Prezentace aplikace PowerPoint

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Iron
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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

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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
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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 monthly by
menstruation (about 1 of total body iron) Body
iron stores are thus greater in men than in women
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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

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Chemical forms of iron Ferric (3) iron
insoluble at physiological pH Ferrous (2)
irondangerous if free, forms free radicals

Since free iron is insoluble or toxic, it must be
bound to proteins
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Two types of iron-containing proteins

• Haemoproteins
• Non-haem iron proteins

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Haemoproteins contain iron in the form of haem
Haem iron inserted in a tetrapyrrole ring
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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

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Haem
Porphyrin
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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

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Non - heme iron proteins

• Ferritin - iron storage protein
• Transferrin iron transport protein

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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/litre women
5-200 µg/litre 15 µg/litre and less
insufficient iron stores
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Transferrin

• 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)

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Transferrin saturation Normal about 30-50
Transferrin saturation under 15 Iron
deficiency
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Ribonucleotide reductase a protein which is
necessary for DNA synthesis
One more iron-containing protein
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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
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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

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•  Primary Haemochromatosis
• Excessive absorption of iron from the gut
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• 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
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Secondary Haemochromatosis

• Transfusion dependent anemias, for example
• thalassemia major
• leukaemia
• Therapy iron chelators

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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)  
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Iron deficiency is more common in women than in
men
Menstruation, pregnancy and birth deplete iron
stores,
men have higher iron stores than women.
Most common cause of iron-deficiency anemia in
women simply lack of iron in the diet.
If iron deficiency anemia is seen in a male
patient, the patient should always be checked
for blood loss from the gastrointestinal tract
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Inflammation-induced changes of iron
distribution Anemia of chronic disease Mild
anemia combined with increased iron stores mild
anemia increased ferritin
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Regulation of iron metabolism
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Transferrin uptake Transferrin receptor
Transferrin
Transferrin receptor
Cells which need iron express high number of
transferrin receptors on their surface
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Transferrin receptor expression is
regulated posttranscriptionally at the level of
transferrin receptor mRNA stability
Lack of iron stabilises mRNA for transferrin
receptor
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Regulation of gene expression

• Transcriptional
• Increasing the amount of mRNA
• Posttranscriptional
• Regulation of mRNA stability (transferrin
  receptor)
• Regulation of mRNA translation (ferritin)

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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)
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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

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Hepcidin Hepatic bactericidal protein
Hepcidin has antibacterial properties
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Control of Iron Export from Cells
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
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Hepcidin blocks iron export from MACROPHAGES
ENTEROCYTES IN THE SMALL INTESTINE
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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

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Juvenile Haemochromatosis (2004)
Extremely severe form of hemochromatosis caused
by mutation of the hepcidin gene
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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)

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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

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2001-2002 Hepcidin expression dramatically
increases during inflammation
Hepcidin is an acute phase protein (a protein
synthesised in the liver, whose synthesis is
increased during inflammation)
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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
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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

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Pathophysiology of both hemochromatosis and
anemia of chronic disease can be easily
explained by the action of hepcidin.
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• 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.