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41 Cards in this Set
- Front
- Back
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give an example of iron used in an enzyme and its medical significance.
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rate limiting step in DNA synthesis is via ribonucleotide reductase which contains an iron for an oxidative step in making deoxynucleotides. thus this is a potential target for chemotherapy
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describe two results of iron deficiency aside from anemia
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in children, it leads to abnormal neural development, in adults it leads to fatigue and thus a decreased capacity to work
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describe the ways that excessive iron is injurious
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hemochromatosis (rare - can eventually lead to end stage organ disease), ischemia and reperfusion (strokes and MI's), sickle cell disease (transfussions and increased iron absorption of the hemolytic anemias leads to more iron which is toxic to the RBC membrane causing more damage and perpetuating sickle cell disease problems), cancer, type 2 diabetes (damaging effects of iron on the pancreas)
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describe the solubility of iron
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Fe3+ is very insoluble and cannot get onto the ferrin proteins or hemo proteins. Fe2 on the otherhand is very soluble
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describe the molecular causes of toxicity of iron.
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it causes fre radicals. for example, Fe2 and H2O2 form Fe3 and OH free radicals. Fe3 and NADH form Fe2 and NADH free radicals. these free radicals can get into larger molecules like lipids and proteins and form free radicals on membranes or surfaces
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describe the intestinal iron transport system.
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has many components including brush border transporter (DMT1), basolateral transporter (FPT1), hephaestin, HFE
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what are the iron related proteins?
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Heme proteins (hemoglobin, myoglobin, cytochromes, respiratory chain electron transport, catalases, etc.)
Iron sulfur proteins Iron dependent enzymes (phenylalanine hydroxylase, ribonucleotide reductase) |
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where does transferrin shuttle iron?
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bw intestinal mucosa, erythroid precurser cells, and reticular endothelial cells (macs)
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describe the binding sites and affinity of transferrin for iron.
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two Fe (III) sites with very high affinity
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describe the process of uptake of iron by the cell via transferrin
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transferrin binds to the transferrin receptor, receptor mediated endocytosis, acidification of endosome to decrease affinity of transferrin for the iron, reduction to Fe2 to facilitate transport across the endosomal membrane via DMT1 transporter (note DMT1 is also present in the brush border of intestinal cells to facilitate iron intake into the body).
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once iron is in the cytosol after transferrin mediated transport, what can it do?
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to the mito for insertion into protoporphyrin for heme synthesis. To the iron storage protein ferritin. to other proteins/enzymes for which iron is a cofactor.
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clinically, serum transferrin is also known as?
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total iron binding capacity (TIBC)
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What is normal TIBC levels and what is the saturation of TIBC in normal individuals? iron deficient individuals?
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normal rates are 150 to 300 mg/dL. normal ppl are 1/3 saturated. iron deficients are less than 10% saturated
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describe the structure of the transferrin receptor. in what cell is it most abundant?
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dimer by disulfide bonds and is expressed in all living cells, but highest numbers are in erythroid precursors
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how is synthesis of transferrin receptor controlled?
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post txn-al level and is inversely proportional to cellular iron levels (has iron response element on 3' end which will stabalize the message if bound by the iron response protein in the abscence of iron), thus iron depleted cells will express more transferrin receptors.
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how can cellular iron storage levels be measured?
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by measuring tha amount of plasma transferrin receptor fragments which are proteolytically cleaved as the erythroid cells develop
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what happens to transferrin after the endosome is acidified?
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it remains bound to the transferrin receptor and is shuttled back to the plasma membrane and released into the plasma for re-use
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# of subunits of ferritin? # of molecules of iron stored per molecule of ferritin? ?
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24, big ol protein. 4000. proportional to iron stores
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describe the form of iron that s stored by ferritin.
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ferritin in cell uptakes Fe2, it becomes Fe3 within ferritin and is then reduced to Fe2 when it is mobilized.
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how can ferritin be used as an assay for iron stores in the cell?
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a fraction of intracellular ferritin is exported into the plasma, and more ferritin means more stores therefore plasma ferritin reflects iron stores
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describe the regulation of ferritin synthesis.
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the iron regulatory element on the 5' end of the start site of ferritin mRNA is a stem loop structure that can bind iron binding proteins (note that IRE is found ona bunch of mRNAs - transferrin receptor, ALA synthetase, mito aconitase, succinyl dehydrogenase). if iron is present, it will bind an IBP (4 irons activate 1 IBP), if IBP has iron it cannot bind the IRE and thus the ferritin message CAN be translated. note this is the oppositte of transferrin receptor synthesis regulation
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where in the body does iron absorption occur?
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in the distal duodenum and the proximal jejunum
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describe total iron loss and total iron absorption in terms of our iron needs.
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need about 25 mg/day for RBC precursors, this comes from our stores. we lose iron when we bleed or slough (slough cells daily from SI). we absorb 1 mg per day to make up for this loss (note we eat 10 mg a day put absorb only 10% of this). no regulation of iron excretion, iron is re-used. our iron stores are about 2500 mgs
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what kind of iron is more readily absorbed?
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heme iron
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describe the absorption of iron at the brush border and the factors that increase absorption
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acid is needed to help make Fe2+ (which was reduced by duodenal cytochrome b reductase) that can cross the DMT1 (divalent metal transporter) transporter. then haephestin can oxidize Fe to Fe3 and it can go systemica via the ferroportin transporter. if it is not oxidized it is stored in ferritin and may be sloughed off with these cells in the intestine (this occurs if the person has normal iron levels). Ascorbate and citris help regulate absorption via acidification. systemic factors like hemolysis and alcohol also increase absorption.
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describe what is known about hepcidin
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it is an iron stores regulator. it is made by the kuppfer cells and transferrin receptor 2 (different than type 1 which is the normal transferrin receptor), hemojuvelin protein, and HFE are all needed to stimulate hepcidin synth. hepcidin goes to the intestine, interacts with ferroportin and blocks the systemic release of iron. inflammation stimulates hepcidin release. iron deficiency leads to low hepcidin levels and thus more iron absorption.
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describe what is known about HFE.
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found in the brush border cell and hepatocytes. purpose of it in brush border is unclear, but it is needed to stimulate synth of hepcidin in the hepatocytes. it is an MHC 2 protein that binds beta 2 microglobulin (B2M). when B2M binds HFE, HFE binds transferrin receptor and regulates how tightly transferrin binds to the transferrin receptor. hemochromatosis occurs in mutated HFE, B2M does not bind and thus transferrin binding its receptor is altered.
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what are the possible etiologies from normal physiology of iron metabolism disorders?
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dietary sources, absorption, tissue distribution, and iron loss
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what can cause 4 pathologies that can cause iron malutilization?
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anemia of chronic disease (due to increased inflamation will induce increased hepcidin and thus no systemic iron absorption). lead poisoning (blocks poisons heme synth and can block the absorption of iron in the intestine wall), sideroblastic anemias (cannot synthesize heme properly), and thalassemias (reduced globulin production)
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ways to evaluate iron stores?
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RBC size and chromicity; ferritin, Fe, TIBC, and transferrin receptor levels. bone marrow iron store analysis is the gold standard.
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3 pathological states of iron metabolism?
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decreased stores (iron def), normal stores but malutilization, excess iron
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describe the normal distribution of iron in a healthy adult
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Hb iron (3000mg, 66%), storage in ferritin (1000mg, 25%), transferrin in plasma (4mg, 0.1%), and Mb and resp. enzymes (300mg, 8%)
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what healthy populations appear at the brink of iron deficiency and why?
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child bearing age women, lose an additional 1 to 2 mg per day of iron during menstruation. also in pregnancy bc of expanded blood mass and fetal requirements ~1000mg of iron needed, thus most take iron supplements.
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causes of iron deficiency due to increased requirements/decreased intake? decreased absorption? increased loss?
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diet, pregnancy, growth spurts, infancy and prematurity. gastric surgery, achlorhydria (decrease in acid production), malabsorption bc mucosa of duodenum or jejunum is altered. menses and gastrointestinal causes like gastritis and colon cancer.
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describe the levels of iron proteins in anemia of chronic disease and why they are this way?
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low serum iron and low serum transferrin due to iron not able to get out of storage and low transferrin bc liver sees iron stores are OK, so it does not make it. Normal/elevated serum ferritin.
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describe the pathogenesis of anemia of chronic disease
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blunted response to EPO with inhibition of erythroid progenitors, impaired marrow erythropoietic response with impaired iron mobilization and utilization. decreased RBC survival. lotsa cytokines cause inhibited EPO response, apoptosis of progenitors. also increased ferritin expression to trap iron, altered NO effects, down regulaition of TIBC receptor. IL6 increases hepcidin production thus decreases ferroportin in intestine and macs.
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benefits of anemia of chronic disease?
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deprive micro-orgs and tumor cells of iron and O2, iron inhibits IFN-y activity,
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two types of iron overload?
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primary (inherited increased absorption capacity) and secondary (acquired from transfusions)
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describe the classification of primary hemochromatosis
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hereditary. classical (HFE hemochrom AKA type 1 is the bulk of them), juvenile is type 2 on chrom 1q and is abnormality of hepcidin due to hemojuvalin screw up, transferrin receptor 2 def is type 3 thus affecting hepcidin, ferroportin def (type 4) and then African iron overload (medd up i iron absorption, some are type 4).
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classification of secondary hemochromatosis?
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hereditary DOs: thalassemia, sickle cell, PK def, dyserythropoietic anemia, G6Pd def, hereditary spherocytosis, sideroblastic anemia. acquired DOs: myelodysplasias, multiple transfusions
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describe the sxs and genetics of hereditary hemochromatosis (type 1)
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diabetes, skin bronzing, cirrhosis. HFE gene with two possible mutations. common celtic ancestor from 70 generations ago, 10% of white americans carry the mutation, homozygous is 5/1000.
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