Iron metabolism

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    06-May-2015

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iron metabolism

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<ul><li>1.Iron metabolism</li></ul> <p>2. </p> <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> <p>3. ( divalent metal transporter 1) 4. 5. </p> <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 calledDuodenal cytochrome b(Dcytb) </li></ul> <ul><li>This enzyme isVitamin C dependent . </li></ul> <p>6. </p> <ul><li>From the gut lumen, iron needs to be moved into theenterocytebefore getting to the bloodstream. </li></ul> <ul><li>Therefore, it needs a transporter to do this. </li></ul> <ul><li>Inorganic iron usesDMT1 </li></ul> <ul><li>Organic iron usesHCP1 </li></ul> <p>7. </p> <ul><li>Once in the enterocyte, iron is moved to the bloodstream. </li></ul> <ul><li>Fe 2+is transported out byferroportin1 (FPN) </li></ul> <ul><li>Once it leaves the enterocyte, the Fe 2+changes back to Fe 3+byHephaestin. </li></ul> <p>8. </p> <ul><li>Once in the bloodstream, Fe 3+couples with Transferrin (Tf) forming aTf-Fe complex. </li></ul> <ul><li>Tf-Fe complex meets up with transferrin receptor 1 ( TfR1 ) in most cells. </li></ul> <ul><li>Proton ATPasedrops the pH in the endosome to release Fe 3+from Tf. </li></ul> <ul><li>This reduction is achieved bySteap3. </li></ul> <p>9. </p> <ul><li>Macrophages engulfs old RBCs and releases heme.</li></ul> <ul><li>Heme containsprotoporphyrinandFe . </li></ul> <ul><li>Heme oxygenaseseparates them and Fe is then stored asferritin. </li></ul> <p>10. Transferrin </p> <ul><li>Major transporterfor iron trafficking through theplasma . </li></ul> <ul><li>Increasedin 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> <p>11. Serum soluble transferrin receptor </p> <ul><li>High transferrin receptor= high Erythroid mass. </li></ul> <ul><li>Causes forlow transferrin receptor : erythroidhypo plasia. </li></ul> <ul><li>Aplastic anemia </li></ul> <ul><li>CRF </li></ul> <ul><li>Causes forraised 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 elevatedin anemia of chronic disease. </li></ul> <p>12. Transferrinsaturation </p> <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> <p>13. Ferritin </p> <ul><li>Cellular storage protein for iron. </li></ul> <ul><li>Plasma level reflectsoverall 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> <p>14. </p> <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> <p>15. Hepcidin </p> <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>Iflow iron stores= hepcidin expressionreduced . </li></ul> <ul><li>Ifhigh iron stores= hepcidin expressionincreased. </li></ul> <ul><li>Molecular targetof Hepcidin isFerroportin. </li></ul> <p>16. Heres how it works </p> <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> <p>17. </p> <ul><li>Hepcidindecreasedin: </li></ul> <ul><li>Hypoxia</li></ul> <ul><li>Anemia </li></ul> <ul><li>Iron deficiency. </li></ul> <ul><li>Hepcidinincreasedin: 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 decreasedin chronic hemolytic anemia and thalassemias. </li></ul> <p>18. Ferro port in </p> <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> <p>19. </p> <ul><li>Whenhepcidinlevelincrease , </li></ul> <ul><li>Hepdicinbinds to ferroportin . </li></ul> <ul><li>Inducesinternalisation and lysosomaldegradation . </li></ul> <ul><li>Therefore,reduces amount of iron releasedinto circulation from duodenal cells and macrophages. </li></ul> <p>20. 21. </p>