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57 Cards in this Set
- Front
- Back
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How is Iron distributed in the body
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- Normal adult has 2-5 g of iron
- 60-70% of iron in body in hemoglobin -10% is in myoglobin - less than 1% in cytochromes & metalloenzymes - variable amount in ferritin/hemosiderin -Highest concentrations of iron are found in the liver, reticuloendothelial cell, erythroid percursor cells - concentrations are highly variable - liver can store up to 10g...an Iron overload primarily affects the liver |
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What are the two forms of iron?
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Heme and non-heme
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What % of iron is absorbed?
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HEME IRON:
- 25-35% absorbed (absorbed as heme) - heme oxygenase is in the mucosa and catalyzes the degregation of heme into Fe+2 adn bilirubin - not affected by other things in diet NON-HEME IRON: - not well absorbed, only 1-3% - influenced by other things in the diet |
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Where is iron homeostasis controlled?
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-at the level of intestinal absorption
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What is most iron deficiency the result of?
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-inadequate dietary intake and failure to absorb iron in the intestine
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Describe non-heme iron absorption
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- 1-3% absorbed
- highly variable - in food it's mostly in the ferric form, which is not well absorbed - dependent on constituents of total meal - common intraluminal pool - MECHANISM: - highly regulated; maintains homeostasis....absorption of iron maintains the iron body pool not excretion |
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What enhances the absorption of non-heme iron?
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- ENHANCERS OF ABSORPTION:
---ascorbate (reductant) ---meat factor in beef, pork, fish, and poultry, something in the meat enhances non-heme absorption |
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What inhibits the absorption of non-heme iron
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-polyphenols (e.g. tannins)
- phytates (rich in cereals) -high levels of calcium |
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What is DMT1
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- transporter that imports Fe+2 (ferrous form) and other minerals into the intestine
- resides on brush border of enterocytes - iron has to be in the reduced form (Fe+2 form...ferrous) before it can be taken up by DMT1 |
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What is Dcytb (duodenal cytochrome b)?
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- brush border protein involved in intestinal absorption of Fe
- it reduces Fe+3 (ferric form) to the Fe+2 (ferrous form) so that it can be taken up by DMT1 |
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What is HCP1 (Heme carrier protein-1)?
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- it's located on the brush border during Fe deficiency and is intracellular in sufficiency
- transports heme into intestinal cells |
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What is Ferroportin 1?
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-involved in the export of iron to the portal circulation
- on basolaterol membrane - exports iron in the Fe+2 form (ferrous) - found in duodenal enterocytes, macrophages, and hepatocytes |
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What is Hephaestin?
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- located on the basolateral membrane
- copper containing proten that is homologous to ceruloplasmin - has ferrioxidase activity - oxidizes Fe+2 to Fe+3...ferrous to ferric form, this is critical because transferrin can only carry iron the the ferric form |
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What is Transferrin?
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- plasma iron transport protein
- transports iron in Fe+3 form - can transport 2 Fe atoms per molecule - carriers iron to tissues - 2/3 of binding sites are available - influenced by Fe status, increases in deficiency and decreases in sufficiency - good measure if iron status |
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What is Hepcidin?
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- iron hormone
- its level regulates the amount of ferroportin present, so it regulate iron export by ferroportin - peptide synthesized in the liver and secreted in response to iron status - interacts with ferroportin (the iron export protein) to cause its internalization and degradation - regulation occurs via transcription but is not well understood - key player in maintaining iron homeostasis....if you don't export iron out of the intestinal cell via ferroportin, then iron is lost and not absorbed |
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What is ferritin?
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- Iron storage protein
- all cells have ferritin, but only a few are able to accumulate large amounts of iron (e.g. liver) - serves as nucleation site for crystal formation STRUCTURE: - large protein - apoferritin, mixture of two subunits |
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What is heme oxygenase?
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Enzyme that breaks down heme and releases Fe in the form of Fe+2
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What are the two fates of intracellular iron?
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- it can be extruded into the portal circulation by ferroportin (then interacts with hephaestin). It can then be incorporated into Fe-dependent proteins:
--- hemoglobin in erythrocytes precursors ---myoglobin in muscle cells ---various enzymes in numerous types of cells - it can be stored in the form of ferritin |
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What are transferrin receptors (TfR)
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- TfR are transmembrane glycoproteins
- high affinity for diferric transferrin - present in large #'s in erythrocyte precursors (for hemoglobin syn.), placenta and liver - # of receptors is regulated by the intracellular iron status (so iron status of each cell) - when cell is deficient in iron, more TfR are expressed and vice versa |
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Describe the regulation of iron homeostasis
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- when the plasma iron pool increases, hepcidin is released from the liver
- hepcidin acts to reduce iron export to the plasma via ferroportin from the enterocytes |
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What is hemosiderin?
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- insoluble protein aggregate formed from ferritin by lyzosomes
increased greatly with iron overload (hemochromatosis) - can lead to liver cirrhosis, fibrosis and death |
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Explain the process of intracellular iron uptake
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- Transferrin bound to fe+3 binds to the transferrin receptor and is taken into the cell via receptor mediated endocytosis
- clatherin coated pits help take into the cell - the complex is taken into the endosome - H-ATPase acts to reduce the pH of the endosome, which causes the Fe to be released from the transferrin (Fe in Fe+3 state) Fe+3 is reduced to Fe+2 and transferred out of the cell by DMT1 - the fate of the iron depends on the tissue and cell need |
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How is iron lost from the body?
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- retained tenaciously
- losses 1mg/d men and 1.5 mg women - lost from skin, gut, epithelial cells, bile, urinary and menstrual losses. - pregnancy, blood donation and intestinal parasites are other significant sources of losses |
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What is hookworm disease?
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- affects 1/5th of planet
- common in tropical, developing countries - enters body through skin - 1/4 of people w/it have anemia - can cause growth retardation and impairment of motor development/cognition in children |
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Describe the regulation of intracellular iron
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- highly regulated
- with low iron status, the # of transferrin receptors increase to bring more iron into cell. Also have less ferritin synthesis - with high iron status, you have fewer transferrin receptors and greater synthesis of ferritin |
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How is the synthesis of ferritin controlled?
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- regulated at the level of translation
- there is a pre-existing pool of mRNA that is relatively constant - translation of this pool is what regulates the amt. of ferritin present - the reason ferritin is regulated by translation rather than transcription is it's faster, which is important because iron is toxic to cells and causes lipid peroxidation |
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How is the synthesis of transferrin receptors controlled (TfR)?
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-regulated by the stability of the mRNA
- so the rate or amount of breakdown of mRNA determines the # of TfR receptors |
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What are the two proteins involved in Fe regulation that are regulated at the point of translation?
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Ferritin - regulated by translation of pre-existing pool of mRNA
TfR - regulated by the maintaining the pool of mRNA by altering how fast it is degraded These two proteins are inversely regulated, when ferritin synthesis is increased, TfR synthesis is decreased and vice versa |
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What is an IRE (Iron response element)?
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- a stem loop structure on the mRNA of ferritin and TfR that is important for the regulation of ferritin/TfR synthesis
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What is IRP (Iron response protein)?
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- dictates the fate of mRNA
- dictates whether TfR mRNA is stable or not AND whetehr the ferritin mRNA is translated or not - cytosolic aconitase - IRP binds to IRE: -----when in binds in ferritin it stops protein synthesis ----when it binds to TfR mRNA, the mRNA is stabilized and the RNAses can't degrade it allowing TfR to be synthesized (this increases Fe uptake into cell and decreased storage of Fe in ferritin) |
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What regulates the binding of the IRP to the IRE?
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- IRP can sense the iron level in the cell
- The IRP exists in two states: ---in the presence of iron, Fe-S complexes form, which bind aconitase causing a low affinity state, whcih does not bind to teh IREs. So low affinity means IRP has a low affinity for IRE on the mRNA - affinity states are based on whether Fe-S clusters form (dependent on Fe status). So formation of clusters is what causes IRP to have a high or low affinity for IRE |
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What is IRP2
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- the other response element binding protein
- appears to be the dominant regulator (vs. IRP1) of iron cellular homeostasis - acts the same way as IRP1 in terms of having a high and low affinity state and binding to IRE, but it is regulated by being degraded or not degraded in response to Fe status -in iron replete cells, IRP2 is degraded |
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Summary of Ferritin and Transferrin receptor regulation
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LOW IRON STATUS:
- IRP has an affinity for IRE which leads to the synthesis of TfR and a lack of synthesis of ferritin mRNa HIGH IRON STATUS: - Tfr mRna is not stable because there is no IRP bound to IRE, so it's degraded and the ferritin mRNA is able to be translated |
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What are the biological roles of non-heme iron?
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- oxygen transport (hemoglobin and myoglobin)
- cytochromes - heme containing enzymes, included components of the electron transport chain, cytochrome P-450 -catalase - degrades hydroperoxide to water and oxygen (H2O2 > H20 + O2 - non-heme iron compounds: iron-sulfur proteins and metalloflavoproteins (NADH dehydrogenase, which is part of the ETC and succinic dehydrogenase which is part of the TCA cycle - more iron found in non-heme vs. heme compounds -Iron dependent enzymes - iron is a cofactor or activator (Trp pyrrolase, which is the 1st enzyme in the kyurnic acid pathway and xanthine oxidase, which converts xanthin to uric acid, this is important in birds) |
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What are the symptoms of iron deficiency anemia?
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- decreased work capacity
- paresthesia (numbness and tingling) - atrophy of epithelium of tongue - angular stomatitis - pica - (linear affect between hemoglobin concentration and ability to do work |
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What is the distribution of iron deficiency?
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- happens pretty much everywhere, particularly in Africa and the Middle east
- 30% or world is estimated to be anemic |
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What are the characteristics of iron deficiency anemia?
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- microcytic, hypochromatic anemia, small cells with not much color
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What happens to the brain in iron deficiency?
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- leads to hypomyelination of the brain, can impair cognitive development in kids and can be irreversible in children under age 3
- Oligodendrocytes are myelin producing cells in the brain, and are the predominant iron-containing cells in the brain. ---- Cholesterol and lipid synthesis rates are highest of any cell in brain -----iron required for cholesterol and lipid synthesis - |
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What are the stages of iron deficiency development?
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1. Iron Depletion
- ferritin depleted - plasma iron decreased - transferrin iron saturation decreases (increased UIBC) 2. Iron deficient erythropoiesis - insufficient iron for heme synthesis - red cell protoporphyrin increased 3. Iron deficiency anemia - normochromic & normocytic>microcytic> microcytic and hypochromic |
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What is UIBC?
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-Unsaturated iron binding capacity = the available binding sites on transferrin.
- Normally around 1/3, as you become iron deficient, the body senses it and the amount of transferrin increases but amount of serum Fe decreased leading to decreased iron saturation |
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What are the acquired iron overload states?
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- excess dietary intake (can be caused of making fermented beverages in iron pots
- iron loading anemias: Thalassemia major and Siderblastic anemia - chronic liver disease (alcoholic liver disease) |
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What is Thalassemia major?
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- an iron loading anemia
- reduced globin synthesis due to a genetic defect - overload due to increased Fe absorption and/or repeated blood transfusions |
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What is Sideroblastic anemia?
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- iron loading anemia
- defect in mitochrondrial part of heme synthesis pathway - |
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What are hereditary Iron overload states?
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- Hereditary hemochromatosis
- juvenile hemochromatosis |
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What is juvenile hemochromatosis?
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- rare type of hereditary iron overload
- different than hereditary hemochromatosis - very high rate of Fe absorption |
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What is transferrin receptor 2 mutation
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- type of hereditary iron overload
- TfR2 is expressed in the liver |
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What is a ferroportin mutation
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- type of hereditary iron overload
- Fe accumulates in the macrophages |
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What is hereditary hemochromatosis (HH)?
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- type of hereditary iron overload
- extensive hemosiderin deposits in liver accompanied and cirrhosis - inborn error of metabolism - common in european descent, affects .5% of US population - characterized by increased iron absorption....absorbing Fe all the time - prevalence 10X greater in males, mutation equal, just shows up slower in females because of their low iron status |
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What are the symptoms of HH
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fatigue, heart palpations, joint pain, stomach pain, impotence and loss of menstrual periods
- hepatomegaly, skin pigmentaation, diabetes, cardiac arrhythmia and hypogonadism - organ damage is usually irreversible |
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What is the treatment for HH?
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periodic phlebotomy
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What is the most common defect in HH?
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- Defect in HFE gene, which is part of the major histocompatibility complex (MHC) class I gene family
- HFE is part of the immune system and presents foreign antibodies to T cells HFE interacts with beta-microglobulin and allows membrane localization of HFE - normally HFE protein binds to TfR and reduces its affinity for differic transferrin - Mutated HFE has no affinity fro beta-microglobulin - so with a mutation, there is no inhibition of iron absorption so iron overload occurs |
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What is the Hepcidin Hypothesis?
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- normally when iron is high, hepciden is released, and hepcidin increases degradation of ferriportin
- with the mutated HFE, hepciden secretion is decreased which results in increased iron uptake |
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What are the biochemical assessment methods for iron status?
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- serum ferritin (measures iron stores)
- Serum TfR - (more TfR implies a greater need for iron) - Blood hemoglobin - advanced iron deficiency |
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What occurs with hemochromatosis?
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- serum iron, transferrin saturation and serum ferritin are all elevated
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Describe acute toxicity of iron...
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- one of the leading causes of accidental poisonings/deaths in children
- clinical toxicity symptoms include diarrhea, vomiting and abdominal pain and periportal liver necrosis - At 20 mg Fe/Kg body wt GI symptoms occur - at 60 mg Fe/Kg body wt - systemic symtoms occur - treatment is stabilization of organs and removal of unabsorbed iron via chealating agents |
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What is the RDI for Iron?
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Adult Males: 8 mg/d
females: 18/mg/d post menopause: 8 mg/d |
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What are sources of iron?
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Dried legumes, nuts, red meats, green leafy veggies, enriched or whole grain breads or cereals
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