REVIEWCurrent consensus on the diagnosis and treatmentof H. pylori-associated gastroduodenal disease
Hidekazu Suzuki1,2, Tatsuhiro Masaoka1,2, Sachiko Nomura2, Yoshinori Hoshino2, Kumiko Kurabayashi2
Yuriko Minegishi2, Masayuki Suzuki3 and Hiromasa Ishii1
1Department of Internal Medicine and 2Center for Integrated Medical Research, School of Medicine
Keio University, 3Department of Gastroenterology, National Tokyo Medical Center, Tokyo, Japan(Received for publication on February 18, 2003)

Abstract. Helicobacter pylori (H. pylori) is a spiral shaped bacterium that resides in the stomachmucosa. Isolation of H. pylori from the stomach mucosa changed the erstwhile widely held belief thatthe stomach contains no bacteria and is actually sterile. Once H. pylori is safely ensconced in the
mucus, it is able to neutralize the acid in the stomach by elaborating an enzyme called urease. Urease
converts urea, of which there is an abundant supply in the stomach (derived from saliva and thegastric juice), into bicarbonate and ammonia, which are strong bases. These bases form a cloud of acidneutralizing chemicals in the vicinity of the organisms, protecting them from the acid in the stomach.
This urea hydrolysis reaction is utilized for the diagnosis of H. pylori infection in the urea breath test
(UBT) and the rapid urease test (RUT). In Japan, both invasive tests, such as bacterial culture, histopathology and RUT, and non-invasive tests such as UBT and serology are conducted for the diagnosisof H. pylori infection. For conﬁrming the results of eradication therapy, UBT is considered to be themost sensitive and speciﬁc. In order to treat H. pylori infection, a new one-week triple therapy regimen(lansoprazole or omeprazoleBamoxicillinBclarithromycin) has been approved for use in patients withpeptic ulcer disease in Japan. As for H. pylori eradication in the case of other diseases in which thebacterium has been implicated (e.g., chronic atrophic gastritis, gastric MALT lymphoma, gastric cancer,
non-ulcer dyspepsia, chronic urticaria, idiopathic thrombocytopenic purpura (ITP)), further basic andclinical investigation is required. (Keio J Med 52 (3): 163–173, September 2003)
Key words: urease, apoptosis, rapid urease test, urea breath test, triple therapy

Introduction
Twenty years ago in Australia, Marshall and Warren
became the ﬁrst in the world to succeed in culturing
Helicobacter pylori (H. pylori) from the gastric mucosa
of patients with gastritis.1 Since Palmer2 denied the existence of micro-organisms in human stomach, it had
been thought that it is nearly impossible for any microorganism to survive in the gastric acidic environment.
However, some micro-organisms had already been discovered in the stomach in the 1890s.3 In Japan also,
Katsuya Kasai and Rokuzo Kobayashi of the Kitasato
Institute reported isolating a spirochete-like organism,that might have been Helicobacter felis, from the stomach of dogs and cats, but not that of laboratory animals,

and demonstrated that when rabbits infected with the
spirochetes isolated from dogs or cats were inoculatedwith the virus ﬁxe, marked hemorrhagic inﬂammation occurred in the gastric mucosa.4 They also demonstrated that spirochetes inoculated into the gastricmucosa of the mouse could be eradicated by the administration of arsaminol4 (a modern equivalent ofarsaminol is thought to be bismuth, a close relative ofarsenic). Seventy years have elapsed before scientists
are again attempting to treat gastritis associated with
Helicobacter infection. To commemorate Kobayashi’s
achievements in the ﬁeld of Helicobacter research, the‘‘Rokuzo Kobayashi Memorial Symposium on Helicobacter pylori’’ was held on May 11, 2002 at the Kitakan Hall of the Keio University Mita Campus.5 In thisPresented in part at the 2002 Keio Medical Science Prize Symposium, November 29, 2002.
Reprint requests to: Dr. Hidekazu Suzuki, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjukuku, Tokyo 160-8582, Japan, facsimile: 81-3-5363-3967, e-mail: hsuzuki@sc.itc.keio.ac.jp
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Suzuki H, et al: H. pylori: current consensus

symposium, Dr. Thomas F. Meyer had a special lecture
entitled ‘‘Helicobacter pylori – From molecular genetics
and pathogenesis studies to vaccine design –’’,6 Dr.
Barry J. Marshall had a historical special lecture entitled, ‘‘Kobayashi and Helicobacter pioneers’’,7 and Dr.
Kenneth E.L. McColl gave a lecture entitled ‘‘How
does H. pylori infection cause gastric cancer?’’.8
H. pylori is a spiral-shaped gram-negative rod, measuring approximately 3–5 microns in length. The bacteria possess numerous long ﬂagella, ﬂailed movementsof which allow them to advance vigorously with forcefulscrew-like movements, much like the spinning of the bitof a drill.9 How does H. pylori survive in the strong acidenvironment of the stomach? The organism elaborates
a large amount of urease, an enzyme that breaks down
urea. When it releases urease, the urea present in the
mucus layer of the stomach is converted into ammonia,
which quickly neutralizes the acid in the immediate
vicinity of the organism, thereby protecting it from thestrong acidic environment of the stomach. The abilityof the bacterium to elaborate urease, which neutralizes
acid, together with its vigorous movements enables H.
pylori to infect and colonize the gastric mucosa.
Mongolian Gerbil Models for H. pylori Infection
A recently established animal model for H. pyloriassociated gastric disease, produced by inoculating thisbacterium to Mongolian gerbils,10 is useful for in vivo
observation of H. pylori-infected gastric mucosa. In thismodel, we previously reported the signiﬁcant levelsof gastric mucosal neutrophil accumulation, and theincrease in the contents of lipid peroxides.11,12 In
the same model, Japanese investigators revealed theformation of gastric cancer by inoculating only H.
pylori.13,14 Although the exact mechanisms by which
H. pylori infection results in gastric mucosal injury areunclear, it has been demonstrated that the extracts ofthe bacterium can induce a number of microvascularalterations within the rat gastric mucosa, including platelet aggregation and macromolecular leakage.
Initial Gastric Mucosal Response to H. pylori
The Mongolian gerbil (MGS/Sea, 5–7 weeks) inoculated with H. pylori10 is a suitable model for observing
H. pylori-associated gastric mucosal response. In ourlaboratory, in vivo microcirculation in the gastricmucosa is visualized through an intravital microscopeusing a digital color 3CCD camera.15 The bacterial
body of H. pylori was detected in the mucus layer. The
velocity of rolling leukocytes on the venular endothelium and the number of adherent leukocytes could be
calculated by the playback image analysis.9

In the normal uninfected gastric mucosa of gerbils,
the mesh of a capillary network is clearly seen between
the large collecting venules. After the intragastric inoculation with H. pylori, the bacterial body moves in the
mucus layer by the screw-like force of the ﬂagella andadheres on the surface of epithelial cells of the pyloric
antrum within several hours. The bacteria force their
way through the mucus, and in large numbers work
themselves closer to the epithelium. Once the tips ofthe bacterial body come into contact with the surface
epithelium, the H. pylori in the mucous layer starts toestablish colonies vigorously, and then ﬁrmly adheresto the surface epithelial cells. As a result of the energetic movement and the activity of urease, the bacteria
break through the mucus layer and establish a colonization of the gastric mucosa.
Four weeks after the bacterial inoculation, no conspicuous changes in the gastric mucosa were seen macroscopically. However, when we observed the gastricmucosal microcirculation with the intravital microscope,some pathophysiological events occurred surrounding
the collecting venules. Particularly, a phenomenon inwhich neutrophils are rolling along the luminal surfaceof the venular endothelium, or are adhering to it isdocumented. Eight weeks after the bacterial inoculation, macroscopic gastric mucosal damage had appearedin the pyloric antrum, near its border with the body ofthe stomach.
At the 12th week after the inoculation, the mucosal
erosive lesion in the antrum was covered with necrotic
tissue. Closer examination revealed considerable exfoliation of the epithelial cells and stagnation of the
microvascular blood ﬂow. There were great numbers ofneutrophils adherent to the venular walls, and many
neutrophils had extravasated. The velocity of rollingleukocytes in the mucosal and submucosal venules
decreased in a time-dependent fashion in the H. pylori
group.9 Histological ﬁndings also showed a large number of leukocytes mainly in the submucosa in the stomach with H. pylori infection. Tissue myeloperoxidase(MPO) activity of the stomach started to increase signiﬁcantly in the H. pylori-colonized gerbils at 12th week
after the inoculation to a level eight fold that of thecontrol.12 Sixteen weeks after the infection, the area ofmucosal injury had expanded and the mucosa itself had
become noticeably thicker. Exfoliated epithelial cells in
the mucus layer fragmented into small particles, suggesting they died as a result of apoptosis. Surrounding
this portion, many leukocytes could be observed (Fig.
1). These leukocytes migrate from the venules to thedeeper layers and then emerge on the mucosal surface.
It is known that, as a result of leukocyte activation,
large amounts of substances with deleterious effects on
the gastric mucosal cells, such as reactive oxygen
metabolites, are produced through the NADPH oxi-

Keio J Med 2003; 52 (3): 163–173

165

Fig. 1 Histological ﬁndings of the H. pylori-colonized-gastric mucosa of Mongolian gerbils at the 16th week after inoculation. a) Control, noninfected gastric corpus mucosa (10 objective lens). b) Control, non-infected gastric corpus mucosa (40 objective lens). c) H. pylori-colonizedgastric corpus mucosa (10 objective lens). d) H. pylori-colonized-gastric corpus mucosa (40 objective lens).

dase on the membrane of neutrophils. Of these substances, the monochloramine (NH2 Cl) which is produced by the H. pylori urease-derived NH3 and neutrophil myeloperoxidase-derived HOCl, plays animportant role on the gasric mucosal cell injury in the
H. pylori-infected stomach.16,17
Gastric Mucosal Cell Turnover and H. pylori Infection
Gastric mucosal cell turnover is regulated by thebalance between cell death and cell proliferation in thegastric mucosal epithelium. Such a regulated cell turnover is mandatory to keep healthy gastric mucosal
integrity. Peek et al. investigated the level of gastricepithelial apoptosis and proliferation in H. pyloricolonized gastric mucosa of Mongolian gerbils at theearlier phase after the bacterial inoculation and de-picted an initial transient enhancement of cell apoptosis(2–4 weeks) and later increase in cell proliferation (16–20 weeks). We also previously reported that while thelevel of apoptosis increased with the extension of H.
pylori-evoked gastric mucosal inﬂammation in C57BL/6
mice, the enhanced level of apoptosis was signiﬁcantly
attenuated in H. pylori-colonized gastric mucosa of
Mongolian gerbils with an enhanced inﬂammation andepithelial proliferation in the gastric mucosa in thelonger-term colonization (36 and 72 weeks after thebacterial inoculation)18 and suggested the possible linkof an attenuated gastric mucosal apoptosis with a speciﬁc carcinogenesis in gerbils after H. pylori colonization.13,14
One of the candidates for an apoptosis regulator
might be p53. Mutations of the p53 tumor suppressor
gene constitute one of the most frequent molecularchanges in a wide variety of human cancers. Fox et al.19

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examined p53þ= mice with H. felis inoculation andreported a signiﬁcant enhancement of gastric mucosal
cell proliferation at 48 weeks after the inoculationcompared with the same strain-colonized stomach ofwild-type p53þ=þ mice. We also reported using thesame p53þ= mice as Fox et al. that no difference in thelevel of apoptosis and proliferation in the gastricmucosa was seen 24 weeks after H. pylori (not H. felis)
inoculation.20 Yamamoto et al.21 investigated the susceptibility of p53 nullizygote = , heterozygote þ= andwild-type þ=þ mice to N-methyl-N-nitrosourea (MNU)
gastric carcinogenesis and reported that no adenocarcinoma in the stomach was observed in a p53þ= mouse.
These results suggest that the heterozygous mutation of
p53 may not be enough to induce mouse gastric preneoplastic and neoplastic lesions even by the administration of a chemical carcinogen. These previous studies
suggest that the additional genetic change is necessary
to evoke a dysregulation of gastric mucosal cell turnover in the H. pylori-colonized stomach.
Although the role of iNOS in the H. pylori-colonizedstomach still remains unclariﬁed, many reports showed
the iNOS involvement in the extension of gastricmucosal inﬂammtion with H. pylori infection. Kisset al.22 examined the actions of a puriﬁed H. pylori
lipopolysaccharide (LPS) on rat gastric antral and duodenal microvascular integrity (determined as radiolabelled albumin leakage) and the expression of
iNOS. According to their study, signiﬁcant increasesof albumin leakage and expression of iNOS in bothantral and duodenal tissues were observed following
LPS challenge. Recently Watanabe et al.23 reported
as in vitro study that chemical iNOS suppression by
iNOS inhibitor (aminoguanidine) attenuated H. pyloriinduced apoptosis of MKN45 cells, suggesting an important role of iNOS for evoking gastric cellularapoptosis. In iNOS= mice, although gastric mucosal
leukocyte accumulation in response to H. pylori wassigniﬁcantly increased, the level of gastric mucosal
apoptosis was signiﬁcantly attenuated, suggesting a keyrole of iNOS-derived NO for the induction of gastricepithelial apoptosis.24
The iNOS may be regulated by the oxidant-sensitivetranscription factor, nuclear factor-kappaB (NF-kB).
Lim et al.25 reported that H. pylori induced cytotocixityof gastric cells time- and dose-dependently, which
occurred with induction in iNOS expression and nitrite
production. In their study,25 while a peroxynitrite donor and a nitric oxide donor induced dose-dependent
cytotoxicity in gastric cells, catalase, an inhibitor of
NF-kappaB activation; pyrrolidine dithiocarbamate(PDTC), iNOS inhibitors; N(G)-nitro-L-argininemethyl ester (L-NAME), and 2-amino-5,6-dihydro-6methyl-4H-1,3-thiazine (AMT) prevented H. pyloriinduced cytotoxicity and apoptosis, suggesting a possi-

Suzuki H, et al: H. pylori: current consensus

ble link between iNOS and its derivatives with gastriccytotoxicity.
The levels of both oxidized and nitrated proteins
were signiﬁcantly higher in inﬂamed gastric tissue samples infected with H. pylori, especially cagAþ strains,and in those with expression of IL-8 and iNOS mRNAs
than in those negative for these parameters,26 indicating that infection with cagAþ H. pylori would induce
signiﬁcant oxidative stress and iNOS expression in thegastric mucosa, contributing to the pathogenesis of H.
pylori-associated gastroduodenal diseases.
Indications for H. pylori Eradication Therapy
There is worldwide consensus that H. pylori eradication prevents ulcer recurrence without any maintenance antisecretory therapy.27 In Japan, similar results
have also been obtained; a large-scale multicenter clinical trial of H. pylori eradication in patients with active
ulcers using proton pump inhibitors plus an antibiotic
demonstrated the inhibitory effect of eradication on
ulcer recurrence. From the medico-economic ponit ofview, it is also clear that H. pylori eradication reduces
medical costs. Thus, the presence of H. pylori-positive
gastric ulcers or duodenal ulcers is an indication for
eradication therapy.
According to the recently revised guidelines published by the Japanese Society for Helicobacter Research on February 24th, 2003,28 H. pylori eradication
therapy is also recommended in patients with gastric
low-grade MALT lymphoma. In patients after endoscopic mucosal resection of gastric cancer, those withatrophic gastritis and those with gastric hyperplastic
polyps, H. pylori eradication therapy might be effective. In terms of patients with non-ulcer dyspepsia(NUD), gastroesophageal reﬂux disease (GERD) or
extra-gastric diseases, the signiﬁcance of H. pylori
eradication therapy is still under evaluation. Considering the high prevalence of gastric cancer in Japan, adrive for eradication of H. pylori should be undertaken
urgently to reduce the incidence of gastric cancer.
Epidemiology of H. pylori Infection in Japan
H. pylori is believed to be transmitted via the oralroute. Many researchers believe that H. pylori is transmitted by the orofecal route through the ingestion offood or water. In addition, it is also possible that H.
pylori is transported from the stomach to the mouth inassociation with gastro-esophagal reﬂux (in which thecontents of the stomach are reﬂuxed in small amounts
into the esophagus) or belching, both common symptoms of gastritis; the bacterium could then be transmitted via the oro-oral route.

Keio J Med 2003; 52 (3): 163–173

The prevalence of H. pylori infection in Japan is extremely low in younger age groups, similar to the casein other developed countries, and subsequently the incidence increases rapidly until it reaches a plateau of
about 70% in 50-year-old subjects.29 This phenomenon
is attributable to people around 50 years of age having
been born soon after World War II and spent theirchildhood under poor hygienic conditions.
It has been reported that H. pylori infection may be
associated with chronic gastritis regardless of the strainof the infecting organism, and that the course of thedisease, however, does depend on such environmental
factors as the diet, duration of infection, the age at
the time of occurrence of H. pylori infection, the virulence of the H. pylori strains, and various host factors,
including genetic make-up.
Little is known about factors, apart from poor living conditions during childhood, that affect either theacquisition or elimination of H. pylori infection.30
Lifestyle factors operating during adulthood, such as
smoking and alcohol consumption, may inﬂuence spontaneous eradication of the organism. Although studies
investigating the relationship between antibody evidence of H. pylori infection and these factors haveprovided inconsistent ﬁndings,31–33 it must be bornein mind that serological tests may misclassify as still
infected those individuals in whom the organism has
already been eradicated. Recent studies on subjects
with evidence of active H. pylori infection, as measured
by the 13 C-urea breath test, found no association between smoking and H. pylori infection, whereas coffee
consumption was positively related to the infection.34,35 A strong inverse association between H.
pylori infection34 and alcohol consumption (especiallywine) was reported from one study, but a subsequent
report indicated that the relationship was U-shaped andunrelated to the type of beverage consumed.36
Although H. pylori has been found throughout thestomach, H. pylori-associated inﬂammation is often
mild, superﬁcial or even absent in the gastric corpus.37
In the natural history of gastritis associated with H.
pylori infection, the inﬂammation progresses from theantrum to the adjacent corpus along a line of advancing
injury, associated with a reduction of acid secretion andeventually, loss of parietal cells and the development ofgastric mucosal atrophy.38–40 This scenario, however, is
not inevitable. In the general population, progression ofgastric mucosal atrophy occurs at the rate of 1–2% per
year.38 Several studies have suggested an annual increase in the severity of gastritis affecting the corpus ofapproximately 6% amongst H. pylori-infected patientswith GERD.41–46 The rate of progression from active
gastritis to gastric mucosal atrophy varies in different
geographical regions in relation to other environmental
factors, and, although diet is probably the most impor-167

tant event causing a reduction of acid secretion, otherfactors, such as childhood infections, may also be very
important.47–49 The rate of development of the disease
and the proportion of the population with atrophic
gastritis are critical determinants of the risk of gastriccancer in the population.47
Intervention Trial of H. pylori in Japan
To investigate whether or not a causal link exists
between H. pylori infection and gastric cancer, an intervention study called JITHP (Japanese Intervention
Trial of H. pylori) was planned in 1994 under the auspices of 2nd Term Comprehensive Strategies for Cancer Control in Japan, organized by the Ministry of
Health and Welfare. Although the trial was performedby 145 afﬁliated institutions (including Keio University
Hospital) from all over Japan, difﬁculties related to patient accrual were confronted during the trial, as a result of which only one of two factors taken into consideration initially could be evaluated in the study. That is,
only the inﬂuence of H. pylori eradication in preventing
the onset and progression of gastric mucosal atrophy
could be studied, and its inﬂuence on the frequency of
stomach cancer. Finally, a total of 682 patients, with 342
in the H. pylori-eradication group and 340 in the nonH. pylori-eradication group were enrolled in the study.
The ﬁnal outcome of the trial is expected to be reported
in March 2004.
Diagnosis of H. pylori Infection
Diagnostic methods for H. pylori infection are categorized into two groups as invasive and non-invasive
tests. While invasive tests need endoscopic biopsy ofgastric mucosal samples, the non-invasive test does notneed an endoscopic procedure (Fig. 2).

Fig. 2 Diagnostic methods for H. pylori infection. Left) non-invasive
tests, Right) invasive tests.

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Invasive tests
Histological diagnosis of H. pylori infection: H. pylori
infection is easily recognizable on histological examination;1 both the organism itself, and the histopathological changes induced by it can be identiﬁed on histopathological examination of biopsy specimens. Fora precise diagnosis, it is important to obtain biopsies
from appropriate sites of the stomach (greater curvature of the antrum and corpus) and to recognize
the characteristic pathological ﬁndings in the gastricmucosa associated with the infection (epithelial cellchanges and neutrophilic and mononuclear cell inﬁltration), besides using special staining methods for identifying H. pylori (i.e. Giemsa staining, Gimenez staining,silver staining and immunohistochemistry, in addition
to Hematoxylin-eosin staining) in the specimens.
Rapid urease test: The rapid urease test (RUT) is oneof the invasive methods that is used for the detection of
H. pylori infection.50 H. pylori, if present in the biopsy
specimen, splits the urea in the test container to yieldammonia. Elevation of the pH by ammonium hydroxide produced is detected by a color change of the pH
indicator. The advantage of RUT is that it is an inexpensive, easy-to-use, and rapid diagnostic test. Its disadvantages, on the other hand, are that endoscopy isrequired and false-negative reactions are frequently
encountered. Although RUT is useful for the diagnosisof H. pylori infection both before and after eradication
treatment, the sensitivity of RUT is comparatively low
during the ﬁrst 6 months after completion of eradication therapy.
Culture method for H. pylori: Among the ﬁve diagnostic tests for H. pylori infection that are recommended by the Japanese guideline,51 the microaerobic
bacterial culture method may be the most difﬁcult to
use in the clinical setting, because of the requirement of
3 to 5 days for the organism to grow, the need for skill
in performance of the test and elaborate equipment,
and the high frequency of false-negative results (Fig. 2).
On the other hand, it has the advantage of having a
speciﬁcity of 100% (direct demonstration of the presence of H. pylori) and of allowing further characterization of the organism (determining its sensitivity to antibiotics, investigating its virulence factors, and typing of
its DNA for epidemiological purposes). This method is
especially useful for cases in whom the infecting strains’sensitivity to antibiotics needs to be determined. Considering the potential increase in the frequency of clarithromycin (CAM)-resistant H. pylori in the future, themicroaerobic bacterial culture method may be the mostsuitable method for the diagnosis of H. pylori infection.
With treatment of H. pylori infection being con-

Suzuki H, et al: H. pylori: current consensus

ducted frequently in Japan, drug resistance has emerged
as a problem that requires attention. However, there
are no standard methods for evaluating the antibiotic
susceptibility of H. pylori in Japan. While in Europe
and the U.S.A., the E-test is being used as the standard
method for testing the drug susceptibility of H. pylori,
the microplate method, which has been reported tohave the same accuracy as the agar dilution method, isnow becoming standard in Japan. In 2000, the JapaneseSociety of Chemotherapy proposed that the drug susceptibility testing of H. pylori be standardized and thatthe break point MIC of amoxicillin (AMOX) and CAM
be listed.
Non-invasive Tests
13

C-urea breath test: Infection with H. pylori has been
implicated as an important factor in the pathogenesis ofgastritis, peptic ulcer and gastric cancer, and the 13 Curea breath test (13 C-UBT) is a convenient and noninvasive method for the detection of H. pylori in thestomach. The 13 CO2 /12 CO2 ratio is measured by using
infra-red spectroscopy (IR) and gas chromatography/
mass spectrometry (GC-MS). The IR analyzer is considered to be particularly useful for the diagnosis of H.
pylori infection by the 13 C-UBT.
The effect of the test meal used for the test was
explored further. It was widely believed that citric acidwas the best test meal for the use in the 13 C-UBT,
hypothesized as being due to the efﬁcient delay in gastric emptying induced by it. Shiotani et al.52 compareda pudding test meal, ascorbic acid and two doses of citric acid in 11 volunteers, and clearly demonstrated thatthe increased intragastric urease activity could not be
attributed to gastric emptying alone. They suggested
that citric acid could have a direct effect on UreI, a
proton gated urea channel, making urea more accessible to the intrabacterial urease.
The reasons for the discrepancies observed between
the results of the 13 C-UBT and serology were assessedby Bode et al. in asymptomatic blood donors.53 They
did not ﬁnd any case showing positive UBT among
serology-negative subjects. The strongest predictive
factor of a negative-UBT in serology-positive subjects
was, not surprisingly, previous H. pylori treatment.
Another signiﬁcant factor was coffee consumption. A
tendency towards increase in the frequency of negative
UBT in subjects over the age 60 years was also noted,
possibly due to increased mucosal atrophy and intestinal metaplasia.
Antibody tests: Serological detection of H. pylori
infection by ELISA has been popularly used. Several
ELISA kits are available in Japan, which, however,
have varying sensitivity and speciﬁcity. The new version

Keio J Med 2003; 52 (3): 163–173

of Pyloriset (EIA-G III) (Orion, Finland) has beenshown to be reliable.54 The immuno chromatographic
ﬂow-injection method, which allows the quantitation of
speciﬁc IgG, has been developed as a new method forthe serological diagnosis of H. pylori infection. Thismethod is rapid, and is associated with minimal wastageof antigen, since the same immunosorbent reactor canbe used for all tests.55 It has been reported that thesensitivity and speciﬁcity of ELISA may be higher when
the Japanese strain of H. pylori is used as the antigen.
CagA antibodies which persist for longer durations
than H. pylori antibodies detected in a global test, canhelp in linking gastric carcinoma to H. pylori infection.56,57 In a study of CagA, while the serologicalstatus as assessed by a commercial CagA immunoblot
test was of no value for predicting the severity of thedisease.58
Quantiﬁcation of the IgG titers may be of interest. In
one study, higher titers were reported to be associatedwith a lesser likelihood of the development of gastriccarcinoma (GC) as compared to lower titers.59 Similarly, lower UBT values corresponded to higher scoresof atrophy, and therefore a higher risk of GC.60
Tests have been developed by Otsuka Pharmaceitical Co. to detect H. pylori antibodies in the urine, forexample, the ‘doctor test’ (Rapirun) using an immuno
chromatographic method using dried anti-human IgGbinding gold colloidal particles. This test was evaluatedas being satisfactory in two studies,61,62 in which thesensitivity and speciﬁcity were determined to be 94.6%
and 95.3%, and 95.3% and 96.7%, respectively. These
results are very promising and deserve to be conﬁrmed,
since this test could possibly become the most suitablenoninvasive test for H. pylori infection.
H. pylori Detection in Stools
The now well-known HpSA test (Meridian) has been
evaluated in adults in three studies, 4–6 weeks after H.
pylori eradication, using the UBT as reference. In the
study of Manes et al. (106 cases, 16 failures), the sensitivity and speciﬁcity were 87.5%, and 95.7%, respectively.63 In the study of Leodolter et al. (113 cases, 30
failures), the sensitivity and speciﬁcity were 76.2%, and93.3%, respectively.64 Based on the ROC curves, they
showed that a slightly lower cut-off value increased theaccuracy of the test. Vaira et al. found a sensitivity andspeciﬁcity of 94% and 97%, respectively in 84 treatedpatients.65 Gisbert and Pajares published a systematic
analysis of 25 published studies including 2078 patients,
in which HpSA was used for post-treatment follow-up.
The sensitivity, speciﬁcity, NPV and PPV were 88%,92%, 75% and 94%, respectively, i.e. not as good as
the pretreatment values of 92%, 92%, 92% and 90%,
respectively.66

169

A novel stool test (FemtoLab H. pylori, Connex,
Germany) using monoclonal antibodies instead of polyclonal antibodies has been developed. There was goodconcordance between the two stool tests.67 Stool tests
can also be used in mice models of infection to facilitate
basic research.68 Monteiro et al. explored the stabilityof H. pylori DNA in stools for 3 days and the impact ofa vegetable-free diet on the detection.69
Conﬁrmation of H. pylori Eradication
In Japan now, it is expected that general practitioners would test peptic ulcer disease patients withthese tests before and after H. pylori eradication. To
obtain highly accurate results after eradication, it is important to conduct the tests over 4 weeks (more desirably over 12 weeks) after cessation of eradication therapy with PPI and antibiotics. The UBT and the stool
antigen test are the most suitable for conﬁrmation of
H. pylori infection after eradication, since these tests
reﬂect all the changes in the stomach associated with H.
pylori infection.
New Triple Therapy for H. pylori Infection in Japan
In Japan, a phase III trial of one-week triple therapy
with lansoprazole (LPZ), amoxicillin (AMOX), andclarithromycin (CAM) was completed in March, 2000.70
Patients were randomized into three groups: LPZ 30
mg bid and placebos, and LPZ 30 mg bid, AMOX 750
mg bid and CAM 200 mg bid or 400 mg bid. The eradication rates were high in the LPZþAMOXþCAM
200 (88–91%) and LPZþAMOXþCAM 400 (84–89%)
groups. Then, a phase III trial of one-week therapy withomeprazole (OPZ), AMOX and CAM was completed
in 2001. The eradication rates were 78.8% in the OPZ
20 mg, AMOX 750 mg and CAM 400 mg bid, and83.0% in the OPZ 20 mg, AMOX 1000 mg and CAM
500 mg bid groups. On the other hand, the eradication
rate of 7-day therapy of rabeprazole (RPZ) 10 mg
bid, AMOX 750 mg bid and CAM 400 mg bid (84%)
was higher than the 5-day therapy with same regimens(66%).71
Second-line Therapy for H. pylori Eradication after
Failure of First-line Therapy
Even though the currently employed H. pylori eradication regimens in Japan fail to cure 10–20% of
patients, an optimal re-treatment therapeutic regimen
for eradication-failure has not been established, yet.
Since patient compliance, bacterial resistance and genotypic differences in CYP2C19 inﬂuence the eradication
rate, re-eradication therapy should be selected, taking
these factors into consideration. In the West, meta-

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Suzuki H, et al: H. pylori: current consensus

analysis of second-line treatment of H. pylori infection
showed that a regimen containing ranitidine bismuth
and two antimicrobials was very effective as a retreatment regimen, irrespective of the factors inﬂuencing failure of the ﬁrst-line H. pylori eradication treatment. However, ranitidine bismuth is not available inJapan and a re-eradication regimen consisiting of PPI,
amoxicillin and metronidazole has often been used anda high eradication rate achieved, even in patients withmetronidazole-resistant H. pylori. In our University
hospital, second-line eradication protocol is decided by
the results of antibiotic susceptibility test after the
failure of ﬁrst-line therapy with lansoprazole (LPZ),AMOX and CAM.72
Problems that May Occur after H. pylori Eradicationand the Countermeasures
Acute esophagogastroduodenal mucosal lesions havebeen demonstrated as an adverse event that may occur after H. pylori eradication therapy. According to
Sakaki et al., acute duodenal erosions were observed in
13.5% of patients who received eradication therapy.
Duodenal erosions which occurred mainly in the earlyphase after eradication were transient and asymptomatic. Acute gastric erosions showed the same clinicalcharacteristics. However, attention should be paid tothe rare occurrence of acute ulcers with severe symptoms. On the other hand, mild but persistent reﬂux
esophagitis occurred at a relatively late phase after
eradication. The occurrence rates were 9.8% after 1
year and 11.4% after 3 years. The acute mucosal lesions
which occurred are probably attributable to the increase in acid secretion asscociated with the resolutionof gastric mucosal inﬂammation. Symptomatic treatment with antacids may be necessary on occasion for
the treatment of acute ulcer formation and reﬂux
esophagitis.
Tailor-made Medicine for H. pylori Eradication
Therapy
The pharmacokinetic proﬁles of omeprazole andlansoprazole have been reported to be correlated with
the CYP2C19 genotype.73 While the drugs are extensively metabolized in heterozygotes as compared tohomozygotes, the difference between the two groups
was not statisitically signiﬁcant. For rabeprazole, on theother hand, the pharmacokinetic proﬁle was independent of the CYP2C19 genotype. Thus, CYP2C19 genotyping may serve as useful new strategy in the choice ofan optimal regimen, and this genotype testing may beespecially useful in Japan, as the frequency of poor
metabolizers among the Japanese is ﬁve times greaterthan that among Caucasians.74

However, the recent increase in the emergence ofantimicrobial-resistant strains of H. pylori may force us
to examine the antimicrobial susceptibility in all patientsin the near future, in order to achieve an eradication
rate with ﬁrst-line therapy of more than 80%. It would
also be imperative to have proper knowledge of theinﬂuence of CYP2C19 genetic polymorphism on thetreatment efﬁcacy according to various PPIs used alone
or in combination with other drugs.
The Present Status and Problems of H. pylori
Eradication Therapy
Since therapy for eradication of H. pylori in thetreatment of peptic ulcer disease was approved forcoverage by the Japanese Governmental Health Insurance System on November 1st in 2000, this therapy has
been widely used in Japan. However, some problems oftreatment have arisen, for example, the emergence ofclarithromycin resistance. On the other hand, investigation of the relation between H. pylori infection andgastric cancer is making progress. In an elegant prospective study conducted in 2001, Uemura, et al. demonstrated that H. pylori infection plays an importantrole in gastric carcinogenesis.75 Under such circumstances, the Japanese society of H. pylori Research has
to reconsider the guidelines for eradication therapy of
H. pylori infection.
New Prophylactic and Therapeutic Approaches against
H. pylori Infection
Probiotics have been shown to be effective against
antibiotic-associated diarrhea in several randomized
controlled studies. The rationale for their use lies mostly
in their ability to restore the normal intestinal ﬂora.
Also, for Lactobacillus GG, inhibition of the prokinetic
action of macrolides has been proposed. Many animal
experiments indicate some degree of immune stimulation by probiotic species, and oral bacteriotherapy isa hot topic in the current experimental therapeutics ofinﬂammatory bowel disease. To date, however, there isno deﬁnitive evidence to explain the mechanisms bywhich these biological agents inﬂuence the course ofhuman disease.
H. pylori Diagnosis and Eradication Therapy at Keio
University HospitalIn the outpatient clinic (Helicobacter clinic; http://
web.sc.itc.keio.ac.jp/medicine/PYLORI/index.html) of
Keio University Hospital, patients are ﬁrst subjected toupper GI endoscopy to diagnose peptic ulcer disease,and at the same time, biopsy is conducted for the diagnosis of H. pylori infection. Our method of choiceKeio J Med 2003; 52 (3): 163–173

171

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5.
6.

7.
8.
9.

10.

Fig. 3 Flow-chart of H. pylori diagnosis and eradication therapy at
Keio University Hospital.

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among the three invasive diagnostic tests is the microaerobic bacterial culture method, because of its highspeciﬁcity. However, this culture method also has ahigher rate of false-negative results. To overcome
this disadvantage, histopathological examination is performed in addition. In H. pylori-positive cases, oneweek triple therapy is administered for H. pylori eradication. Twelve to 16 weeks after completion of theeradication protocol, disappearance of H. pylori fromthe stomach is usually conﬁrmed by the UBT (Fig. 3).
The H. pylori eradication rate of our outpatient clinic in
2002 was 72.4%. In case of eradication failure, an antibiotic susceptibility test is performed. Based on the
results of this test, second-line therapy for eradication isadministered.
Further investigations to establish an effective therapeutic regimen should be performed to reduce theemergence of antibiotic resistance and prevent eradication failure.
Acknowledgments: This study was supported by a Grant-in-Aid for
Scientiﬁc Research C (2) from the Japan Society for the Promotion of
Science (JSPS) (13670555, to H.S.), a grant from Keio University.

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