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Javed
Yakoob, Wasim Jafri, Shahab Abid, Section of Gastroenterology,
Department of Medicine, Aga Khan University Hospital, Stadium Road,
Karachi, Pakistan
Correspondence to: Javed Yakoob, MBBS, PhD. Section of
Gastroe-nterology, Department of Medicine, Agha Khan University
Hospital, Stadium Road, Karachi-74800, Pakistan. yakoobjaved@hotmail.com
Telephone: +92-21-48594661
Fax: +92-21-4934294
Received: 2003-06-05
Accepted: 2003-08-19
Abstract
It is known that deficiencies of micronutrients due to
infections increase morbidity and mortality. This phenomenon depicts
itself conspicuously in developing countries. Deficiencies of iron,
vitamins A, E, C, B12, etc are widely prevalent among populations
living in the third world countries. Helicobacter pylori (H
pylori) infection has a high prevalence throughout the world.
Deficiencies of several micronutrients due to H pylori
infection may be concomitantly present and vary from subtle
sub-clinical states to severe clinical disorders. These essential
trace elements/micronutrients are involved in host defense
mechanisms, maintaining epithelial cell integrity, glycoprotein
synthesis, transport mechanisms, myocardial contractility, brain
development, cholesterol and glucose metabolism. In this paper H
pylori infection in associaed with various micronutrients
deficiencies is briefly reviewed.
Yakoob
J, Jafri W, Abid S. Helicobacter pylori infection and
micronutrient deficiencies. World J Gastroenterol
2003; 9(10): 2137-2139
http://www.wjgnet.com/1007-9327/9/2137.asp
INTRODUCTION
Helicobacter
pylori (H pylori) is a gram negative, microaerophilic
human pathogen which colonizes the gastric mucosa. Infection with H
pylori leads to gastritis and is associated with the development
of peptic ulcer disease, gastric carcinoma and lymphoma[1].
H pylori may be acquired at any age, and the infection
persists for years once acquired. The age specific prevalence of H
pylori infection is higher in developing countries and
particularly in lower socioeconomic group[2]. In
developing countries H pylori infection occurs early in life,
and hypochlorhydria commonly seen in the malnourished predisposes
them to repeated gastrointestinal infection, persistent diarrhea and
malnutrition[3]. H pylori infection usually causes
both acute and chronic inflammatory cell infiltration, leading to an
increase in reactive oxygen species (ROS) which have been shown to
accumulate in H pylori gastritis[4]. Excessive
production of reactive oxygen metabolites (ROMs) by phagocytic cells
is thought to contribute to mucosal lesions produced by H pylori
infection. These are highly reactive compounds capable of combining
with DNA in a number of potentially genotoxic ways[5].
Reactive oxygen species can react with the lipid-bilayers releasing
peroxidation products such as malondialdehyde. These processes could
lead to alterations in the structure of DNA facilitating mutations
and carcinogenesis.
Nutrition is a critical determinant of the outcome of host
microbe interactions through a modulation of the immune response.
"Micronutrient" or "trace elements" are
generally defined as constituting less than 0.01 % of body mass and
are needed in much smaller amounts. Trace minerals and vitamins are
essential for life and include iron (Fe), zinc (Zn), copper (Cu),
nickel (Ni), etc. They act as essential cofactors of enzymes and as
organizers of the molecular structures of the cell, e.g.
mitochondria and its membrane. Deficiencies of micronutrients
influence immune homeostasis and thus affect infection-related
morbidity and mortality. Micronutrients like b
carotene, vitamin C, selenium, copper and others are powerful
antioxidants and have a significant impact on infection related
morbidity in humans. Subclinical deficiencies are known to impair
biological and immune functions in the host. Antioxidants play a
part in gastric mucosal defense by protecting against damage caused
by excessive oxygen derived free radicals. b-carotene
and b-tocopherol
are lipophilic and have been shown to suppress the oxidation induced
by either lipophilic or hydrophilic radical species[6].
In addition, they could act as anti-carcinogens through their
ability to prevent the formation of N-nitrosamines which are
important in the development of gastric carcinoma[7].
These vitamins are the major oxidant scavengers in biomembranes in
contrast to vitamin C, which is mainly responsible for scavenging
free radicals in the aqueous phase. However, compensatory mechanisms
may become defective while gastric inflammation develops from normal
to chronic gastritis and finally to gastric atrophy/intestinal
metaplasia, perhaps due to reduced infiltration of inflammatory
cells, loss of gastric gland cells and increased ROM production.
IRON
Iron deficiency anemia affects all groups of the under
privileged population in most developing countries. Iron is an
essential growth factor for H pylori, which contains Fe in
their outer membrane protein and a system for intracellular storage
of iron, consisting of ferritin like molecules pfr and napA[8].
Patients with H pylori associated iron deficiency anemia
(IDA) would have involvement of both antral and corporal mucosa when
compared with controls (90 % vs 42.7 %; P=0.0001)[9].
Iron deficiency anemia associated with H pylori gastritis is
characterized by a concomitant increase in median intragastric pH
value >3 and lowering of intragastric concentrations of ascorbic
acid. A significant percentage (43 %) of H pylori positive
IDA patients presented atrophic changes in the gastric body, and the
remaining had a superficial gastritis extended to the fundic mucosa,
in contrast with H pylori positive controls[10]. H
pylori eradication has also been shown to improve the absorption
of other nutrients besides iron, and produce more rapid and complete
clinical responses in patients with iron deficiency anemia[11].
COPPER
Copper is involved in the function of several enzymes. It is
required for infant growth, host defense mechanisms, bone strength,
red and white cell maturation, iron transport, etc. Acquired
deficiency is mainly seen in infants. However, it has been diagnosed
also in malnourished children and adults[12]. A gene,
copA, associated with copper transport, has been isolated from H
pylori UA802. The adenosine triphosphatase-derived
copper-transporting mechanism is employed by various H pylori
strains[13]. As a cofactor in various redox enzymes and
an essential trace metal required for the synthesis of
metalloproteins, copper plays a role in the pathogenesis of H
pylori. H pylori has a differential effect on some
gastric mucosal scavenger enzymes of ROMs, namely mitochondrial and
cytoplasmic superoxide dismutases reflected by a large increase in
the cytokine inducible manganese superoxide dismutase and a decrease
in the constitutive copper/zinc superoxide dismutase[14].
VITAMIN
B12
The mechanisms of vitamin B12 malabsorption caused by H
pylori infection are unclear but following are the
possibilities: a) The diminished acid secretion in H pylori
induced gastritis may lead to a failure of critical splitting of
vitamin B12 from food binders and its subsequent transfer to R
binder in the stomach. b) A secretory dysfunction of the intrinsic
factor. c) Decreased secretion of ascorbic acid from the gastric
mucosa and increased gastric pH[15,16]. Annibale et al,
studied the prevalence of H pylori infection in pernicious
anemia patients and have demonstrated that almost two thirds of
pernicious anemia patients had evidence of H pylori but only
those with an active H pylori infection had distinctively
functional and histological features[17]. These findings
support the hypothesis that H pylori infection could play a
triggering role in a subgroup of pernicious anemia patients, and
suggest the possibility that H pylori is involved in the
early stages of PA that lead to severe corpus atrophy. The later
progress of gastritis seems to be dependent on factors other than H
pylori, most likely "autoimmune" mechanisms[18].
H pylori may also be involved in the pathogenesis of
pernicious anemia via antigenic mimicry as antibodies directed
against the H+, K+- adenosine-triphosphate protein that has been
found in high numbers of patients with H pylori infection[19].
Food cobalamin malabsorption may occur without gastric atrophy or
achlorhydria. Malabsorption can respond to antibiotics, but only in
some patients[20].
VITAMIN
A
Vitamin A has effects on important determinants of immune
function and epithelial cell integrity such as gene expression,
cellular proliferation and differentiation and also glycoprotein
synthesis. Loss of integrity of the epithelial lining of mucus
membranes in a vitamin A deficient state could explain its close
association with increased susceptibility to infections particularly
of gastrointestinal, respiratory and genitourinary tracts especially
in children and pregnant women[21]. Even mild or
subclinical vitamin A deficiency could induce keratinizing
metaplasia of the epithelium and depletes goblet cells from mucosal
linings thus causing xerosis of the membrane[22]. The
xerotic surfaces form potential sites for increased bacterial
adherence thus leading to bacterial colonization. The antimicrobial
enzyme lysozyme depends on vitamin A for its synthesis. A decrease
in T cell number with no change in proliferative activity has been
demonstrated in children suffering from mild xerophthalmia due to
vitamin A deficiency. H pylori infection and low b-carotene
in plasma contribute to the increased risk of gastric atrophy,
indicating that H pylori infection might be associated with
low plasma b-carotene[23].
VITAMIN
E
Vitamin E is composed of a group of compounds termed tocopherols
and tocotrienols. a-tocopherol
is the major active form in the human body, accounting for 95 % of
vitamin E and is the most effective lipid soluble anti-oxidant in
biomembranes. It acts as the major chain breaking antioxidant and is
able to interfere with the propagation of lipid peroxidation. It
plays an immune modulatory part and is capable of increasing natural
killer cell activity. Concentrations of a-tocopherol
in H pylori negative subjects were higher in the corpus than
in the antrum or duodenum[6]. This distribution of a-tocopherol
is reversed in the presence of antral H pylori infection.
These findings may reflect a mobilization of antioxidant defenses to
the sites of maximal inflammation in the stomach.
VITAMIN
C
Vitamin C exists as ascorbic acid (AA) or dehydroascorbic acid.
The stomach secretes ascorbic acid across the gastric mucosa into
the gastric juice against a concentration gradient. Ascorbic acid is
the reduced form of the vitamin and can act as a potent antioxidant,
and is able to scavenge ROS in gastric mucosa. This has been
proposed as one means by which it exerts an anti-carcinogenic
effect. Ascorbic acid may also prevent formation of N-nitroso
compounds in gastric juice by scavenging nitrite. It has been
observed that diets poor in foods containing AA were associated with
an increased risk of gastric cancer[24]. Wei-cheng et
al showed that presence of H pylori infection at the
baseline and smoking were strongly associated with progression to
dysplasia or gastric cancer, whereas the risk of progression was
decreased by 80 % among subjects with baseline ascorbic acid levels
in the highest tertile compared with those in the lowest tertile[25].
A number of studies have demonstrated that gastric juice but not
gastric mucosal AA levels were reduced in the presence of H
pylori gastritis and that successful eradication restored the
juice/plasma AA ratio[23, 26]. The lower plasma AA
concentration in H pylori positive subjects could be due to
reduced bioavailability, active secretion from plasma to gastric
juice in attempts to restore the positive gastric juice/plasma ratio
or both[27]. In some studies no difference was found in
the gastric juice AA concentration between patients with antral-limited
gastritis and H pylori negative healthy controls, while lower
AA levels were observed in patients with gastric body involvement
and increased pH[28]. These observations suggest that AA,
which is very unstable in the presence of increased pH, is converted
to the less active form of dehydroascorbic acid, in the presence of
gastric damage extending to the corporal mucosa with consequent
hypochlorhydria[29,30]. It has been demonstrated that
eradication of H pylori could lead to a reduction in ROS
activity in gastric mucosa[31]. Ascorbic acid has also
been shown to inhibit H pylori urease activity and growth in
vitro[32]. H pylori infection associated low
gastric juice-ascorbic acid levels return to normal after successful
eradication of the infection[33]. A study of antibiotic
treatment failure showed that compliant patients in whom H pylori
infection did not clear had lower baseline plasma and gastric juice
vitamin C concentrations than patients whose infection was cleared[26].
In
developing countries micronutrient deficiencies facilitated by H
pylori infection are a clinical and public health problem. It is
essential to define the precise extent of the problem. Several micro
and macronutrient deficiencies could be concomitantly present in the
population with several other deficits. They will require correction
to achieve significant effects on the over all health of the
population.
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