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Helicobacter pylori infection: several studies on epidemiology, eradication andgastric epithelial cell turnover
Liu, W.
Publication date1999
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Citation for published version (APA):Liu, W. (1999). Helicobacter pylori infection: several studies on epidemiology, eradication andgastric epithelial cell turnover.
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CHAPTER 1
General Introduction
Wen-Zhong Liu
Shanghai Institute of Digestive Disease,
Shanghai Second Medical University,
Shanghai
INTRODUCTION
Helicobacter pylori was brought to the world attention in 1983 when Warren and
Marshall, two Australian investigator, reported isolation of spiral organisms from
mucosal biopsy specimens of patients with chronic active gastritis and pepetic ulcer
disease(l). Now the organism is accepted as the causative agent of gastritis, peptic
ulcer disease, gastric adenocarcinoma and gastric B-cell lymphoma (MALT
lymphoma). H. pylori infection may also play a role in some cases of nonulcer
dyspepsia. H. pylori-related diseases are among the most prevalent in the world. This
chapter will review the literature of H, pylori infection in the epidemiology, eradication
and its relation with gastric epithelial cell turnover.
EPIDEMIOLOGY
H. pylori infects more than half the people in the world. The prevalence of
infection varies among countries and among different groups within the same country
(2-11). In developing countries the infection rates are much higher, compared with
those of developed countries. In all areas of the world the infection rate increases with
age. In developed countries less than 10% of the children are infected with H. pylori;
the prevalence of infection increases to approximately 60% at the age of 60 or above.
In developing countries about 50% of the children are infected with H. pylori and
infection rate increases with age up to 70-80% in adulthood. The highest rates of
infection are associated with low socio-economic status, crowding, poor sanitation and
unclean water supplies (5-7,11).
Although H. pylori has been isolated from cats (12) and non-human primates (13),
these animals do not seem to be a natural reservoir (14). Most data suggest that the
organism is transmitted from person to person. Support for this concept comes from
studies that infection rates are higher in institutions (15,16) and H pylori strains within
families are closely related (17-20). The exact means by which H. pylori is transmitted
among individuals is uncertain (21) and arguments can be made for and against each
possibility. The first possibility is fecal-oral transmission. H. pylori has been detected
in stool by polymerase chain reaction (PCR) (22) and culture (23, 24). Unfortunately,
culture of H. pylori from stool has proved to be extremely difficult, and detection by
PCR does not ensure that the organisms are living. Further evidence against fecal-oral
transmission comes from studies in mice infected with H. felis, in which infection
could not be transmitted from infected mice to coprophageous uninfected mice. A
second possibility is oral-oral routes, for which evidence of H. pylori in dental plaque
and saliva has been found by culture (25,26) and PCR (27). Evidence against oral-oral
transmission is that couples without children have a low prevalence of concordance of
H. pylori infection (28) and dental staff are not at increased risk of infection (29). A
third mean of transmission is gastro-oral (30). Evidence to support such a model
include well-described epidemics of Hpylori gastritis in volunteers undergoing gastric
intubation experiments (31-33), transmission of infection from one patient to another
by inadequately disinfected endoscopes (34,35) and a higher-than-expected prevalence
of H pylori among gastroenterologists (36-40), especially those who had not worn
gloves in the past. It appears that any mechanism that allows H. pylori enter the
stomach of an uninfected host probably is a route of transmission.
ERADICATION OF HELICOBACTER PYLORI INFECTION
Treatment of H. pylori infection is recommended in patients with peptic ulcer
disease, MALT lymphoma, gastritis with severe abnormalities and post early gastric
cancer resection (41-43). Cure of H. pylori infection is not easy, and requires
combinations of one or two antibiotics with one or two nonantibiotic adjunctive agents.
Single agents are ineffective. Cure of infection is defined as absence of the organism
by tests performed no sooner than 4 weeks after cessation of antimicrobial therapy (44).
Because proton pump inhibitors (PPIs) alone can suppress the infection, PPI therapy
should be discontinued for at least 1 week before evaluation of effectiveness of therapy.
Although a cure rate of 80% was once considered acceptable, rates of 90% or higher
are now achievable, especially if the organism is susceptible to the antibiotics used.
Antibiotics Used in Regimens to Eradicate H. pylori
Amoxicillin
H. pylori is very sensitive in vitro to this antibiotic (45), but in vivo it has little
effect when used as monotherapy (46). This may be a result of relative inactivity of the
antibiotic at acidic pH. Better results are achieved if antisecretory agents are given with
amoxicillin-containing regimens (47). Resistance to amoxicillin has been observed, but
is rare . The most common side effects are rash, candidiasis, and diarrhea.
Tetracycline
Tetracycline is effective in vitro against H. pylori and is active at low pH, and
resistance has not yet reported. It is quite useful as a part of triple therapy with bismuth
and metronidazole (48) but is contraindicated in children because of the staining of
teeth.
Metronidazole
Metronidazole is actively secretory into gastric juice and saliva, and whose
activity is independent of pH. Primary resistance of H. pylori to metronidazole is
generally associated with a reduction in cure rates (49) This is important, because the
frequency of primary resistance to metronidazole is increasing substantially throughout
the world (50-53). Side effects of metronidazole include a metallic taste, diarrhea, and
nausea, the latter occurring primarily at doses over lg/day. Tinidazole, a nitroimidazole,
produces results that are comparable with those of metronidazole.
Clarithromycin
This antibiotic is a macrolide with an antibacterial spectrum similar to that of
erythromycin but is more acid stable, better absorbed, and more active against H.
pylori (54,55). When given as monotherapy in a dose of 2000mg/day, clarithromycin
cured H. pylori infection in about 50% of patients(56). As with metronidazole, H.
pylori can become resistant to clarithromycin, although primary resistance to
clarithromycin is found less frequently than resistance to metronidazole (57,58). Its
main side effect is taste perversion.
Furazolidone
Furazolidone, a nitrofuran, is an old drug with clinical use for over 40 years. It
was used in China for the treatment of peptic ulcer disease long before H. pylori was
discovered as an causative agent in this disease(59, 60). In the last decade,
furazolidone has been found to be effective for eradication of H. pylori (61-69). When
given as monotherapy in a dose of 300mg/day for 3 weeks, furazolidone cured H.
pylori infection in about 50% of patients (62). This results is comparable with that of
clarithromycin. Resistance to furazolidone has not yet been observed in vitro serial
passage and in vivo studies(62, 70). Side effects include dizziness, rash and nausea..
Adjunctive Agents Used in Regimens to Treat H. pylori Infection
Bismuth.
Bismuth compounds are topical antimicrobial agents that act directly on bacterial
cell walls to disrupt their integrity by accumulating in the periplasmic spaces and along
membranes(71). Bismuth is available as bismuth subsalicylate.(United States) and
colloidal bismuth subcitrate (elsewhere ). Side effects with these two bismuth
compounds are minimal, although blackening of the stool may occur.
Proton-pump Inhibitors.
Omeprazole may be used as a model for all PPIs. Although omeprazole has
bacteriostatic activity against H. pylori both in vitro and in vivo (72,73), it is especially
useful as part of combination therapy with antimicrobial agents to cure H. pylori
infection (74-77). One major activity is related to increasing intragastric pH, which
may enhance the effectiveness of the local immune response, reduce the washout of
antibiotics from the mucosa, and improve the minimal inhibitory concentrations of pH-
sensitive antibacterial agents. The decrease in gastric juice volume that results from
these antisecretory drugs may also increase intragastric concentration of antibacterial
agents.
H2 Receptor Antagonists.
This class of drugs has long been used to promote healing of peptic ulcers. They
have no effect by themselves against H. pylori, but they have been used in some
studies instead of PPIs in combination with antibiotics(78).
Ranitidine Bismuth Citrate (RBC).
This is a novel compound with characteristics of both ranitidine and bismuth.
RBC is useful when combined with antibiotics, such as clarithromycin (79,80). Side
effects are minimal.
Therapeutic Regimens to Treat H. pylori Infection
Dual Therapy
This combination consists of an antibiotic plus a PPI or RBC. The regimen
initially touted was amoxicillin plus omeprazole. Initial studies suggested that infection
was cured in over 80% of patients (81) and one study involving a very high dose of
omeprazole reported over 95% cured (82). However, such good results have not been
confirmed (83-85) and this regimen can no longer be recommended. Although more
consistent results have been achieved with clarithromycin plus omeprazole or RBC
with cure rates after 14 days of therapy of about 70-85 %(86-88), they do not achieve
the goal of a 90% cure rate.
Triple Therapy
Traditional bismuth triple therapy consisting of bismuth, metronidazole and
tetracycline produces cure rates of 85% to 90%, especially with organisms sensitive to
10
metronidazole(49,89). Amoxicillin should be substituted for tetracycline in children to
avoid staining of teeth. Depending on the dose of metronidazole, over 30% of patients
taking this regimen report some side effect (i.e., nausea, sore mouth, taste disturbance,
diarrhea, and Candida infection), which results in cessation of treatment in about 5% of
patients (90). These side effects and the increasing prevalence of H. pylori strains
resistant to metronidazole make this otherwise excellent regimen less desirable.
More recent studies have combined two antibiotics with a PPI (PPI-based triple
therapy) with generally good results so far. One early study found that a combination
of clarithromycin, tinidazole and omeprazole for 1 week cured H. pylori infection in
95% patients (91). A large European trial compared five different regimens containing
two antibiotics plus omeprazole given for 7 days (76). Best results were achieved with
combinations containing clarithromycin plus either amoxicillin or metronidazole. Two
antibiotics plus RBC is be more effective than clarithromycin alone plus RBC, with the
results comparable with PPI-based triple therapies (88, 92). Short-term triple therapies
containing furazolidone, clarithromycin plus either bismuth or PPI give high cure rates
of Helicobacter pylori Infection, furazolidone may become an efficacious alternative
to metronidazole in light of a world-wide increase in H. pylori resistance to
metronidazole (68,69).
Quadruple Therapy
Several studies have added an antisecretory agent to traditional bismuth triple
therapy. Early studies of traditional bismuth triple therapy with omeprazole (PPI
quadruple therapy) have shown cure rates of over 95% after only 7 days of therapy(93).
It has also been suggested that results with such a regimen may be only minimally
affected by metronidazole-resistant organism (94).
Therapeutic Strategy
The important factors in selecting therapy are efficacy of eradication, prevention
11
of resistance, avoidance or minimization of adverse effects, patient compliance, and
cost. The most effective regimens for curing H. pylori infection are combinations of
two antibiotics and one or two adjunctive agents taken for 7 to 14 days. Dual therapies
are not recommended. Triple or quadruple regimens are more likely to eradicate H
pylori and less likely to generate resistant strains among surviving organisms.
Antibiotic resistance is an important consideration in choosing therapy, resistance to
metronidazole or clarithromycin may lead to reduced efficacy with either antibiotic.
When treatment fails, antibiotic combinations should not be repeated. Compliance is
important for successful cure of the infection. Thus regimens should be designed so
that side effects that may reduce compliance are minimized.
H. PYLORI INFECTION AND GASTRIC EPITHELIAL TURNOVER
Although International Agency for Research on Cancer has classified H. pylori as
a class I carcinogen in 1994(95), some investigator still feel that this conclusion has
been based on simple association rather than a true causal link, they dispute the quality
of epidemiological evidence in its favor. One of main criticism that has been raised
concerns the paradoxically low gastric cancer rates found in some populations with
high rates of infection (96, 97). Another arises from the low incidence of gastric cancer
among patients with duodenal ulcer (98, 99), a disease known to be caused by H.
pylori infection. Many hypothesis have been advanced to explain theses discrepancies.
The virulence differences between various strains of H. pylori, genetic makeup of host,
diet, immunological status (100-104), and age (105 at the time of infection have all
been proposed as factors potentially capable of influencing the outcome of H. pylori
infection in different geographical area and in different individuals. From biological
point of view, malignancy is known to be the results of an accumulation of genetic
alterations and mutations that are responsible for the different phenotypes within the
carcinogenic cascade. Up to now there has been no evidence that H. pylori directly
12
induces any sort of irreversible DNA damage.
Disturbances in cell turnover in the gastrointestinal tract are believed to
predispose to cancer development, and increased cell proliferation was considered to
be a marker of increased gastric cancer risk(106,107). Recently cumulative evidence
strongly suggest that H. pylori infection alters the kinetic pattern of gastric
epithelium( 108-120),
The homeostasis of gastric epithelial cells is maintained by the balance between
cell proliferation and apoptosis. Alterations of these physiological cellular events result
in chronic pathological conditions of the stomach (121,122). An increase in the total
number of epithelial proliferating cells and an abnormal distribution of the latter are
frequently observed in chronic gastritis, gastric atrophy, intestinal metaplasia, gastric
dysplasia and gastric cancer(113,114). Conversely, apoptosis has been found to be
impaired in intestinal metaplasia, gastric dysplasia and cancer (123). Helicobacter
pylori infection is associated with changes in epithelial-cell turnover. An increase in
overall epithelial cell proliferation and the upward shift of replicating cells toward the
superficial part of the gastric pits are patterns usually observed during Helicobacter
pylori infection and these changes can be reversed by successful eradication of the
infection (108-112). However, it seems that this reversibility will be lost during
progression through the steps of gastric carcinogenesis, such as intestinal metaplasia
and dysplasia (113,114), probably representing the phenotypic expression of the true
initiating phase of the carcinogenetic process. The influence of Helicobacter pylori
infection on gastric epithelial apoptosis in humans is still controversial. Moss et al(l 16)
reported that gastric epithelial apoptosis was clearly enhanced in duodenal ulcer
patients with H. pylori infection, and this was later confirmed by others (117,118).But
in some studies no such association was found (124). It seems that in vivo situation the
status of H. pylori cagA influences the effect of Helicobacter pylori on epithelial
apoptosis. In patients infected with cagA+ strains of H pylori gastric epithelial cell
13
proliferation was not accompanied by a parallel increase in apoptosis (124-126).
Increased cell proliferation in the absence of a corresponding increase in apoptosis may
explain the heightened risk for gastric carcinoma.
The mechanisms underlying the altered proliferation by H. pylori infection are
thought to be caused by an increase in the mucosal content of ammonia, known to be a
strong stimulus of cell proliferation (127,128), provoked by the bacterium itself. H.
pylori infection associated hypergastrinemia is also believed to play a role in
increasing epithelial cell turnover (129). Whether the hyperproliferation is also related
to inflammatory infiltrate is controversial (130). As for the mechanisms involving the
possible effects of H. pylori infection on gastric epithelial apoptosis, several recently
finding may be relevant, including up-regulating expression of the CD95 (or apo-1
FAS) (131, 132,133), altered expression of bcl-2 family (134,135), immune activation
and nitric oxide (136). H. pylori lipopolysaccharide as a virulence factor is responsible
for the induction of gastric epithelial cell apoptosis (137).
14
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Outline of This Thesis
Since successful isolation of H. pylori from the human stomach by Warren and
Marshall in 1983, the study of this microorganism has gained significant impetus. A
great deal of research has been done and astonishing amount of papers has appeared in
the world literatures over past decade. These research and papers cover a broad
spectrum of issues varying from epidemiology, detection of the infection, its relation to
gastritis, peptic ulcer disease and gastric malignancies, its virulence factors, its role in
disturbance of gastric homeostasis and therapy.
Despite this unrivaled scientific exploring and research, many questions remain
unsolved. The aim of this thesis is to contribute to the knowledge of : 1. the risk of H.
pylori infection in medical staff in area with high infection rates; 2. the role of
furazolidone and new non-metronidazole triple regimens in anti-//, pylori therapy; 3.
the effects of H. pylori infection on gastric epithelial cell turnover.
In chapter 2 the issue whether medical staff, especially endoscopy unit personnel, are
at increased risk of infection with H. pylori is investigated. Previous reports of the
seroprevalence of H. pylori in endoscopy staff have yielded conflicting results. The
risk of H. pylori infection was evaluated through the comparisons of seroprevalence of
H. pylori infection between a large group of medical staff and healthy controls with
stratification of age.
In chapter 3 the efficacy of furazolidone against H. pylori is explored in vitro and in
vivo. Furazolidone a nitrofuran in clinical use for over 30 years, was used in China for
the treatment of peptic ulcer disease long before H. pylori was discovered as an
etiological agent in this disease. The anti-ulcer role of furazolidone might be explained
29
by its anti-//: pylori action. In a randomized double-blind placebo-controlled clinical
trial the efficacy of furazolidone as monotherapy for anti-//, pylori was assessed and in
vitro sensitivity test with MICs for H. pylori was determined.
In chapter 4 efficacious furazolidone-containing triple therapies for H. pylori have
been explored. Furazolidone has been proved highly efficacious against H. pylori, and
resistance of H. pylori to it is not easily emerged. A furazolidone-containing
therapeutic regimen for H. pylori infection has attracted special interest in the face of a
world-wide rising resistance of K.pylori to metronidazole. In the present study we use
furazolidone and clarithromycin in combination with either colloidal bismuth
subcitrate (CBS), also called tripotassium dicitrato bismuthate (TDB) or a proton pump
inhibitor to evaluate the efficacy of furazolidone as a replacement for metronidazole in
standard "triple therapy " regimens currently advocated to eradicate H. pylori.
In chapter 5 the efficacy of non-metronidazole bismuth-based triple therapies for H.
pylori infection was evaluated. Resistance strains of// pylori to metronidazole, a key
antibiotic agent of anti-//, pylori therapy are increasing in frequency worldwide, such
resistance will limit the usefulness of metronidazole-containing regimens. This concern
has prompted the search for effective, inexpensive, non-metronidazole therapies. Three
bismuth-based, non-metronidazole triple regimens were investigated. The therapy
consisting of TDB, clarithromycin and furazolidone provides a satisfactory result, and
the combination of TDB, josamycin and furazolidone achieved sub-optimal result.
In chapter 6, 7 and 8 effects of H. pylori infection on gastric epithelial cell turnover,
including cell proliferation and apoptosis, were studied. Chapter 6 elaborates on the
effect of//, pylori infection on gastric epithelial apoptosis by comparisons between //.
#y/orz-associated chronic gastritis and H. pylori negative normal controls and between
30
pre- and post-eradication therapy. H. pylori infection appears to induce gastric
epithelial apoptosis in patients with chronic gastritis. In chapter 7 the effect of H.
pylori infection on apoptosis of gastric precancerous lesions was investigated. The
apoptosis in gastric precancerous lesions is reduced, H. pylori infection
apparently has no effect on apoptosis in these lesions. In chapter 8 the effect
of H. pylori infection on gastric epithelial proliferation in progression from normal
mucosa to gastric carcinoma is studied. H. pylori infection causes increased gastric
epithelial cell proliferation in the stages of superficial and mild atrophic gastritis, and
may play a part in triggering gastric carcinogenesis.
31
