iron deprivation anemia · iron deprivation anemia j. f. prchal hematologist / oncologist saint...
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Iron deprivation anemia
J. F. PrchalHematologist / Oncologist
Saint Mary’s Hospital
McGill University
Montreal , November 2018
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Disclosures
• Employment: St Mary’s, McGill,
• Consultancy: Novartis, Health Life Sciences
• Research: Oncology clinical trials
• Honoraria: Celgene, Roche, GSK, Pfizer, Novartis, HLS
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IRON DEPRIVATION ANEMIA
• The most common type of anemia
• Anemia is microcytic (to normocytic) < 87 flnormal MCV is 87 (80 – 99)
• It is caused by decreased content within each red blood cell(% of which is hemoglobin)
• Hemoglobin is composed of 4 globin chains, each chain is composed of:
1 heme (protoporphyrin + iron) molecule1 globin molecule
• Decreased synthesis of either heme or globin leads to microcytic anemia
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MICROCYTIC ANEMIA
1. Decreased production of heme
- IRON DEPRIVATION ANEMIA
- SIDEROBLASTIC ANEMIA
2. Decreased production of globin chains:
either alpha, beta, gamma, delta
- THALASSEMIA
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IRON DEPRIVATION ANEMIA
There has to be a steady supply of iron to make heme (hemoglobin)
• 1. Iron is not available to the erythron because of lack of iron within the organism
IRON DEFICIENCY ANEMIA
• 2. Iron is not available to the erythron while there is plenty of iron within the organism
ANEMIA OF INFLAMATION
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Iron
Indispensable for lifeO2 transport (Hb)
Electron transfer (Cytochromes)
DNA synthesis (Ribonucleotide Reductase)
Neurotransmitter production (Tyrosine Hydroxylase)
Insoluble (10-17M)
Toxic (Fenton chemistry):
H2O2 OH- + OH•
Fe2+ + H2O2 Fe3+ OH- + OH•
courtesy P Ponka
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Fe “CONCENTRATION” [M]
• Water (pH 7.0)
Max [Fe3+] 0.000 000 000 000 000 01
• Plasma
Fe2-Tf 0.000 002
• Erythrocyte
Heme 0.020
Non-heme 0.000 001
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~ 3 g of Fe are in
Erythrocytes:
80% Total Body Iron
(3.8 g Fe)
3 mg Fe
Total Plasma Fe Turnover = 30 mg/d
The Mammalian Iron Cycle
courtesy P Ponka
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Proteins of iron metabolism
PROTEIN FUNCTION
ALAS2/eALAS 1st enzyme of heme synthesis; deficiency leads to x-linked sideroblastic anemia
Ceruloplasmin (Cp) Plasma protein with ferroxidase activity; cellular export
DMT1/DCT1/Nramp2 Membrane Fe2+ transporter; cellular uptake
Duodenal cytochrome b (Dcytb) Membrane ferric reductase; cellular uptake
Erythroferrone Produced by erythroblasts, inhibits the action of hepcidin; it increases the amount of Fe available for Hb
synthesis
Ferritin (Ft; H and L) Cytosolic Fe storage protein
Ferrochelatase Mitochondrial protein; insert Fe into protoporphyrin IX ring to form heme
Ferroportin1/Ireg1/MTP1 Membrane Fe2+ transporter; cellular export
Frataxin Involved in mitochondrial iron export
Heme oxygenase 1 Microsomal protein; recycle Hb iron
Hepcidin Plasma peptide; deficiency leads to iron hyperabsorption
Hephaestin Membrane Cp homolog; enterocyte export
HFE Unknown; binds TfR; mutated in >85% of hereditary hemochromatosis
IRP (-1 and –2) Cytosolic iron sensors; post-transcriptional regulation
Mitochondrial ferritin Mitochondrial Fe storage; H-Ft homolog
Mitoferrin/Mrs3/4 Mitochondrial inner membrane Fe transporter
Sec15l1/Sec15 Mutated in “haemoglobin deficit mouse”; yeast homolog is part of exocyst pathway
Steap3 Possible (?) endosomal ferrireductase
Transferrin (Tf) Plasma Fe3+ carrier
Tf Receptor Cognate membrane receptor for Tf
Tf Receptor 2 Unknown; similar to “classical” Tf receptor
PROTEIN FUNCTION
ALAS2/eALAS 1st enzyme of heme synthesis; deficiency leads to x-linked sideroblastic anemia
Ceruloplasmin (Cp) Plasma protein with ferroxidase activity; cellular export
DMT1/DCT1/Nramp2 Membrane Fe2+ transporter; cellular uptake
Duodenal cytochrome b (Dcytb) Membrane ferric reductase; cellular uptake
Erythroferrone Produced by erythroblasts, inhibits the action of hepcidin; it increases the amount of Fe available for Hb
synthesis
Ferritin (Ft; H and L) Cytosolic Fe storage protein
Ferrochelatase Mitochondrial protein; insert Fe into protoporphyrin IX ring to form heme
Ferroportin1/Ireg1/MTP1 Membrane Fe2+ transporter; cellular export
Frataxin Involved in mitochondrial iron export
Heme oxygenase 1 Microsomal protein; recycle Hb iron
Hepcidin Plasma peptide; deficiency leads to iron hyperabsorption
Hephaestin Membrane Cp homolog; enterocyte export
HFE Unknown; binds TfR; mutated in >85% of hereditary hemochromatosis
IRP (-1 and –2) Cytosolic iron sensors; post-transcriptional regulation
Mitochondrial ferritin Mitochondrial Fe storage; H-Ft homolog
Mitoferrin/Mrs3/4 Mitochondrial inner membrane Fe transporter
Sec15l1/Sec15 Mutated in “haemoglobin deficit mouse”; yeast homolog is part of exocyst pathway
Steap3 Possible (?) endosomal ferrireductase
Transferrin (Tf) Plasma Fe3+ carrier
Tf Receptor Cognate membrane receptor for Tf
Tf Receptor 2 Unknown; similar to “classical” Tf receptor
PROTEIN FUNCTION
ALAS2/eALAS 1st enzyme of heme synthesis; deficiency leads to x-linked sideroblastic anemia
Ceruloplasmin (Cp) Plasma protein with ferroxidase activity; cellular export
DMT1/DCT1/Nramp2 Membrane Fe2+ transporter; cellular uptake
Duodenal cytochrome b (Dcytb) Membrane ferric reductase; cellular uptake
Erythroferrone Produced by erythroblasts, inhibits the action of hepcidin; it increases the amount of Fe available for Hb
synthesis
Ferritin (Ft; H and L) Cytosolic Fe storage protein
Ferrochelatase Mitochondrial protein; insert Fe into protoporphyrin IX ring to form heme
Ferroportin1/Ireg1/MTP1 Membrane Fe2+ transporter; cellular export
Frataxin Involved in mitochondrial iron export
Heme oxygenase 1 Microsomal protein; recycle Hb iron
Hepcidin Plasma peptide; deficiency leads to iron hyperabsorption
Hephaestin Membrane Cp homolog; enterocyte export
HFE Unknown; binds TfR; mutated in >85% of hereditary hemochromatosis
IRP (-1 and –2) Cytosolic iron sensors; post-transcriptional regulation
Mitochondrial ferritin Mitochondrial Fe storage; H-Ft homolog
Mitoferrin/Mrs3/4 Mitochondrial inner membrane Fe transporter
Sec15l1/Sec15 Mutated in “haemoglobin deficit mouse”; yeast homolog is part of exocyst pathway
Steap3 Possible (?) endosomal ferrireductase
Transferrin (Tf) Plasma Fe3+ carrier
Tf Receptor Cognate membrane receptor for Tf
Tf Receptor 2 Unknown; similar to “classical” Tf receptor
PROTEIN FUNCTION
ALAS2/eALAS 1st enzyme of heme synthesis; deficiency leads to x-linked sideroblastic anemia
Ceruloplasmin (Cp) Plasma protein with ferroxidase activity; cellular export
DMT1/DCT1/Nramp2 Membrane Fe2+ transporter; cellular uptake
Duodenal cytochrome b (Dcytb) Membrane ferric reductase; cellular uptake
Erythroferrone Produced by erythroblasts, inhibits the action of hepcidin; it increases the amount of Fe available for Hb
synthesis
Ferritin (Ft; H and L) Cytosolic Fe storage protein
Ferrochelatase Mitochondrial protein; insert Fe into protoporphyrin IX ring to form heme
Ferroportin1/Ireg1/MTP1 Membrane Fe2+ transporter; cellular export
Frataxin Involved in mitochondrial iron export
Heme oxygenase 1 Microsomal protein; recycle Hb iron
Hepcidin Plasma peptide; deficiency leads to iron hyperabsorption
Hephaestin Membrane Cp homolog; enterocyte export
HFE Unknown; binds TfR; mutated in >85% of hereditary hemochromatosis
IRP (-1 and –2) Cytosolic iron sensors; post-transcriptional regulation
Mitochondrial ferritin Mitochondrial Fe storage; H-Ft homolog
Mitoferrin/Mrs3/4 Mitochondrial inner membrane Fe transporter
Sec15l1/Sec15 Mutated in “haemoglobin deficit mouse”; yeast homolog is part of exocyst pathway
Steap3 Possible (?) endosomal ferrireductase
Transferrin (Tf) Plasma Fe3+ carrier
Tf Receptor Cognate membrane receptor for Tf
Tf Receptor 2 Unknown; similar to “classical” Tf receptor
PROTEIN FUNCTION
ALAS2/eALAS 1st enzyme of heme synthesis; deficiency leads to x-linked sideroblastic anemia
Ceruloplasmin (Cp) Plasma protein with ferroxidase activity; cellular export
DMT1/DCT1/Nramp2 Membrane Fe2+ transporter; cellular uptake
Duodenal cytochrome b (Dcytb) Membrane ferric reductase; cellular uptake
Erythroferrone Produced by erythroblasts, inhibits the action of hepcidin; it increases the amount of Fe available for Hb
synthesis
Ferritin (Ft; H and L) Cytosolic Fe storage protein
Ferrochelatase Mitochondrial protein; insert Fe into protoporphyrin IX ring to form heme
Ferroportin1/Ireg1/MTP1 Membrane Fe2+ transporter; cellular export
Frataxin Involved in mitochondrial iron export
Heme oxygenase 1 Microsomal protein; recycle Hb iron
Hepcidin Plasma peptide; deficiency leads to iron hyperabsorption
Hephaestin Membrane Cp homolog; enterocyte export
HFE Unknown; binds TfR; mutated in >85% of hereditary hemochromatosis
IRP (-1 and –2) Cytosolic iron sensors; post-transcriptional regulation
Mitochondrial ferritin Mitochondrial Fe storage; H-Ft homolog
Mitoferrin/Mrs3/4 Mitochondrial inner membrane Fe transporter
Sec15l1/Sec15 Mutated in “haemoglobin deficit mouse”; yeast homolog is part of exocyst pathway
Steap3 Possible (?) endosomal ferrireductase
Transferrin (Tf) Plasma Fe3+ carrier
Tf Receptor Cognate membrane receptor for Tf
Tf Receptor 2 Unknown; similar to “classical” Tf receptor
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Duodenal Enterocytes
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Soe-Lin et al. Exp Hematol 38: 609, 2010
Featured on the Frontpage
Macrophages Attach to and Begin Engulfing RBC
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Hemoglobin Iron Recycling
courtesy P Ponka
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• 2 million red blood cells are ingested/s
• 24 mg of iron are recycled daily through macrophages with remarkable efficiency
Essential Cell Biology.
Garland Publishing, 1998.
Macrophages and Erythrophagocytosis
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• Expressed in hepatocytes
• Induced by iron via an incompletely characterized pathway requiring bone morphogenic proteins (BMPs)
• Downregulated in response to increased erythropoietic demand or hypoxia
HEPCIDIN
• Induced during inflammation by IL-6, involved in innate immune responses
courtesy P Ponka
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courtesy P Ponka
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Fe Transport across Biological Membranes
II
ferroportinaka MTP1 (metal transport protein 1) or Ireg1
- exports iron (Fe2+ ?) from “donor” cells
(enterocytes, macrophages)
to plasma transferrin
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IRON DEFICIENCY ANEMIA
• Low MCV
• Low ferritin
• Low serum iron
• High transferrin (TIBC)
• Low Fe/transferrin saturation
• Absent marrow iron
• Serum zinc protoporphyrin
• Serum transferrin receptor
• Reticulocyte hemoglobin content
• Therapeutic trial
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MICROCYTIC ANEMIA (low MCV)
Differential diagnosis:• Hemoglobinopathies
Thalassemia trait (alpha, beta, beta/delta)
Thalassemia major beta, Hemoglobin H disease
Hemoglobin E disease
Hemoglobin Lepore trait, Hemoglobin E trait
• Anemia of inflamation
• Blockade of heme synthesis (lead, INH)
• Sideroblastic anemia
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MICROCYTIC ANEMIA (low MCV)iron deficiency versus thalassemia trait
• Iron deficiency anemia
low MCV / high RDW
• Thalassemia trait
low MCV / normal or mildly increased RDW
• Compound cases
(frequent in pregnancy)
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IRON DEFICIENCY ANEMIA
Symptoms:
Symptoms of anemia
Decreased work performance
Hair loss
Pica
Delayed infant and child development
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IRON DEFICIENCY ANEMIA
• There is an obligatory iron loss ( 1 mg/day ) due to shedding of cells of mucosae, skin and small amount of blood
• In majority of subjects iron loses and iron intake are perfectly balanced
• Diagnosis of iron deficiency obliges us to identify the cause of iron loss, that is of hemorrhage
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IRON DEFICIENCY ANEMIA
Causes of hemorrhage:
• GI
• GU
• GYN• Respiratory tract
• Biliary tract
• Factious anemia
• Iatrogenic anemia
• Vascular disorders
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IRON DEFICIENCY ANEMIA
Treatment: must be calculated to rectify anemia and
replenish iron stores
Oral iron preparations many !
- use the cheapest, non-enterocoated
(IM iron)painful, leaves stains
Intravenous iron succrose or dextran
- possible anaphylactoid reaction
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IRON DEFICIENCY ANEMIA
Useful numbers 1 :• Obligatory blood loss 1mg
• 1 gm of red cell mass 1mg
• Average menstrual blood loss 40 mls (20 mg of Fe)
• 1 unit blood donation 200 mg
• 1 unit blood transfusion 200 mg
• Iron given to the baby and peripartum blood loss 300 – 900 mg
• daily iron requirement 1mg
young women 1.7 – 2mg
pregnancy 3 mg
breast feeding 2 mg
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IRON DEFICIENCY ANEMIA
Useful numbers 2 :
Fe content of standard diet 20 mgAbsorption of ingested oral iron 6 – 10 %
Usual iron oral tbl 50-60 mg of elemental iron
Duration of oral iron therapy:time to correct anemiaplus6 to 12 months
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IRON DEFICIENCY ANEMIA
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ANEMIA OF INFLAMATION
1. Anemia of chronic disease
develops over weeks, months
2. Anemia of critical illness
develops within days (ICU)
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ANEMIA OF INFLAMATION
• mild to moderate anemia
• normocytic to microcytic
• low serum iron
• low TIBC (transferrin)
• high ferritin
• high sed rate and or CRP
• presence of an underlying illness
• high hepcitidin
• high IL-6 and or other cytokines
• low transferrin receptor
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ANEMIA OF INFLAMATION
• Principal cause is restriction of erythropoeisis
due to non-availability of iron
• Additional minor causes:
- decrease life span of rbc
- decrease synthesis of erythropoietin
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ANEMIA OF INFLAMATION
Treatment:
• Treatment of underlying disease
• If not possible or not completely satisfactory:
- transfusion
- erythropoietin
- iron therapy ( IV infusion) usually to
supplement epo therapy
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TAKE HOME MESSAGE
• when Hb low, check MCV, then RDW
• do Iron studies, or Hb electrophoresis, or both
• try to fully diagnose pts’ anemia
• ( if you cannot , refer )
• ALWAYS identify the site and cause of bleeding (IDA)
• treat COMPLETELY with oral iron preps (IDA)
• identify and treat underlying disorder (AI)
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Iron Deprivation Anemia
• THANK YOU
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IRON DEFICIENCY ANEMIA
• Iron depletion
low ferritin, normal serum iron/TIBC
• Iron deficiency without anemia
low ferritin, low serum iron/TIBC, normal Hb
• Iron deficiency anaemia
low ferritin, low serum iron, low Hb