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IRON
content of iron in the body – male: 4g 70% in hemoglobinfemale:
3,5 g children: 3g
requirement: 1 – 1,5 mg/24 h., intake 10mgIn increased
requirement/increased loss: increased absorption to 3 – 3,5 mg/24
h.Tolerated limit of intake: 45 mg/24 h.
Excretion of iron: minimum, daily loss: 0,01% (1-2mg) (by
intestine, bleeding, skin. Hair
pregnancy, menstrual bleeding)
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Distribution of iron:
Tissue Form % of iron
erytrocytes hemoglobin 70,5
muscle myoglobin 3,2
Stores – liver
spleen
ferritin
hemosiderin
26,0
Blood plasma transferrin 0,1
other cytochromes
catalase
peroxidase
Fe - proteins
0,15
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Iron Significance
Essential Element
Key functional component of O2 transportation and storage
molecules (Hb, Mb)Many redox enzymes (cytochromes)Production of
various metabolic intermediatesHost defence (NADPH oxidase)Iron is
toxic to human cells
Iron Balance
Strictly regulated
Total body iron of 3 – 4gMinimal loss 1 – 2mg/dErythropoietic
iron requirement only 20mg/d
Important homeostatic mechanisms prevent excessive
ironabsorption in duodenum and regulate rate of iron release from
RES
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Chemical forms of iron:
Ferric (3+) iron: insoluble at physiological pH
Ferrous (2+) iron: dangerous if free, forms free radicals
Since free iron is insoluble or toxic, it must be bound to
proteins
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Cytochromes of the mitochondrial respiratory chain(100 mg of
iron)
Hemoglobin: more than one half of total body iron (2.5
grams)
Myoglobin: about 0.3 grams Fe, muscle oxygen storage protein
Cytochrome P450: most abundant hemeprotein of the liver (about 1
mg)detoxifies foreign compoundsis strongly inducible by drugs
(phenobarbital)Its induction forms the basis of drug-drug
interactions
Hemeproteins
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Ferritin - iron storage protein
Transferrin: iron transport protein
Non - heme iron proteins
Ferritin: iron storage proteinIn men, contains up to 1 gram of
iron
Reflects the amount of BODY IRON STORES
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Transports iron in the blood
Contains only 2 atoms of iron (Fe3+)
Transferrin is the only source of iron for hemoglobin
Transferrin saturation is clinically useful for iron metabolism
studies(iron-saturated Tf / total Tf)
Transferrin
Transferrin saturation:
Normal about 30-50 %,
Transferrin saturation under 15 % = Iron deficiency
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Cellular Iron Homeostasis
Concerned with each cells requirements for iron
Systemic Iron Homeostasis
Concerned with the body’s need for iron
Regulation of iron metabolism:
There is no pathway for iron excretion from the
bodytherefore
Total body iron level is regulated at the level of iron
absorption from the small intestine
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Intestinal iron absorption increases with
•Decreased iron stores
•Increased erythropoietic activity
•Anaemia
•Hypoxia
Intestinal iron absorption decreases in inflammation
Excess iron absorption relative to body iron stores – hereditary
haemochromatosis
Absorption of iron
Factors affecting absorption:
1. Quality of iron in food: heme iron (meat, liver) – 10-30%
non-heme iron (plant origin) – 1-5%
2. Form of iron: heme Fe2+ Fe3+
3. Other components of food: - inhibitory: salts of Ca2+,
phosphate, milk, cheese,
tea (tanin), coffee, oxalates
- stimulatory: ascorbate, citrate, amino acids
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enterocyte
Fe2+
Fe2+ Fe3+
ferroxidaseferritin
heme
heme
DMT1
ferroportin
Fe3+ transferrin
ferroxidase
hephaestin – in enterocytes ceruloplasmin – in blood
spleen
heme
erytrocytes
Fe2+feroportin
20mg/d.
1-2mg/d.
cells
TfR1
Fe2+
heme
Fe3+
ferritin
hemosiderin
HCP1
HCP1 – „hem carrier protein“DMT – „divalent metal
transporter“
Regulatory places of iron homeostasis
Blood stream
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Iron Absorption (into enterocyte)Luminal surface
Dietary free iron (Fe3+) is reduced to Fe2+Occurs at brush
border by duodenal ferric reductase (Dcytb)
Transluminal transportDMT1/Nramp2 (divalent metal transporter 1)
Dietary haeme iron via transporter and released from heme or
absorbed into the circulation.
Iron Absorption (out of enterocyte)
Basolateral absorption via ferroportin or haeme
transporter.Hephaestin facilitates enterocyte iron releaseReleased
by way of ferroportin into the circulation
FerroportinPresent on the basolateral membrane of
enterocytesPresent on macrophages and other RES cellsPresent on
hepatocytes
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Iron TansportVia transferrin
Iron Storage (Hepatic - major site)Hepatic uptake of transferrin
bound Fe viaclassic transferrin receptor TfR1 (and homologous
TfR2)
Hepatocytes are storage reservoir for ironTaking up dietary iron
from portal bloodReleasing iron into the circulation via
ferroportin in times of increased demand
Iron UtilisationErythropoiesis for heme synthhesis / general
cellular respirationvia TfRs on erythroid precursors and other
cells
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Transferrin uptake - transferrin receptor
Transferrin
Transferrin receptor
Cells which need iron express high number of transferrin
receptors on their surface
Transferrin receptor expression is
regulatedposttranscriptionally
at the level of transferrin receptor mRNA stability
Lack of iron stabilises mRNA for transferrin receptor
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• ferritransferrin binds to receptors at the surface of the
cells
• internalization of the complex ito endosome
• in endosome iron is released from tranferrin (by help of low
pH & reduction Fe3+ → Fe2+) and is relesed into cytosol
• iron is transported to the place of its utilization resp. Is
bound to ferritin (Fe2+ → Fe3+ and stored)
• apotransferrin connected with receptor returns back to the
membrane
• apotransferrin releases from receptor into blood plasma for
binding of next iron ions
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The IRE/IRP Regulatory System
Each cell has the capacity to regulate its own utilisation of
iron.
This is co-ordinated via Iron regulatory proteins (IRP) and
their binding to Iron regulatory elements (IRE) which are presents
on nucleic acids.
In this manner proteins involved in iron storage, erythroid
haeme synthesis, the TCA cycle, iron export, and iron uptake are
coordinately regulate.
IRP act as the cell sensor to iron availability
Cellular Iron Regulation
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IRP1IRP2
lower iron level
3'
5'
binds on IRES
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IRP1IRP2
3'
5'
stabilisation of mRNA
stop translation
TfR1DMT1
synthesis of new proteinsfor other iron intake
FerritinALA synthaseFeroportin
lower iron level
binds on IRES
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IRP1IRP2
higher iron level
3'
5'
stop translation
stabilisation of mRNA
FerritinALA synthaseFeroportin
TfR1DMT1
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Hepcidin
Intestinal iron absorption varies inversely with liver hepcidin
expression
Hepcidin decrease the functional activity of ferroportin by
directly binding to it and causing it to be internalised from the
cell surface and deregulated
Decreases basolateral iron transfer and thus dietary iron
absorption
Decrease in iron export by hepatocyte and macrophage and a
resultant increase in stored iron
Systemic Iron Homeostasis
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Hepcidin
25 aa peptide. Identified 2000
Antimicrobial activity. Hepatic bacteriocidal protein
Main iron regulatory hormone
Factors regulating intestinal iron absorption also regulate the
expression of hepcidin •Decreased iron stores•Increased
erythropoietic activity•Anaemia•Hypoxia
Cellular targets of hepcidin are villous enterocyte, RE
macrophage and hepatocyte
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Disorders of iron metabolism
1) Increased absorption of iron from the gut:HEMOCHROMATOSIS
2) Decreased amount of iron in the body:IRON DEFICIENCY
ANEMIA
3) Inflammation-induced change of iron distributrion:ANEMIA OF
CHRONIC DISEASE
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Excessive absorption of iron from the gut:
Hemochromatosis
Iron accumulates in the liver, heart and pancreas,excess iron
damages these organs by free radical production
Transferrin saturation increases, serum ferritin increases
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Lack of iron in the body:
Iron deficiency anemia
(most common anemia)
Hypochromic microcytic erythrocytes
Serum ferritin decreases (iron stores are depleted)transferrin
saturation decreases (15 % or less)
Iron deficiency is more common in women than in men
Menstruation, pregnancy and birth deplete iron stores,men have
higher iron stores than women
If iron deficiency anemia is seen in a male patient, the patient
should always be checked forblood loss from the gastrointestinal
tract
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Absorption curve of iron
• dif. dg. od iron deficit • determination of basal level of
iron in serum• administration of 200mg Fe2+ p.o. (Ferronat),• blood
taken after 2, 4 a 6 hours• determination of iron
Ref. Values of iron in blood serum: 10,5 – 28 mol/l (males) 9,0
– 25,6 mol/l (females)
In case of normal absorption – increase of iron at least to 28
mol/l
Practical part: