ORIGINAL ARTICLE

Different Gastric Mucosa and CagA Status of Patients in Indiaand Japan Infected with Helicobacter pylori

Keiichi Fujiya • Naoyoshi Nagata • Tomohisa Uchida • Masao Kobayakawa •

Naoki Asayama • Junichi Akiyama • Takuro Shimbo • Toru Igari •

Rupa Banerjee • D. Nageshwar Reddy • Masashi Mizokami • Naomi Uemura

Received: 29 August 2013 / Accepted: 14 November 2013 / Published online: 27 November 2013

� Springer Science+Business Media New York 2013

Abstracts

Background and Aim Despite similar incidence of Heli-

cobacter pylori infection, the frequency of gastric cancer is

sevenfold higher in Japan than in India. The objective of

this work was to define differences in H. pylori-induced

gastritis and to identify the bacterial virulence factors

involved.

Materials and Methods We prospectively enrolled 353

consecutive patients who underwent endoscopy and

received three gastric biopsies in Tokyo, Japan, and Hy-

derabad, India. Immunohistochemistry against H. pylori

and East Asian CagA and hematoxylin–eosin and Giemsa

stain were used to examine gastric mucosal biopsy speci-

mens. Histological scores were assessed in accordance with

the updated Sydney System. Subjects with H. pylori

infection were matched by age and sex to compare histo-

pathology and bacterial virulence.

Results Sixty patients infected with H. pylori were pro-

spectively selected. Median histological scores for neu-

trophil and mononuclear cell infiltration and for atrophy

were significantly higher in Japan than in India (neutrophils

4.0 vs 3.0, p \ 0.01; mononuclear cells 5.0 vs 4.5,

p = 0.03; atrophy 3.0 vs 2.0, p \ 0.01, respectively).

Scores for H. pylori density and intestinal metaplasia were

K. Fujiya � N. Nagata (&) � M. Kobayakawa � N. Asayama �J. Akiyama

Department of Gastroenterology and Hepatology, National

Center for Global Health and Medicine, 1-21-1 Toyama,

Shinjuku-ku, Tokyo 162-8655, Japan

e-mail: nnagata_ncgm@yahoo.co.jp

K. Fujiya

e-mail: fuji.kei.01@gmail.com

M. Kobayakawa

e-mail: mkobaya@hosp.ncgm.go.jp

N. Asayama

e-mail: a-s-ayama@hotmail.co.jp

J. Akiyama

e-mail: akiyama@fc4.so-net.ne.jp

T. Uchida

Department of Molecular Pathology, Oita University, 1-1

Hazamacho, Yufu City, Oita 879-5593, Japan

e-mail: tomohisa@oita-u.ac.jp

T. Shimbo

Department of Clinical Research and Informatics, National

Center for Global Health and Medicine, 1-21-1 Toyama,

Shinjuku-ku, Tokyo 162-8655, Japan

e-mail: tshimbo@hosp.ncgm.go.jp

T. Igari

Department of Clinical Pathology, National Center for Global

Health and Medicine, 1-21-1 Toyama, Shinjuku-ku,

Tokyo 162-8655, Japan

e-mail: tigari@hosp.ncgm.go.jp

R. Banerjee � D. N. Reddy

Department of Gastroenterology, Asian Institute of

Gastroenterology, 6-3-661 Somajiguda, Hyderabad 500082,

India

e-mail: dr_rupa_banerjee@hotmail.com

D. N. Reddy

e-mail: aigindia@yahoo.co.in

M. Mizokami

The Research Center for Hepatitis and Immunology, Kohnodai

Hospital, National Center for Global Health and Medicine, 1-7-1

Kohnodai, Ichikawa City, Chiba 272-8516, Japan

e-mail: mizokami0810@gmail.com

N. Uemura

Department of Gastroenterology and Hepatology, Kohnodai

Hospital, National Center for Global Health and Medicine, 1-7-1

Kohnodai, Ichikawa City, Chiba 272-8516, Japan

e-mail: nuemura@hospk.ncgm.go.jp

123

Dig Dis Sci (2014) 59:631–637

DOI 10.1007/s10620-013-2961-x

also higher in Japan, albeit without statistical significance

(H. pylori 5.0 vs 3.0, p = 0.08; intestinal metaplasia 0.0 vs

0.0, p = 0.08). Prevalence of East Asian CagA-positive H.

pylori was significantly higher in Japan (73.3 vs 0.0 %,

p \ 0.01).

Conclusion The significantly higher prevalence of histo-

logically severe gastritis and East Asian CagA in patients

from Japan with H. pylori infection may be involved in the

pathogenesis of gastric cancer.

Keywords East Asian CagA � Endoscopy � Gastric

cancer risk � H. pylori-associated gastritis � Updated

Sydney System

Abbreviations

H. pylori Helicobacter pylori

CagA Cytotoxin-associated antigen A

NCGM National Center for Global Health and

Medicine

AIG Asian Institute of Gastroenterology

Introduction

Gastric cancer is the second most frequent cause of cancer

death, resulting in 600,000 deaths per year worldwide [1].

Death from gastric cancer is more common in Asia, par-

ticularly in China, Japan, and Korea, where the prevalence

of H. pylori infection is high [2]. The different incidence of

gastric cancer compared with other countries may be

affected by several factors, including the prevalence of H.

pylori infection [3], H. pylori-associated gastritis [4],

bacterial virulence [5], host genetic factors, and diet [6].

Comparative studies to evaluate differences in the devel-

opment of gastric cancer among countries have been con-

ducted [7–11]. Here, we focus specifically on the

differences between patients from India and Japan.

Although the prevalence of H. pylori infection is similar in

India and Japan, the prevalence of gastric cancer in Japan is

approximately seven times higher than that in India [2, 3].

We hypothesized that the difference in the development of

gastric cancer results from the difference in the severity of

H. pylori -induced gastric mucosal inflammation. Inflam-

mation of the gastric mucosa, which is usually assessed

histologically by use of the updated Sydney System [12], is

rare in subjects who are H. pylori-negative, and the inci-

dence of gastric cancer in these patients is extremely low

[4].

To compare gastric mucosal inflammation among

patients residing in different countries, it is important to

evaluate those infected with H. pylori. However, previous

histological comparisons of gastritis among countries

included subjects who were H. pylori-negative [9] or

unmatched for age or sex [8, 10, 11].

Here, we endoscopically and histologically evaluated

differences in gastric mucosal inflammation between sub-

jects in India and Japan with H. pylori infection. Further, to

assess gastric cancer risk, we also determined the presence

of the gene encoding the H. pylori virulence factor cyto-

toxin-associated antigen A (CagA) [13].

Methods

Subjects

The study was conducted under a prospective cross-sectional

two-center design for all adults undergoing diagnostic

endoscopy between December 2010 and March 2011 at the

Endoscopy Unit, National Center for Global Health and

Medicine (NCGM), Tokyo, Japan, and the Asian Institute of

Gastroenterology (AIG), Hyderabad, India. Inclusion crite-

ria were age 25–75 years, presence of dyspepsia, consecu-

tive scheduled upper gastrointestinal endoscopies, and

Japanese or Indian ethnicity. We excluded patients with a

history of H. pylori eradication and those with upper gas-

trointestinal surgery, concomitant severe illness, regular use

of aspirin, treatment with nonsteroidal anti-inflammatory

drugs, or treatment with proton-pump inhibitors within four

weeks before enrollment. Endoscopic biopsy was performed

for all patients ultimately enrolled. The institutional review

boards of the NCGM and the AIG approved the study pro-

tocol. Informed consent was obtained from all subjects in

accordance with the Declaration of Helsinki.

Endoscopy

All endoscopies were performed by experienced endosco-

pists. Endoscopic diagnosis included reflux esophagitis,

hyperplastic polyp, gastric ulcer, and duodenal ulcer.

Histology

Biopsy specimens were taken from three sites of the gastric

mucosa as follows: the greater curvature of the antrum, the

incisura angulus, and the greater curvature of the upper body.

Three biopsy specimens were taken from each patient. The

biopsied specimens were fixed in 10 % (v/v) formalin,

embedded in paraffin, stained with hematoxylin–eosin and

Giemsa, and analyzed immunohistochemically as described

elsewhere using a polyclonal anti-H. pylori antibody (Dako,

Glostrup, Denmark) and an anti-East Asian CagA-specific

antibody prepared in our laboratory (Fig. 1) [14]. The latter

632 Dig Dis Sci (2014) 59:631–637

123

mouse monoclonal antibody was raised against the peptide

AINRKIDRINKIASAGKG, which is specific to East Asian

CagA. Tissue sections from patients with Western CagA or

CagA-negative status do not react with this antibody. The

sensitivity, specificity, and accuracy of this immunohisto-

chemical method were 96.7, 97.9, and 97.1 %, respectively

[15]. Slides were interpreted by an expert pathologist (T.U.)

who was not informed of the patients’ clinical and endo-

scopic findings.

Updated Sydney System Score

In accordance with the Updated Sydney System, a score of

0–3 (0, absent; 1, mild; 2, moderate; 3, marked) was

assigned for the variables as follows: H. pylori density,

neutrophil and mononuclear cell infiltration, glandular

atrophy, and intestinal metaplasia [16]. Scores for each of

the three biopsy specimens were summed, giving a possible

range in scores of 0–9. We calculated the corpus-pre-

dominant gastritis/antrum-predominant gastritis ratio from

the scores for neutrophil infiltration from the antrum and

from the upper body.

Assessment of H. pylori Status

Helicobacter pylori infection was evaluated by staining

tissue sections with hematoxylin–eosin and Giemsa com-

bined with immunostaining using antibodies against H.

pylori. When all of these methods yielded negative results,

H. pylori infection was considered negative.

Statistical Analysis

All statistical analysis was performed by use of SPSS

statistical software version 17.0 (SPSS, Chicago, IL, USA).

Patient characteristics, endoscopic diagnosis, and CagA

status were compared by use of Fisher’s exact test. Total

histological scores between patients from India and Japan

were compared by use of the Mann–Whitney test.

Results

Patient Characteristics

Three-hundred and fifty-three patients who met the initial

set of inclusion criteria were examined by endoscopy

(Fig. 2). At the end of the selection process, 30 patients

from India were individually matched by age and sex with

30 from Japan. During the matching process, we regarded

the Indian patients as cases and randomly selected controls

from among Japanese patients according to sex and

decennial age. The characteristics of the 30 patients from

each country who met all of the inclusion criteria are

summarized in Table 1. There were no significant age or

sex differences between the two groups. The frequency of

reflux esophagitis was significantly higher in the Indian

group than in the Japanese group. There were no significant

differences in the other endoscopic findings, for example

gastric hyperplastic polyp, gastric ulcer, and duodenal

ulcer.

Severity of Gastritis

Among the 60 patients, median scores for H. pylori, neu-

trophils, mononuclear cells, atrophy, and intestinal meta-

plasia were 4.0, 4.0, 5.0, 3.0, and 0.0, respectively. The

scores for neutrophils, mononuclear cells, and atrophy were

significantly higher for subjects from Japan (neutrophils

4.0 vs 3.0, p \ 0.01; mononuclear cells 5.0 vs 4.5,

p = 0.03; atrophy 3.0 vs 2.0, p \ 0.01) (Fig. 3). The scores

for H. pylori density and intestinal metaplasia were also

higher in patients from Japan but without statistical signifi-

cance (H. pylori 5.0 vs 3.0, p = 0.08; IM 0.0 vs 0.0, p =

0.08). The corpus-predominant gastritis/antrum-predominant

Fig. 1 Immunohistochemistry of gastric mucosa biopsy specimens with anti-Helicobacter pylori antibody (a) and anti-East Asian-specific

antibody (b)

Dig Dis Sci (2014) 59:631–637 633

123

gastritis ratio in Japan (0.75) was significantly higher than

that in India (0.55) (p \ 0.01).

CagA Status

Biopsies were analyzed with anti-East Asian CagA-specific

antibody against H. pylori. Twenty-two (73.3 %) samples

from patients from Japan were positive. In contrast, biop-

sies of all patients from India were negative (p \ 0.01).

Discussion

The incidence of gastric cancer in Africa (11.8/100,000)

and South Asia (10.7/100,000) is very low, although the

prevalence of H. pylori infection is high [2]. Even among

Asian countries where the prevalence of H. pylori infection

is high, the incidence of gastric cancer varies, and is higher

in East Asia (37.5/100,000) than in South (26.5/100,000)

and Central Asia (2.3/100,000) [3]. We speculated that this

difference is associated with bacterial virulence and the

host’s inflammatory response to H. pylori. Therefore, we

Fig. 2 Study flow chart. Three-hundred and fifty-three patients who met the initial set of inclusion criteria were examined by endoscopy. At the

end of the selection process, 30 patients from India were individually matched by age and sex with 30 from Japan

Table 1 Patient characteristics and endoscopic diagnosis

India

(n = 30)

Japan

(n = 30)

p value

Age (median (IQR)) 50.0 (36.5–59.0) 50 (38.3–54.3)

Sex (M/F) 16/14 16/14

Symptoms n (%)

Epigastric pain 7 (23.3) 7 (23.3) 0.54*

Reflux symptoms 22 (73.3) 0 (0) 0.01*

Bloating 8 (26.7) 0 (0) 0.02*

Other 12 (40) 4 (13.3) 0.13*

Endoscopic biopsy n (%) 30 (100) 30 (100)

Endoscopic findings n (%)

Reflux esophagitis 9 (30) 2 (6.7) 0.04*

Gastric hyperplastic

polyps

0 (0) 0 (0) N.A.

Active gastric ulcer 3 (10) 2 (6.7) 1.00*

Active duodenal ulcer 9 (30) 3 (10) 0.10*

Macroscopically

normal

14 (46.7) 23 (76.7) 0.03*

IQR interquartile range, N.A. not applicable

* Fisher’s exact test

634 Dig Dis Sci (2014) 59:631–637

123

assessed inflammation of the gastric mucosa by use of

endoscopy and histopathology. Endoscopic assessment

showed that the frequency of reflux esophagitis was sig-

nificantly higher in study patients from India than in those

from Japan. This suggests that reflux esophagitis correlates

with the high prevalence of increased acid secretion by the

gastric mucosa of patients from India. This assumption is

supported by the finding that pathological atrophy in

patients from India was mild, because severe atrophy

resulted in hypoacidity, because of reduced numbers of

parietal cells.

In contrast, even though gastric ulcer correlates posi-

tively with gastric cancer and is more prevalent in Japan

than in other Asian countries [17], our study showed no

significant difference between countries in ulcer preva-

lence. These results might be because of differences in

endoscopic diagnostic standards between the two countries.

Despite standard endoscopic diagnosis defining gastric

ulcer as a mucosal defect that is 3 mm or larger [18],

lesions that are typically diagnosed as erosions in Japan

might have been diagnosed as ulceration in India. Despite

efforts to ensure that endoscopic atrophic gastritis was

assessed in accordance with the classification of Kimura

and Takemoto [19], endoscopists in India might not be

sufficiently familiar with the classification of atrophic

borders to enable accurate assessment.

Gastric cancer may develop through H. pylori-related

chronic inflammation of the gastric mucosa followed by

atrophic gastritis, intestinal metaplasia, and dysplasia [20].

The development of gastric cancer is associated with

neutrophil infiltration [4], atrophy [21], and intestinal

metaplasia [21]. Several studies have evaluated differences

in the development of gastric cancer between countries, on

the basis of histological inflammation of the gastric mucosa

[7, 11, 22]. In their comparison of H. pylori-positive Tai-

wanese, Lithuanian, and Latvian subjects, Jonaitis et al.

[10] found no significant differences in atrophy or intesti-

nal metaplasia. In contrast, in a comparison of H. pylori-

positive Japanese, Korean, and American subjects, Lee

et al. [8] found that neutrophils, atrophy, and intestinal

metaplasia in the antrum were significantly more frequent

in Korea than in the United States. Naylor et al. [9] found

that corpus-predominant gastritis, pangastritis, severe

atrophy, and intestinal metaplasia were significantly more

frequent in subjects in Japan than in those in the United

Kingdom. Although the present study included a few H.

pylori-negative subjects, it matched subjects by age and

sex.

Fig. 3 Median histology scores for H. pylori-infected patients and

cumulative biopsy scores. a H. pylori density (p = 0.08), b neutrophil

infiltration (p \ 0.01), c mononuclear cell infiltration (p \ 0.01),

d glandular atrophy (p \ 0.01), and e intestinal metaplasia

(p = 0.08). The horizontal line inside each box indicates the median,

and the top and bottom of each box indicate the 25th and 75th

percentiles, respectively. The I bars indicate maximum and minimum

values

Dig Dis Sci (2014) 59:631–637 635

123

Similar studies have also been conducted among Asia

populations. In a comparison between Japanese and Indo-

nesian subjects who were H. pylori-positive, Abdullah

et al. [11] found that neutrophil and mononuclear cell

infiltration, atrophy, and intestinal metaplasia were more

frequent in Japanese patients. In a multilateral comparison

among Japanese (n = 120), Chinese (n = 105), Thai

(n = 145), and Vietnamese (n = 80) subjects matched by

age, sex, and endoscopic diagnosis, Matsuhisa et al. [7]

demonstrated that gastric ulcer, atrophy in the angulus, and

intestinal metaplasia were significantly more frequent in

Japan. These authors also demonstrated that the corpus-

predominant/antrum-predominant gastritis ratio was higher

in Japan than in China (Beijing), Thailand, and Vietnam

[22].

This study included only subjects who were H. pylori-

positive, and subjects were matched by age and sex. This

might have led to a more accurate comparison of gastritis.

Scores for inflammation of the gastric mucosa were sig-

nificantly higher in Japanese patients than in Indian

patients, which is consistent with the findings of other

studies of patients in Asia [7, 11, 22]. The results suggest

that this variable is associated with the high prevalence of

gastric cancer in Japan and reflects similar comparisons

between patients in Japan and those in other Asian

countries.

We show here that the prevalence of infection with East

Asian CagA-positive H. pylori was 73.3 % in Japan and

0 % in India. The cagA gene is polymorphic and is pri-

marily classified into East Asian and Western types

according to sequences located in the 30 coding region [23].

In East Asia, at least 90 % of H. pylori-positive subjects

are CagA-positive, versus approximately 40 % in the West

and Africa [24]. East Asian-type H. pylori is particularly

prevalent in Japan, Korea, and China, and less so in South

and Central Asia [25]. Gastritis, atrophy, and peptic ulcer

are more severe in subjects infected with East Asian CagA-

positive H. pylori than in subjects with Western CagA-

positive H. pylori or CagA-negative H. pylori, and mor-

tality from gastric cancer is 2.7-times higher [26]. There-

fore, East Asian CagA status may be an important

determinant of the differences in histology scores between

Indian and Japanese patients.

The strengths of this study include its exclusion of

patients with a history of H. pylori eradication [27], or with

regular use of aspirin [28], nonsteroidal anti-inflammatory

drugs, [29] or proton-pump inhibitors [30]. These drugs can

affect the gastric mucosa and preclude accurate assessment

of the inflammatory effects of H. pylori infection on the

gastric mucosa. Moreover, Giemsa staining and immuno-

histochemistry using anti-H. pylori antibody, with hema-

toxylin–eosin staining, facilitated more accurate diagnosis

of H. pylori infection. One limitation is that the inclusion of

patients positive only for H. pylori reduced the number of

subjects. Inclusion of a larger number of samples might

have enabled the detection of significant differences in H.

pylori density and intestinal metaplasia. Moreover, all

examinations of gastritis were performed by a gastroin-

testinal pathologist in Japan, and reproducibility could

therefore not be assessed. Another limitation is that

molecular genetic tests were not used to detect H. pylori

infection.

In conclusion, this study clarifies differences in H.

pylori-infected gastric mucosa between Indian and Japa-

nese patients matched for age and sex. The frequency of

reflux esophagitis was higher in patients from India. In

contrast, histology scores for H. pylori, neutrophil and

mononuclear cell infiltration, atrophy, and intestinal

metaplasia were higher in patients from Japan. East Asian

CagA-positive H. pylori was detected in patients from

Japan only. These differences may account for the different

incidence of gastric cancer in these two countries.

Acknowledgments This work was supported by a Grant-in-Aid

from the Ministry of Health Labor and Welfare of Japan and a Grant-

in-Aid from the Ministry of Education, Culture, Sports, Science, and

Technology of Japan (271000) and a grant from the National Center

for Global Health and Medicine. The funders were not involved in

study design, data collection and analysis, decision to publish, or

preparation of the manuscript. We thank Hisae Kawashiro, Clinical

Research Coordinator, NCGM, Tokyo, Japan, for assistance with data

collection. We express our sincere gratitude to Drs Anuradha Sekaran

and Mitnala Sasikala, AIG, Hyderabad, India for the pathological

specimens and blood samples.

Conflict of interest None.

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