 mg/dl • Crigler-Najjar (Type II) - 5to20 mg/dl Algorithm for differentiating the familial causes of Hyperbilirubinemia Conjugated Unconjugated
- 40. Autosomal recessive diseases Deficiency of hepatic glucuronyl transferase enzyme. Significant elevation of unconjugated bilirubin in serum Type 1 ▪ No bilirubin glucuronidation (complete absence of enzyme) ▪ It causes sever jaundice and early death. Type 2 (rare) ▪ Some bilirubin glucuronidation (partial absence of enzyme) ▪ Less sever.
- 41. Mild elevation of unconjugated bilirubin in serum. Impaired hepatic uptake of bilirubin & Reduced activity of UDP-glucuronyl transferase. Could cause neonatal jaundice Could result in kernicterus, brain damage due to high bilirubin concentrations, with overt hemolysis
- 42. It is a benign (harmless), autosomal recessive condition Characterized by jaundice with predominantly elevated conjugated bilirubin and a minor elevation of unconjugated bilirubin. Defective hepatic secretion of conjugated bilirubin into bile. The Liver has a characteristic greenish black pigment in hepatocytes. Imparting a dark brown to black colour to the liver.
- 43. It is another form of conjugated hyperbilirubinemia. It is similar to dubin-johnson syndrome but without pigmentation in liver.
- 44. ….