F. Wolff, LHUB-ULB, February 18, 2016

Iron metabolism in the red blood cells

pathologies

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

1. Introduction

• Multiple cell functions • Generation of free oxygen radicals

(Fenton / Haber-Weiss reaction)

Transferrin

Ferritin

Heme

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

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

2. Iron metabolism

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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

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

2. Iron metabolism

Systemic iron regulation and hepcidin

Cellular iron regulation and Iron-Regulatory Proteins/Iron Responsive

Elements (IRP/IRE)

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2. Iron metabolism

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Hepcidin: actions and consequences

Raghupathy R 2010

Hepcidin ↑

→ Duodenal iron

absorption ↓

→ Iron release from

macrophages and

hepatocytes ↓

2. Iron metabolism

Hepcidin transcription

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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 ↑

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

3. Iron and hematological disorders

Hemoglobin disorders

Increased iron

absorption

Repeated

transfusion

Iron overload → Morbidity and mortality ↑

Different iron distribution

Genetics

Environmental

factors

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

4. Iron overload and increased iron absorption

15

Coates TD, 2014

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) ↑↑

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The effect of increased erythropoiesis (hepcidin ↓) dominates the

effect of iron overload (hepcidin ↑)

Ginzburg Y, 2011

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

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)

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Brissot P, 2012

4. Iron overload and increased iron absorption

NTBI and cellular uptake:

o Exocrine pancreas (ZIP14, DMT1)

o Cardiomyocytes (L-type voltage-dependent calcium channels)

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Coates TD, 2014

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)

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Piga A, 2009

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

5. Iron in repeated transfusions

22

Coates TD, 2014

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

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

5. Iron in repeated transfusions

Transfusion related iron overload in Sickle cell disease (SCD):

o Impact of transfusion regime

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Age of blood

transfusion

initiation

Rate of blood

transfusion

Nature of

transfusion

regime

Porter J, 2013

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

6. Iron overload: Thalassemia major (TM) versus

SCD

Different patterns of iron distribution

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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

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

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)

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Thank you