Journal of

Clinical Medicine

Review
Helicobacter pylori-Associated Iron Deficiency Anemia in
Childhood and Adolescence-Pathogenesis and Clinical
Management Strategy
Seiichi Kato 1, *, Benjamin D. Gold 2 and Ayumu Kato 3

1 Kato Children’s Clinic, Natori 981-1227, Japan

2 Gi Care for Kids, Children’s Center for Digestive Healthcare, LLC, Atlanta, GA 30342, USA
3 Department of General Pediatrics and Gastroenterology, Miyagi Children’s Hospital, Sendai 989-3126, Japan
* Correspondence: [email protected]; Tel.: +81-22-399-9152; Fax: +81-22-399-9153

Abstract: Many epidemiological studies and meta-analyses show that persistent Helicobacter pylori
infection in the gastric mucosa can lead to iron deficiency or iron deficiency anemia (IDA), particularly
in certain populations of children and adolescents. Moreover, it has been demonstrated that H. pylori
infection can lead to and be closely associated with recurrent and/or refractory iron deficiency
and IDA. However, the pathogenesis and specific risk factors leading to this clinical outcome in
H. pylori-infected children remain poorly understood. In general, most of pediatric patients with
H. pylori-associated IDA do not show evidence of overt blood loss due to gastrointestinal hemorrhagic
lesions. In adult populations, H. pylori atrophic gastritis is reported to cause impaired iron absorption
due to impaired gastric acid secretion, which, subsequently, results in IDA. However, significant
gastric atrophy, and the resultant substantial reduction in gastric acid secretion, has not been shown
in H. pylori-infected children. Recently, it has been hypothesized that competition between H. pylori
and humans for iron availability in the upper gastrointestinal tract could lead to IDA. Many genes,
Citation: Kato, S.; Gold, B.D.; Kato, A. including those encoding major outer membrane proteins (OMPs), are known to be involved in
Helicobacter pylori-Associated Iron iron-uptake mechanisms in H. pylori. Recent studies have been published that describe H. pylori
Deficiency Anemia in Childhood and virulence factors, including specific OMP genes that may be associated with the pathogenesis of IDA.
Adolescence-Pathogenesis and Daily iron demand substantively increases in children as they begin pubertal development starting
Clinical Management Strategy. J. Clin. with the associated growth spurt, and this important physiological mechanism may play a synergistic
Med. 2022, 11, 7351. https://doi.org/
role for the microorganisms as a host pathogenetic factor of IDA. Like in the most recent pediatric
10.3390/jcm11247351
guidelines, a test-and-treat strategy in H. pylori infection should be considered, especially for children
Academic Editors: Mariko Hojo and and adolescents in whom IDA is recurrent or refractory to iron supplementation and other definitive
Tamaki Ikuse causes have not been identified. This review will focus on providing the evidence that supports a
clear biological plausibility for H. pylori infection and iron deficiency, as well as IDA.
Received: 31 October 2022
Accepted: 8 December 2022
Published: 10 December 2022
Keywords: child; gastritis; Helicobacter pylori; host genetic factor; iron deficiency anemia; iron demand;
iron uptake; sports activity; virulence factor
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations.
1. Introduction
Helicobacter pylori infection is quite common and this organism colonizes an estimated
fifty percent of the world’s populations [1]. However, there is a wide difference in H. pylori
Copyright: © 2022 by the authors. prevalence among different countries, with infection rates in Latin America and Africa up-
Licensee MDPI, Basel, Switzerland. wards of 70–80% of adults compared to infection prevalence of 20–30% of adults in Canada
This article is an open access article and U.S. [2]. Gastric colonization with H. pylori is usually life-long, which then, eventually
distributed under the terms and and inevitably, induces persistent mucosal inflammation. Long-term H. pylori infection
conditions of the Creative Commons can cause pre-cancerous pathology, including gastric atrophy and intestinal metaplasia
Attribution (CC BY) license (https:// in adulthood, leading to especially intestinal-type gastric cancer, particularly in at-risk
creativecommons.org/licenses/by/ populations [3,4]. Since 1994, H. pylori has been classified as a class I carcinogen associated
4.0/).

J. Clin. Med. 2022, 11, 7351. https://doi.org/10.3390/jcm11247351 https://www.mdpi.com/journal/jcm

 iron deficiency (ID)/iron deficiency anemia (IDA) and idiopathic thrombocytopenic pur-
pura [6,7]. However, the majority of H. pylori-infected children remain relatively asymp-
tomatic without any readily apparent clinical diseases. Significantly, atrophy and intesti-
nal metaplasia are rarely found in H. pylori-infected children, and gastric cancer is ex-
J. Clin. Med. 2022, 11, 7351 tremely rare [6,7] (Figure 1). The fact that compared to adults, an abundance of H. pylori- 2 of 14
infected children demonstrate less severe gastritis and the resultant outcome of severe
clinical diseases indicates a down-regulation of host immune response in the early natural
historywith
of infection [8]. Withofdata
the development thatadenocarcinoma
gastric suggests that H. bypylori is anHealth
the World “old” pathogen
Organization with(WHO),
respectastowell
human evolution, this dampening of the host
as by the International Agency for Research on Cancer [5]. response in the initial or early
infection after gastric
In the mucosal
pediatric colonization
population, makesisbiological
H. pylori sense in
also associated order
with thetodevelopment
facilitate of
immune gastritis, peptic ulcer disease (duodenal more than gastric ulcers), in rare casesThe
evasion and establish persistent infection in a unique biological niche. mucosal-
knowledge that there
associated is a wide tissue
lymphoid-type difference in a clinical
lymphoma, spectrum of H. pylori-associated
and extra-gastrointestinal diseases, including
disease, including
iron deficiencyH. pylori-associated
(ID)/iron deficiency IDA,anemia
between both and
(IDA) pediatric and adult
idiopathic populations pur-
thrombocytopenic
is verypura
important
[6,7]. However, the majority of H. pylori-infected children remainpylori
in understanding the complex pathobiology of human H. infec-asymp-
relatively
tion. tomatic without any readily apparent clinical diseases. Significantly, atrophy and intestinal
Itmetaplasia
is known that H. pylori
are rarely is closely
found associated withchildren,
in H. pylori-infected the development
and gastric ofcancer
IDA inischil-
extremely
dren. Unlike in gastric cancer, H. pylori-associated IDA occurs commonly in
rare [6,7] (Figure 1). The fact that compared to adults, an abundance of H. pylori-infected children and
adolescents
children [9]. demonstrate
Improvementless of the associated
severe IDA
gastritis andbythe
eradication
resultantofoutcome
H. pyloriof appears
severetoclinical
be dependent
diseasesprimarily
indicates aupon pediatric ageof
down-regulation groups, which might
host immune responsenotinbethe
generalizable
early naturaltohistory
adult populations
of infection [10]. Thesedata
[8]. With facts
thatlead to a hypothesis
suggests that the
that H. pylori is anpathogenesis
“old” pathogen of the IDArespect
with
differstofrom that of gastric ulcer or cancer caused by long-term infection of H.
human evolution, this dampening of the host response in the initial or early infection pylori (Figure
1). There is agastric
after possibility that the
mucosal development
colonization of H.biological
makes pylori-associated
sense inIDA in children
order might
to facilitate immune
not depend
evasion solely upon mucosal
and establish injury
persistent and pathologies
infection in a uniquesuch as gastric
biological atrophy
niche. and in- that
The knowledge
testinalthere
metaplasia.
is a wide difference in a clinical spectrum of H. pylori-associated disease, including
H. pylori-associated IDA, between both pediatric and adult populations is very important
in understanding the complex pathobiology of human H. pylori infection.

Figure 1. H. pylori infection and the related diseases.

It is known
Figure 1. H. pylori infection andH.
that thepylori is diseases.
related closely associated with the development of IDA in chil-
dren. Unlike in gastric cancer, H. pylori-associated IDA occurs commonly in children and
adolescents [9]. Improvement of the associated IDA by eradication of H. pylori appears
to be dependent primarily upon pediatric age groups, which might not be generalizable
to adult populations [10]. These facts lead to a hypothesis that the pathogenesis of the
IDA differs from that of gastric ulcer or cancer caused by long-term infection of H. pylori
(Figure 1). There is a possibility that the development of H. pylori-associated IDA in children
might not depend solely upon mucosal injury and pathologies such as gastric atrophy and
intestinal metaplasia.
It is thought that the pathogenesis and clinical outcome of H. pylori-associated diseases,
including IDA, depend upon multiple factors, including but not limited to bacterial viru-
lence and environmental factors, as well as host genetic and acquired factors. Furthermore,
it is the interaction between these bacterial and host factors and the modulation or influence
by environmental exposures that affects the host microbiome, i.e., synergistic mechanisms
that then result in gastro-duodenal mucosal disease outcome. However, the specific mech-
anisms underlying H. pylori-associated IDA remain poorly understood. In the present
J. Clin. Med. 2022, 11, 7351 3 of 14

review, the biologically plausible and possible pathogenesis of H. pylori-associated IDA in

childhood and adolescence and the clinical aspects, including management are discussed.

2. Clinical Aspects of H. pylori-Associated IDA

2.1. Iron Absorption in Humans
Non-heme iron accounts for >80% of dietary iron in developed countries [11]. Re-
duction from ferric (Fe+++ ) to the ferrous (Fe++ ) forms of iron is essential for intestinal
absorption, and in this process gastric acid and ascorbic acid play important roles [11].
Non-heme iron is absorbed primarily in the proximal small intestine via the divalent metal
transporter-1 expressed in the proximal duodenum mucosa [10]. On the other hand, the
mechanism of absorption of heme iron remains to be poorly understood. Important regu-
lators of hepcidin produced by hepatocytes, and, therefore, of systemic iron homeostasis,
include the following components; plasma iron concentration, body iron stores, infection
and inflammation, and erythropoiesis [10].

2.2. Clinical Evidence

It is reported that up to ID or IDA occurs in one-fourth of children with H. pylori
infection [12]. H. pylori infection prevalence increases in the pre-teen and adolescent age
groups, and IDA is also more prevalent in those age groups, irrespective of cause [6]. In
a pediatric study in Alaska [13], ID was highly prevalent among school-aged children,
and H. pylori infection was independently associated with ID and IDA. On the other hand,
several studies showed no causal relationship between IDA and H. pylori infection in
children [14–16]. In a randomized controlled study in Bangladeshi children [17], it was
shown that H. pylori infection is neither a cause of ID/IDA nor a reason for treatment failure
with iron supplementation.
However, many epidemiological and interventional studies have shown an associ-
ation between H. pylori infection and ID/IDA in children [13,18,19]. In an international
multi-center pediatric study [20], there was a significant association observed between
H. pylori infection and low ferritin concentration in Chile and Brazil but not in United
Kingdom. We speculate that these differences could be explained by different host factors
in the populations infected in Chile and Brazil, compared to the U.K., and/or different
environmental exposures in these geographically distinct populations, thereby leading to
specific indigenous microbiome differences in these population, leading to ID/IDA in one
and not in the other population. Meta-analyses have shown that a risk of ID and IDA,
particularly that which is unexplained, is higher in individuals with H. pylori infection than
in those without the infection [21,22]. H. pylori eradication can reduce the prevalence of ID
in children [20]. It has been demonstrated that the eradication of H. pylori could improve
iron status with IDA [23]. In a meta-analysis with 16 randomized controlled trials [24],
it was demonstrated that H. pylori eradication therapy plus oral iron supplementation
significantly increased levels of hemoglobin, serum iron, and ferritin more than iron sup-
plementation alone. In particular, such effect for hematological indices with anti-H. pylori
treatment was also shown in patients with moderate or severe IDA.
Recent studies have reported that H. pylori-associated IDA is frequently refractory
to iron-supplementation therapy or shows recurrent episodes of the IDA once supple-
mentation has been discontinued [25,26]. Such refractory or recurrent natures of H. pylori-
associated IDA can be resolved by eradication of the bacteria [23,25,27]. Eradication of
H. pylori results in reversal of long-standing IDA [28,29]. Furthermore, successful eradica-
tion of H. pylori leads to long-term resolution of refractory or recurrent IDA in Japanese
teenagers [27]. Taking together the cumulative evidence described above, it is concluded
that H. pylori causality on childhood IDA has been established. In addition, it is thought
that H. pylori plays a central role in the pathogenesis of H. pylori-associated IDA.
 of H. pylori leads to long-term resolution of refractory or recurrent IDA in Japanese teen-
agers [27]. Taking together the cumulative evidence described above, it is concluded that
H. pylori causality on childhood IDA has been established. In addition, it is thought that
H. pylori plays a central role in the pathogenesis of H. pylori-associated IDA.
J. Clin. Med. 2022, 11, 7351 4 of 14
3. Pathogenesis
3.1. Gastrointestinal Mucosal Lesions and IDA
3. Pathogenesis
IDA can be directly caused by blood loss from H. pylori-induced mucosal injury and
gastroduodenal
3.1. Gastrointestinal lesions
Mucosalsuch as erosions
Lesions and IDA and ulcerations. A previous study showed that
hemorrhagic
IDA can be directly caused by blood lossfinding
gastritis was consistent and key from H.inpylori-induced
the Alaska native population
mucosal injury who
and
have a long history of refractory ID and in whom H. pylori
gastroduodenal lesions such as erosions and ulcerations. A previous study showed that infection is prevalent [30].
Moreover, some
hemorrhagic of H. was
gastritis pylori-infected
consistentAlaska
and key native children
finding in thehad pepticnative
Alaska ulcerspopulation
with active
bleeding
who have that
a long is clinically
history ofsevere enough
refractory ID andto require
in whom endoscopic hemostasis
H. pylori infection [31,32]. AGA
is prevalent [30].
technical review stresses that any gastrointestinal lesion that causes
Moreover, some of H. pylori-infected Alaska native children had peptic ulcers with active a mucosal defect can
bleed enough to lead to both overt and/or occult blood loss and,
bleeding that is clinically severe enough to require endoscopic hemostasis [31,32]. AGA therefore, cause IDA [10].
This review
technical reviewalsostresses
mentioned that gastrointestinal
that any the clinical spectrumlesion is broad
that causesbecause
a mucosalmany different
defect can
lesions
bleed in distinct
enough gastrointestinal
to lead sites areoccult
to both overt and/or capable of bleeding
blood loss and,in an occultcause
therefore, manner.
IDAIn H.
[10].
pylori-infected
This review also children,
mentioned however, the clinical
that the most common
spectrum clinical diagnosis
is broad becauseat diagnostic upper
many different
endoscopy
lesions is chronic
in distinct gastritis without
gastrointestinal sites any
are hemorrhagic mucosalinlesions
capable of bleeding an occult[32,33]. In a pe-
manner. In
diatric
H. multi-center
pylori-infected study inhowever,
children, Japan [33],theitmost
is suggested
commonthat blooddiagnosis
clinical loss fromatthe gastroin-
diagnostic
testinalendoscopy
upper tract rarelyiscauses
chronic IDA in children
gastritis withany
without H. pylori infection.mucosal
hemorrhagic Childrenlesions
with H.[32,33].
pylori-
In a pediatric
associated IDA multi-center
often have study in Japan [33],
no endoscopic it is suggested
hemorrhagic lesionsthat
andblood
negativelossresults
from the for
gastrointestinal
fecal occult blood tract rarely
tests usingcauses IDA in children
ant-hemoglobin with H.[27,34].
antibodies pylori infection.
Blood lossChildren
from thewithgas-
H. pylori-associated
trointestinal mucosa IDA often
does nothave no endoscopic
appear hemorrhagic
to be the primary lesions and
pathogenetic negative
cause of H.results
pylori-
for fecal occult
associated IDAblood
/ID in tests
Alaska using
nativeant-hemoglobin
children. Thus,antibodies [27,34]. Blood
upper gastrointestinal loss from
mucosal the
lesions
gastrointestinal mucosa does not appear to be the primary pathogenetic
do not appear to play a direct or central role for IDA pathogenesis in H. pylori-infected cause of H. pylori-
associated IDA /ID
children (Figure 2).in Alaska native children. Thus, upper gastrointestinal mucosal lesions
do not appear to play a direct or central role for IDA pathogenesis in H. pylori-infected
children (Figure 2).

Figure 2. Possible pathogenesis of H. pylori-associated IDA in childhood and adolescence.

In 2.
Figure some Western
Possible countries,
pathogenesis Celiac
of H. disease is important
pylori-associated as a cause
IDA in childhood and of IDA, irrespective
adolescence.
of H. pylori infection [20,35]. In developing countries, other non-H. pylori infections, in
particular gastrointestinal parasitic infection, should be considered as risk factors of ID/IDA
in addition to contributing factors of poor iron intake and low dietary iron bioavailability
that occur in parasite endemic regions of the world [20].

3.2. Impaired Gastric Acid Secretion

Impaired iron absorption due to reduced gastric acidity and ascorbic acid concentra-
tion, both of which are related to H. pylori gastritis and, in particular, atrophic gastritis,
are suggested as important pathogenetic factors of H. pylori-associated IDA in adults [36].
J. Clin. Med. 2022, 11, 7351 5 of 14

In addition, an association between transient hypochlorhydria often observed as a con-

sequence of acute H. pylori infection and IDA is suggested [37,38]. However, H. pylori
chronic gastritis is often not atrophic in the majority of the infected children [39] (Figure 1).
In an international study with H. pylori-associated IDA, corpus atrophy was observed in
only two patients and no intestinal metaplasia in any children studied [21]. In a recent
Chinese study [40], chronic atrophic gastritis was observed in only 4.4% of H. pylori-infected
children and neither marked atrophy nor intestinal metaplasia was detected in any patients.
Conversely, it is reported that interleukin (IL)-1β may influence ID/IDA risk in H. pylori-
infected children [41,42]. IL-1β is one of the earliest and most important pro-inflammatory
cytokines, and has been detected in both in vitro and in vivo studies of H. pylori infection,
and IL-1β is also a powerful inhibitor of gastric acid secretion [43]. However, gastric acid
secretion is not universally impaired in children with H. pylori chronic gastritis, although
the secretion is markedly increased in those with H. pylori-associated duodenal ulcers [44].
It can be concluded that impaired gastric acid secretion does not appear to be a primary or
direct cause of H. pylori-associated IDA in childhood and adolescents.

3.3. Hepcidin
Hepcidin is an iron-regulatory hormone and inhibits macrophage iron release and
intestinal absorption, leading to hypoferremia [45]. Hepcidin plays a key mediator of
hypoferremia observed and associated with inflammation. Studies have demonstrated that
IL-6 induces hepcidin expression in hepatic cells [46]. In H. pylori-infected children, IDA
may be caused by increased serum hepcidin [47] (Figure 2). Anemia of chronic inflammation
is mediated, in part, by the stimulation of hepcidin by cytokines [48]. Therefore, it has
been suggested that refractory-increased hepcidin levels may be involved in the failure of
patients with H. pylori infection to respond to iron [48].

3.4. Recent Pathogenetic Hypothesis

It has been recently hypothesized that competition between H. pylori and humans for
iron availability could lead to IDA [9]. Iron is essential for cell growth and maintenance
not only in human hosts but also in the principle metabolic processes of a number of
bacteria, in particular H. pylori. Most strains of H. pylori likely perform some degree of iron
metabolism necessary for their survival and reproduction in the gastric environment, may
not, by themselves harm the health of most infected hosts. If this hypothesis is right, it is
speculated that some of H. pylori strains are not harmful for the host [49], and the others
aggressively steal bioavailable iron from the host, resulting in ID/IDA. It has been reported
that H. pylori strains from IDA patients show more rapid growth and enhanced uptake of
both ferrous and ferric ions compared to those from non-IDA patients [50]. In the other
study [34], however, the degree of bacterial growth was not significantly different between
the IDA and control strains. Thus, further studies will be needed to determine the specific
phenotype(s) of the infecting H. pylori strains and whether the patient is then at risk for ID
or IDA.

3.4.1. Iron-Uptake Mechanisms in H. pylori

Knowledge of iron-uptake mechanisms in H. pylori is still limited. Many bacteria
secrete siderophores, high-affinity ferric chelators, and take up ferric iron-siderophore
complexes via specific outer membrane proteins (OMPs) [51]. Although H. pylori does not
have an identified siderophore or its specific receptor, the microorganism expresses several
proteins associated with iron metabolism, including the ferric uptake regulator (Fur), high-
affinity transporters of ferrous iron (FeoB) and ferric dicitrate (FecA), as well as non-heme
iron-containing ferritin (Pfr) [52] (Table 1). In addition, several iron-responsive OMPs are
suggested to play roles in H. pylori heme uptake [53,54]. Under iron-restricted conditions,
fecA gene and frpB encoding iron-regulated OMP were up-regulated [34], while in iron-
replete environments, H. pylori expresses a single fecA3 and frpB4 OMP [52]. Contrarily, pfr
gene is down-regulated under iron-restricted conditions. Under iron-restricted conditions,
J. Clin. Med. 2022, 11, 7351 6 of 14

the expression of several genes is up-regulated in a Fur-dependent manner [52,55]. H. pylori

Fur protein is also a versatile regulator involved in many pathways essential for gastric
colonization [55].

Table 1. Primary genes associated with iron uptake in H. pylori host infection and regulation of their
expression by iron.

Gene Function (Hypothetical) Iron-Deplete Condition Fur-Regulated

fur Ferric uptake regulator up-regulation -
fecA Ferric dicitrate transportor up-regulation Yes
feoB Ferrous iron transportor up-regulation Yes
frpB Iron-regulated OMP * up-regulation Yes
pfr Iron-containing ferritin down-regulation Yes
ceuE Iron-transport protein no regulation? No
* Outer membrane protein.

3.4.2. Bacterial Virulence Factors

A number of studies demonstrated that H. pylori colonizes the stomach with multiple
or plural strains and that the degree, severity and phenotype of gastric pathology depends
on complex interplay between various H. pylori virulence genes, host genetics, and environ-
mental factors [56]. In particular, it is not known at what stage during the natural history
of the infection a certain H. pylori strain genotype predominates the persisting infection,
thereby resulting in a specific disease phenotype or outcome. It is also known that H. pylori
shows the genetic diversity across species [57]. H. pylori virulence genes can be mainly
categorized into three classes: those related to adhesion and colonization, those related to
their virulence and ability to confer gastroduodenal mucosal injury, and others [58]. With
regard to the initial stage of the colonization of H. pylori in the stomach, OMPs expressed
on the bacterial surface are important as virulence factors and can bind to gastric epithelial
cells [59]. The H. pylori genome has nearly 60 genes encoding the OMPs [60].

H. pylori Colonization and Adhesins

Establishment of H. pylori colonization in the stomach is the initial and important step
for the development of the subsequent related diseases (Figure 2). H. pylori neutralizes the
gastric mucosal local environment using its urease activity, which, thereby, enables this
organism to occupy the unique biologic microaerophilic neutral pH niche at the mucosal
surface underneath the strong acidic gastric environment. H. pylori move freely in the dense
mucosal layer with a bundle of 2–6 unipolar flagella. However, these specific virulent
determinants are similar across all viable H. pylori strains and, thus, are thought to be
non-specific factor for IDA developments. On the other hand, it is suggested that genes that
regulate flagellar synthesis might be involved in the regulation of other virulence factors
such as adhesins [61].
Among OMPs, the members of H. pylori outer membrane protein (Hop) group, sialic
acid-binding adhesin (SabA), and blood group antigen-binding adhesin (BabA) are some
of the most frequently studied OMPs [62]. H. pylori attaches to the surface-adherent mucus
and directly to the gastric epithelial cells with several adhesins, such as SabA and BabA [62]
(Figure 2). Once H. pylori colonization on the epithelium is established, the bacteria release
toxins, including cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA),
leading to gastric inflammation and injury. Risk factors of H. pylori-associated diseases
include the presence of the cag pathogenicity island (cagPAI) encoding Type IV secretion
system and CagA, vacA genotypes, OMPs, including BabA and SabA, and outer membrane
inflammatory protein OipA [63,64].
BabA and SabA of H. pylori allow the bacteria to persistently colonize in the stomach
via interaction with Lewis (Le) and sialylated Lewis (sLe) antigens on gastric epithelia
cells, respectively [62,65,66]. It is thought that SabA adhesin plays a key role for gastric
colonization in the stage of persistent infection, whereas BabA is an important adhesin in
J. Clin. Med. 2022, 11, 7351 7 of 14

the early stage of the infection [62]. The sLex and sLea antigens are thought to be important
for H. pylori adherence and colonization in the stomach [56]. Although these antigens are
rarely present in normal gastric mucosa, gastric inflammation induced by H. pylori promotes
up-regulation of sLex antigens, resulting in enhancement of especially the SabA-mediated
attachment to the gastric epithelium [65]. Among sLe antigens, the main target receptor of
SabA protein is sLex [62]. On the other hand, the majority of H. pylori strains express at least
one type of Le antigens. Thus, H. pylori molecular mimicry in the form of Le antigens on the
bacterial cell surface provides effective mechanisms enabling H. pylori colonization within
the gastric mucosa, thereby effectively evading the host immune response [67]. SabA also
plays a role in non-opsonic activation of human neutrophils [68].

Major Cytotoxins
Pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS)
and flagella, are also the major pathogenetic factors of virulent colonizing H. pylori strains [69].
The cytotoxins, such as CagA, VacA and PAMPs, activate antigen-presenting cells, dendritic
cells, and macrophages, resulting in stimulation of the adaptive immune response through
the production of cytokines, including IL-12 and IL-23 [70].
CagA along with a type IV secretion system is thought to play an important role in
the development of gastric cancer [67]. However, H. pylori strains can be divided into two
types, those that possesses CagA and those that do not express the protein, therefore, the
presence or absence of CagA is not always a key pathogenetic factor for H. pylori-associated
disorders [67]. In a Slovenian study, the cagA genotype in children was associated with
the degree of gastric inflammation [71]. However, H. pylori strains isolated from Japanese
children exclusively carried the cagA gene, but there were no associations between this gene
and the severity of gastritis or peptic ulcer disease [72]. The adherence of H. pylori to the
gastric epithelial cells induces the expression of CagA, which is reported to be regulated by
the Fur protein [73]. In a Japanese study [34], however, there was no association observed
between expression of cagA gene and development of childhood IDA.
VacA is also an important cytotoxin as H. pylori virulence factors, which promotes
bacterial colonization and survival in the host cells [74,75]. VacA is considered a multifunc-
tional toxin inducing host cell damage [21,30]. VacA stimulates the regulatory T cells and
promotes differentiation to effector T cells, resulting in persistent colonization of H. pylori
in the gastric mucosa [76]. It is suggested that VacA escapes host immune defenses by
differentially regulating the expression of host genes related to immune evasion [77]. It is
reported that co-expression of CagA with OipA, VacA, and BabA plays synergic effects
in the outcome of H. pylori-induced gastric pathologies and disorders [78]. It has been
further suggested that VacA is synergistically involved in the pathogenesis of childhood
H. pylori-associated IDA [34].

IDA-Specific Bacterial Factors

Studies on an association between H. pylori-specific genes and IDA are limited. It
must be noted that expression profiles of genes related to iron metabolism can dynamically
change under both iron-replete and depleted conditions. Comparative proteomic analysis
suggests that particular H. pylori polymorphisms could promote IDA [79]. On the other
hand, it was also reported that variation of feoB or pfr gene is not implicated in IDA devel-
opment [13,80]. Besides these two genes, known genes related to iron uptake/regulation
such as fecA and fur, were not also involved in IDA pathogenesis [34].
Neutrophil-activating protein (NAP) stimulates neutrophil adherence to the gastric
mucosa and its activation, leading to a release of IL-12 and IL-23 that facilitate the Th-1
immune response [81,82]. It is reported that genetic polymorphisms in the napA gene may
be associated with the pathogenesis of IDA [83,84] (Figure 2). Recently, a high expression
of sabA gene in H. pylori has been reported to be associated with IDA in childhood and
adolescence [34]. Interestingly, as previously mentioned, this study also shows that vacA
may play a synergic role in the development of IDA. The sabA gene is highly divergent
J. Clin. Med. 2022, 11, 7351 8 of 14

and regulated with complex mechanisms [62]. Although the SabA expression is thought
to enable rapid response to changing conditions in the stomach by switching the “on”
(functional) “off” (non-functional), its mechanism remains to be elucidated [62]. A higher
salt concentration induces a higher SabA transcription level [85]. As mentioned above,
SabA is an important adhesin and detectable in approximately 40% of H. pylori strains [67].
SabA has an ability of activating neutrophils through non-opsonic mechanism resulting in
damages of the gastric epithelial cells [70]. Sab A is associated with an increased risk of
atrophic gastritis and gastric cancer, although causative mechanisms to explain this disease-
related association remain controversial [65]. These facts lead to the recognition that sabA
gene is an important virulence factor in the development of childhood H. pylori-associated
diseases, including H. pylori-associated IDA.

3.4.3. Host Factors

Increased Iron Demands as Acquired Factors
It is well known that children, particularly during the first five years of life, are
at risk of IDA, which is mainly associated with an increased iron demand due to their
rapid growth [86]. H. pylori acquisition mainly occurs in infants and younger children
via oral–oral or fecal–oral routes. However, H. pylori-associated IDA rarely occurs in the
early years of life. A randomized control study reported that H. pylori is not a cause for
treatment failure of iron supplementation in children 2–5 years of age [17]. Contrarily,
H. pylori-associated IDA frequently occurs in school-aged children, suggesting that in-
creased iron demand due to growth spurt and/or participation in sports-related activities
is also important in the pathogenesis [9,25]. Choe et al. reported that increased daily
iron demand is important in H. pylori-associated IDA in adolescent female athletes [87].
However, sporting activity itself is reported to have no association to H. pylori-associated
IDA/ID, although the number of female adolescents studied is small [88]. Although both
pre-school and school-aged children have increased daily iron demand, H. pylori seems to
play some causal role for IDA development in the latter but not in the former. It is strongly
suggested that on underlying mechanisms of H. pylori-associated IDA, the infection itself is
a necessary condition but not the primary etiological agent.

Host Genetic Factors

Host immune response gene polymorphism affects the susceptibility to H. pylori
infection and the outcome of H. pylori-related disorders [42]. In one study of twins with
H. pylori infection [89], it was suggested that host genetic factors are important in the
development of ID or IDA. In a recent study [27], one sibling case with recurrent H. pylori-
associated IDA showed long-term resolution after successful eradication therapy.
Toll-like receptors (TLRs) belong to the large family of pattern recognition receptors
(PRRs) and are important in the innate immunity of the host [90]. Among the 10 types of
TLRs identified in humans [91], TLR2 and TLR4 on the gastric epithelial and immune cells
are both associated with recognition of LPS composing the cell wall of H. pylori, acting as a
primary defense against H. pylori [60,92]. However, it seems that TLRs, including these two
molecules can play opposite roles, either promotion or suppression of H. pylori infection
as innate immunity [90]. TLR5 initially plays some role for the recognition of H. pylori
flagellin, but this bacterium appears to develop mechanisms to escape such recognition
for the persistent infection [90]. Although this genetic variation may be advantageous for
some individuals, such variation may be less favorable outcomes for other ones that harbor
certain genotypes associated with excessive immune response [93]. The LPS recognition
receptor TLR4 has been shown to be associated with a higher risk of gastric cancer [90].
Thus, we believe that the roles of TLRs for H. pylori-associated IDA remain to be studied.
Host genetic factors that affect cytokines may determine differences in the susceptibil-
ity or risk of infected individuals to specific H. pylori-associated diseases [70]. It is reported
that various single-nucleotide polymorphisms (SNPs) of cytokines genes, such as tumor
necrosis factor (TNF)-α, IL-1β, and IL-10, are associated with the risk of precancerous
J. Clin. Med. 2022, 11, 7351 9 of 14

gastric pathology, including atrophic gastritis and intestinal metaplasia [60], although
such an association remains controversial [70]. The allelic distribution of IL-1β is one of
the most popular candidate gene studied on H. pylori infection [59]. Polymorphism of
pro-inflammatory cytokine genes encoding IL-1, IL-8, IL-10, and TNF-α is associated with
increased risk of H. pylori-related gastric cancer and duodenal ulcer disease [58,94,95]. The
expression of IL-1β gene increases in H. pylori-infected children with ID [96] (Figure 2). A
study in Brazilian children has shown that high gastric levels of IL-1β can be the link be-
tween H. pylori infection and ID/IDA in childhood [41]. Increased concentration of gastric
IL-1β was an independent predictor for low blood concentration of ferritin and hemoglobin.
In a case–control study from Taiwan, it was reported that IL-1β gene polymorphism may
influence ID risk in H. pylori-infected children [42]. Pediatric patients with H. pylori gastritis
showed significantly lower levels of serum ferritin, prohepcidin, and IL-6 compared to
those with H. pylori-negative gastritis and the healthy control [97]. In this latter study,
however, H. pylori eradication therapy revealed no significant difference in serum ferritin,
prohepcidin, or IL-6 levels.
TNF-α is involved in persistent colonization with H. pylori in the stomach [98]. It has
been shown that specific TNF-α genotypes are at risk for duodenal ulcer and gastric cancer,
but other TNF-α genotypes have a protective function against cancer development [59].
TNF-α has no association with H. pylori-associated ID/IDA in children [41].

4. Clinical Management Strategies

Although H. pylori infection once established persists almost for the host life span,
an overwhelming majority of the infected persons remain clinically asymptomatic and
suffer no consequences related to their infection. Despite H. pylori infection being the
primary causative agent for gastric cancer, the microorganisms can produce detrimental
or beneficial effects [49]. In a recent systematic review and meta-analysis [99,100], there
is some evidence of an inverse association between atopy/allergic diseases and H. pylori
infection. On clinical strategies, it is very important to consider that universal eradication
of H. pylori may cause more harm than good for the host with the infection [49]. Pediatric
guidelines recommend against a test-and-treat strategy in asymptomatic children, even if
the purpose of the strategy is prophylaxis for of gastric cancer [6,7]. Such a consideration is
necessary especially for the management of this infection in children.
The Maastricht V/Florence Consensus Report has recommended H. pylori testing and
eradication therapy for patients with unexplained IDA [101]. On this recommendation,
however, the level of evidence is very low. Such a low evidence level suggests that the data
on H. pylori-associated IDA is insufficient, especially in the adult population. The American
Gastroenterological Association (AGA) technical review identified low-quality evidence
supporting H. pylori testing for patients with IDA [10]. This review has suggested the
causal role of H. pylori for IDA in the select population, in particular in children, although
the relationship is unclear in the majority of adult men and postmenopausal women [10].
In this issue, it has been indicated that two of three RTCs that met the inclusion criteria
were in the pediatric population. AGA clinical practice guidelines suggest noninvasive
H. pylori testing for patients with IDA without other identifiable etiology for bidirectional
endoscopy, followed by treatment if positive [102]. On the other hand, in the Houston
consensus conference [103], idiopathic thrombocytopenia was discussed regarding the
identification of appropriate patients for H. pylori testing but not IDA.
The updated North American and European joint pediatric guidelines suggest H. pylori
testing in children with refractory IDA in which other causes have been ruled out [6]. On
the other hand, these guidelines strongly recommend against diagnostic testing for H. pylori
infection as part of the initial investigation in children with IDA. Pediatric guidelines from
Japan recommend eradication therapy for H. pylori-infected children with IDA in whom
IDA is recurrent or refractory over iron supplementation therapy [7]. The level of evidence
for this recommendation from the Japanese guidelines is strong. In summary, “test-and-
J. Clin. Med. 2022, 11, 7351 10 of 14

treat” strategy in H. pylori infection should be considered for children and adolescents with
recurrent or refractory IDA of unknown causes.

5. Perspectives
It is beyond doubt that increased iron demands play an important pathogenetic part
in H. pylori-associated IDA in children and adolescents. On the other hand, both bacterial
virulence and host genetic factors remain to be investigated. Definitive factors are also
still not identified on gastric carcinogenesis by H. pylori infection in adults. In any case, as
mentioned previously, physicians should keep H. pylori infection in mind as an important
differential diagnosis for children with recurrent or refractory IDA.
It is indicated that H. pylori is an important causative factor in the vicious cycle of
malnutrition and growth impairments [38], although the literature has many confounding
variables and H pylori infection is a marker of low economic status. These authors also
suggested that direct competition between H. pylori and the host for iron is an important
contributor to IDA. In Gambia, H. pylori colonization in early infancy predisposes the
child for subsequent development of malnutrition and growth faltering, although the
effect did not persist into later childhood [104]. Furthermore, decreased growth velocity
improved significantly over time once H. pylori eradication was successful in Colombian
children [105]. However, the relationship between H. pylori-associated ID/IDA and growth
impairment in the H. pylori-infected children, especially in developing countries, remains
to be further characterized. Clearly, further well-designed, population-based investigations
are needed on this issue.

Author Contributions: Original draft preparation, S.K.; Review and editing, B.D.G. and A.K. All
authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Acknowledgments: We thank Katsuhisa Hashimoto for assistance preparing the figures.
Conflicts of Interest: The authors declare no conflict of interest.

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