iron. micronutrients : (intake does not exceed 100 mg daily) daily intake body stores zinc 10 mg2200...
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Iron
Micronutrients :(intake does not exceed 100 mg daily)
Daily intake Body stores
• Zinc 10 mg 2200 mg• Copper 2.5 mg 70 mg• Iron 1-2 mg 4000 mg• Manganese 10 mg• Molybdenum 10 mg• Cobalt 1.5 mg• Chromium 1.5 mg
Body contains:
4 grams of iron (men) 3 grams (women)
2.5 grams of total body iron exist as haemoglobin
Only 1-2 mg of iron is taken up daily from the diet(which contains 10-20mg iron)
Iron metabolism in the body is a closed system
little intake and little loss
Only 1 mg of iron is lost daily from the body(about 0.025% of total body iron)
nonspecific pathways(sloughing of dead cells, iron excretion in bile)
In women, additional 30 mg of iron is lost monthlyby menstruation
(about 1% of total body iron)
Body iron stores are thus greater in men than in women
The basic rule about body iron regulation:
There is no special pathway for iron excretion
The amount of total body iron is determined only at the level of iron uptake from the duodenum
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
Two types of iron-containing proteins:
1) Haemoproteins
2) Non-haem iron proteins
Haemoproteins: contain iron in the form of haem
Haem: iron inserted in a tetrapyrrole ring
Porphyrins:
• They are intensely red• Under ultraviolet light, they display very strong red
fluorescence• Accumulation of porphyrins is harmful, and results in
rare inherited diseases called porphyrias
• Porphyrin plus iron gives Haem• Heme is an exceptional porphyrin compound:
HAEM IS NOT FLUORESCENT
Porphyrin Haem
Iron in Haemoproteins• Cytochromes of the mitochondrial respiratory chain
(100 mg of iron)
• Haemoglobin: 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 haemoprotein of the liver (about 1 mg)
detoxifies foreign compounds
Non - heme iron proteins
• Ferritin - iron storage protein
• Transferrin: iron transport protein
Ferritin: iron storage protein. In men, contains up to 1 gram of iron
450 kDa protein consisting of 24 subunits Inside the ferritin shell, iron ions form crystallites together with phosphate and hydroxide
ions. The resulting particle is similar to the mineral ferrihydrite. Each ferritin complex can store about 4500 iron (Fe3+) ions.
Reflects the amount of BODY IRON STORES
men: 20-275 μg/litrewomen: 5-200 μg/litre
15 μg/litre and less: insufficient iron stores
• Transports iron in the blood
• Contains only 2 atoms of iron
• 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
Ribonucleotide reductase a protein which is necessary for DNA synthesis:
One more iron-containing protein:
Regulation of iron metabolism:
There is no pathway for iron excretion from the body
therefore
Total body iron level is regulated only at the level of iron absorption from the small intestine
Disorders of iron metabolism• 1) Increased absorption of iron from the gut:
HAEMOCHROMATOSIS
• 2) Decreased amount of iron in the body:
IRON DEFICIENCY ANAEMIA
• 3) Inflammation-induced change of iron distributrion:
ANAEMIA OF CHRONIC DISEASE
Primary Haemochromatosis
Excessive absorption of iron from the gut:
Iron accumulates in the liver, heart and pancreas,
excess iron damages these organs by free radical production
Transferrin saturation increases, serum ferritin increases
Therapy:Phlebotomy (removal of 0.5 l of blood): a decrease of iron in
the circulation leads to iron mobilisation from stores
• Transfusion dependent anemias, for example • thalassemia major
• leukaemia
• Therapy: iron chelators
Secondary Haemochromatosis
Lack of iron in the body: Iron deficiency (anaemia)
(most common anaemia)
Hypochromic microcytic erythrocytes
Serum ferritin decreases (iron stores are depleted)
transferrin saturation decreases (15 % or less)
If iron deficiency anemia is seen in a male patient, the patient should always be checked for blood loss from the gastrointestinal tract
men have higher iron stores than women.
Menstruation, pregnancy and birth deplete iron stores,
Iron deficiency is more common in women than in men
Most common cause of iron-deficiency anemia in women:simply lack of iron in the diet.
Inflammation-induced changes of iron distribution:
Anemia of chronic disease
Mild anemia combined with increased iron stores
mild anemia + increased ferritin
Regulation of iron metabolism
Transferrin uptake
Transferrin receptor
Transferrin
Transferrin receptor
Cells which need iron express high number of transferrin receptors on their surface
Transferrin receptor expression is regulated
posttranscriptionally
at the level of transferrin receptor mRNA stability:
Lack of iron stabilises mRNA for transferrin receptor
Regulation of gene expression:
• Transcriptional: • Increasing the amount of mRNA
• Posttranscriptional:• Regulation of mRNA stability (transferrin receptor)
• Regulation of mRNA translation (ferritin)
Recent (2001) look at iron metabolism:
Iron metabolism is regulated mainly at the level of
IRON EXPORT FROM THE CELL
Iron is transported from the cell by
FERROPORTIN
(a recently discovered iron export protein)
Which cells must be able to export iron?
• Macrophages: • they must recycle about 30 mg daily from old erythrocytes
• Enterocytes (endothelial cells in small intestine):• daily uptake and export of about 1 mg of iron from the diet
• Hepatocytes: • Able to mobilise stored iron from ferritin if needed
Hepcidin: Hepatic bactericidal protein
Hepcidin has antibacterial properties
Discovery of HEPCIDIN (2000)
Hepcidin: "iron regulatory hormone"
Hepcidin is produced in the liver, is transported in the blood stream, and
BLOCKS IRON EXPORT FROM THE CELL
Control of Iron Export from Cells:
Hepcidin blocks iron export from:
MACROPHAGES
ENTEROCYTES IN THE SMALL INTESTINE
Pathophysiology of hereditary hemochromatosis
All hereditary hemochromatosis subtypes display
decreased hepcidin levels
Decreased hepcidin allows more iron to be exported from the enterocytes into blood
Juvenile Haemochromatosis (2004):
Extremely severe form of hemochromatosis
caused by mutation of the hepcidin gene
Regulation of hepcidin expression:
• Iron overload increases hepcidin expression
• Iron deficiency decreases hepcidin expression
• Increased erythropoiesis decreases hepcidin expression
• (Vokurka M et al, 2006: Hepcidin mRNA levels in mouse liver respond
to inhibition of erythropoiesis)
Pathophysiology of x-linked sideroblastic anemia:
• A mutation of porphyrin biosynthesis enzyme causes ineffective erythropoiesis
• Ineffective erythropoiesis decreases hepcidin • Lack of hepcidin leads to increased iron absorption• Iron overload damages pancreas and myocardium
• Patients are treated by repeated phlebotomies
Hepcidin is an acute phase protein
(a protein synthesised in the liver, whose synthesis is increased during inflammation)
2001-2002:
Hepcidin expression dramatically increases during inflammation
Hepcidin demonstrates the strong connection between
iron metabolism and defence against pathogens
Bacteria need iron for their ribonucleotide reductase(DNA synthesis)
Host needs iron for his antibacterial enzymes(Nitric oxide synthase and others)
Bacteria and host compete for free iron
Pathophysiology of anemia of chronic disease
1) Inflammation increases hepcidin synthesis
2) Hepcidin decreases iron export from macrophages
3) Iron is locked up inside the macrophages
4) Iron is locked up in enterocytes, and does not enter the body
Pathophysiology of both hemochromatosis and
anemia of chronic disease can be easily explained
by the action of hepcidin.
Hepcidin summary:
Hepcidin is released from the liver according to body iron status: • iron overload increases hepcidin, • iron deficiency decreases hepcidin expression.
Hepcidin blocks iron export from macrophages and enterocytes.
Inflammation increases hepcidin production.
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