Iron Metabolism and Hemochromatosis
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- What are Myeloperoxidases?
- enzymes in neutrophils that utilize iron.
- What are the physical characterists of RBCs in iron deficiency induced anemia?
- microcytic hypochromatic⬦ that is the cells are small and not colored⬦ also decreased rate of hemoglobin synthesis.
- What is the treatment of iron deficiency anemia?
- Oral ferrous sulfate⬦ also intravenous iron therapy or packed RBC transfusion
- What is lactoferrin? What is the double benefit of this protein?
- it is a Fe binding protein found in mother's milk for storage and transport, (b) nurishment and intimicrobial action.
- How does lactoferrin help the neonate deal with gut bacteria?
- it competes with the bacteria for the iron.
- What are haptoglobins?
- involved in capturing oxyhemoglobin dimmers Hb∂-Hbß… and prevents loss through kidney… it is also involved in the process where heme is separated from the globin.
- What happens to Fe when the heme is converted to Fe (free), CO and Bilirubin?
- Transferrin binds it for transport
- Where are transferrin and haptoglobin made?
- liver
- What is the role of transferrin?
- Transferrin binds free Fe so that it doesn't readily deposit into cells, rather when bound to transferrin, Fe will only enter cells as a function of receptor mediated transport (Tf receptors)
- What is the function of Ferritin?
- storage of Fe in tissues
- What is ferritin used for in the clinical setting?
- the small level found in the plasma allow for a measure of the total Fe content of our body stores.
- What are 3 signs of iron deficiency?
- (a) plasma ferritin = 0⬦ (b) transferrin binding capacity upper limit is about 300 ub/dL⬦ (c) Fe saturation for transferrin is <16%
- What is an IRE?
- it's nucleotide sequence on mRNA.
- What is the role of IRE-BP with respect to ferritin?
- It binds to IRE and inhibits translation of Ferritin (tissue storage) when [Fe] is low.
- What happens to IRE-BP during high [Fe] with respect to ferritin?
- it dissociates and allows translation of ferritin to accommodate influx of Fe.
- What is the role of IRE-BP with respect to transferrin receptors?
- It stabilizes transferin receptor mRNA during low [Fe]
- What happens to IRE-BP during high [Fe] with respect to transferrin receptors?
- In high [Fe] IRE-BP dissociates from the transferrin receptor mRNA and the mRNA strand degrades.
- What is the locational difference between IRE-BP for transferrin and ferritin?
- Ferritin is at the beging of the mRNA strand, while transferrin is at the end.
- What is hemochromatosis? And what is the gene associated with this disorder?
- Fe overload⬦ HFE
- What is mechanism of hemochromatosis?
- it causes the increase in the amount of transferrin receptors made, and thus transferred into the cells.
- What are symptoms of hemochromatosis?
- bronze skin, cirrhosis of the liver and damage to the pancreas could lead to diabetes I, fatigue and arthalgia (painfull joints)⬦ iron is toxic
- How would you measure this diagnostically?
- transferrin saturation levels would rise from 10-30% to 35-50%
- How is it that free Fe are toxic? (Hint: Fenton Reaction)
- Oxidized to from ferrous to ferric by H2O2 forming OH⬢ (hydroxyl radical) , this radical can react with lipid and protein to damage tissues.
- given that there are 1/300 afflicted with hemochromatosis, what is the frequency for carriers?
- q^2= 1/300, thus,(1/300)^.5 = q⬦ p=1-q⬦ heterozygotes=2pq = .11 =11%
- (a) Where is the HFE gene located? (b) And what does this mean in terms of it's function
- (a)in the HLA-A3 region⬦ (b) such that the region no longer functions in antigen presentation⬦ it's too small⬦ it now facilitates Fe transport
- What is significant about losing a cysteine to a tyrosine in HFE muations?
- the lack of a cystein makes the amino acid unable to form a dissulfide bond.
- In terms of macrophages, what change of function does the HFE mutation cause?
- uncontrolled release of Fe