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Biology of Disease - CH 0576

Biology of Disease - CH 0576. Hyperbilirubinaemia & Jaundice. Introduction. Jaundice is not a disease state in itself It is a non-specific symptom which is a feature of a range of disease states

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Biology of Disease - CH 0576

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  1. Biology of Disease - CH 0576 Hyperbilirubinaemia & Jaundice

  2. Introduction • Jaundice is not a disease state in itself • It is a non-specific symptom which is a feature of a range of disease states • The clinical approach to jaundice must be based on a clear understanding of the metabolism of bilirubin and an appreciation of the potential blocks which can occur in the pathways. RHY/CH0576

  3. Bilirubin Metabolism • Several factors lead to the removal of aged red cells from the circulation: • They have lost their ability to deform • They have lost enzyme activities • They have compromised their ATP levels • They are unable to staunch the flow of Ca2+ ions into the cell, across the plasma membrane RHY/CH0576

  4. Bilirubin Metabolism • The aged red cells are removed from the circulation by the RES cells of the spleen and the bone marrow. • The aged cells are unable to negotiate the torturous route through the red pulp of the spleen. • Following phagocytosis, the bulk of the red cell constituents are recycled RHY/CH0576

  5. Bilirubin Metabolism • Recycling includes; • Fe transported on transferrin • Amino acids enter the plasma pool • Lipids from membranes enter the plasma pool • The only part of the haemoglobin molecule which is not reutilised is the tetra-pyrolle ring from HAEM. RHY/CH0576

  6. Bilirubin Metabolism • Haem is the portion of the Hb molecule which is catabolised to form bilirubin. • Bilirubin is then handled by the liver prior to its excretion in urine and in faeces. • Haem also forms the prosthetic group in molecules other than haemoglobin. RHY/CH0576

  7. Bilirubin Metabolism • Molecules, other than Hb, containing haem as a prosthetic group include: • Cytochromes • Myoglobin • Peroxidases • These all contribute to bilirubin production, via haem breakdown. RHY/CH0576

  8. Bilirubin Metabolism • Daily bilirubin production in Man averages between 250 - 350 mg. • 85% of this amount is the result of the breakdown of Hb from aged red cells. • The remaining 15% from other sources includes the destruction of red cell precursors in the marrow. RHY/CH0576

  9. Bilirubin Metabolism • Initial stage in the degredation of haem is under the control of the microsomal enzyme, haem oxygenase, acting along with NADPH-cytochrome c reductase. • This reaction involves the cleavage of the tetra-pyrolle ring at the  methene bridge. • During this step, iron is liberated. RHY/CH0576

  10. Bilirubin Metabolism • The iron passes out of the RES cell and is bound onto the transport protein, transferrin, for passage back to the red marrow. • The  carbon atom from haem is excreted at the lungs in the form of carbon monoxide. • Assessment of CO indicates level of red cell breakdown. RHY/CH0576

  11. Bilirubin Metabolism • The product of this initial stage in bilirubin production is a colourless, non-toxic molecule : biliverdin. • This is the main excretory product in the lower animal phyla. • Mammals then undertake an apparent retrograde step, by converting this into a toxic molecule : bilirubin. RHY/CH0576

  12. Bilirubin Metabolism • This conversion step must have some evolutionary advantage: • bilirubin crosses the placenta, whereas biliverdin doesn’t. • The conversion of bilverdin involves the action of a cytoplasmic enzyme in the RES cell : biliverdin reductase. • Bilirubin is transported from the RES cell to the liver for processing. RHY/CH0576

  13. Bilirubin Metabolism • Bilirubin is transported, in the plasma, bound onto the protein albumin. • Albumin has two binding sites for bilirubin, of greatly varying affinities. • Bilirubin is displaced from the lower affinity binding site by certain drugs including: • barbiturates, sulphonamides, salicylates. RHY/CH0576

  14. Bilirubin Metabolism • Bilirubin displaced from albumin has a very high affinity for lipid-rich tissues, and it tends to be taken up by the brain. • Bilirubin is very toxic to the CNS and causes enlargement and oedema of the brain. • KERNICTERUS. RHY/CH0576

  15. Bilirubin Metabolism • This is a potential very serious problem in neonates, which often have a mild ‘physiological jaundice’. • It is a potentially very damaging side effect in HDN. • Adults are protected from this problem by a fully functioning blood-brain barrier. RHY/CH0576

  16. Unconjugated Bilirubin • Bilirubin, bound onto albumin, prior to processing in the liver is often referred to as ‘unconjugated’. • Unconjugated bilirubin, bound onto albumin, is non-toxic and remains in solution for its transportation, in the blood, to the liver for processing. • A small amount, 20g/L is free in plasma. RHY/CH0576

  17. Liver Handling of Bilirubin • On arrival at the liver the bilirubin is dissociated from the albumin and is actively transported across the sinusoidal membranes into the hepatocyte. • This is a carrier mediated process. • In the liver cell the unconjugated bilirubin is bound onto two soluble cytoplasmic binding proteins. RHY/CH0576

  18. Liver Handling of Bilirubin • The two proteins are: • Z-protein • Ligandin. • This binding greatly increases the solubility of the bilirubin, allowing it to be transported across the aqueous cytoplasm, to the ER of the liver cell. • The next stage is CONJUGATION. RHY/CH0576

  19. Liver Handling of Bilirubin • Within the ER of the hepatocytes the bilirubin is conjugated with UDP-glucuronic acid to form glucuronides. • This process is under the control of two ER enzymes termed the glucuronyl transferases. • Di- and monoglucuronides are produced under various circumstances. RHY/CH0576

  20. Liver Handling of Bilirubin • Conjugated bilirubin (mono- or di-) is actively transported across the canalicular membrane, forming part of the secretion, bile. • Conjugated bilirubin is non-toxic. • Bile passes down the bile ductules and into the common hepatic duct, and, if required, into the intestine. RHY/CH0576

  21. Bilirubin Metabolism • Once within the small intestine the glucuronides are acted upon by the bacterial flora of the gut. • Bacterial -glucuronidases hydrolyse the glucuronides into free bilirubin and glucuronic acid. • Further bacterial action leads to the conversion of bilirubin into a range of products : urobilinogens. RHY/CH0576

  22. Bilirubin Metabolism • The majority , about 80% of these are excreted in faeces, following conversion to stercobilinogens. • The remaining 20% of the urobilinogens are reabsorbed into the entero-hepatic circulation. • The majority of these are re-exreted by the liver in bile. RHY/CH0576

  23. Bilirubin Metabolism • Between 2% and 5% of the reabsorbed urobilinogens enter the general circulation and are excreted via the kidneys, in urine. • Around 1 - 2 mg of bile pigments are excreted in the urine daily, with about 250 - 350 mg excreted in faeces daily. RHY/CH0576

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