Iron metabolism


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iron metabolism

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Iron metabolism

  1. 1. Iron metabolism
  2. 2. <ul><li>Iron in the body exists in the following forms: </li></ul><ul><li>Incorporated into Hb (80%) </li></ul><ul><li>Myoglobin, Enzymes,Cytochromes (15%) </li></ul><ul><li>Stored iron in the form of ferritin/hemosiderin. </li></ul><ul><li>Plasma transferrin-bound iron. </li></ul>
  3. 3. ( divalent metal transporter 1)
  4. 5. <ul><li>Iron exists in 2 forms: </li></ul><ul><li>Inorganic/non-heme iron (90%) Fe 3+ (less soluble) </li></ul><ul><li>Organic/heme iron (10%) Fe 2+ (more soluble) </li></ul><ul><li>To be soluble, Ferric (Fe 3+ ) needs to be reduced to Ferrous (Fe 2+ ). </li></ul><ul><li>The enzyme that does this is called Duodenal cytochrome b (Dcytb) </li></ul><ul><li>This enzyme is Vitamin C dependent . </li></ul>
  5. 6. <ul><li>From the gut lumen, iron needs to be moved into the enterocyte before getting to the bloodstream. </li></ul><ul><li>Therefore, it needs a transporter to do this. </li></ul><ul><li>Inorganic iron uses DMT1 </li></ul><ul><li>Organic iron uses HCP1 </li></ul>
  6. 7. <ul><li>Once in the enterocyte, iron is moved to the bloodstream. </li></ul><ul><li>Fe 2+ is transported out by ferroportin1 (FPN) </li></ul><ul><li>Once it leaves the enterocyte, the Fe 2+ changes back to Fe 3+ by Hephaestin. </li></ul>
  7. 8. <ul><li>Once in the bloodstream, Fe 3+ couples with Transferrin (Tf) forming a Tf-Fe complex. </li></ul><ul><li>Tf-Fe complex meets up with transferrin receptor 1 ( TfR1 ) in most cells. </li></ul><ul><li>Proton ATPase drops the pH in the endosome to release Fe 3+ from Tf. </li></ul><ul><li>This reduction is achieved by Steap3. </li></ul>
  8. 9. <ul><li>Macrophages engulfs old RBCs and releases heme. </li></ul><ul><li>Heme contains protoporphyrin and Fe . </li></ul><ul><li>Heme oxygenase separates them and Fe is then stored as ferritin. </li></ul>
  9. 10. Transferrin <ul><li>Major transporter for iron trafficking through the plasma . </li></ul><ul><li>Increased in iron deficiency. </li></ul><ul><li>Rare disease: Hypotransferrinemia . </li></ul><ul><li>Characterized by low transferrin level, severe iron deficiency anemia and iron overloading. </li></ul>
  10. 11. Serum soluble transferrin receptor <ul><li>High transferrin receptor= high Erythroid mass. </li></ul><ul><li>Causes for low transferrin receptor : erythroid hypo plasia. </li></ul><ul><li>Aplastic anemia </li></ul><ul><li>CRF </li></ul><ul><li>Causes for raised transferrin receptor : erythroid hyperplasia. </li></ul><ul><li>Chronic hemolysis </li></ul><ul><li>Thalassemia </li></ul><ul><li>Iron deficiency (absence of erythroid hyperplasia) </li></ul><ul><li>Not elevated in anemia of chronic disease. </li></ul>
  11. 12. Transferrin saturation <ul><li>Reduced : when iron supply is reduced. </li></ul><ul><li>Iron deficiency anemia </li></ul><ul><li>Anemia of chronic disease </li></ul><ul><li>Ferroportin mutation </li></ul><ul><li>Increased : when iron supply is in excess. </li></ul><ul><li>Hemochromatosis </li></ul><ul><li>Aplastic anemia </li></ul><ul><li>Sideroblastic anemia </li></ul><ul><li>Ineffective erythropoiesis. </li></ul><ul><li>Liver disease with reduced transferrin synthesis. </li></ul>
  12. 13. Ferritin <ul><li>Cellular storage protein for iron. </li></ul><ul><li>Plasma level reflects overall iron stores. </li></ul><ul><li>Also an acute phase reactant. </li></ul><ul><li>Orchestrates cellular defense against oxidative stress and inflammation. </li></ul>
  13. 14. <ul><li>When body gets inflammation, the normal response is to save the iron (keep it in storage) so that it will be less available to the microbes. </li></ul><ul><li>Raised ferritin = Inflammation. </li></ul><ul><li>Low ferritin = iron deficiency anemia (99%) </li></ul><ul><li>Raised ferritin but no infection/inflammation = Iron overload. </li></ul><ul><li>Extremely high ferritin = hemophagocytic lymphohistiocytosis. </li></ul>
  14. 15. Hepcidin <ul><li>Hepatic Bactericidal Protein. </li></ul><ul><li>Negative regulator of iron metabolism. </li></ul><ul><li>Actions: </li></ul><ul><li>It inhibits intestinal transport. </li></ul><ul><li>Blocks Fe transport across placenta. </li></ul><ul><li>Induces Fe sequestration in macrophages. </li></ul><ul><li>If low iron stores = hepcidin expression reduced . </li></ul><ul><li>If high iron stores = hepcidin expression increased. </li></ul><ul><li>Molecular target of Hepcidin is Ferroportin. </li></ul>
  15. 16. Here’s how it works… <ul><li>When iron is low, </li></ul><ul><li>Hepcidin expression is reduced. </li></ul><ul><li>Leads to increased ferroportin expression. </li></ul><ul><li>Therefore, more transport of Fe from cells to blood bound by Tf. </li></ul>
  16. 17. <ul><li>Hepcidin decreased in: </li></ul><ul><li>Hypoxia </li></ul><ul><li>Anemia </li></ul><ul><li>Iron deficiency. </li></ul><ul><li>Hepcidin increased in: Inflammation </li></ul><ul><li>leading to: </li></ul><ul><li>low transferrin Sat (low iron saturation) </li></ul><ul><li>increased ferritin (storage of iron) </li></ul><ul><li>anemia. </li></ul><ul><li>Inappropriately decreased in chronic hemolytic anemia and thalassemias. </li></ul>
  17. 18. Ferro port in <ul><li>Major ex port er of iron. </li></ul><ul><li>Transports iron from mother to fetus </li></ul><ul><li>Transferring absorbed iron from enterocytes into the circulation. </li></ul><ul><li>Allow macrophages to recycle iron from damaged red cells back into the circulation. </li></ul>
  18. 19. <ul><li>When hepcidin level increase , </li></ul><ul><li>Hepdicin binds to ferroportin . </li></ul><ul><li>Induces internalisation and lysosomal degradation . </li></ul><ul><li>Therefore, reduces amount of iron released into circulation from duodenal cells and macrophages. </li></ul>