J. Physiol.

(Paris) 94 (2000) 139−152

© 2000 Elsevier Science Ltd. Published by Éditions scientifiques et médicales Elsevier SAS. All rights reserved
S0928425700001601/FLA

Helicobacter pylori. One bacterium and a broad spectrum

of human disease! An overview

Ferenc Pakodi, Omar M.E. Abdel-Salam,

Andras Debreceni, Gyula Mózsik*
First Department of Medicine, Medical University of Pécs, Pécs, Hungary

Abstract — Since the historical rediscovery of gastric spiral Helicobacter pylori in the gastric mucosa of patients with chronic gastritis
by Warren and Marshall in 1983, peptic ulcer disease has been largely viewed as being of infectious aetiology. Indeed, there is a strong
association between the presence of H. pylori and chronic active gastritis in histology. The bacterium can be isolated in not less than
70% of gastric and in over 90% of duodenal ulcer patients. Eradication of the organism has been associated with histologic improvement
of gastritis, lower relapse rate and less risk of bleeding from duodenal ulcer. The bacterium possesses several virulence factors enabling
it to survive the strong acid milieu inside the stomach and possibly damaging host tissues. The sequence of events by which the
bacterium might cause gastric or duodenal ulcer is still not fully elucidated and Koch’s postulates have never been fulfilled. In the
majority of individuals, H. pylori infection is largely or entirely asymptomatic and there is no convincing data to suggest an increase
in the prevalence of peptic ulcer disease among these subjects. An increasingly growing body of literature suggests an association
between colonization by H. pylori in the stomach and a risk for developing gastric mucosa-associated lymphoid tissue (MALT), MALT
lymphoma, gastric adenocarcinoma and even pancreatic adenocarcinoma. The bacterium has been implicated also in a number of
extra-gastrointestinal disorders such as ischaemic heart disease, ischaemic cerebrovascular disease, atherosclerosis, and skin diseases
such as rosacea, but a causal role for the bacterium is missing. Eradication of H. pylori thus seems to be a beneficial impact on human
health. Various drug regimens are in use to eradicate H. pylori involving the administration of three or four drugs including bismuth
compounds, metronidazole, clarithromycin, tetracyclines, amoxycillin, ranitidine, omeprazole for 1–2 weeks. The financial burden, side
effects and emergence of drug resistant strains due to an increase in the use in antibiotics for H. pylori eradication therapy need further
reconsideration. © 2000 Elsevier Science Ltd. Published by Éditions scientifiques et médicales Elsevier SAS
Helicobacter pylori / peptic ulcer / MALT lymphoma / gastric cancer

1. Introduction constitute the gastric mucosal defence against damag-

Peptic ulcer is a chronic disease which can be
associated with serious and life threatening complica-
tions such as bleeding or perforation that may neces-
sitate surgery or if untreated can cause death. The
disease is characterized by life-long symptomatic re-
currences which exert negative economical and health
impact from disability and absence from work. Peptic
ulcer is a common disorder with an annual incidence
of 3% and a life time prevalence of 5–10% in Western
countries [95, 165]. A breakdown in what is called the
balance between aggressive factors and gastric mu-
cosal defences was hypothesized to account for the
occurrence of peptic ulcers [67, 147]. Aggression is
considered to be inflicted by hydrochloric acid and
pepsin secreted by the gastric mucosa itself, and a
number of exogenous factors e.g., drugs such as
steroidal [112], non-steroidal anti-inflammatory drugs
(NSAIDs) [6, 71, 96], ethanol [62], smoking [43],
stress [50]. A number of factors on the other hand
* Correspondence and reprints
ing agents tight junctions between the surface epithe-
lial cells, rapid cell turnover, epithelial restitution,
gastric mucus gel and bicarbonate secretion, gastric
mucus phospholipids, sulphydryl compounds, prostag-
landins, gastric mucosal blood flow [49, 100, 114,
115].
The historical rediscovery of gastric H. pylori in the
stomach of patients with chronic gastritis by Warren
and Marshall [87], was considered an important event
with regard to our understanding of the pathogenesis
of peptic ulcer ulceration. The bacterium turned out to
be one of the most if not the only important aggressive
factors. Indeed, since that time peptic ulcer disease has
been largely viewed as being only of infectious aeti-
ology, as can be seen from the huge number of
publications in that field dealing with the bacterium.
Further, an increasingly growing body of literature
suggests an association between colonization by H.
pylori in the stomach and a risk for developing gastric
mucosa-associated lymphoid tissue (MALT), MALT
lymphoma [196], gastric adenocarcinoma [28], and
even pancreatic adenocarcinoma [28]. The importance
of the bacterium is now moving from gastric diseases
towards a number of extra-gastrointestinal disorders
140 Pakodi et al.
such as ischaemic heart disease, ischaemic cerebrovas-
cular disease, atherosclerosis, Raynaud’s phenom-
enon, and skin diseases [57, 58, 137, 192]. Eradication
of H. pylori thus seems to be of beneficial impact on
human health. It would seem pertinent therefore to try
to survey and discuss the data and relevant literature
concerning the role proposed for this bacterium in
different disease processes and especially in pathogen-
esis of gastric cancer and primary gastric lymphoma.
2. Helicobacter pylori: Searching for an infectious
aetiology of peptic ulcer disease
The presence of bacteria in the human stomach is
not a new finding. Bacteria (initially thought to be
spirochaetes) have been noted in human gastric biop-
sies by Krientiz as early as 1906 [93] and this was later
confirmed by several authors [42, 54, 168]. Interest in
bacteria as a possible aetiological agent of peptic ulcer
disease, however, was renewed when Warren and
Marshall [187], described the presence of a new spiral
Gram negative organism similar to that of the genus
Campylobacter from the gastric mucosa of patients
having chronic active gastritis. Ever since their histori-
cal rediscovery, interest in this bacterium as a possible
pathogen in peptic ulcer disease has been growing.
This was reflected in a rapid surge of publications
dealing with different aspects of the bacterium and its
relationship to the gastric mucosa and peptic ulcer
disease. A dramatic change in the way to treat peptic
ulcer disease occurred from trying to suppress or
neutralize gastric acidity to regimens aimed at eradi-
cating the bacterium. The bacterium was initially given
the name Campylobacter pyloridis, then Campylo-
bacter pylori and since 1989, the bacterium has been
named, Helicobacter pylori [61].
H. pylori establish itself in the near neutral,
bicarbonate-rich mucus on the surface of the gastric
epithelium where it is protected from the damaging
effect of acid and pepsin. Few, if any bacteria invade
the tissue [15]. With its urease enzyme, the bacterium
can split urea to produce ammonia, which provides a
microenvironment with relatively high pH around the
acid sensitive H. pylori [108, 119]. In most studies, H.
pylori could be identified in at least 70% of antral
biopsy specimens from patients with chronic active
gastritis, gastric ulcer, in 90% of those with duodenal
ulcer, and in about 20% of normal human volun-
teers [64, 131, 179, 180]. In the majority of individu-
als, H. pylori infection is largely or entirely asymp-
tomatic [14]. In the USA, the prevalence of H. pylori
infection among healthy asymptomatic subjects be-
tween the age of 15 and 80 was age-related with 50%
of the older population being infected [63], whereas a
total world-wide prevalence of about 50% has been
suggested [81, 106].
Eradication of the bacterium results in healing of
gastritis seen on histology [145]. The density of H.
pylori infection correlates with the degree of inflam-
mation in the stomach and in the duodenal bulb [177].
The strongest evidence linking the bacterium to duode-
nal ulcer is the finding that the relapse rates after H.
pylori has been eradicated is much less (2.6–7%) as
compared with patients in whom the bacterium is not
eradicated (58–67%) and compared to that after other
traditional antisecretory drug therapy (68%) [138,
177]. Indeed, it was the fact that treatment of duodenal
ulcer patients with bismuth compounds with possess
antibacterial activity against H. pylori has resulted in
histological improvement of gastritis and lower relapse
rates for duodenal ulcers than that after treatment with
the histamine H2-receptor blockers [97, 109] that led
many researchers to suggest that the bacterium is not
an opportunist, but has a causal role in duodenal ulcer
relapse [177]. Also after eradication of the bacterium,
duodenal ulcers were less likely to rebleed [65, 151].
Further, the presence of H. pylori colonization was
shown in several studies to be associated with hyper-
gastrinaemia and hyperpepsinogenaemia [46, 124,
139, 183]. The above mentioned changes in gastrin,
and pepsinogen levels were reported to resolve after
eradication of the organism. In patients with gastric
ulcer, the integrated gastrin response to meal but not
fasting gastrin concentration and serum pepsinogen I
levels were reported to decrease markedly in patients
in whom H. pylori has been eradicated [103]. The rate
of gastric ulcer relapse was also reported in several
studies to be reduced markedly at one year following
eradication of the bacterium (9%) as compared with
those who remained positive for H. pylori
(26%) [158]. It was suggested thus that the eradication
of H. pylori constitutes a cure of gastric and duodenal
peptic ulceration [144, 158].
How H. pylori would lead to peptic ulceration is not
yet understood. It was suggested that high acid secre-
tion promotes gastric metaplasia in the duodenal cap,
thus providing a suitable habitat for H. pylori coloni-
zation, leading to further epithelial cell injury and
making the cells more vulnerable to attack by acid and
pepsin, perhaps bile, eventually causing ulcer-
ation [116]. Several factors associated with the pres-
ence of H. pylori were suggested. The organism is
capable of producing several enzymes including ure-
ase, catalase, proteases, lipases, phospholipases, and
alcohol dehydrogenase [64, 72, 108, 150]. Several
cytotoxins are also produced by H. pylori. A vacuolat-
ing cytotoxin, a 87-kDa protein is expressed in about
65% of H. pylori strains and induces vacuole forma-
tion in eukaryotic cells. The gene encoding for the
protein is called vacA, whereas a second protein at
128 kDa is called the cytotoxic associated gene or
CagA. The gene (cagA) encoding for the CagA protein
 H. pylori. An overview
is present in H. pylori strains that produce the protein.
VacA is present in virually all H. pylori strains, while
the CagA is present in only 60–80%. Strains that
express CagA are thought to be more virulent than
those which do not express the protein. Infection by
vacuolating cytotoxic strains of H. pylori are thought
to impose an increased risk of the occurrence of peptic
ulcer and gastric cancer. Antibodies to the cagA are
virally present in all duodenal ulcer patients [14, 29,
30, 51, 98, 99, 105, 118].
Production of platelet activating factor, leukotriene
B4 [55], enhanced mucosa IL-6 and IL-8 activity [33,
59, 121], activation of neutrophils with generation of
oxygen free radicals [34, 69, 129], stimulation of
pepsinogen secretion [25], release of histamine from
mast cells [13], reduction of gastric mucosal hydro-
phobicity [7], impairment of gastric mucus gel [157,
161, 164], increased cathepsin D [141], increased
gastric mucosa levels of the iron binding glycoprotein,
lactoferrin [128], promotion of platelet aggregation in
gastric microcirculation [87], induction of proinflam-
matory cytokines [104], and increased mast cells in
gastric mucosa [127] have all been ascribed to H.
pylori. It would appear as if H. pylori increases the
aggressive side of the balance, while interfering with
several components of the gastric mucosal barrier. A
recent study, however, showed that H. pylori isolated
from patients with gastritis were found to have no
direct cellular effect on isolated rat gastric parietal
cells [17]. Interestingly enough, the presence of H.
pylori in the stomach has been reported to be associ-
ated with elevated gastric body, gastric antral, and
duodenal mucosal PGE2 generation and this was noted
even in the absence of duodenal inflammation. It was
suggested then that the close attachment of H. pylori to
the cell membrane of the epithelial cells may stimulate
the release of arachidonic acid and the synthesis of
prostaglandins [8]. Thus, in a way similar to the
phenomenon of adaptive cytoprotection, the presence
of the bacterium may stimulate the epithelial cells to
produce prostaglandins.
Evidence to suggest that H. pylori plays a causal
role in peptic ulcer disease is rather indirect. Koch’s
postulates have not yet been fulfilled, since most
infected individuals are asymptomatic and do not
develop overt clinical disease [140]. When Mar-
shall [107] drank broth containing isolates of the
bacterium, he developed overt acute gastritis, which
however cleared on the 10th day as showed by
histology and did not progress to chronic gastritis. The
problem is therefore that in the majority of infected
individuals with H. pylori, ulcers do not develop. In
healthy individuals infected with H. pylori, the preva-
lence of peptic ulcer disease was around 2% [5, 117].
Further and as noted by Graham [66], most of the
regimens used to eradicate the bacterium included
141
antisecretory (histamine H2-antagonists, proton pump
inhibitors) or ulcer coating agents (bismuth subcitrate)
that are by themselves capable of achieving ulcer
healing and until now there is no single study pub-
lished demonstrating that antibiotics alone heal peptic
ulcer better than placebo. Although the presence of H.
pylori colonization is associated with hypergastri-
naemia and hyperpepsinogenaemia, it is not clear
whether these are caused by the presence of the
bacterium. These abnormalities can be seen also in
duodenal ulcer patients who are negative for H.
pylori [111]. Wagner et al. [182] found that intragastric
acidity was specifically higher in patients with duode-
nal ulcer and H. pylori infection compared with
gastritis patients and normal subjects. There was,
however, no significant difference in the intragastric
acidity between the H. pylori positive and negative
gastritis patients, thereby suggesting that most patients
with chronic H. pylori infection have a normal gastric
acidity. In one study, an increase in basal acid output
by 3-fold, and a 6-fold increase in the acid response to
gastrin releasing peptide together with increased maxi-
mal acid response to exogenous gastrin were reported
to be present in H. pylori positive duodenal ulcer
patients compared with H. pylori-negative healthy
persons [47]. In another study, parietal cell mass and
maximal acid output are significantly increased in
duodenal ulcer patients, but no difference was found
between H. pylori positive and negative duodenal
ulcer patients [171]. In addition, serum pepsinogen I
levels were reported to be lower in H. pylori positive
duodenal ulcer patients who are on NSAIDs compared
with those who are not using the drugs [90]. Other
investigators found no difference in pentagastrin
stimulation between H. pylori positive and negative
subjects, but considerable variations in the basal and
maximal acid output of the H. pylori infected individu-
als. The conclusions was that H. pylori gastritis does
not regularly enhance maximal acid output in normal
patients [79].
3. Helicobacter pylori and gastric adenocarcinoma
The bacterium has been connected with the intesti-
nal form of gastric adenocarcinoma through a se-
quence of events that starts as acute gastritis and
progress through chronic gastritis, chronic atrophic
gastritis, intestinal metaplasia, dysplasia, finally ad-
enocarcinoma [31, 94, 134, 156, 188]. Several studies
have demonstrated an association between infection
with H. pylori and the risk for developing gastric
adenocarcinoma [28, 130, 162]. The Eurogast study
group [173] showed a statistically significant associa-
tion between gastric cancer incidence and mortality
rates and H. pylori seropositivity in seventeen popu-
142 Pakodi et al.
lations from thirteen countries (Germany, USA, UK,
Greece, Denmark, Italy, Slovenia, Algeria, Poland,
Belgium, Iceland, Japan, Portugal). Findings indicated
a ≈6-fold increased risk of gastric carcinoma in popu-
lations with 100% H. pylori infection compared with
populations that have no infections. Yet, another study
in a large cohort of hospital patients with gastric or
duodenal ulcer in Sweden (1965–1983) showed a
decrease by 40% in the risk of developing gastric
cancer among duodenal ulcer patients [70]. It is not
clear why H. pylori infection can progress to gastric
cancer or duodenal ulcer but not both. It has been
assumed that gastric ulcer disease and gastric cancer
have aetiological factors in common; a likely cause for
both is atrophic gastritis caused by H. pylori infec-
tion [70]. Parsonnet [135] suggested that other factors
beside the bacterium must favour one disease, while
militating against the other e.g., genetic characteristics
of the host and the bacterium, exogenous elements,
time of life when the infection was first acquired.
The prevalence of Helicobacter pylori infection in
patients with gastric cancer is very variable in different
studies. Forman [52] found that ten retrospective stud-
ies reported a prevalence rate ranging between
52–89% among cancer patients and between 38–78%
among the control subjects. Sprung and Apter [167] in
a retrospective review of thirty patients with gastric
cancer found only two (6.6%) to be infected with H.
pylori. Komoto et al. [92] reported a 93% prevalence.
In their study to assess the relationship between H.
pylori, histological gastritis and intestinal metaplasia
in gastric cancer of different histological types, Wee et
al. [190] found that the tumour histology had no
influence on the occurrence of H. pylori. Also, the
tumour site had no effect on the presence or absence of
gastritis, atrophic changes, intestinal metaplasia or H.
pylori. It was concluded that, while both H. pylori and
gastritis are associated with gastric cancer, the asso-
ciation may not be a causal one. Komoto et al. [92]
found that histologic types and tumour stage showed
no difference in H. pylori prevalence. Rugge et
al. [154] observed an inverse relation between H.
pylori infection and progression of gastric epithelial
dysplasia, which they attributed to the inverse relation
between atrophic/metaplstic lesions and H. pylori.
Other researchers were more convinced that the asso-
ciation between H. pylori and gastric cancer merely
signal exposure to some other environmental factor(s)
and that early acquisition of the bacterium may be one
of several factors including genetic and environmental
determinants that ultimately lead to evolution of can-
cer. For example, it has been noted in ethnically
similar Chinese populations, that H. pylori infection is
acquired at an early age, but the outcome of infection
is quite different. Thus one region had more duodenal
ulcer and fewer gastric cancer, whereas the other
region had more gastric ulcer and cancer. It was also
noted that fresh vegetables were available all year
round in the former region in contrast to sera-seasonal
fresh vegetables and salted and spiced food in the latter
region [152].
Another issue is whether eradication of H. pylori
reverts/stops the progression of atrophic gastritis, in-
testinal metaplasia or gastric dysplasia. In a short
follow up period (3 months), eradication of the bacte-
rium had no effect on atrophy or intestinal metapla-
sia [103]. Helicobacter pylori eradication do not ap-
pear to revert precancerous lesions such as intestinal
metaplasia and atrophy after one year of follow-
up [146]. Similar results were reported by Tham et
al. [172] in patients infected with H. pylori and fol-
lowed for 8 years. Transient apparent regression of
gastric dysplasia was reported in two cases after
elimination of H. pylori, but progression to gastric
cancer was inevitable [19].
How can Helicobacter pylori cause cancer? Several
mechanisms were postulated to link H. pylori infection
and gastric carcinogenesis: (1) increased cellular pro-
liferation and increased occurrence of apoptosis in
gastric epithelial cells [2, 3, 74, 85, 102, 155, 184]; (2)
increased oxidative DNA damage and increased ex-
pression of inducible NO synthase in gastric tissue
neutrophils and mononuclear cells [68]; (3) increased
ammonia production leading to gastric mucosal atro-
phy [89, 110]; (4) production of antigastric auto-
antibodies (H. pylori infection was seen to be associ-
ated with antigastric auto-antibodies reactive with the
luminal membrane of the foveolar epithelium and with
canalicular structures within the parietal cells. The
presence of the latter correlated with the severity of
gastritis, gastric mucosal atrophy [48]): (5) increased
production of mutagenic free radicals; (6) increased
production of N-nitroso compounds [105, 134]; (7)
decreased intragastric levels of the antioxidant ascor-
bic acid [76]; infection with vacA- or CagA-producing
H. pylori strains [16, 153]. Most of the abnormalities
were reported to decrease following eradication of the
bacterium.
Other authors noted that the reduction in epithelial
cell proliferation in the body and antrum after triple
therapy (with bismuth, tetracycline and metronidazole)
was independent of whether H. pylori has been eradi-
cated or not. It was suggested that the reduction in
epithelial cell proliferation is due to the anti-
inflammatory effect of the drugs used [53]. Still some
investigators found no significant difference in gastric
epithelial cell proliferation between H. pylori negative
and positive subjects [27]. In a large multicentre study,
no association was noted between plasma levels of
vitamin C, as indicator of vitamin C intake and either
gastric cancer mortality or incidence rates in the
 H. pylori. An overview
population studied. Further, there was no association
between plasma vitamin C levels, H. pylori infec-
tion [189].
4. Helicobacter pylori and primary gastric
lymphoma of the mucosa-associated lymphoid
tissue (MALT)
This is an interesting issue in view of the fact that
the gastric mucosa normally does not contain lym-
phoid tissue and only acquires MALT (mucosa-
associated lymphoid tissue) in the presence of chronic
H. pylori infection. Infection with H. pylori is strongly
associated with the appearance of lymphoid
follicles [197].These appear to be a specific immuno-
logical response to infection with H. pylori [169].
Several studies indicated a strong association between
H. pylori infection and gastric-mucosa-associated lym-
phoid tissue (MALT) lymphoma. These tumours can
be divided into high-grade, low-grade tumours or a
mixture of the two grades [82]. It is the low-grade
variety that H. pylori has been associated with. The
organism has been detected in 58–98% of gastric
biopsies from patients with gastric low-grade MALT
type lymphoma [20, 45, 60, 83, 136, 195].
A number of studies and case reports indicated that
these tumours regress following successful eradication
of the bacterium [22, 80, 122, 123, 170, 174, 176,
196]. This has been taken as evidence that the rela-
tionship is casual rather than coincidence. In vitro, the
response of low-grade B-cell lymphoma to stimulating
strains of H. pylori was dependent on H. pylori specific
T cells and their products, especially IL 2, rather than
the bacteria themselves [80]. In patients with H. pylori
infection and low grade MALT lymphoma, an allele
imbalance was noted at loci for tumour suppressor
genes in sections containing the MALT lymphoma, but
not in those sections with only gastritis. This suggested
ongoing genetic damage to the cells, possibly caused
by the bacterium [20]. Cytotoxic associated gene
(cagA), a 127-kD protein, is a marker for the vacu-
olating toxin effect and the gene for cagA is only
present when the gene for vacuolating toxin (vacA)
cytotoxic effect is present [105]. The relationship be-
tween the cagA status of H. pylori and the develop-
ment of gastric mucosa-associated lymphoid tissue
(MALT)-type lymphoma was also studied by several
investigators. Crabtree and Spencer [32] reported an
equal prevalence of cagA+ serology in patients with
gastric MALT lymphoma and healthy volunteers and
patients with dyspepsia. Eck et al. [44] reported a
98.5% of cagA seropositivity of H. pylori in 68 pa-
tients with gastric MALT lymphoma. On the basis of
these results, the authors suggested that almost all
patients with gastric MALT lymphoma are infected
with the cagA+ stain of H. pylori. Similar findings
143
were reported by Rudi et al. [153] in patients with
gastric adenocarcinoma as they found that antibodies
against vacA or cagA were more frequent in patients
with cancer (97.4%) than in control subjects (84.5%).
On the contrary, in their smaller patient sample with
MALT lymphoma, de Jong and van der Hulst [38]
found cagA sequences in 58% as compared with 94%
of patients with peptic ulcer disease and in 65% of
patients with functional dyspepsia. The authors thus
suggested that in contrast to peptic ulcer disease, the
cagA status of H. pylori strains do not play a major
role in the pathogenesis of MALT lymphoma. Wither-
ell et al. [193] found that among H. pylori infected
subjects, the cagA+ status was not associated with
increased risk for gastric non-Hodgkin’s lymphoma.
In the oesophagus, Weston et al. [191] noted the
presence of Barrett’s MALT in seven and gastric
MALT in sixteen and gastric MALT lymphoma in
twopatients among 122 patients with Barrett’s oe-
sophagus. None of the 101 control patients has oe-
sophageal MALT, while 2/7 patients with Barrett’s
MALT had gastric MALT. Barrett’s MALT was asso-
ciated with oesophageal H. pylori in 57.1% of cases
and gastric H. pylori in 71.4%. The prevalence of
gastric and oesophageal H. pylori in patients with
Barrett’s MALT was significantly higher compared to
patients with Barrett’s without MALT. Thus, oesoph-
ageal MALT was associated with Barrettás oesophagi-
tis and Barrett’s MALT was associated with both
oesophageal and gastric H. pylori colonization.
Resolution of duodenal MALT lymphoma was also
seen after eradication of H. pylori [126] and more
interestingly, was the resolution of parotid and sub-
maxillary salivary gland MALT lymphoma in response
to antibiotic therapy aimed at eradicating gastric H.
pylori [4, 91]. As in the stomach, the salivary glands
do not normally contain lymphoid tissue and only
acquire it in the sitting of auto-immune disease e.g.
Sjögren’s syndrome. The authors thus suggested that
chronic exposure to H. pylori-related antigens in this
case may have induced hyperplasia of the MALT from
which the neoplastic population developed. In another
study, however, in salivary lymphoepithelial lesions,
which shows histological features of MALT, the au-
thors did not find H. pylori DNA, thereby suggesting
that the bacterium antigens do not seem to play a local
role in the development of MALT or MALT lympho-
mas of the salivary glands [86]. With regard to large
cell lymphoma, Boot et al. [18] reported five cases in
which H. pylori infection was present. Large cell
lymphoma has also been reported to regress following
eradication therapy for H. pylori, although such
therapy did not eradicate the bacterium or regressed
chronic active gastritis or peripheral lymphadenopa-
thy [159].
144 Pakodi et al.
It is to be noted, however that permanent regression
of MALT lymphoma was not obtained in all cases. In
three studies, the incidence of complete regression was
34, 70 and 88%, for a follow up period of
6 months–1 year [12, 21, 123]. In addition, relapses
and even associated with more severe and extensive
form of the gastric neoplastic condition have been
reported by several authors [21, 24, 75]. Recurrence of
the MALT lymphoma was associated in many in-
stances with re-infection rather than recrudescence of
H. pylori and which might represent reactivation of
undetected residual lymphoma population or perhaps
re-infection with a more virulent strain of H. pylori.
This led Montalban et al. [122] to suggest that poly-
merase chain reaction (PCR) analysis is necessary to
assess the disappearance of the lymphoma, since a
monoclonal population might persist despite the ab-
sence of any histological evidence of the lymphoma.
In other cases, gastric MALT lymphoma appeared to
develop or persist despite eradication of H. py-
lori [166]. It was also suggested that regression of the
MALT lymphomas may be caused by non-specific
effects of the antibiotic therapy or its effect on other
yet unidentified enterobacteria, rather than H. pylori
eradication [23]. In their study, Gisbertz et al. [60]
found that H. pylori occurred in the same frequency
(76 and 53%) as non-H. pylori bacterial flora (53 and
76%) in both small and large cell primary gastric
non-Hodgkin’s lymphoma, respectively. This led the
authors to suggest that H. pylori may not be the only
aetiological factor in primary gastric lymphoma.
Carlson et al. [24] followed a patient with H.
pylori-associated gastritis and observed a progression
through lymphoid hyperplasia to a monoclonal B-cell
lymphoma. Resolution of the lymphoma was seen on
eradication of the bacterium, but subsequently re-
curred 15 months despite continued absence of H.
pylori on histology and negative urease test. It was
suggested that the development of B-cell lymphoma is
initially driven by H. pylori, but may subsequently
become an autonomous process as genetic damage is
accumulated. Another study showed that acquired
MALT appeared after re-infection with H. pylori only
in patients who previously had that condition. In one
patient, the recurred MALT was of the same grade as
the previously present one before eradication therapy
for H. pylori. This led the authors to suggest that not
only the H. pylori infection, but also individual sus-
ceptibility determine both the presence of acquired
MALT and it grade [176]. There were reports of
simultaneous gastric adenocarcinoma and MALT-type
lymphoma [73, 194]. Herbay et al. [73] reported a case
of simultaneous gastric adenocarcinoma and MALT in
a patient with serological evidence of H. pylori infec-
tion. Histopathology of the gastric tumour revealed
adenocarcinoma and primary B-cell lymphoma com-
prising both a low grade (MALT) and high grade
component (large cell lymphoma). Wotherspoon and
Isaacson [194] described nine cases of gastric adeno-
carcinoma (six intestinal and three diffuse type) occur-
ring synchronously with primary low-grade gastric
B-cell MALT lymphoma. Seven out of these nine
cases were infected with H. pylori. More interesting is
a study, in which the authors noted an unexpected large
number of patients with other malignancies among
83 patients with low grade MALT gastric lymphoma.
One or more additional tumour was observed in
17/83 patients, with a total of 23 tumours [199]. This
might indicate that it is the genetic host factors which
play the most crucial role in the development of gastric
MALT lymphomas than the bacterium itself. In a
recent study, consistent loss of chromosome 3 was
detected in two MALT patients and in five MALT
lymphoma patients, suggesting that this genetic alter-
ation might be of importance in the transformation of
H. pylori-associated gastric MALT into low-grade
B-cell gastric MALT lymphoma [11].
5. Helicobacter pylori and other tumours
Association with pancreatic cancer was suggested
based on the finding of increased seroprevalence of H.
pylori infection in patients (65%) with pancreatic
adenocarcinoma compared with 45% of colorectal
cancer patients in addition to healthy volunteers [143].
In other study, 71.4% of patients with colonic polyps
were reported to be seropositive for H. pylori com-
pared with 49% of control subjects and 55% of
patients with colorectal cancer [113].
6. Helicobacter pylori and ischaemic heart disease
Increased seroprevalence of H. pylori infection in
patients with coronary heart disease has been noted
compared with controls. Seropositivity to H. pylori
conferred a 2-fold risk for coronary heart disease.
Raised serum fibrinogen levels, increased procoagu-
lant activity from mononuclear cells, have been sug-
gested as the underlying mechanism to account for the
role of H. pylori in coronary heart disease [137].
Similar findings were reported by Ponzetto et al. [142]
that, in patients with myocardial infarction, 88% were
seropositive for H. pylori compared with 59% of
control subjects. In addition, the prevalence of H.
pylori antibodies was also reported to be higher in
patients with hypertension 85% than in control sub-
jects 66%, thereby pointing to a relationship between
H. pylori and hypertension [101]. These data were,
however, inconsistent and other researchers using
histology alone reported even lower prevalence of H.
pylori (63%) in patients with angina pectoris and
 H. pylori. An overview
myocardial infarction compared with those subjects
without ischaemic heart disease [39].
Others were unconvinced that the association is not
causal. This was based on the findings that deaths from
ischaemic heart disease in nine developed nations,
were negatively associated with the seroprevalence of
antibodies to H. pylori. In another large study, systolic
and diastolic blood pressure, plasma viscosity and
cholesterol were not associated with H. pylori infec-
tion. A weak, negative association existed between H.
pylori infection and fibrinogen level and between
infection in women and ischaemic heart disease. A
weak association was also seen between H. pylori
infection and ischaemic heart disease. The conclusion
reached was thus that H. pylori may be independently
associated with the development of ischaemic heart
disease, but if this is so, the mechanism by which this
effect is exerted is not through increased concentration
of plasma fibrinogen [125]. Further, in a large prospec-
tive study, no relationship was found between H.
pylori infection and ischaemic heart disease. In addi-
tion, plasma fibrinogen levels were virtually the same
in H. pylori negative and positive subjects [186]. Thus,
although the association between the bacterium and
coronary heart disease is a strong one, the sequence of
infection and disease is uncertain [36]. Therefore, the
weight of available evidence do not support a causal
role for H. pylori in coronary heart disease.
7. Helicobacter pylori and other diseases
In patients with renal impairment, the prevalence of
H. pylori (histology and urease test) was reported to be
lower (22.6%) than that in subjects with normal renal
function (37%) [84]. In patients with inflammatory
bowel disease, the seroprevalence of the bacterium
(IGG titres) was 48% compared with 59% in control
subjects. Patients with Crohn’s disease showed lower
prevalence of H. pylori (41%) than in ulcerative colitis
(56%). It was also noted that prior therapy with
sulphasalazine was associated with a reduced risk of
infection with the organism in inflammatory bowel
disease [133]. Similar findings were reported by Wagt-
mans et al. [185] as they noted lower a H. pylori
seroprevalence of 12.2% among patients with Crohn’s
disease compared with 35.4% among control subjects.
In diabetic patients, the prevalence of H. pylori infec-
tion was found to be 22.5%, which is not different
from that of the general population. The diagnosis of
the presence of the organism was based on histology
and urease and catalase reactions. Interestingly, infec-
tion with Candida albicans was noted in the same
frequency as H. pylori in antral biopsies of these
patients. Ninety percent of patients had upper gas-
trointestinal symptoms at time of presentation and in
25% of them, H. pylori was isolated. Data thus
145
suggested that diabetic patients with upper gastrointes-
tinal symptoms are no more infected with the bacte-
rium than the normal population [1]. A serological
study (H. pylori IgA and IgG) found that the frequency
of infection was high compared with control group in
nearly all age groups, reaching significance in three
age categories for non-insulin dependent diabetics and
in one age category in insulin-dependent diabetic
patients [132]. A 43.5% prevalence of H. pylori among
cirrhotic patients with peptic ulcer has been re-
ported [26]. Siringo et al. [163] found that 76.5% of
cirrhotics had H. pylori IgG, which can be attributed to
hospital and upper GI-endoscopy. The authors con-
cluded that their data do not confirm a role for H.
pylori as a risk factor for peptic ulcer in patients with
liver cirrhosis. Similar conclusion was reached by Tsai
et al. [175]. The authors reported a 76.2% prevalence
for H. pylori in cirrhotic patients. Further, they noted
that the prevalence of H. pylori did not differ in respect
to the presence or absence of gastropathy, varices and
peptic ulcer in these patients.
Rosacea patients have been reported to have a
higher prevalence of H. pylori infection 84% [148,
149]. A prevalence rate of H. pylori of 55% was
reported in one study among patients suffering from
idiopathic chronic urticaria. In patients who received
treatment with amoxycillin, clarithromycin and lanso-
prazole for eradicating the bacterium, a partial or total
remission of urticaria symptoms was seen compared
with the non-infected group, which did not receive
antibiotic therapy [40]. Without treating patients with
urticaria who are not infected with H. pylori with the
same therapy, it cannot be judged whether the resolu-
tion of symptoms seen is due to eradicating the
bacterium or to a non-specific effect(s) of the antibiotic
therapy employed. Further, the severity of the urticaria
symptoms and the prevalence of gastrointestinal symp-
toms was the same in the infected and non-infected
urticaria patients. In another study, there was no
difference in the prevalence of the bacterium between
rosacea patients (26.7%) and healthy subjects (34.9%).
Although patients with this inflammatory skin disorder
were found to complain more frequently of indiges-
tion, their symptoms were not due to infection with H.
pylori [160]. In patients with primary Raynaud’s phe-
nomenon, more patients were found to be infected
with H. pylori (81%) compared with the control group
(20%) [56] and in another study 78% of patients with
this phenomenon were found to harbour H. pylori [58].
There were no differences in the discomfort, duration
and frequency of the attacks between the infected and
non-infected patients. Yet triple therapy (amoxycillin,
clarithromycin, lancoprazole) aimed at eradicating the
bacterium was found to result in the disappearance of
the attacks in 17% of those in whom the bacterium has
146 Pakodi et al.
been eradicated and to improve symptoms in another
percentage of patients [58].
8. Treatment of Helicobacter pylori
Several drug schedules have been tried for the
treatment of H. pylori infection. The aim of treatment
is eradication of the bacterium, defined as negative
tests for the organism for one month after completion
of the course of the antimicrobial. Repeat testing
should thus be done a minimum of 4 weeks after
ceasing treatment [88]. Eradication of the bacterium,
however, is proved to be difficult [77, 78]. Three
therapeutic regimens were recommended by an Inter-
national Working Party. One is omeprazole and
amoxycillin; the other two comprise bismuth, metron-
idazole and either tetracycline or amoxycillin [178].
Triple therapy with bismuth, metronidazole and an
antibiotic achieves eradication rates of 60–80% in
most studies. Apart from the patient compliance due to
the many tablets which he has to ingest, the real
problems with this regimen lie in the resistance to
metronidazole and the high side effect profile. An
increase in metronidazole resistance from 5–7% in
1993 to 28–32% in 1996 has been observed in Western
countries among non-ulcer dyspepsia and peptic ulcer
patients [181]. The triple therapy is ineffective in about
20% of patients, especially those already treated with
metronidazole. Side effects to the triple therapy occur
in about one-third of patients which can include
headache, dizziness, nausea, diarrhoea, pseudomem-
braneous colitis, mycosis, sore mouth and tongue, drug
hypersensitivity and paraesthesia [41, 120].
Another regimen involves the use of omeprazole
plus amoxycillin or clarithromycin. When taken alone,
omeprazole only temporarily suppress the bacterium
and once therapy is stopped, colonization reverts to
normal. When an antibiotic such as amoxyxillin is
given together with omprazole, the bacterium is re-
ported by some workers to be eradicated in a high
proportion of patients, but results were inconsistent.
Fourteen days of therapy with omeprazole 20–40 mg
once or twice daily together with 1.5–3.0 mg of
amoxycillin was reported to result in eradication rate
of 47 and 84%, respectively, in most studies but some
reported a cure rate as low as 0–38% [9, 10, 37].
Another problem which should be considered when
dealing with treatment of H. pylori infection is recur-
rence of infection. As reviewed by Xia et al. [198], the
12-month recurrence rate varied among different stud-
ies between 0 and 41.5%, while a few studies showed
a 18–24 month recurrence rates, and these ranged
between 0–21.4%. Recurrence of H. pylori infection is
thought to be due to recrudescence rather than re-
infection with the bacterium. Whether these figures
represent the real magnitude of the problem is also not
clear, since it has recently been shown that in patients
who had been successfully treated for H. pylori with
triple therapy (metronidazole, tetracycline, bismuth
subcitrate), the H. pylori IgG titres decreased to a
mean of 51% from base line and remained stable from
1 to a mean of 3.5 years after therapy. It was suggested
that H. pylori serology will yield false positive results
in patients who have previously been treated for the
bacterium [35].
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