Iron deficiency anemia among the children in India- An Overview

A. Venkateshwari1*, K. Srimanjari1, Pratibha Nallari2, A. Jyothy1

1
Institute of Genetics and Hospital for Genetic Diseases, Osmania University, Begumpet,
Hyderabad – 500 016, India
2
Department of Genetics, Osmania University, Hyderabad – 500 007
*
Corresponding Author, Email: venkateshwari@yahoo.com

Short Abstract:
Iron deficiency anemia, a major health problem in children with serious
consequences is of great public health importance. It is attributed mainly due to poor
nutritional iron intake, low iron bio-availability and genetic factors. Thus, anemia control
through primary health care should be an integral part of total health care and socio-
economic development of the country.

Long Abstract:

Iron deficiency anemia is a major health problem of children with adverse effects
on the development of the children. It afflicts millions of people all over the world,
primarily affecting women of child bearing age, pregnant women and their young
children particularly in the developing countries. The World Health Organization (WHO)
has estimated that, globally, 1.62 billion people are anemic, with the highest prevalence
of anemia (47.4%) among preschool-aged children; of these 293 million children, 89
million live in India. The third National Family Health Survey (NFHS) 2005-2006
revealed that at least 80% of India among rural children aged between 12 to 23 months
were anemic. Anemia was especially prevalent as the majority of India's population is
rural(72.2%). However, despite recent economic development and the existence of a
national anemia-control program, the prevalence of anemia in India is increasing at a fast
pace in children aged 6 to 36 months. It is the most common type of anemia caused by
inadequate iron availability for hemoglobin production due to the lack of dietary iron or
insufficient uptake of iron. A number of conditions are associated with anemia, including

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nutritional or absorptional deficiency, infectious diseases, blood loss and genetic
mutations. The genes involved in iron metabolism such as transferrin (TF) and its
receptors 1 and 2 (TFR1 and TFR2) and matriptase (TMPRSS6) are essential proteins for
the uptake of iron by the cell. The present study highlights the role of these genes in iron
deficiency anemia.

Introduction:

Iron deficiency is one of the leading risk factors for disability and mortality
worldwide, affecting both developing and developed countries with major consequences
for human health as well as social and economic improvement [1]. It is the most frequent
nutritional problem on a worldwide scale, affecting approximately two billion people,
85% of whom suffer as a consequence of deficient iron ingestion and low absorption
capacity. Thus, it can be estimated that, at present, 34% of the world’s population suffers
from iron deficiency, with 80% belonging to developing countries, in which the incidence
of anemia and iron deficiency is approximately 40%, whereas in developed countries, its
prevalence is lower than 10% [2]. In total, 800,000 (15%) of deaths are attributed to iron
deficiency. WHO lists iron deficiency (ID) as one of “Top Ten Risk Factors contributing
to Death” [3]. IDA is more common in South Asian countries especially, India,
Bangladesh and Pakistan. By contrast, the prevalence of IDA in neighboring countries
such as Bangladesh and Pakistan has declined to 55% [4]. The reduction of IDA
prevalence in China is especially remarkable i.e., the prevalence was halved from 20% to
the current level of 8% within a decade [5]. It is very difficult to ascertain the true
incidence of IDA, as the etiology of anemia is multifactorial. In a large scale study
conducted by ICMR (Indian Council Medical Research) about 53% of children were
found to be anemic [6]. A study by NFHS 2002 [7] found that anemia prevalence among
children aged 1–5 years is little lower than pre-school children, adolescents and women
of child bearing age who are at risk of developing anemia [8]. IDA is an extremely
serious public health problem in India especially among pregnant and lactating women,
children and adolescents [9]. Over the last 50 years, the prevalence of iron deficiency
anemia has ranged between 68 to 97 percent in the children. [10,11].

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Iron Absorption and Balance:

Plasma and cellular iron levels are tightly regulated by mechanisms that control
iron absorption, storage, recycling and release. To absorb iron, the insoluble ferric iron
(Fe3+) from vegetables and grains needs to be converted into the ferrous form (Fe2+) by
a brush border ferric reductase in the duodenum and upper jejunum. The ferrous iron is
then transferred across the enterocyte membrane by divalent metal transporter (DMT) 1.
In blood, iron is carried by transferrin to various tissues to be taken by cells in a
transferrin receptor-mediated endocytotic process[12]. Once inside the cell, iron is
released from transferrin in the acidic endosome and stored in the form of ferritin. A
significant portion, up to ~75%, of plasma iron is taken up by bone marrow to synthesize
hemoglobin in red blood precursors. Several other cell types including enterocytes,
hepatocytes, and reticuloendothelial macrophages also serve as major iron storage sites.
When plasma iron levels are low, iron release is increased from enterocytes, hepatocytes
and macrophages to meet the physiological demand. Conversely, when plasma iron levels
are high, iron will remain stored in these cells. The body loses iron when cells are shed
from the gastrointestinal tract or blood during hemodialysis [13].

Iron Deficiency Anemia, Infants and Children:

Iron deficiency is common in children, largely because of the demands for a

positive iron balance that is imposed by growth and partly because diets rich in milk are
not a good source of iron. Adverse effects of iron deficiency on behavioral patterns are of
special concern in the infants because the later part of the brain growth spurt coincides
with the period in which iron deficiency anemia is most prevalent in the age group
between 6–24 months. Earlier studies have suggested that iron deficient children have
lower IQ scores, decreased attentiveness and lower scores on tests of academic
performance compared with non-anemic controls. However, a cause and effect
relationship could not be established because of associated multiple confounding factors
in most of the studies including low socioeconomic status, poverty, lack of stimulation at
home, poor parental education, maternal depression, low birth weight, faulty feeding,
malnutrition, parasitic infestations and elevated lead levels. Several studies have

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suggested that iron deficiency in infancy may be associated with impaired cognitive
function during the school years [14].

Iron is essential for all tissues in a young child’s developing body. Presence of
iron in the brain from early life is essential as it participates in the neural myelination
processes, along with growth and immune function [15]. Iron, which is essential to both
the host and invading pathogens, must be carefully regulated to promote optimal
conditions that preserve the health of young children. Furthermore, iron can interfere with
the absorption of other nutrients and, in excess, can generate free radicals that impair
cellular functions and suppress enzymatic activity [16].Observational studies in children
over 2 years have reported poorer cognition and school achievement in iron deficient
children [17]. Adolescent girls are particularly susceptible to iron deficiency because of
poor dietary intake along with increased iron requirement related to rapid growth and
menstrual blood loss and are at greater risk of cognitive impairment. In therapeutic trials,
few randomized controlled trials are available, as withholding iron to iron deficient
children was considered unethical. Hence, most of the studies have no controls. Pollitt et
al (1985) studied children with iron deficiency anemia where mean age was 9.5 years.
Oral ferrous sulphate 50 mg daily was given in this randomized controlled trial, wherein
a significant improvement in mental scores in iron treated anemic children compared to
placebo treated anemic children was observed [18]. Further efficiency scores of iron
treated anemic children became similar to that of non-anemic children.

Role af genes in Iron Metabolism:

Iron is an essential element required for the growth and survival of most
organisms, and the iron balance is therefore tightly regulated by several interacting iron
binding factors [19]. Heritable differences in the expression of the genes like transferrin,
transferring receptors, matriptase-2, hepcidin seems to exist which may determine the
phenotypic variation in iron metabolism between individuals.

Transferrin in Iron Metabolism and Anemia:

Serum transferrin plays a crucial role in iron metabolism as it provides most of the
iron required for various functions of an organism [20]. Cells obtain iron from plasma

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where it circulates in a complex with a carrier protein transferrin (Tf). Iron loaded Tf is
then bound to transferrin receptor (TfR), and their complex passes into cells by means of
internalization, wherein iron releases by pH-dependent mechanism [21].

Transferrin receptor is a transmembrane protein that participates in iron transport

from plasma into cells. It consists of two identical subunits of 95 kDa linked by two
disulfide bonds. Each TfR subunit contains an N-terminal cytoplasmic domain (1-67
amino acid residues), a transmembrane domain (68-88 amino acid residues) and a C-
terminal extracellular domain (89-760 amino acid residues) [22]. The main pool of TfR
molecules is located on erythroblasts which demand a lot of iron for hemoglobin
synthesis. After the erythroid cells have matured, the extracellular part of the TfR
molecule is truncated from the cell surface by cleavage of an R100 – L101 bond. TfR
released into the blood stream consists of 101-760 amino acid residues of cell TfR and is
called soluble (or serum) transferrin receptor (sTfR) [23]. The expression of transferrin
receptor depends on the concentration of iron in the cellular cytoplasm. The
concentration of soluble transferrin receptor (sTfR) has been reported to be proportional
to the total amount of cell-associated transferrin receptor. In blood, soluble TfR is
completely bound to Tf and circulates as sTfR-Tf complex. Transferrin receptor is the
main receptor for transferrin and allows transferrin-bound iron uptake by the cell. Its
expression is regulated by cellular iron requirements. Conserved iron-response elements
in the 3'-untranslated region of transferrin receptor mRNA enhances binding of iron
regulatory proteins 1 and 2. The hereditary hemochromatosis protein HFE competes
binding with transferrin for an overlapping binding site. It is also involved in materno-
fetal iron transport via the placenta.

The determination of the sTfR level in blood has become widely used in clinical
practice [24]. The normal concentration of sTfR in blood ranges within 2 – 5 µg/ml. An
increase in the sTfR level was found in iron deficiency anemia, autoimmune hemolytic
anemia, hereditary spherocytosis, β-thalassemia, sickle cell anemia etc. Soluble TfR is
indispensable marker of iron deficiency anemia and is mainly used for the differentiation
between iron deficiency anemia (accompanied by an increase in the sTfR level) and
anemia of chronic disease (proceeded at the normal sTfR level) [25]. The measurement of

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Tf is also widely used in diagnosis of anemia together with the determination of sTfR,
ferritin and iron concentration in serum. Because the synthesis of TfR is upregulated with
tissue iron deficiency, IDA can be identified readily by an elevated serum TfR
Importantly, the serum TfR is normal in anemic and chronic diseased individuals but gets
elevated if they develop IDA [26].

There are no disease-causing mutations in the TFRC gene. However, missense

coding region variants that may have functional effects was observed. The only one with
appreciable frequency (rs3817672) is in exon 4 and encodes S142G amino acid
substitution, which is ethnic/geographic influenced. The minor allele of the gene in
Caucasians is the major allele in Asians and Africans. Tfrc knockout mice are not viable
and die during embryonic development due to erythropoietic and neuronal development
abnormalities. The short arm of chromosome 3 also harbors other iron-related genes:
transferrin (3q22.1), lactotransferrin (3q21-q23), melanotransferrin (3q28-q29) and
ceruloplasmin (3q23-q25), which as a gene family may be involved in compound
heterozygotes in anemic individuals [27].

Matriptase/TMPRSS6 in Iron Metabolism and Anemia:

Matriptase-2, also called TMPRSS6, is a type II transmembrane serine protease

[28]. The 811-amino-acid (aa) human protein is synthesized as an inactive zymogen and
autoactivated by proteolytic cleavage. Structurally, matriptase-2 contains a short 54-aa N-
terminal cytoplasmic domain, a membrane-spanning region, an SEA (sea urchin sperm
protein, enteropeptidase, and agrin) domain, 2 CUB [Cls/Clr, urchin embryonic growth
factor, and bone morphogeneic protein (BMP)-1] domains, three LDLa (low-density-
lipoprotein receptor, class A) domains, and a trypsin-like serine protease domain
containing the catalytic triad of histidine, aspartate, and serine residues.

Recently, TMPRSS6 has been identified as a modifier of iron homeostasis because

it regulates the expression of the systemic iron regulatory hormone hepcidin [29] and
inhibits hepcidin activation by cleaving membrane hemojuvelin [30]. Hepcidin controls
iron absorption by binding to the only known cellular iron export protein ferroportin
thereby leading to ferroportin degradation and blockage of iron entering from the

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enterocyte into the circulation[31]. In addition, hepcidin blocks the transfer of iron from
macrophages into the circulation, which is the major iron source for erythropoiesis
following erythrophagocytosis and re-utilization of the metal from senescent erythrocytes
[32, 33]. In iron deficiency, however, low iron levels inhibit hepcidin formation and thus
enable iron to be transferred from the gut to the blood. Part of the iron-mediated control
of hepcidin can be referred to the action of TMPRSS6 and thus functional mutations in
this gene are associated with insufficient iron absorption and increased hepcidin levels
[34]. A recent study by Falco et al, (2010) have shown novel mutations in TMPRSS6
gene predicted to result in truncated protein lacking the catalytic domain associated with
iron-refractory iron deficiency anemia (IRIDA) [35]. In recent years, association and
genome-wide association (GWA) studies of this gene has revealed various mutations and
furthered our understanding of iron metabolism.

Currently, there is a limited understanding of genetically acquired iron-limited

anemias. In accordance with its role in co-ordinating body iron levels, alterations in the
genes encoding hepcidin or its key regulators induce iron overload syndromes such as
hereditary hemochromatosis (HH). Consistently, HH disorders result from inadequate
hepcidin production relative to body iron stores [36]. Conversely, elevated hepcidin
levels have been described in iron deficiency anemia patients that are insensitive to oral
iron therapy and display an incomplete hematologic recovery with parenteral iron
administrations, a condition termed iron refractory iron deficiency anemia (IRIDA) [37].
Heterozygous and homozygous biallelic human matriptase-2 mutations have been
identified by 3 independent studies in 14 IRIDA patients from Northern European,
African and Afro-American, Mediterranean and English ancestries [38]. Predominately
identified mutations like 1906_1907insGC, 1813delG, IVS13+1G>A, IVS15-1G>C,
1383delA, IVS6+1G>C, 1179T>G and 1795C>T, encode for matriptase-2 proteins which
lack functional protease domains. Associations between SNP in TMPRSS6 gene on
chromosome 22q12 variants and hemoglobin levels were found in individuals with Indian
Asian ancestry as well as in those with European ancestry [39, 40]. Overexpression of the
protease domain deficient mask human matriptase-2 in zebrafish resulted in reduced
hemoglobinization in comparison to wild-type human matriptase-2, illustrating the in
vivo impact a deficiency in matriptase-2 proteolytic activity [41]. In fact, a splicing error

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in Tmprss6 has been detected in Mask mice, which have a recessive chemically, induced
phenotype characterized by progressive loss of body hair and severe iron deficiency due
to reduced absorption of iron from the gastrointestinal tract. Mask mice produce a
truncated copy of the Tmprss6 protein lacking the serine protease domain and express
inappropriately high levels of hepcidin. These high levels can be responsible for iron
deficiency and severe microcytic anemia was previously observed in transgenic mice
over expressing hepcidin [42]. Collectively these data suggest that further studies of
matriptase-2 gene may contribute to a better understanding of the functional relevance of
matriptase-2 in regulating iron homeostasis and to translate this information into clinical
answers for patients with IRIDA or other deficiencies in iron metabolism.

Hepcidin in Iron Metabolism and Anemia:

Hepcidin, a small acute phase antimicrobial peptide appears to synchronously

orchestrate the response of iron transporter and regulatory genes to ensure proper balance
between dietary iron absorbption by the small intestine or circulatory hepcidin released
by macrophages [43]. Hepcidin, encoded by HAMP gene, is a recently discovered 25
amino acid peptide that, in addition to being involved in innate immunity, appears to play
a crucial role in iron homeostasis in humans, regulating both iron absorption from the
intestine and recycling by macrophages [44].

Anemia induced by mutations in mice that restrict the uptake of iron in the small
intestine (sla and mk mice) showed markedly decreased hepatic hepcidin mRNA. Anemia
induced by phlebotomy, or by hemolysis from phenylhydrazine, also suppressed hepatic
hepcidin mRNA. Importantly, the suppressive effect of hemolytic anemia was seen even
in iron-overloaded mice, suggesting that the suppression of hepcidin by anemia is a
stronger effect than the stimulation of hepcidin by iron overload [45]. Several studies
suggest that there are strong genetic components that underlie hepcidin regulation beyond
the usual suspects (i.e. infection, inflammation, erythropoiesis, hypoxia and iron), in a
manner that could impinge on phenotypic differences in susceptibility to iron-overload or
anemia. Based on variation in hepcidin expression phenotypes, new emerging data
suggest that heritable regulatory polymorphisms within the promoter may be linked to
diseases of iron metabolism.

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 A CCAAT-enhancer-binding protein (C/EBP) recognition site within the hepcidin
promoter provided the first evidence for cis-acting regulation of its expression by
C/EBPα. [46] In support of the contribution of regulatory SNPs in hepcidin expression
variation and iron metabolism, Island et al.(2009) found a C>T polymorphism in one of
two bone morphogenetic protein response elements, BMP-RE, (GGCGCC→GGTGCC)
in the promoter that impaired transcription of the gene, its IL-6-responsiveness and
binding by Smads [47]. Similarly, Andreani et al (2009) found association between a
−582A>G polymorphism in the hepcidin promoter and iron overload in thalassemia
major [48]. Porto et al (2005) previously reported a SNP (G to A substitution) in the
5′UTR of the human hepcidin gene which correlated with severe hemochromatosis [49].

A very recent study by An et al (2012) in a Chinese population identified that

TMPRSS6 polymorphisms were not only associated with lower serum iron and
hemoglobin levels, but are also genetic risk factors for iron deficiency and IDA. They
hypothesized that the altered inhibitory effect of matriptase-2 on hepcidin secretion was
possibly the underlying mechanism of the increased risk of iron deficiency and IDA.
SNPs in TF and TFR2, although associated with several important iron traits, did not
show significant effects on iron deficiency or anemia risk [50].

Conclusions:

Currently, the precise underlying mechanisms of IDA are undefined. Considering

the complexity of the regulatory network required to maintain iron homeostasis,
collaborative efforts will be required to further dissect the risk factors for initiation and
progression of disease. In conclusion, genetic variations in these genes may lead to
differences in iron metabolism and modulate the development of iron deficiency anemia.
Thus, it is necessary to reduce iron deficiency anemia through primary health care which
is an integral part of total health care and socio-economic development of the country.

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