Role of hepcidin hormone in patients of ² thalassemia major

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  • ROLE OF HEPCIDIN HORMONE IN PATIENTS OF -THALASSEMIA MAJOR

    A thesis

    Submitted for Partial Fulfillment of the Requirements

    of Master Degree in clinical Pathology

    By Abeer Elsayed Ahmed Badawy

    M.B.B.CH

    Faculty of Medicine-Cairo University

    Under Supervision Of

    Prof. Dr. Nagelaa Ali Khalifa

    Professor of clinical &chemical pathology Faculty of Medicine Zagazig University

    Prof. Dr.

    Mervat Abdallah Hesham

    Professor of Pediatrics Faculty of Medicine Zagazig University

    Dr. Ibtessam Ibrahim Ahmed Assist. Professor of Clinical and

    Chemical Pathology Faculty of Medicine Zagazig University

    Faculty of Medicine Zagazig University

    2010

  • ROLE OF HEPCIDIN HORMONE IN PATIENTS OF -

    THALASSEMIA MAJOR

    A thesis

    Submitted for Partial Fulfillment of the Requirements of Master Degree in clinical Pathology

    By

    Abeer Elsayed Ahmed Badawy M. B. B. CH.

    Faculty of Medicine - Cairo University

    Under Supervision Of

    Prof. Dr. Nagelaa Ali Khalifa

    Professor of clinical & chemical pathology Faculty of Medicine Zagazig University

    Prof. Dr.

    Mervat Abdallah Hesham Professor of Pediatrics Faculty of Medicine Zagazig University

    Dr. Ibtessam Ibrahim Ahmed

    Assist. Professor of Clinical and Chemical Pathology Faculty of Medicine Zagazig University

    Faculty of Medicine Zagazig University

    2010

  • ii

    (23) :

    TNEMGDELWONKCA

  • iii

    First and foremost, thanks to Allah who helped me to finish this work.

    I am honered to express my deepest appreciation and profound gratitude

    to Prof. Dr.Nagelaa Ali Khalifa Professor of clinical & chemical pathology,

    Faculty of Medicine, Zagazig University, for her kind supervision,

    encouragement and constant guidance.

    My deepest thanks and gratefulness to Prof. Dr. Mervat Abdallah

    Hesham, Professor of Pediatrics, Faculty of Medicine, Zagazig University,

    for her continuous support and advice.

    I would like to express my deepest sense of gratitude and obligations to

    Prof. Dr. Ibtessam Ibrahim Ahmed, Assist.Professor at department of

    Clinical and Chemical Pathology, Faculty of Medicine, Zagazig University.

    Lastly, I would like to express my deepest thanks to all my colleges in

    clinical & chemical pathology department for their help and encouragement.

    Dr. Abeer Badawy

    2010

    LIST OF ABBREVIATIONS

    BMP: Bone morphogenetic protein.

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    BMT:

    Bp:

    Dcytb:

    DFO:

    DMT1:

    FEP:

    GVHD:

    HFE:

    HIF:

    HIV:

    HJV:

    HLA:

    LCR:

    MOD:

    NGAL:

    NMD:

    Nrmap2:

    NTBI:

    PASP:

    PHT:

    sTfR:

    TfR:

    UGTIA:

    VSS:

    Bone marrow transplantation.

    Base pair.

    Duodenal cytochrome b.

    Desferrioxamine.

    Divalent Metal ion Transporter 1.

    Free Erythrocyte Porphyrin.

    Chronic graft-Versus-Host Disease.

    High iron Fe.

    Hypoxia-inducible factor.

    Human Immune deficiency virus.

    Hemojuvelin.

    Human leukocyte antigen.

    Locus control region.

    Multi - organ dysfunctions.

    Neutrophil gelatinase-associated lipocalin.

    Nonsense- mediated mRNA decay.

    Natural resistance macrophage-associated protein 2.

    Non-transferrin bound iron.

    Pulmonary artery systolic pressure.

    Pulmonary hypertension.

    Soluble Transferrin receptors.

    Transferrin receptors.

    Uridine diphosphate-glucoronyl transferase IA.

    Volume of distribution at steady state.

    LIST OF TABLES

    Table 1 Main characteristics of genetic iron overload disorders

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    Table 2

    Table 3

    Table 4

    Table 5

    Table 6

    Table 7

    Table 8

    Table 9

    (Deugnier et al., 2008)...

    The clinical data of the studied groups.......

    Liver and kidney functions results of the studied groups.........

    Complete blood count results of the studied groups..

    Results of iron study of the studied groups

    Hemoglobin Electrophoresis data...

    Hepcidin concentration levels....

    Ratio between hepcidin and Serum Ferritin...

    Correlation between hepcidin and other parameters.....

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    LIST OF FIGURES

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    Fig. 1

    Fig. 2

    Fig. 3

    Fig. 4

    Fig. 5

    Fig. 6

    Fig. 7

    Fig. 8

    Fig. 9

    Fig. 10

    Fig. 11

    Fig. 12

    The -Globin Gene Cluster on the Short Arm of

    Chromosome 11 (Nancy & Livieri, 1999)..

    The Normal Structure of the -Globin Gene and the

    Locations and Types of Mutations Resulting in -

    Thalassemia (Nancy & Livieri, 1999).

    Effects of Excess Production of Free -Globin Chains

    (Nancy & Livieri, 1999)..

    Complications of beta thalassemia..

    Peripheral blood film in Cooley anemia.

    Essential roles of iron (Taketani, 2005)..

    Normal distribution and storage of body iron (Andrews,

    1999)...

    Major pathways of iron transfer between cells and tissues

    (Andrews, 2000)..

    Iron absorption (Andrews, 2000)

    Hepatic Iron Burden over Time and the Effect of Various

    Hepatic Iron Concentrations in Patients with Thalassemia

    Major, Homozygous Hemochromatosis, and Heterozygous

    Hemochromatosis (Nancy & Livieri, 1999)...

    Amino acid sequence and a model of the major form of

    human hepcidin. The amino and carboxy termini are labeled

    as N and C, The pattern of disulfide linkages between the 8

    cysteines is also shown in the amino acid sequence (Ganz,

    2003)...

    Physiology of hepcidin-ferroportin interaction (Rivera et al.,

    2005b).

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    Fig. 13

    Fig. 14

    Fig. 15

    Fig. 16

    Fig. 17

    Fig. 18

    Fig. 19

    Fig. 20

    Fig. 21

    Normal iron homeostasis mediated by an iron-sensing

    feedback loop (Wrighting & Andrews, 2008)

    Hepcidin mRNA expression (Nicolas et al., 2002).

    Concentration of hepcidine of patients (in circles) and

    concentration of hecidin of control (in squares).

    The variations of RBCs, HB, MCV, HCT (PCV) for 40

    patients (30 patients and 10 controls).

    Hepcidin and Serum Ferritin for 40 patients (30 patients and

    10 controls)..

    Correlation between hepcidin and Hb

    Correlation between hepcidin and HCT.

    Correlation between hepcidin and MCV

    Correlation between hepcidin and Serium Ferritin.

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    CONTENTS

    INTRODUCTION

    AIM OF THE WORK..

    LITERATURE REVIEW.

    THALASSEMIA.

    IRON METABOLISM....

    HEPCIDIN..

    SUBJECTS AND METHODS.

    RESULTS....

    DISCUSSION..

    CONCLUSIONS..

    RECOMMENDATION...

    SUMMARY.

    REFERENCES.....

    .........................................................................................

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  • INTRODUCTION

  • Introduction

    1

    INTRODUCTION

    The thalassemias are a heterogeneous group of genetic disorders of

    haemoglobin synthesis, occurring more frequently in the Mediterranean

    region, the Indian subcontinent, Southeast Asia, and West Africa .The

    thalassemias are divided according to their severity into major which is

    severe and transfusion dependent, intermediate and minor forms of illness.

    The -thalassemias are the most important types of thalassemia because

    they are so common and usually produce severe anemia in their

    homozygous and compound heterozygous states (Hillman et al., 2005).

    In -thalassemia major, the neonate is well at birth but develops severe

    anemia, bone abnormalities, failure to thrive, and life-threatening

    complications. In many cases, the first signs are pallor, yellow skin and

    scleras in infants ages 3 to 6 months. Later clinical features, in addition to

    severe anemia, include splenomegaly or hepatomegaly, with abdominal

    enlargement, frequent infections, bleeding tendencies (especially toward

    epistaxis), and anorexia (Fucharoen et al., 2000).

    Transfusional iron overload is the most important complication of -

    thalassemia and is a major focus of management, which can be prevented

    by adequate iron chelation. Extensive iron deposits are associated with

    cardiac hypertrophy and dilatation, degeneration of myocardial fibers

    (Aessopos et al., 1995; Du et al., 1997).

    Hepcidin is a 25-amino-acid iron peptide hormone. Initially identified in

    human plasma and urine as an anti-microbial molecule. Hepcidin is the key

    regulator of systemic iron homeostasis and a pathogenic factor in anemia of

    inflammation and hereditary hemochromatosis. Hepcidin inhibits iron

    influx into plasma from duodenal enterocytes that absorb dietary iron, from

  • Introduction

    2

    macrophages that recycle iron from senescent erythrocytes and from

    hepatocytes that store iron (Park et al., 2001).

    IronLoading anemias are characterized by ineffective erythropo