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WelcomeHaematology joint seminar
14/11/2012
Dr Kishore & Dr Ashutosh
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15-year-old male
WBC 4.5 x 109/L, Hgb 8.6 g/dl, PLT 350 x 109/L with
MCV of 76 fl.
Hypochromic, microcytic RBCs
No GI symptoms
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Serum Fe of 15, transferrin saturation of 5 percent.
Given oral iron supplementation – No use.
IV iron supplementation –subsequent partial
improvement in Hgb
Two cousins have similar history..
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In the next 30 mins lets try to understand what's happening in him…
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Iron Metabolism
Kishore Kumar
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Basic facts
Absorption
Transport & Recycling
Transferrin cycle & storage
Systemic Homeostasis
Cellular level regulation
Pathogenesis of IDA
Outline
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Historical aspect:
It was depicted in many paintings by Dutch masters .
A disease believed to be Iron Deficiency Anemia was
described in 1554 by Johannes Lange.
It was termed cholorsis or green sickness and iron salt was used for its treatment.
Almost exclusively in adolescent girls between 14 and 17.
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Most common element on earth.
Still iron deficiency is the most common nutritional disorder in
the world.
Thanks to low bioavailability and complex metabolic
pathways..
Apart from the commonly known overload states, is also
involved in neurodegenerative diseases, Sideroblastic anemia ,
MDS etc..
Some basic facts..
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May be 2+ or 3+
◦ Ferrous (2+) “reduced” - gained an electron
◦ Ferric (3+) “oxidised” - lost an electron
Fe+++ + e- Fe++
Redox states allows activity passing electrons around
body
Redox change required for iron metabolism
Basic facts..
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Stable state of iron in most of its biological complexes
is Fe(III).
Reduction needed for transport.
These properties render it potentially toxic.
Haber-Weis-Fenton´s reaction.
Double distress in living organisms..
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Oxygen transporting Heme containing proteins (Hemoglobin ,
myoglobin)
Heme containing enzymes like cytochromes, catalases and
peroxidases.
Iron-Sulfur containing proteins like Aconitase , ferrochelatase.
Iron transport proteins
Iron storage proteins.
Key Iron containing proteins in humans
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In a 70 kg male=3.5gms In females= 250-300mg less than males
Normal Iron Balance
Full term infants
75mg/kg
Adult males 50mg/kg
Adult females 35mg/kg
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DMT1(Nramp, DCT1) – apical membrane of
enterocytes & endosomes.
Ferroprotein (IREG1) – Export of ferrous iron.
HCP-1 – Heme transporter in enterocytes.
Integrin- Mobilferrin complex – Ferric iron transport
TfR1 – Binds Tf-Fe2 & initiates Transferrin cycle
Proteins involved in Transport
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DcytB – Ferrireductase on enterocyte surface
Hephaestin – Ferro-oxidase in basolateral membrane
Ceruloplasmin – oxidase in other tissues
Heme Oxygenase-1 – release of iron from heme
Proteins assisting in iron transport
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Lactoferrin – free iron scavenger in body fluids
Siderocalcin – Acute phase reactant
Hemopexin
Haptoglobin
Iron binding proteins
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No known regulated pathway of iron excretion
Intestinal mucosa responds to changes in body iron
stores, tissue hypoxia, and demand for iron, and it alters
absorption accordingly.
Duodenum and jejunum – excess Ferroprotein conc.
For optimal nutrition a daily intake of 8-10 mg of iron is
required.
Intestinal iron absorption
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Acidic pH, vitamin C and some low - molecular -
weight chelates (e.g. sugars, amino acids) enhance
absorption.
Therapeutic ferrous iron salts are well absorbed on an
empty stomach.
Phytates, tannates in tea and bran inhibit absorption.
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Understanding Heme Transport - N.C Andrews - New England Journal of Medicine:353;23 - 2508
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DMT1
DMT1 is not specific for iron transport but also
mediates transport of other divalent metal cations
expressed on the membrane of endosomes
DMT-1 seems to have a role in transport of non
transferrin bounded iron (NTBI)
Murine microcytic anemia
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While ferrous iron uses DMT-1, ferric uses integrin-
mobilferrin pathway (IMT) that solely transports
ferric iron.
In the cell cytosol these proteins are integrated into a
large protein complex called paraferritin
Contains beta-2-microglobulin and DMT-1
Is IRON absorbed in ferric state?
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Transport of iron associated with some proteins (chaperones)
or transcytosis
Sequestrated as ferritin or transported into circulation
Enterocytes shed in two days
Transport of iron by ferroportin decides whether to keep or
discard
These cells also express transferrin receptors type 1 (TfR1)
and iron from the plasma can enter.
Intracellular iron transport
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Ferroportin represents the only known iron exporter
Basolateral membranes of duodenal enterocytes,
RES macrophages, hepatocytes and placental cells
Requires change of redox state by ferroxidase -
hephaestin in the duodenum and ceruloplasmin
elsewhere in the body
Type IV hemochromatosis
Basolateral iron transport
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Intestinal iron absorption increases withDecreased iron storesIncreased erythropoietic activityIneffective erythropoiesisAnaemiaHypoxia
Intestinal iron absorption decreases in inflammation
Iron absorption regulations
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Two models have been proposed to explain
how the absorption of iron is regulated
◦Crypt programming model
◦Hepcidin model
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Increased iron in plasma
Increased iron in
enterocyte
Forms a complex
with IRP/IRE
Translocates to nucleus
Inhibits Transcription of DMT1,hephestin, ferroportin and
increases ferritin
Crypt programming model
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Iron Absorption DcytB
◦Reduction Fe+++ to Fe++
DMT1◦Transport into cell
Ferritin◦Storage in cell
Hephaestin◦Oxidises Fe++ to Fe+++
Ferroportin◦Transport out
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Iron transport in plasma
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Fleming, R. E. et al. N Engl J Med 2009;352:1741-1744
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Transferrin provides solubility, reduced reactivity and thus provides
a safe and controlled delivery of iron to all cells in the body.
Due to high affinity all non-heme iron in circulation is bounded to
transferrin
NTBI refers to all forms binding to ligands other than transferrin.
Capable of free entry into cells. very reactive and could enter
Fenton reaction.
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Transferrin has two iron binding sites which binds one iron
atom each
Transferrin exists in 3 forms-apotransferrin, monoferric,
diferric
30-40% of these sites are occupied under normal
physiological conditions.
Contains only about 3 mg of body iron at any time, it is vital
to iron transport, with over 20 mg iron passing
through this compartment each day
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Iron uptake in the tissues - Transferrin cycle
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TfR1 andTfR2.
TfR1 is expressed by all iron-requiring cells but level of
expression varies.
Diferric transferrin has a higher affinity for TfR1
Soluble transferrin receptor (sTfR) is released by proteolytic
cleavage of the protein C-terminal end and regulated by
transferrin
The level of sTfR reflects the availability of functional iron.
Transferrin receptors
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TfR2 - liver, hematopoetic cells, duodenal crypt cells.
TfR2 binds to HFE and transferrin in different
domains
It is assumed that TfR2/HFE complex is required for
transcriptional regulation of hepcidin production
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Pool of iron complexed with low affinity ligands (citrate, ATP,
amino acids, ascorbic acid or by unidentified chaperones)
LIP represents < 5% of the total cellular iron.
Supplies iron to the mitochondrion, synthesis of iron-containing
proteins in cytosol thereby controlling numerous metabolic
reactions.
LIP is catalytically active and capable of initiating free radical
reactions
Labile iron pool (LIP)
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Ferritin has got dual function of iron detoxification and reserve.
The protein shell is constructed of 24 molecules of two distinct ferritin subunits, designated H (for heavy or heart) and L (for light or liver). ◦H chains contain a ferroxidase - oxidize iron &
acquire iron more rapidly. ◦L chains are more stable and resistant to denaturation.◦Theoretically 4500 atoms but usually 2000 atoms
Body iron stores- Ferritin and Hemosiderin
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Dia-13nmCentral core-6nm6 channels
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Small quantities are present in nucleus and mitochondria
Biosynthesis of heme and enzymes that contain Fe-S group
Very small amount enters into circulation - lysosomal secretory pathway
Non-ferous, and its exact biologic purpose is still unknown
Plasma ferritin concentration of 1 µg/L corresponds to 8-10 mg tissue iron stores
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Incompletely degraded ferritin
Conglomerate of iron, ferritin proteins,lipids, sialic
acids and porphyrin in small amounts
Less soluble
Stains with prussian blue
More stable and less available form of storage iron .
Hemosiderin
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ONE WORD TO REMEMBER
HEPCIDIN
Regulation of systemic iron homeostasis
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25 aa peptide secreted from liver.
Antimicrobial activity & “Hypoferremic hormone”
In 2000,by accident, investigators studying gluconeogenesis in
infections silenced the gene for hepcidin in the mouse –
Unusual increase in PARENCHYMAL IRON. Decreased iron stores
Increased erythropoietic activity
Anemia
Hypoxia
Hepatic bacteriocidal protein
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1.Regulation by iron status, dietary iron and iron
stores.
2. Regulation by inflammation.
3. Regulation by hypoxia/anemia.
4. Regulation by erythroid factors.
What regulates HEPCIDIN
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HFE/TfR2/Tf Regulation of Hepcidin Transcription
TfR1 is hypothesized to sequester HFE.
Tf and HFE compete for binding to TfR1
TFR2 is predominantly expressed in hepatocytes
Tf induced release of HFE from TfR1 - to increase the
association of HFE with TfR2 and to stimulate
hepcidin transcription.
Hepcidin regulation by iron status
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HJV is a GPI-linked membrane protein encoded by the gene,
HFE2
Homozygous or compound heterozygous mutations in HFE2
result in a juvenile form of HH.
HJV is a co-receptor for BMP2, BMP4, BMP5, and BMP6
and enhances hepatic hepcidin expression by enhancing BMP
signaling
HJV, BMP6, and Matriptase-2
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The HJV-BMP ligand-BMP receptors complex induces an
intracellular BMP signalling pathway which in turn activates
the SMAD4 signalling pathway, which translocates from the
cytoplasm to the nucleus to regulate gene expression
Two potential BMP-responsive elements critical for BMP6
and HJV responsiveness are present in both the distal and
the proximal regions of the hepcidin promoter
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Essential component of a pathway that detects
iron deficiency
Cleaves membrane bound HJV increasing
sHJV that competitively impairs BMP
signaling.
Matriptase-2 (type II transmembrane serine proteinase; TMPRSS6)
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Hepcidin regulation by inflammation, hypoxia/anemia and erythroid factors
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Each cell has the capacity to regulate its own
utilisation of iron
Cells replete in iron, ferritin TFRC
In contrast, iron-depleted cells, TFRC, Ferritin
The IRE/IRP Regulatory System
IRP act as the cell sensor to iron availability
Regulation of cell iron homeostasis
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IRP1, when saturated with iron, acts as a cytosolic aconitase
and catalyzes the conversion of citrate to isocitrate .
IRP2 is less abundant and does not have an identified enzyme
function.
IRE at 5´-UTR mRNA ferritin, ferroportin - Not repressed
IRE at 3´-UTR mRNA TfR1, DMT1 - Unstable
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DcytB Hemochromatosis(HFE)
IRP1
DMT 1 STEAP3 IRP2
Hemojuvelin Transferrin IRE
FLVCR TFR1 TMPRSS6
Ferroprotein TFR2 GDF-1
Hepcidin Ferritin (H) TWSG
Hephaestin Ferritin (L) EPO
Let's try to consolidate…
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Some future directions to this understanding.. Directly or indirectly modulate hepcidin for ACD
Cancer cells have a high iron demands - clinical studies
using iron chelators as anticancer therapy
Recombinant lactoferrin for treating bacterial and viral
infections
Iron chelators - neuroprotective and neurorestorative
effects
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Iron Deficiency
Extremely common
Due to reduced intake, increased loss or increased demands
Stores reduced before deficiency seen
Iron deficiency is not a diagnosis
◦ A cause needs to be identified!
◦ Eg obstetric causes, low intake, malabsorption, bowel
cancer, haemorrhoids, inflammatory bowel disease
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IRON DEFICENCY - STAGES
Prelatent
◦ Reduction in iron stores without reduced serum iron levels
detected by a low serum ferritin measurement
Latent
◦ Iron stores are exhausted, but the blood hemoglobin level
remains normal
Iron deficiency anemia
◦ Blood hemoglobin concentration falls below the lower limit of
normal
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Increased iron requirements •Blood loss •Rapid growth in body size between 2 and 36 months of age •Pregnancy and lactation
Inadequate iron supply •Poor nutritional intake in children (not a common independent mechanism in adults but often a contributing factor)
Malabsorption • Gastric bypass surgery for ulcers or obesity • Achlorhydria from gastritis or drug therapy • Severe malabsorption (for example, celiac disease [nontropical sprue]) • Abnormal transferrin function • Autoantibodies to transferrin receptors
Causes
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IRON DEFICIENCY ANEMIA GENERAL ANEMIA’S SYMPTOMS:
Fatigability
Dizzeness
Headache
Irritability
Palpitation
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CHARACTERISTICS SYMPTOMS
Glossitis, stomatitis DYSPHAGIA ( Plummer-Vinson syndrome)
Atrophic gastritis
Dry, pale skin
Spoon shaped nails, koilonychia,
Blue sclerae
Hair loss
Pica (apetite for non food substances such as an clay)
Increased platelet count
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Thanks for your attention..
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Suggested Reading…
Now we have to manage the case…
Now we have to manage the case..