iron metabolism in the red blood cells pathologies · pathologies . plan 1. introduction 2. iron...
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F. Wolff, LHUB-ULB, February 18, 2016
Iron metabolism in the red blood cells
pathologies
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Plan
1. Introduction
2. Iron metabolism
3. Iron and hematological disorders
4. Iron overload and increased absorption
5. Iron overload in repeated transfusions
6. Iron overload: Thalassemia major (TM) versus SCD
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1. Introduction
• Multiple cell functions • Generation of free oxygen radicals
(Fenton / Haber-Weiss reaction)
Transferrin
Ferritin
Heme
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Plan
1. Introduction
2. Iron metabolism
3. Iron and hematological disorders
4. Iron overload and increased absorption
5. Iron overload in repeated transfusions
6. Iron overload: Thalassemia major (TM) versus SCD
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2. Iron metabolism
Iron absorption
Non-heme iron: Fe³+→ Fe²+
Transport by the proton-coupled
divalent metal transporter 1
(Dmt1)
Iron exported (Fpn1) or stored in
ferritin
Fe²+ oxidized by ferroxidases and
transported associated with Tf
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2. Iron metabolism
6
Iron utilization by erythroblats
Cellular uptake by transferrin
receptor 1 (TfR1)
Complex endocyted
Reduction of Fe3+ by Steap3
Transport of Fe2+ by Dmt1
Transport in mitochondria by a
cytosolic iron chaperon (PCBP1)
Fe2+ used for the biosynthesis of
heme and ISCs
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2. Iron metabolism
Iron recycling by macrophages
7
Hydrolytic enzymes in the
phagolysosome → release of
heme
Action of HO1
Transport of Fe2+ by Dmt1
Export of Fe2+ through Fpn1
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2. Iron metabolism
Systemic iron regulation and hepcidin
Cellular iron regulation and Iron-Regulatory Proteins/Iron Responsive
Elements (IRP/IRE)
8
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2. Iron metabolism
9
Hepcidin: actions and consequences
Raghupathy R 2010
Hepcidin ↑
→ Duodenal iron
absorption ↓
→ Iron release from
macrophages and
hepatocytes ↓
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2. Iron metabolism
Hepcidin transcription
10
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2. Iron metabolism
Erythropoiesis and hepcidin:
11
Kautz L, 2015
Erythropoietic activity ↑
→ Hepcidin synthesis ↓
→ Duodenal iron
absorption ↑
→ Iron release from
macrophages and
hepatocytes ↑
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Plan
1. Introduction
2. Iron metabolism
3. Iron and hematological disorders
4. Iron overload and increased absorption
5. Iron overload in repeated transfusions
6. Iron overload: Thalassemia major (TM) versus SCD
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3. Iron and hematological disorders
Hemoglobin disorders
Increased iron
absorption
Repeated
transfusion
Iron overload → Morbidity and mortality ↑
Different iron distribution
Genetics
Environmental
factors
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Plan
1. Introduction
2. Iron metabolism
3. Iron and hematological disorders
4. Iron overload and increased absorption
5. Iron overload in repeated transfusions
6. Iron overload: Thalassemia major (TM) versus SCD
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4. Iron overload and increased iron absorption
15
Coates TD, 2014
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4. Iron overload and increased iron absorption
Thalassemia major (TM):
o Disorders with anemia and ineffective erythropoiesis
o Apoptosis of erythroid precursors
o Hepcidin transcription ↓
o Duodenal iron absorption ↑↑
o Non Transferrin Bound Iron (NTBI) ↑↑
16
The effect of increased erythropoiesis (hepcidin ↓) dominates the
effect of iron overload (hepcidin ↑)
Ginzburg Y, 2011
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4. Iron overload and increased iron absorption
NTBI:
o Exact nature remains to be determined
o Iron-citrate, iron-acetate, iron-albumin, LPI (Labile plasma Iron → engaged in
redox cycling/cytotoxic activity)
17 Brissot P, 2012
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4. Iron overload and increased iron absorption
NTBI and cellular uptake:
o Hepatocytes
→ Main target of NTBI
→ NTBI uptake by hepatocyte NOT REGULATED by cellular iron excess (ZIP14,
DMT1)
18
Brissot P, 2012
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4. Iron overload and increased iron absorption
NTBI and cellular uptake:
o Exocrine pancreas (ZIP14, DMT1)
o Cardiomyocytes (L-type voltage-dependent calcium channels)
19
Coates TD, 2014
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4. Iron overload and increased iron absorption
NTBI and organ toxicity:
o Promote ROS production (Fenton / Haber-Weiss reaction)
o Lipid peroxidation (plasma membranes, hepatic lysosomal membranes,
hepatic and cardiac mitochondria, nuclei)
20
Piga A, 2009
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Plan
1. Introduction
2. Iron metabolism
3. Iron and hematological disorders
4. Iron overload and increased absorption
5. Iron overload in repeated transfusions
6. Iron overload: Thalassemia major (TM) versus SCD
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5. Iron in repeated transfusions
22
Coates TD, 2014
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5. Iron in repeated transfusions
Transfusion related iron overload in Sickle cell disease (SCD):
Indications for transfusions (concerned ±25% of patients with SCD)
→Preoperative prophylaxis
→Treatment of acute chest syndrome
→Prophylaxis and treatment of stroke (Telen MJ, 2001)
23 Switzer J, 2006
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5. Iron in repeated transfusions
Transfusion related iron overload:
o Hematological disorders requiring repeated blood transfusion
o One unit of RBCs contains ± 200mg of iron
o Accumulation of iron from RBCs in macrophages, later in hepatocytes
24
Coates TD, 2014
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5. Iron in repeated transfusions
Transfusion related iron overload in Sickle cell disease (SCD):
o Impact of transfusion regime
25
Age of blood
transfusion
initiation
Rate of blood
transfusion
Nature of
transfusion
regime
Porter J, 2013
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Plan
1. Introduction
2. Iron metabolism
3. Iron and hematological disorders
4. Iron overload and increased absorption
5. Iron overload in repeated transfusions
6. Iron overload: Thalassemia major (TM) versus SCD
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6. Iron overload: Thalassemia major (TM) versus
SCD
Different patterns of iron distribution
27
TM:
Increased iron release from
overload macrophages
(transfused RBCs)
Increased iron release from
enterocytes (ineffective
erythropoiesis
→hepcidin deficiency)
NTBI and LPI ↑↑
SCD:
Increased iron release from
overload macrophages (for
patients for whom repeated
transfusions are indicated)
NTBI and LPI ↔
Porter JB, 2014
Consequences of iron
overload appear later and
at lower frequencies
Wood JC, 2015
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6. Iron overload: Thalassemia major (TM) versus
SCD
Potential mechanisms for low NTBI generation in SCD
o high hepcidin levels (controversial)
o high level of intravascular hemolysis (induction of tissue HO-1 and
clearance of heme)
28 Porter JB, 2014
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7. Take home messages
Iron overload and toxicity → major causes of morbidity and mortality
Physiopathology of iron overload (erythropoietic regulation of hepcidin)
Tissue iron distribution related to the transfusion regime (SCD & TM)
and the impact of ineffective erythropoiesis (TM)
29