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The Frequency of Iron Deficiency and Iron

Deficiency Anemia in Children with Cyanotic

Heart Disease and Non-Cyanotic Heart Disease

Thesis

" Submitted for partial fulfillment of

Master Degree in Pediatrics"

Presented By

Zahraa Mohamed Hussein

M.B.B.CH- Ain Shams University (2012)

Under supervision of

Prof. Dr. Mohsen Saleh El-Alfy Professor of Pediatrics

Faculty of Medicine- Ain Shams University

Dr. Ahmed Moawad EL-Emam Consultant of Pediatric Cardiology

Pediatric Cardiology department, National Heart Institute

Dr. Nadia Youssef Riad Assistant Consultant of Clinical Pathology

Clinical pathology department, National Heart Institute

Faculty of Medicine

Ain Shams University

2019

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Key Words

Congenital Heart Disease

Cyanotic Congenital Heart Disease

Acyanotic Congenital Heart Disease

Echocardiogram

Electrocardiogram

Cardiac Catheterization

Magnetic resonance imaging

Iron Deficiency

Iron Deficiency Anemia

Hemoglobin

Ferritin

Transferrin receptor

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Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iv

List of Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vi

List of Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . viii

List of Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . x

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Aim of the Work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ۳

Chapter (I)

Review of Literature

I.1 Congenital Heart Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

I.1.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4

I.1.2 Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4

I.1.3 Mortality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

I.1.4 Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

I.1.5 Anatomical classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

I.1.6 Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13

I.1.7 Diagnosis of Congenital Heart Disease . . . . . . . . . . . . . . . . . 14

I.1.8 Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

I.2 Iron Deficiency and Iron Deficiency Anemia . . . . . . . . . . . . . . . . . 19

I.2.1 Structure of hemoglobin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

I.2.2 Iron Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

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I.2.3 Iron Deficiency Anemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

I.2.4 Clinical findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

I.2.5 Effect of anemia on the cardiovascular system . . . . . . . . . . . 35

I.2.6 Treatment of IDA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

Chapter (II)

Subjects and Methods

II.1 Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

II.1.1 Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

II.1.2 Sample collection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .43

II.1.3 Ready-made reagents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

II.2 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

II.2.1 Determination of Serum Iron . . . . . . . . . . . . . . . . . . . . . . . . 44

II.2.2 Determination of Total Iron Binding Capacity (TIBC) . . . . 45

II.2.3 Determination of Serum Ferritin . . . . . . . . . . . . . . . . . . . . . 47

II.2.4 Determination of soluble transferrin receptor . . . . . . . . . . . .52

II.2.5 Statistical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .57

Chapter (III)

Results

III.1 Statistical analysis of result data . . . . . . . . . . . . . . . . . . . . . . . . . . 58

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Chapter (IV)

Discussion

IV. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

Chapter (IIV)

Summary

IIV. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81

References

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

Arabic abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ۱

Arabic summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ۲

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Abstract

Anaemia which occur from insufficient iron for synthesis of

hemoglobin is the most frequent hematological disease of infancy and

childhood. The incidence of IDA is related to multiple factors in its

metabolism and nutrition. IDA is especially often present in children with

CHD caused by multiple different factors. To determine the frequency of

unrecognized anemia in pediatric patient with different CHD we carried out

a cross sectional study including 80 Egyptian patients with congenital heart

disease who were diagnosed and have been followed up at cardiology clinic,

National Heart Institute from June, 2018 to January, 2019. These 80 patients

had been divided into two group ; (1) CCHD group included 40 patients, 27

male (67.5%) and 13 female (32.5%). (2) ACHD group included 40 patients,

21 males (52.5%) and 19 females(47.5%). All of patients aged from 3 months

to 3 years. Lab investigations, CBC and Iron profile have been performed to

all patients and the results were analyzed. The frequency of anemia in

cyanotic group was 60.0% and in acyanotic group was 42.5%. Patients that

had ID in CCHD was (32.5 %) and that had IDA was (22.5%). But those of

ACHD that had ID was (30 %) and that had IDA was (20%). This study

detected that ID and IDA are commonly encountered in children with CHD

Routine check up for ID is recommended for these children and those found

to be deficient must to be treated.

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List of Abbreviations

ACD Anemia of chronic illness

ACHD Acyanotic congenital heart disease

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ALCAPA Anomalous left coronary artery from the pulmonary artery

AS Aortic stenosis

ASD Atrial septal defect

AVSD Atrioventricular septal defect

BAV Bicuspid aortic valve

CCHD Cyanotic congenital heart disease

CCVM Congenital cardiovascular malformation

CHD Congenital heart disease

CoA Coarctation of the Aorta

CT Computed tomography

DILV Double inlet left ventricular

DORV Double outlet right ventricle

ECG Electrocardiogram

Hb Hemoglobin

HCT Hematocrit

HLHS Hypoplastic left heart syndrome

ID Iron Deficiency

IDA Iron Deficiency Anemia

LV Left ventricular

LVH Left ventricular hypertrophy

MCH Mean corpuscular hemoglobin

MCV Mean corpuscular volume

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MR Mitral regurge

MRI Magnetic resonance imaging

MVP Mitral valve prolapse

PDA patent ductus arteriosus

PPS peripheral Pulmonary stenosis

PS Pulmonary stenosis

SD Standard deviation

sTfR Soluble Transferrin Receptor

TGA Transposition of great arteries

TIBC Total iron binding capacity

TOF Tetralogy of Fallot

VSD Ventricular septal defect

List of Figures

Figure No. Title Page No.

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Figure No. Title Page No.

(1) Structure of adult hemoglobin. 20

(2) Regulation of iron absorption 21

(3) The transferrin cycle and the transferrin receptor 1-. 24

(4) Calculation of ferritin results. 51

(5) Calculation of sTfR results. 56

(6)

Bar chart between group I: cyanotic heart disease and

group II: acyanotic heart disease according to age

(months).

59

(7) Bar chart between group I: cyanotic heart disease and

group II: acyanotic heart disease according to sex. 60

(8)

Bar chart between group I: cyanotic heart disease and

group II: acyanotic heart disease according to echo

findings.

64

(9)

Bar chart between group I: cyanotic heart disease and

group II: acyanotic heart disease according to

symptoms.

65

(10) Bar chart between group I: cyanotic heart disease and

group II: acyanotic heart disease according to Anemia. 66

(11)

Bar chart between group I: cyanotic heart disease and

group II: acyanotic heart disease according to iron

profile.

67

(12) Bar chart between group I: cyanotic heart disease and

group II: a cyanotic heart disease according to anemia. 68

(13)

Bar chart between group I: cyanotic heart disease and

group II: acyanotic heart disease according to Ferritin

level.

69

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Figure No. Title Page No.

(14)

Bar chart between group I: cyanotic heart disease and

group II: acyanotic heart disease according to anemic

& iron deficiency.

70

(15)

Bar chart between group ICCHD and group II: ACHD

according to normal Hb and iron deficiency.

72

List of Tables

Table No. Title Page No.

(1) Incidence of cardiac malformation at birth. 5

12

(2) Genetic and Environmentally Induced Disorder with

CHD. 7

(3) Common syndromes 8

(4) Common syndromes associated with CHD 9

(5) Extracardiac malformations most frequently reported

among patients with congenital heart diseases. 10

(6) Classification of CHD 11

(7) Another Classification of CHD 12

(8) The clinical findings observed in IDA 31

(9) Laboratory findings in IDA. 34

(10) Demographic data of patients. 59

(11) Anthropometric measurements of patients. 61

(12) Comparison between group I: CCHDand group

II:ACHDaccording to history. 62

(13) Comparison between group I: CCHDand group II:

ACHD according to nutrition. 63

(14) Clinical diagnosis of CHD 64

(15) Symptoms of CHD 65

(16) Anaemia investigation in patients. 66

(17) Investigation of Iron profile in patients. 67

(18) Comparison between group I: CCHDand group II:

ACHD according to anemic. 68

(19) Prevalence of body iron storage in CHD. 69

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(20)

Comparison between group I: cyanotic heart disease

and group II: acyanotic heart disease according to

anemic and deficiency.

70

(21) Investigation of S. Transferrin receptor in in cyanotic

and acyanotic patients with IDA 71

(22)

Comparison between group I: cyanotic heart disease

and group II: acyanotic heart disease according to

normal Hb and deficiency.

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Introduction

IDA arises when disturbance occur between iron intake, stores, and

the body's loss of iron and iron became insufficient to fully support

production of erythrocytes. The impact on children is very significant. the

definition of anaemia depends on hemoglobin values vary according to age,

sex .race. Symptoms and signs are related to the degree of the anemia.

Patient may complain of poor mental performance or cold intolerance

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(Rosenzweig and Volpe, 1999). Dyspnea and fatigue are regularly occured.

Although rare, dysphagia or glossitis may be seen at presentation (Cook,

2005).

Iron deficiency anemia is associated with some rather striking

neurological complication . Pica is another associated neurological

manifestation . ID is also known to cause cognitive dysfunction.

Neurological effect is particularly relevant during infancy brain

development. Long-lasting cognitive effects occur despite therapy later in

life. Therefore, iron deficiency anemia during infancy must be aggressively

treated to avoid the potential for cognitive effects (Lozoff et al., 1991).

Laboratory evaluation reveals characteristic changes in blood

parameters for iron regulation storage, transport, and utilization. Currently,

the central parameter for determination of significant ID as well as

therapeutic response is ferritin (Mei et al. 2005). The ferritin protein

complex structure acts as a cage to contain up to 4500 iron molecules

(Harrison and Arosio, 1996). A serum ferritin level of 15 μg/L or less is

diagnostic of ID , and correlates specifically with the absence of stainable

bone marrow iron (Baker, 2000).

Even at higher ferritin levels, around 40 μg/L, erythropoiesis may be

affected. ID also causes increased release of soluble transferrin from

erythroblasts. Therefore, ratios of STRS and ferritin are used to detect iron-

deficient erythropoiesis. Complete blood count and serum iron level are also

essential for diagnosis (Cable et al., 2011).

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Transferrin receptor is a membrane receptor involved in the control of

iron supply to the cell through the binding of transferrin, the major iron-

carrier protein. This receptor plays a major role in cell proliferation because

iron is essential for sustaining ribonucleotide reductase activity, and is the

enzyme that catalyzes the conversion of ribonucleotides to

deoxyribonucleotide (Crichton and Charloteaux-Wauters, 1987).

Transferrin receptors may be increased in persons with ID . Thereby

aiding in the evaluation of ID and in the diagnosis of IDA . Its main function

is to control the level of free iron. Unlike ferritin, the transferrin receptor

level is not affected by infection or inflammation and is therefore useful in

distinguishing IDA from ACI(Weiner and Cairo, 2002).

Anemia is an important effect factor for morbidity and mortality in

patients with CCHDand ACHD. There is high frequency of IDA among

CHD patient, so routine check up for ID is recommended for these children

.Those found to be deficient must to be treated (Ootaki et al., 2007).

Heart failure may occur and worsens by anemia. In CCHD with a right

to left flow , arterial oxygen saturation decreases and red blood cell count

may reach a big level and hyperviscosity develops. In addition, in anemic

patients especially those with microcytic IDA , permeability of microcytic

erythrocytes decreases in comparison to normocytic cells, therefore

thromboembolic and CVS events are more frequently encountered

(Broberg et al., 2006).