Term
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Definition
Too much iron
iron accumulates in: liver, heart, pancreas, skin, joints
causes: cirrhosis, cardiomyopathy, diabetes, bronzing, arthritis
AR disorder due to mutation in *Hfe* gene
-has a big impact on cell iron trafficking and indirectly on intestinal iron absorption
-not regulated by iron status
-Hfe regulates iron uptake (from BL membrane to Tf)
32 mln (1 in 8)
1.5 mln have double mutation |
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Term
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Definition
iron can damage tissues: catalyzes the conversion of H2O2 to free-radical ions
free radicals can attack: cellular membranes, proteins, DNA
possibly related to cancer, cardiac toxicity, others |
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Term
Iron transport in blood
-red cells
-plasma |
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Definition
red cells: as Hb, can't be exchanged
plasma: bound to transferrin, carries iron b/t body locations (gut, liver, BM, macrophages)
iron taken up into cells by transferin receptors |
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Term
| Factors that influence iron absorption |
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Definition
Bioavailability: heme > Fe2+ > Fe3+
Inhibitors: phytates, tannins, soil clay, antacids, iron overload
Competitors: cobalt, lead, strontium, manganese, zinc
Facilitators: ascorbate, citrate, AA, iron deficiency |
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Term
Fate of dietary iron
-luminal surface
-transluminal transport |
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Definition
dietary free iron (Fe3+) is reduced to Fe2+
occurs at brush border by duodenal ferric reductase
DMT1/Nramp2 (divalent metal transporter 1)
dietary heme iron via transporter
released from heme or absorbed into circulation |
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Term
Transferrin
-where is it synthesized?
-molecular composition?
-how many molecules can it bind?
-how much serum Fe does it contain?
-how does iron status affect its production?
-normal TIBC values
-normal total serum transferrin levels |
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Definition
made in the liver
2 carbohydrate chains
each molecule can bind two Fe3+ (oxidized)
contains 95% of serum Fe
production decreased in iron overload
production increased in iron def
measured in blood as marker of iron status
normal TIBC:
adult males: 300-400 mcg/dL
females: 300-450 mcg/dL
normal total transferrin levels:
adults: 200-400 mg/dL
children: 203-360 mg/dL
newborns: 130-275 mg/dL |
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Term
Iron transport
Tf = transferrin |
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Definition
Fe2+TF binds TFR1 on RBC
Fe2+TF/TFR1 localize to clathrin-coated pits which invaginate to form endosomes
A proton pump decreases pH leading to iron release
DMT1 moves across endosomal membrane to cytoplasm
Apo-Tf & TfR1 are recycled to cell surface for further use
In RBC most iron is incorporated into protoporphyrin to make heme (motochondria) |
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Term
| Murine microcytic anemia (mk) mutation |
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Definition
when homozygous, results in impairment of iron absorption by reducing DMT1 expression
DMT1, Nramp2, DCT1 - major apical ferrous transporter |
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Term
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Definition
Induced by iron deficiency
mediates cellular ion efflux in conjuction with ferroxidase, hephaestin
-hephaestin facilitates enterocyte iron release
-released by way of ferroportin into circulation
localizes to the basolateral membrane of polarized cells (present on the BL membrane of RBCs)
Present on macrophages
Present on hepatocytes |
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Term
| Storage reservoir for iron |
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Definition
Hepatocytes
-take up dietary iron from portal blood (FeTf/TfR1)
-release iron into circulation via ferroportin in times of increased demand |
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Term
| Generic cellular iron regulation |
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Definition
IRE (iron regulatory element)/IRP (iron regulatory protein) Regulatory System
each cell can regulate its own utilization of iron
coordinate via IRPs and their binding to IREs present on nucleic acids
proteins involved in iron storage, erythroid heme synthesis, the TCA cycle, iron export, and iron uptake are coordinately regulated
IRP act as the cell sensor to iron availability |
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Term
Hepcidin
function?
regulation?
impact on ferroportin |
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Definition
Antimicrobial activity (hepatic bacteriocidal protein)
*master iron regulatory hormone*
factors regulating intestinal iron absorption also regulate expression of hepcidin
-d/c iron stores
-i/c erythropoietic activity
-anemia
-hypoxia
intestinal iron absorption varies inversely with liver hepcidin expression
hepcidin decreases the functional activity of ferroportin by directly binding to it and causing it to be internalized from the cell surface and deregulated
-d/c basolateral iron transfer and thus dietary iron absorption
-d/c in iron export by hepatocyte and macrophage and a resultant i/c in stored iron |
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Term
Hephaestin
sex-linked anemia |
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Definition
ferroxidase activity
oxidizes iron as part of the transmembrane transfer process/loading of iron onto plasma Tf
sex-linked anemia mutation: partial loss of hephaestin function & resultant iron def due in part to hephaestin mislocalization away from BL membrane |
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Term
Hepcidin deficiency
-hereditary hemochromatosis
-ineffective erythropoiesis
Hepcidin excess
-anemia of chronic disease (HCD) |
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Definition
Hemochromatosis: absorb excessive iron relative to body stores, implying the set-point for the stores regulator is altered
Ineffective eryth: i/c destruction of erythroid precursors (e.g. thalassemia), coupled to increased iron absorption
ACD: infxn/inflammation induce iron sequestration in macrophages and decrease intestinal absorption |
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Term
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Definition
TfR2 may serve as a sensor of circulating Tf-bound iron, thereby influencing expression of hepcidin
hepcidin response is also modulated by HFE and hemojuvelin
Inflammatory cytokines including IL-6 and LPS increase hepcidin secretion |
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Term
| Compare, contrast iron deficiency anemia and vitamin B6 deficiency |
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Definition
both produce microcytic, hypochromic anemia
iron stores are low in iron def anemia |
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Term
Hereditary Hemochromatosis
Type I
Type II
Type III
Type IV |
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Definition
Type I: classic hereditary HH - Hfe gene mutations
Type II: juvenile-onset
-type 2A: hemojuvelin HJV mutation
-type 2B: mutation in HAMP gene which encodes hepcidin
Type III: TfR2-related HH
-TfR2 gene mutation
Type IV: ferroportin-associated iron overload
-ferroportin-1 gene mutation |
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Term
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Definition
rare AR hereditary disorder
iron overload & hypochromic anemia
reduced delivery of iron to BM & reduced Hb synthesis
2 mutations have been identified:
-deletion creating frameshift resulting in null transferrin allele
-Ala 477Pro - defective ptn unstable |
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Term
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Definition
AR disorder of iron overload
loss of function mutation in ceruloplasmin gene 3q23-q24
ceruloplasmin has ferroxidase activity involved in the release of iron from cells
Pts have accumulation of iron in neural & glial cells of brain, hepatocytes, and pancreatic islet cells
aggressive chelation with deferoxamine
plasma or ceruloplasmin concentrate
phlebotomy may exacerbate microcytic hypochromic anemia |
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Term
| Anemia of chronic disease |
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Definition
syndrome of hepcidin excess
increased uptake, retention of iron within the RES
Common, thought to be closely related to hepcidin abnormalities
Inflammatory mediators:
-Increase - DMT1, ferritin, hepcidin
-Decrease - transferrin, ferroportin
Iron absorption from GIT is d/c, iron availability for erythropoiesis is d/c, circulating Tf-Fe is d/c |
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Term
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Definition
Hypochromic microcytic anemia
low serum iron
high TIBC-transferrin
low serum ferritin
absent BM stores |
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Term
nutritional iron requirements
(amt that must be absorbed for iron synthesis, minimal amt that must be ingested daily)
infants
children
young women, nonpregnant
pregnant women
men and postmenopausal women |
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Definition
infants - 1 mg, 10 mg
children - 0.5 mg, 5 mg
young women, nonpregnant - 2, 20 mg
pregnant women - 3, 30 mg
men and postmenopausal women - 1, 10 mg |
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