ORIGINAL ARTICLE

Gastric Acid Secretion of Normal Japanese Subjects in Relation to

Helicobacter pylori Infection, Aging, and Gender
K. Iijima, S. Ohara, T. Koike, H. Sekine & T. Shimosegawa
Dept. of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
Scand J Gastroenterol Downloaded from informahealthcare.com by SUNY State University of New York at Stony Brook on 11/01/14

Iijima K, Ohara S, Koike T, Sekine H, Shimosegawa T. Gastric acid secretion of normal Japanese
subjects in relation to Helicobacter pylori infection, aging, and gender. Scand J Gastroenterol
2004;39:709–716.
Background: In Japan, where the incidence of gastric cancer is high, Helicobacter pylori infection could
affect gastric acid secretion differently from that in Western countries. The aim of this study was to
investigate the relationship between H. pylori infection, acid secretion, aging, and gender in normal
Japanese subjects. Methods: The study comprised 193 Japanese subjects who had undergone routine
endoscopy. Gastrin-stimulated acid output was performed during the routine endoscopic examination
using the endoscopic method of gastric acid secretory testing (EGT: endoscopic gastrin test), which has
been reported previously. H. pylori status was determined by histology, rapid urease test, and serology.
Results: Mean EGT values were 3.9  1.5 mEq/10 min in H. pylori-negative men, 1.6  2.5 in H. pylori-
positive men, 2.2  0.9 in H. pylori-negative women, and 1.5  1.2 in H. pylori-positive women.
Although acid secretion was lower in H. pylori-positive subjects compared with H. pylori-negative
subjects in both men and women, the decrease was more marked in men with H. pylori infection.
Multiple linear regression analysis showed that aging is positively associated with gastric acid secretion
in the H. pylori-negative subjects, whereas a negative association was found between them in the H.
pylori-positive subjects. Conclusions: In Japanese subjects, aging affects gastric acid secretion
differently depending on the status of H. pylori infection. H. pylori infection showed a stronger
For personal use only.

inhibitory effect on the acid secretion in men than in women. This gender-related difference in the
susceptibility of acid secretion to H. pylori infection may explain the higher rates of gastric cancer in men
in Japan.
Key words: Aging; gastric acid secretion; gender; H. pylori infection
Katsunori Iijima, M.D., Dept. of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1
Seiryo-machi, Aobaku, Sendai 980–8574 Japan (fax. ‡81 22 717 7177, e-mail. jiijima@int3.med.
tohoku.ac.jp)

A
fter the discovery of Helicobacter pylori, there have
been several attempts to re-evaluate the effect of
aging on gastric acid secretion in healthy subjects,
giving consideration to H. pylori infection (1–5). However,
most of these sutdies demonstrated the results of H. pylori-
negative and -positive subjects together (1–4), and very few
showed the relation between aging and acid secretion in H.
pylori-negative and -positive subjects separately (5). H. pylori
infection has been demonstrated to have various effects on
gastric acid secretion (6, 7); stimulation through hyper-
gastrinemia (8) or inhibition by gastric body gastritis and
consequent atrophic gastritis (9, 10). In Western countries, the
bi-directional effects on gastric acid secretion are counter-
balanced in the majority of H. pylori-positive subjects,
leading to no overall change in acid secretion (11–14). As a
result, gastric acid secretion in healthy Western men is
comparatively preserved despite aging (1–4, 15) and is
independent of H. pylori status (2).
On the other hand, in Japan where the incidence of gastric
cancer is the highest in the world, gastric acid secretion is
thought to decline sharply with aging (16) as a result of
advances of body gastritis and gastric mucosal atrophy with
aging (17). However, because it was clarified that the
development of gastric mucosal atrophy was confined mostly
to H. pylori-positive subjects (18), even in the Japanese
population (19), the relation between age and gastric acid
secretion could be different between H. pylori-negative and
-positive subjects. So far, there have been two reports on the
Japanese population examining the relation between gastric
acid secretion and aging that have taken H. pylori infection
into account (5, 20). However, one of them was a retro-
spective study based on the data of decades ago (5). The other
aimed to compare the data of acid secretion obtained in the
1970s and 1990s, but they involved relatively small numbers
of subjects in each period (n = 56 or 54, respectively) and
included few young subjects in their 20s or 30s (20).
Gender is another variable suggested as important in gastric
acid secretion (21, 22). Most previous studies have reported
higher gastric acid secretion in men than in women, which
was ascribed to the variation in gastric surface area (23) or the

 2004 Taylor & Francis DOI 10.1080/00365520410005911

 710 K. Iijima et al.
difference in parietal cell sensitivity to gastrin (24). However,
few studies have been undertaken to investigate the gender-
related difference in gastric acid secretion specifically in
relation to H. pylori infection.
Recently, we have developed a rapid, simple endoscopic
method for evaluating gastrin-stimulated maximal acid output
(the endoscopic gastrin test (EGT)) (25). The EGT facilitates
the performance of routine endoscopic examination and
stimulated acid secretory testing simultaneously within about
15 min. Using this method, we have reported the relation
between acid secretion and status of H. pylori infection (7),
Scand J Gastroenterol Downloaded from informahealthcare.com by SUNY State University of New York at Stony Brook on 11/01/14
and its relevance to reflux esophagitis (26, 27). In this study,
we evaluated the gastrin-stimulated acid output by EGT
prospectively in a large number of subjects who underwent
routine upper endoscopy and compared the gastric acid
secretion between H. pylori-positive and -negative normal
Japanese subjects. We also investigated the effects of aging
on gastric acid secretion separately in the H. pylori-positive
and -negative subjects, and of gender on gastric acid
secretion.
Methods
Subjects
Initially, 165 subjects aged 20 to 79 years who were
attending Tohoku University outpatient clinic for routine
For personal use only.
upper gastrointestinal (GI) endoscopy were prospectively
enrolled in this study over a period of 2 years, from April 1997
to March 1999. Subjects with clinical symptoms suggestive of
upper GI disease such as heartburn, nausea, or epigastralgia
were excluded. Individuals with malignant diseases, systemic
diseases, history of peptic ulcer, gastric surgery including
endoscopic surgery were also excluded. None of the subjects
enrolled were taking any drug inhibiting gastric acid secre-
tion. Therefore the study group consisted mainly of asympto-
matic subjects who attended the clinic for an annual
endoscopic check-up, and a small proportion of subjects
with various mild to moderate symptoms unrelated to upper
GI (lower abdominal pain in 8, right hypochondriasis in 3,
mild anemia in 2, body weight loss in 2, diarrhea in 2,
dysphasia in 1, chest pain in 1, and bloody stools in 1 subject).
If the diagnoses of carcinoma, peptic ulcer, polyp, or reflux
esophagitis (more than Los grade B) were made on
endoscopic examination, these subjects were excluded from
the analysis. Consequently, 3 subjects with peptic ulcer scar, 3
with gastric hyperplastic polyps, and 2 with reflux esophagitis
were excluded, and the remaining 157 subjects were finally
included for the analysis. To assess the effect of age on the
parameters of interest, these subjects were divided into three
groups according to age: young (20–39 years old, n = 23),
middle-aged (40–59 years old, n = 77), and elderly (60–79
years old, n = 57). Because of a relatively small number of
subjects of young age in our original study group from the
outpatients’ clinic, 36 healthy volunteers aged 20 to 39 years
were also recruited to the study and analyzed together with the
Scand J Gastroenterol 2004 (8)
others. To rationalize the inclusion of young healthy
volunteers into the study group and the analysis in unifying
them as a group, the acid secretion was compared between the
young volunteer group and the young non-volunteer group.
No statistical difference was found in the acid secretion
between these two groups using Student’s t test (mean  s
(standard deviation) = 2.4  1.2, and 2.8  1.2 mEq/10 min.
respectively, P > 0.1). In addition, even if analyzed by
multiple linear regression with regard to the acid secretion
as a dependent variable and with regard to the entry status
(volunteers or non-volunteers), age, H. pylori status, smoking
habits, body weight as the independent variables, the entry
status did not show any independent influence on the acid
secretion (P > 0.5). The study was conducted in accordance
with the Helsinki Declaration as revised in Tokyo, and
informed consent was obtained from each subject.
EGT (endoscopic gastrin test)
The details of EGT have been reported previously (25).
Briefly, after an overnight fast, subjects were injected
intramuscularly with tetragastrin (Gastopsin Nippon Kayaku,
Tokyo, Japan) at a dose of 4 mg/kg about 15 min before the
endoscopy. During the endoscopic test, gastric fluid pooled in
the stomach was aspirated first and discarded. Gastric juice
secreted between 20 and 30 min after the tetragastrin injection
was aspirated and collected under direct visualization during
the routine endoscopic examination of the stomach and
duodenal bulb. After the collection of gastric juice, biopsy
specimens were taken if indicated, and the endoscope was
removed. The volume of gastric juice collected during the 10-
min period was recorded, and its H‡ concentration was
determined by titration. Acid output in the 10 min period was
calculated by multiplying the volume by H‡ concentration,
and the EGT value was expressed as mEq/10 min. We have
shown previously that EGT values correlate well with peak
acid output determined by conventional methods (correlation
efficient = 0.92) with high reproducibility (coefficient of
variation = 5.6%) (25).
Histology
Biopsy specimens were taken endoscopically from the
gastric antrum and upper body in the greater curvature and
evaluated histologically. Using the updated Sydney system,
the degrees of inflammation (lymphocyte and plasma cell
infiltration of the lamina propria), activity (neutrophilic
infiltration), and atrophy were scored from 0 to 3. If
inflammation or activity was found to be positive, a diagnosis
of superficial or active gastritis was made, respectively. If
atrophy of gastric mucosa was present, a diagnosis of atrophic
gastritis was made irrespective of the presence of superficial
or active gastritis. Histological assessment was performed by
two independent pathologists in a blinded manner (SO and
HS).
 H. pylori Infection and Gastric Acid Secretion 711
Scand J Gastroenterol Downloaded from informahealthcare.com by SUNY State University of New York at Stony Brook on 11/01/14

Fig. 1. Distribution of endoscopic gastrin test (EGT) values (mEq/10 min) in normal male and female
subjects as a function of Helicobacter pylori status. Mean values are represented by the horizontal bars.
An asterisk (*) = P < 0.01; N.S = not significant.

H. pylori determination
Biopsy specimens of the stomach taken endoscopically, as
above, were also evaluated histologically for the presence of
H. pylori. At the same time, another set of biopsy specimens
was taken for rapid urease testing. In addition, a blood sample
For personal use only.
and smoking habits are considered to be two other important
variables in gastric secretory function. Hence, these four
variables were included in the analysis model as independent
variables with the EGT value as a dependent variable. A P
value <0.05 was considered to be statistically significant.

was obtained to determine the titer of serum IgG antibodies

against H. pylori. The patient was considered to be H. pylori
positive if one or more of the diagnostic methods applied were
positive, and H. pylori negative if all the methods were
negative.
Statistical methods
The EGT values are expressed as means  s. The Mann-
Whitney U test was used to make a comparison between the
H. pylori-negative and -positive groups within each subgroup
set. Each demographic, serologic, secretory, and histological
value was compared among the three age groups using
analysis of variance (ANOVA). A multiple linear regression
analysis was used to further assess which factors were related
to the acid secretion among H. pylori-negative and -positive
groups separately. Other than age and gender, body weight
Results
A total of 193 Japanese subjects (157 outpatients plus 36
healthy volunteers) who were free from upper GI symptoms
and had normal endoscopic findings were analyzed. The
demographic features of the three age groups are presented in
Table I. The mean ages of these three groups were 29.6, 51.3,
and 67.6 years, respectively. The three age groups did not
show any difference in gender distribution, body weight, and
smoking habits. The prevalence of H. pylori infection
increased with aging; 36%, 68%, and 80% in the respective
age groups, these percentages being similar to those reported
elsewhere in an asymptomatic Japanese population (28). As a
whole, gastric acid secretion decreased significantly with

Table I. Comparison of demographics among three age groups

Young Middle-aged Elderly
Parameters/Age group (Less than 39) (40 to 59) (More than 60) P value
Number (n) 59 77 57
Mean age (years) 29.6  6.2 51.3  5.2 67.6  4.3
% of male subjects 54 53 48 ns
Body weight (kg) 61.6  13.3 60.4  10.1 59.2  11.1 ns
H. pylori positive rate (%) 36 68 80 P < 0.01
% of smoker 19 29 19 ns
EGT values (mEq/10 min) 2.6  1.2 2.2  1.6 1.6  1.8 P < 0.01
Continuous variables are represented in means  s (standard deviation).
ns = Not significant; EGT = endoscopic gastrin test.

Scand J Gastroenterol 2004 (8)

 712 K. Iijima et al.
Scand J Gastroenterol Downloaded from informahealthcare.com by SUNY State University of New York at Stony Brook on 11/01/14

Fig. 2. Distribution of endoscopic gastrin test (EGT) values (mEq/10 min) in Helicobacter pylori-
For personal use only.

negative and -positive subjects as a function of age groups in men (upper panel) and women (lower
panel). Open circles represent H. pylori-negative individuals and closed circles represent H. pylori-
positive individuals. Mean values are represented by the horizontal bars. In the statistical analysis
between H. pylori-negative and -positive subjects within each age group, an asterisk (*) indicates
P < 0.01 and others are not significant. In the statistical analysis among three age groups within H.
pylori-negative or -positive subjects, # and ## indicate P < 0.05 and P < 0.01, respectively, and others
are not significant.

aging, in concordance with the results shown in a previous
study of a Japanese population (16) (Table I).
Comparison of acid secretion between H. pylori-positive
and H. pylori-negative subjects was shown separately in men
and women (Fig. 1). The mean EGT value in H. pylori-
positive men was 1.6  2.5 mEq/10 min, which was much
lower than H. pylori-negative men (3.9  1.5 mEq/10 min).
The level of acid secretion in the majority of H. pylori-
positive men was below the value of most H. pylori-negative
men, although there was a relatively large variation in the
level of acid secretion in the former. In women, this difference
in acid secretion by H. pylori status was less prominent.
Although the mean EGT value in H. pylori-positive women
was 1.5  1.2 mEq/10 min, which was significantly lower
than that of H. pylori-negative women (2.2  0.9 mEq/
10 min), there was a large overlap in the value between H.
pylori-negative and -positive women. Consequently, the
gender difference in acid secretion was obvious among the
H. pylori-negative subjects with the mean value of women
being 56% that of men, whereas it was similar irrespective of
gender among H. pylori-positive subjects.
Acid secretion in relation to gender and H. pylori status is
further illustrated in Fig. 2 according to the three age groups.
In H. pylori-negative men, the mean EGT values of the
young, middle-aged, and elderly groups were 3.6  1.0 mEq/
10 min, 4.6  1.0, or 5.2  2.1, respectively. The values of
the middle-aged or elderly groups were significantly higher
than those of the young group (P < 0.05, P < 0.01, respec-
tively). The mean EGT values of the respective age groups in
H. pylori-positive men were as follows; young: 1.7 
1.3 mEq/10 min, middle-aged: 1.9  1.8, elderly: 1.0  1.2.
The value of the elderly group was significantly lower than
that of the middle-aged group (P < 0.05). Furthermore, a
substantial number of H. pylori-positive subjects in the
middle-aged or elderly group showed extremely low acid
secretion, verging on achlorhydria. When the level of acid
secretion in men was compared between H. pylori-positive
and -negative subjects in the respective age groups, H. pylori-
positive subjects in all three age groups showed significantly
lower acid secretion levels than those of the H. pylori-
negative subjects. In particular, the majority of H. pylori-
positive subjects in the middle-aged or elderly group showed
acid secretion below the lower limit of H. pylori-negative
subjects.

Scand J Gastroenterol 2004 (8)


Table II. Stratum analysis using multiple linear regression analysis
by H. pylori status to predict gastric acid secretion (EGT values)
H. pylori H. pylori
negative group positive group
Independent
variables Association P values Association P values
Age Positive P < 0.01 Negative P < 0.01
Male gender Positive P < 0.01 ns
Body weight ns ns
Smoking habits ns Positive P < 0.01
ns = Not significant; EGT = endoscopic gastrin test.
Scand J Gastroenterol Downloaded from informahealthcare.com by SUNY State University of New York at Stony Brook on 11/01/14
The mean EGT values of H. pylori-negative women were
2.1  0.6 mEq/10 min, 2.1  0.9, and 2.6  0.8 in the young,
middle-aged, and elderly groups, respectively. There was a
tendency towards an increased mean level with aging,
although there was no significant difference among the three
groups. The mean EGT values of H. pylori-positive women
were 2.3  0.9 mEq/10 min in the young, 1.6  1.1 in the
middle-aged, and 1.1  1.1 in the elderly groups. The value
for the elderly group was significantly lower than that for the
young group (P < 0.01). When acid secretion was compared
between H. pylori-positive and -negative women in the
respective age groups, there was no significant difference
between them in the young and middle-aged groups, but the
difference was significant in the elderly group.
Furthermore, because the effect of aging on acid secretion
For personal use only.
seemed to be different in association with the presence of H.
pylori infection, stratum specific analyses were performed
separately in H. pylori-negative and -positive subjects using
multiple linear regressions to predict the factors affecting acid
secretion (Table II). Aging was positively associated with
gastric acid secretion among H. pylori-negative subjects,
whereas it showed a negative association with gastric acid
secretion. Male gender was positively associated with gastric
acid secretion only in the H. pylori-negative subjects. In
addition, smoking was found to be a positive predictor for
gastric acid secretion in the H. pylori-positive subjects.
The prevalence of gastritis and atrophy of gastric body in
118 H. pylori-positive subjects are presented in Table III
according to the three age groups. Superficial gastritis of the
body was observed in over 95% of H. pylori-positive subjects,
irrespective of the age. Active gastritis of the body was also
seen in a high portion (around 70%) in all three age groups. In
contrast, atrophy of the gastric body was more prevalently
seen with increasing age, being 10%, 26%, and 44% in the
young, middle-aged, and elderly group, respectively. The
Table III. Prevalence of gastritis and atrophy in the stomach body of 118 H. pylori-positive subjects according to three age groups
Prevalence of grade of body gastritis/ Young
Age group (Less than 39)
Superficial gastritis (%) 95
Active gastritis (%) 67
Atrophic gastritis (%) 10
ns = Not significant.
H. pylori Infection and Gastric Acid Secretion 713
prevalence or the severity of those histologic findings seen in
the gastric body of H. pylori-positive subjects did not differ
between men and women in the respective age groups (data
not shown). In H. pylori-negative subjects, gastritis and
atrophy of the gastric body were seen in only a few cases (data
not shown). Of 32 subjects who showed atrophy in the gastric
body, only 2 were free from atrophy in the antrum; one was H.
pylori positive and the other H. pylori negative. Therefore,
although intrinsic factors were not measured in this study, it is
considered that inclusion of autoimmune (type A) gastritis
was rare in this study population.
Discussion
In this study, 193 normal Japanese subjects were carefully
divided into H. pylori-negative and -positive groups using
three determination methods for H. pylori infection in order
separately to analyze the relation between aging and gastric
acid secretion in the respective groups. The first major finding
of this study was that gastric acid secretion was well
preserved irrespective of aging, rather it seemed to increase
with aging in the H. pylori-negative subjects, although it
declined with aging in the H. pylori-positive subjects.
Since our study group contained a relatively small number
of H. pylori-negative elderly subjects, as is always the case in
the general Japanese population (28), it may not be sufficient
to conclude that gastric acid secretion increases with aging in
H. pylori-negative Japanese subjects. However, the present
finding in the H. pylori-negative subjects seems to be
consistent with two previous studies performed in Western
populations (1, 23). Although it was reported before identi-
fication of H. pylori, one study of a Finnish population
showed that acid secretion in the group of subjects with
normal gastric body mucosa did not decrease with aging in
men, and in women, it actually increased significantly with
aging (23). The other study of healthy Americans, most of
whom were H. pylori-negative, demonstrated that aging was
associated with an increase in gastric acid secretion,
especially in men (1). The mechanism promoting the increase
in acid secretion with aging is unknown. However, since the
alteration of acid secretion by the inflammation of oxyntic
mucosa can be ignored in the H. pylori-free stomach, two
main possibilities could be considered: one is an increase in
the total parietal cell mass with age, and the second is an
increase in the reactivity of parietal cells. Because the
previous studies failed to find any change in parietal cell
Middle-aged Elderly
(40 to 59) (More than 60) P value
100 95 ns
69 68 ns
26 44 P < 0.01
Scand J Gastroenterol 2004 (8)
 714 K. Iijima et al.
mass with aging (29, 30), the second possibility is more
likely. Alternatively, different mechanisms may be respon-
sible according to gender for the increase in acid secretion
with aging. In that case, the female sex hormone estradiol,
which is known to have an inhibitory effect on acid secretion
(31–33), may be partly associated with the increase in acid
secretion after the menopause in H. pylori-negative women.
Anyway, since it has not been confirmed whether gastric acid
secretion actually increases with aging in H. pylori-negative
subjects, its relation to acid-related disease such as gastro-
esophageal reflux (GERD) in elderly subjects is unclear.
Scand J Gastroenterol Downloaded from informahealthcare.com by SUNY State University of New York at Stony Brook on 11/01/14
On the other hand, this study showed that gastric acid
secretion decreased with aging in the H. pylori-positive
subjects, which is consistent with two previous studies on
Japanese population (5, 20). In particular, the acid secretion in
H. pylori-positive subjects was extremely low in some
middle-aged and elderly subjects; these subjects in fact
were verging on achlorhydria. It is recognized that H. pylori
infection in gastric mucosa can inhibit gastric acid secretion
in humans either through body gastritis or through subse-
quently progressing body atrophy (10). In the current study,
the prevalence of active body gastritis was similarly high in
all age groups, even in young subjects (about 70%). This high
prevalence of body gastritis could therefore be associated
with hypochlorhydria seen in all age groups of H. pylori-
positive Japanese subjects. Since the prevalence of gastric
For personal use only.
atrophy progressed with aging in this study group, body
atrophy rather than body gastritis could be responsible for a
decline in the gastric acid secretion in H. pylori-positive
elderly Japanese subjects. The high prevalence of gastritis and
atrophy of the gastric body in Japanese subjects contrasts with
the results of recent reports from Western countries (34–36),
as has already been suggested in a paper elsewhere (37).
Another important finding of this study was that there is a
substantial gender-related difference in the effect of H. pylori
infection on gastric acid secretion. Among the H. pylori-
negative subjects in this study, there was a considerable
difference in acid secretory capacity between men and
women; acid secretion in women is 56% of that in men.
The difference in acid secretion according to gender has been
reported in a number of earlier papers, before the recognition
of H. pylori, on the study of Western control subjects (21–23)
and Japanese subjects (16). In this study population, there was
a substantial difference in mean body weight between men
and women (66  10 kg, 54  9 kg, respectively). In a pre-
vious study it was demonstrated that when the dose of hista-
mine, as a stimulant for gastric acid secretion, was calculated
in relation to body weight, it did not yield maximal acid
stimulation in lean populations (38, 39). Although 4 mg/kg
tetragastrin was used in this study, a smaller dose of tetra-
gastrin administered to women may partly explain the
difference in gastric acid secretion between male and female
H. pylori-negative subjects. In contrast, our present study also
demonstrated that when analyses were confined to H. pylori-
positive individuals, the level of acid secretion did not show
Scand J Gastroenterol 2004 (8)
any difference between men and women. This observation is
due to the fact that the difference in the level of gastric acid
secretion between H. pylori-positive and H. pylori-negative
men was greater than that of women, suggesting that H. pylori
infection may affect gastric acid secretion differently accord-
ing to gender. Consequently, the congenital male predomi-
nance in gastric acid secretion, as seen in H. pylori-negative
subjects, may be abolished by H. pylori infection. In com-
parisons of men among the three age groups, it was found that
the gastric acid secretion in H. pylori-positive men is already
decreased significantly at a younger age, followed by a further
decline in acid secretion with elderly subjects. In contrast, the
acid secretion in H. pylori-positive women is relatively pre-
served until over 60 years of age, and it showed a significant
difference only in this elderly group compared with the H.
pylori-negative counterpart.
The mechanism of this gender-related difference in the
susceptibility of gastric acid secretion to H. pylori infection is
unknown. The high prevalence of body gastritis seen
extensively among all age groups could be associated with
hypochlorhydria in H. pylori-positive subjects, as already
mentioned. However, the degree of body gastritis itself cannot
explain the difference in the acid secretion between genders
because H. pylori-induced gastritis infiltrates oxyntic mucosa
to the same degree in both genders in this study. It is therefore
likely that gastric parietal cells in male oxyntic mucosa are
more vulnerable to H. pylori-induced gastritis than in females,
leading to a greater inhibition of acid secretion in H. pylori-
infected men. Again, the interrelationship between sex
hormones such as testosterone or estradiol and H. pylori
infection may be involved in the gender-related difference in
the susceptibility since it has been recognized that sex
hormones have various effects on acid secretion (31–33).
Interestingly, in an earlier paper it was demonstrated that
parietal cells themselves might produce testosterone that
shows a stimulating effect on acid secretion (40). H. pylori-
induced gastritis in the oxyntic mucosa may abolish this
testosterone-related acid secretion in men. Whatever the
mechanism involved, the greater susceptibility of male gastric
acid secretion to H. pylori infection appears to be consistent
with the higher rates of gastric cancer in men, because hypo-
chlorhydria or achlorhydria is a well-known risk factor for
intestinal-type gastric cancer (41). In addition, the difference
according to gender in the human is also supported by a recent
study using the hypergastrinemic mouse model, which
demonstrated that the stomachs of male mice were injured
more rapidly and aggressively by H. pylori infection and that
gastric cancer developed only in H. pylori-infected male mice
after the 7-month observation period (42). However, it
remains uncertain whether a gender-related difference in the
susceptibility of gastric acid secretion to H. pylori infection is
a unique phenomenon seen only in a specific area with a high
incidence of gastric cancer such as Japan, or a universal one
that is also true in other areas with a lower incidence of gastric
cancer like Western countries.

Although there was a decline in acid secretion in the
majority of H. pylori-positive men in this study and therefore
H. pylori infection seemed to exert a greater inhibitory effect
in male subjects, it should be noted that the level of acid
secretion varied widely within the group. This suggests that
H. pylori infection does not always cause a reduction of acid
secretion, even in men. In fact, a few H. pylori-positive men
showed quite high levels of acid secretion. Furthermore, we
reported previously that the level of acid secretion is
significantly more elevated in H. pylori-positive men with
duodenal ulcers (mean  s = 5.3  2.5 mEq/10 min) than in
Scand J Gastroenterol Downloaded from informahealthcare.com by SUNY State University of New York at Stony Brook on 11/01/14
H. pylori-negative male controls (4.1  1.6 mEq/10 min) or
than in H. pylori-positive women with duodenal ulcer
(3.2  1.2 mEq/10 min) (25). Therefore, it is considered that
H. pylori infection causes an increase of acid secretion in a
small proportion of Japanese subjects leading to a predis-
position to duodenal ulcer, but that it causes a decrease in acid
secretion in the majority of Japanese subjects, in some of
them to a degree of remarkable hypochlorhydria, predispos-
ing to the development of intestinal-type gastric cancer.
Concerning this issue, a crucial question is which factors
keep the level of acid secretion above normal in a small
number of H. pylori-positive Japanese subjects. In some
studies researchers sought to explain this by IL-1b poly-
morphism (43, 44). Dietary factors such as salt intake or
antioxidant intake may also be important for the mechanism
For personal use only.
(45, 46). In addition, it is intriguing that in this study it was
demonstrated by multiple regression analysis that smoking
habit is an independent factor responsible for the increase in
acid secretion among H. pylori-positive subjects, but not so
among H. pylori-negative subjects. Although it is reported
that smoking increases gastric acid secretion not only in
duodenal ulcer patients but also in healthy controls subjects
(47), our study demonstrated that such a phenomenon was
only seen in the H. pylori-positive individuals. This finding is
in concordance with the results of a recent prospective cohort
study showing that smoking produced ulcer diathesis only in
individuals who were infected with H. pylori (48).
In conclusion, based on the results of 193 normal Japanese
subjects, this study reveals that gastric acid secretion is
preserved or may even be increased with aging in H. pylori-
negative subjects, but declines in H. pylori-positive subjects
with aging. In addition, there is a gender-related difference in
the susceptibility of gastric acid secretion to H. pylori
infection, which may explain the tendency towards a male
predominance of gastric cancer, at least in areas of high
incidence like Japan.
References
1. Goldschmiedt M, Barnett CC, Schwarz BE, Karnes WE, Redfern
JS, Feldman M. Effect of age on gastric acid secretion and serum
gastrin concentrations in healthy men and women. Gastroenter-
ology 1991;101:977–90.
2. Katelaris PH, Seow F, Lin BPC, Napoli J, Ngu MC, Jones DB.
Effect of age, Helicobacter pylori infection, and gastritis with
H. pylori Infection and Gastric Acid Secretion 715
atrophy on serum gastrin and gastric acid secretion in healthy
men. Gut 1993;34:1032–7.
3. Collen MJ, Abdulian JD, Chen YK. Age does not affect basal
gastric acid secretion in normal subjects or in patients with acid-
peptic disease. Am J Gastroenterol 1994;89:712–6.
4. Feldman M, Cryer B, McArthur KE, Huet BA, Lee E. Effects of
aging and gastritis on gastric acid and pepsin secretion in
humans: a prospective study. Gastroenterology 1996;110:1043–
52.
5. Haruma K, Kamada T, Kawaguchi H, Okamoto S, Yoshihara M,
Sumi K, et al. Effect of age and Helicobacter pylori infection on
gastric acid secretion. J Gastroenterol Hepatol 2000;15:277–83.
6. McColl KEL, El-Omar EM. Helicobacter pylori and disturbance
of gastric function associated with duodenal ulcer disease and
gastric cancer. Scand J Gastroenterol 1996;Suppl 215:32–7.
7. Iijima K, Ohara S, Sekine H, Kioke T, Kato K, Asaki S, et al.
Changes in gastric acid secretion assayed by endoscopic gastrin
test before and after Helicobacter pylori eradication. Gut 2000;
46:20–6.
8. El-Omar EM, Penman I, Ardill JES, Chittajallu RS, Howie C,
McColl KEL. Helicobacter pylori infection and abnormalities of
acid secretion in patients with duodenal ulcer disease. Gastro-
enterology 1995;109:681–91.
9. Rohrer GV, Welsh JD. Correlative study: gastric secretion and
histology. Gastroenterology 1967;52:185–91.
10. El-Omar EM, Oien K, El-Nujumi A, Gillen D, Wirz A, Dahill S,
et al. Helicobacter pylori infection and chronic gastric acid
hyposecretion. Gastroenterology 1997;113:15–24.
11. Tucci A, Corinaldesi R, Stanghellini V, Tosetti C, Febo GD,
Paparo GF, et al. Helicobacter pylori infection and gastric
function in patients with chronic idiopathic dyspepsia. Gastro-
enterology 1992;103:768–74.
12. Peterson WL, Barnett CC, Evans DJ, Feldman M, Carmody T,
Richardson C, et al. Acid secretion and serum gastrin in normal
subjects and patients with duodenal ulcer: The role of Helico-
bacter pylori. Am J Gastroenterol 1993;88:2038–43.
13. Hurlimann S, Dur S, Schwab P, Varga L, Mazzucchelli L, Brand
R, et al. Effect of Helicobacter pylori on gastritis, pentagastrin-
stimulated gastric acid secretion, and meal-stimulated plasma
gastrin release in the absence of peptic ulcer disease. Am J
Gastroenterol 1998;93:1277–85.
14. El-Omar EM, Oien K, Murray LS, El-Nujumi A, Wirz A, Gillen
D, et al. Increased prevalence of precancerous change in relatives
of gastric cancer patients: critical role of H. pylori. Gastroenter-
ology 2000;188:22–30.
15. Hurwitz A, Brady DA, Schaal SE, Samloff M, Dedon J, Ruhl CE.
Gastric acidity in older adults. JAMA 1997;278:659–62.
16. Yamagata S, Ishimori A, Sato H, Ishihara K, Masuda M, Kasugai
T, et al. Secretory function of the stomach of Japanese with
endoscopically normal gastric mucosa. Gastroenterol J 1975;10:
162–7.
17. Kimura K. Chronological transition of the fundic-pyloric border
determined by stepwise biopsy of the lesser and greater
curvatures of the stomach. Gastroenterology 1972;63:584–92.
18. Kuipers EJ, Uyterlinde AM, Pena AS, Roosendaal R, Pals G,
Nelis GF, et al. Long-term sequelae of Helicobacter pylori
gastritis. Lancet 1995;345:1525–8.
19. Kawaguchi H, Haruma K, Komoto K, Yoshihara M, Sumii K,
Kajiyama G. Helicobacter pylori infection is the major risk
factor for atrophic gastritis. Am J Gastroenterol 1996;91:959–62.
20. Kinoshita Y, Kawanami C, Kishi K, Nakata H, Seino Y, Chiba T.
Helicobacter pylori independent chronological change in gastric
acid secretion in the Japanese. Gut 1997;41:452–8.
21. Grossman MI, Kirsner JB, Gillespie IE. Basal and histalog-
stimulated gastric acid secretion in control subjects and in
patients with peptic ulcer or gastric cancer. Gastroenterology
1963;45:14–26.
22. Baron JH. Studies of basal and peak acid output with an
augmented histamine test. Gut 1963;4:136–44.
23. Kekki M, Samloff IM, Ihamaki T, Varis K, Siurala M. Age- and
sex-related behaviour of gastric acid secretion at the population.
Scand J Gastroenterol 1982;17:737–43.
24. Feldman M, Richardson CT, Walsh JH. Sex-related difference in
Scand J Gastroenterol 2004 (8)
 716 K. Iijima et al.
gastrin release and parietal cell sensitivity to gastrin in healthy
human beings. J Clin Invest 1983;71:715–20.
25. Iijima K, Ohara S, Sekine H, Koike T, Kubata Y, Kato K, et al. A
new endoscopic method of gastric acid secretory testing. Am J
Gastroenterol 1998;93:2113–8.
26. Koike T, Ohara S, Sekine H, Iijima K, Kato K, Toyota T, et al.
Increased gastric acid secretion after H. pylori eradication may
be a factor for developing reflux oesophagitis. Aliment
Pharmacol Ther 2001;15:813–20.
27. Koike T, Ohara S, Sekine H, Iijima K, Kato K, Toyota T, et al.
Helicobacter pylori infection prevents erosive reflux oesophagi-
tis by decreasing gastric acid secretion. Gut 2001;49:330–4.
28. Asaka M, Kimura T, Kudo M, Takeda H, Mitani S, Miyazaki T,
et al. Relationship of Helicobacter pylori to serum pepsinogens
Scand J Gastroenterol Downloaded from informahealthcare.com by SUNY State University of New York at Stony Brook on 11/01/14
in an asymptomatic Japanese population. Gastroenterology 1992;
102:760–6.
29. Kekki M, Sipponen P, Siurala M. Age behaviour of gastric acid
secretion in males and females with a normal antral and body
mucosa. Scand J Gastroenterol 1983;18:1009–16.
30. Farinati F, Formentini S, Della Libera G, Valiante F, Fanton MC,
Di Mario F, et al. Changes in parietal and mucus cell mass in the
gastric mucosa of normal subjects with age: a morphometric
study. Gerontology 1993;39:146–51.
31. Amure BO, Omole AA. Sex hormones and acid gastric secretion
induced with carbacol, histamine, and gastrin. Gut 1970; 11:
641–5.
32. Adeniyi AO. Gastric acid secretion and parietal cell mass: effect
of sex hormones. Gastroenterology 1991;101:66–9.
33. Girma K, Janczewska I, Romell B, Seensalu R, Sandin A,
Wilander E, et al. Twenty-four-hour basal and repetitive penta-
gastrin-stimulated gastric acid secretion in normal and sham-
operated rats and in rats after gonadectomy or treatment with
estradiol or testosterone. Scand J Gastroenterol 1997;32:669–75.
34. Dooley CP, Cohen H, Fitzgibbons PL, Bauer M, Appleman MD,
For personal use only.
Perez-Perez GI, Blaser MJ. Prevalence of Helicobacter pylori
infection and histologic gastritis in asymptomatic persons. N
Engl J Med 1989;321:1562–6.
35. Hackelsberger A, Gunther T, Schultze V, Peitz U, Malfertheiner
P. Role of aging in expression of Helicobacter pylori gastritis in
the antrum, corpus, and cardia. Scand J Gastroenterol 1999;34:
138–43.
36. Oksanen A, Sipponen P, Karttunen R, Miettinen A, Veijola L,
Sarna S, et al. Atrophic gastritis and Helicobacter pylori infec-
tion in outpatients referred for gastroscopy. Gut 2000;46:460–3.
Received 3 October 2004
Accepted 29 February 2004
Scand J Gastroenterol 2004 (8)
37. Imai T, Kudo T, Watanabe H. Chronic gastritis in Japanese with
reference to high incidence of gastric carcinoma. J Natl Cancer
Inst 1971;47:179–95.
38. Desai HG, Borkar AV, Jeejeebhoy KN. Dose–weight relation-
ship of histamine for maximal stimulation of gastric acid
secretion. Gastroenterology 1967;53:712–8.
39. Desai HG, Antia FP, Gupte UV, Potnis PR. Dose of histamine
for_maximal stimulation of gastric acid secretion. Gastroenter-
ology 1969;57:636–40.
40. Goascogne CL, Sananes N, Eychenne B, Gouezou M, Baulieu
EE, Robel P. Androgen biosynthesis in the stomach: expression
of cytochrome P450 17a-hydroxylase/17, 20-lyase messenger
ribonucleic acid and protein, and metabolism of pregnenolone
and progesterone by parietal cells of the rats gastric mucosa.
Endocrinology 1995;136:1744–52.
41. Svendsen JH, Dahl C, Svendsen LB, Christiansen PM. Gastric
cancer risk in achlorhydric patients. A long-term follow-up
study. Scand J Gastroenterol 1986;21:16–20.
42. Fox JG, Rogers AB, Lhrig M, Taylor NS, Whary MT, Dockray
G, et al. Helicobacter pylori-associated gastric cancer in INS-
GAS mice is gender specific. Cancer Res 2003;63:942–50.
43. El-Omar EM, Carrington M, Chow WH, McColl KEL, Bream
JH, Young HA, et al. Interleukin-1 polymorphism associated
with increased risk of gastric cancer. Nature 2000;404:398–402.
[correction published in Nature 2001;412:99].
44. Furuta T, El-Omar EM, Xiao F, Shirai N, Takashima M,
Sugimurra H. Interleukin 1b polymorphism increases risk of
hypochlorhydria and atrophic gastritis and reduces risk of duo-
denal ulcer recurrence in Japan. Gastroenterology 2002;123:92–
105.
45. Tsugane S, Kabuto M, Imai H, Grey F, Tei Y, Hanaoka T, et al.
Helicobacter pylori, dietary factors, and atrophic gastritis in five
Japanese populations with different gastric cancer mortality.
Cancer Causes Control 1993;4:297–305.
46. Lee AS, Kang D, Shim KN, Choe JW, Hong WS, Choi H. Effect
of diet and Helicobacter pylori infection to the risk of early
gastric cancer. J Epidemiol 2003;13:162–8.
47. Whitfield PF, Hobsley M. Comparison of maximal gastric
secretion in smokers and non-smokers with and without duodenal
ulcer. Gut 1987;28:557–60.
48. Rosenstock S, Jorgensen T, Bonnevie O, Anderson L. Risk
factors for peptic ulcer disease: a population based prospective
cohort study comprising 2416 Danish adults. Gut 2003;52:186–
93.