THE AMERICAN JOURNAL OF GASTROENTEROLOGY
© 1999 by Am. Coll. of Gastroenterology
Published by Elsevier Science Inc.
Vol. 94, No. 12, 1999
ISSN 0002-9270/99/$20.00
PII S0002-9270(99)00652-8
Helicobacter pylori Infection Inhibits
Reflux Esophagitis by Inducing Atrophic Gastritis
Tomoyuki Koike, M.D., Shuichi Ohara, M.D., Hitoshi Sekine, M.D., Katsunori Iijima, M.D.,
Katsuaki Kato, M.D., Tooru Shimosegawa, M.D., and Takayoshi Toyota, M.D.
The Third Department of Internal Medicine, Tohoku University School of Medicine, Sendai, Miyagi, Japan
OBJECTIVE: Although it is widely accepted that Helicobacter pylori (H. pylori) infection is an important cause of
atrophic gastritis, few studies have examined the relationship between H. pylori-induced atrophic gastritis and the
occurrence of reflux esophagitis. The present study was
aimed to examine the relationship between H. pylori infection, atrophic gastritis, and reflux esophagitis in Japan.
METHODS: A total of 175 patients with reflux esophagitis
were compared with sex- and age-matched 175 control
subjects. Diagnosis of H. pylori infection was made by
gastric mucosal biopsy, rapid urease test, and serum IgG
antibodies. Severity of atrophic gastritis was assessed by
histology and serum pepsinogen I/II ratio.
RESULTS: H. pylori infection was found in 59 (33.7%) patients with reflux esophagitis, whereas it was found in 126
(72.0%) control subjects. The grade of atrophic gastritis was
significantly lower in the former than in the latter. Among
the H. pylori-positive patients, atrophic gastritis was milder
in the patients with reflux esophagitis than in the patients
without it.
CONCLUSIONS: These findings suggest that most cases of
reflux esophagitis in Japan occur in the absence of H. pylori
infection and atrophic gastritis, and it may also tend to occur
in patients with milder gastritis even in the presence of H.
pylori infection. Therefore, H. pylori infection may be an
inhibitory factor of reflux esophagitis through inducing atrophic gastritis and concomitant hypoacidity. (Am J Gastroenterol 1999;94:3468 –3472. © 1999 by Am. Coll. of Gastroenterology)
INTRODUCTION
Regurgitation of acidic gastric contents into the esophagus
is a key mechanism of reflux esophatitis (1– 4), and effective
treatments are therefore based upon the suppression of gastric acid secretion (5–7). It develops more commonly in
elderly individuals (8, 9). However, in Japan, gastric acid
secretion decreases in aged persons because of increasing
incidence of atrophic gastritis (10). The apparent paradox of
the prevalence of reflux esophagitis in a population of higher
incidence of atrophic gastritis warrants further explanation.
Recent studies have shown that Helicobacter pylori (H.
pylori) infection is one of the most important factors contributing to the development of atrophic gastritis (11, 12).
However, few studies have examined the relation between
atrophic gastritis due to H. pylori infection and reflux esophagitis.
The aim of this study was to investigate the relationship
between the incidence of H. pylori infection, atrophic gastritis, and reflux esophagitis in Japan.
MATERIALS AND METHODS
Subjects
Patients who were both self- and physician-referred to our
university hospital and affiliated institutions between March
1995 and January 1998 were enrolled in the present study.
The reflux esophagitis group included 175 patients (97 men
and 78 women, mean age 63.4 ⫾ 1.2 yr, range 23–91 yr)
with endoscopically diagnosed erosive reflux esophagitis
but no other localized lesions in the upper gastrointestinal
tract. The degree of reflux esophagitis was classified into
grade A, B, C, or D according to the Los Angeles Classification (13) (grade A, 35 patients; grade B, 102 patients;
grade C, 30 patients; grade D, 8 patients). For each case, we
randomly selected age- and sex-matched asymptomatic control subjects (total 175 patients; 97 men and 78 women,
mean age 63.4 ⫾ 1.2 yr, range from 23–91 yr) from the
patients who visited our university hospital and affiliated
institutions during the same period. These individuals underwent upper gastrointestinal endoscopy but showed no
localized lesions in the esophagus, stomach, and duodenum.
They also denied a history of upper gastrointestinal diseases
or any related symptoms including heart burn and acid
regurgitation. Patients were excluded if they had taken antibiotics, H2-receptor antagonists or proton pump inhibitors
within 4 wk before endoscopic examinations. Informed consent was obtained from every subject. This study was approved by the Ethics Committee for the Human Research of
Tohoku University School of Medicine.
Study Design
DIAGNOSIS OF H. PYLORI INFECTION. Biopsy specimens of the stomach were taken endoscopically from the
gastric antrum and upper body along the greater curvature
from all patient for standard hematoxylin and eosin staining
AJG – December, 1999
Figure 1. The H. pylori infection was present in 59 (33.7%) out of
175 patients with reflux esophagitis, whereas it was in 126 (72.0%)
out of 175 sex- and age-matched control subjects. The prevalence
of H. pylori infection was significantly lower in patients with reflux
esophagitis than control subjects (p ⬍ 0.0001, ␹2 test). HP ⫽
Helicobacter pylori.
and rapid urease test. In addition, a blood sample was
obtained to determine the titer of serum IgG antibodies
against H. pylori. A patient was considered H. pylori-positive if one or more of the diagnostic methods applied was
positive, and H. pylori negative if all methods were negative.
DIAGNOSIS OF ATROPHIC GASTRITIS. Biopsy specimens were evaluated histologically, and the degree of atrophy was scored from 0 to 3 according to the updated Sydney
system (14). Histological assessment was performed by two
independent and blinded pathologists (TK and HS). As it
has been verified that progress of atrophic gastritis correlates well with stepwise reduction in the serum pepsinogen
I/II ratio (15, 16), serum pepsinogen I and II concentrations
were measured by the radioimmunoassay according to Ichinose et al. (17) in order to estimate the severity of atrophic
gastritis. The blood samples were taken before endoscopic
examinations, centrifuged, and the sera stored frozen at
⫺20°C until the assay.
Statistical Analysis
Results were expressed as the mean ⫾ SD. For statistical
analysis, the ␹2 test or Mann-Whitney U test was employed;
p values ⬍0.01 were considered to be statistically significant.
RESULTS
The diagnosis of H. pylori infection was made in 59 among
175 patients with reflux esophagitis (33.7%), whereas it was
made in 126 among 175 sex- and age-matched control
subjects (72.0%) (Fig. 1). The incidence was significantly
H. pylori Infection Inhibits Reflux Esophagitis
3469
lower in the patients with reflux esophagitis than in the
control subjects (p ⬍ 0.0001, ␹2 test).
The mean atrophy score of the antrum assessed by the
Updated Sydney system was significantly lower in the patients with reflux esophagitis than the control subjects
(0.52 ⫾ 0.86 vs 1.20 ⫾ 0.98, p ⬍ 0.0001 by Mann-Whitney
U test) (Fig. 2A). Similarly, the mean atrophy score of the
gastric body was significantly lower in the patients with
reflux esophagitis than the controls (0.09 ⫾ 0.29 vs 0.54 ⫾
0.89, p ⬍ 0.0001 by Mann-Whitney U test) (Fig. 2A). Next,
all patients and control subjects were divided into two
groups according to the presence (H. pylori-positive, n ⫽
185) or absence (H. pylori-negative, n ⫽ 165) of H. pylori
infection, and the mean atrophy score of the antrum and
body was compared. The mean atrophy score of the antrum
was not different between the reflux esophagitis group and
the control group when examined in the H. pylori-negative
subjects, but it was significantly lower in the reflux esophagitis group than the control when examined in the H.
pylori-positive subjects (0.97 ⫾ 0.90 vs 1.59 ⫾ 0.81, p ⬍
0.001 by Mann-Whitney U test) (Fig. 2B). Similarly, the
mean atrophy score of the gastric body was not different
between the two groups when examined in the H. pylorinegative subjects, but it was significantly lower in the
esophagitis group than the control when examined in the H.
pylori-positive subjects (0.21 ⫾ 0.41 vs 0.72 ⫾ 0.96, p ⬍
0.01 by Mann-Whitney U test) (Fig. 2B).
The mean serum pepsinogen I/II ratio, an indicator of
gastric acid secretion, was significantly higher in the patients with reflux esophagitis than in the control subjects
(4.74 ⫾ 1.66 vs 3.19 ⫾ 1.65, p ⬍ 0.0001 by Mann-Whitney
U test) (Fig. 3A). All patients and control subjects were
divided into two groups according to the presence (H. pylori-positive, n ⫽ 185) or absence (H. pylori-negative, n ⫽
165) of H. pylori infection, and the mean serum pepsinogen
I/II ratio was compared. The mean pepsinogen I/II ratio was
not different between the reflux esophagitis group and the
control group when examined in the H. pylori-negative
subjects, but it was significantly higher in the esophagitis
group than the control when examined in the H. pyloripositive subjects (3.73 ⫾ 1.58 vs 2.48 ⫾ 1.00, p ⬍ 0.0001
by Mann-Whitney U test) (Fig. 3B).
DISCUSSION
The pathophysiology of reflux esophagitis has been studied
extensively. Important factors predisposing to this disease
include the presence of hiatal hernia (18), transient relaxation of lower esophageal sphincter (1– 4), and impaired
clearance of regurgitated gastric contents in the esophagus
(19). Although acidity in the esophagus is a key factor in the
pathogenesis of reflux esophagitis, it has been reported that
no difference was found in the gastric acid secretion between patients with reflux esophagitis and matched controls
(20). The finding suggested the importance of inhibitory
mechanism for the regurgitation of acidic gastric contents.
3470
Koike et al.
AJG – Vol. 94, No. 12, 1999
Figure 2. A: The mean atrophy scores of the antrum (left) and the body (right) assessed by the Updated Sydney system were significantly
lower in the patients with reflux esophagitis than in the control subjects (antrum; 0.52 ⫾ 0.86 vs 1.20 ⫾ 0.98, p ⬍ 0.0001, body; 0.09 ⫾
0.29 vs 0.54 ⫾ 0.89, p ⬍ 0.0001 by Mann-Whitney U test). B: The mean atrophy scores of both the antrum (left) and body (right) were
not different between the reflux esophagitis group and the control in the H. pylori-negative subjects, whereas they were significantly lower
in the former than the latter in the H. pylori-positive subjects (antrum; 0.97 ⫾ 0.90 vs 1.59 ⫾ 0.81, p ⬍ 0.001, body; 0.21 ⫾ 0.41 vs 0.72 ⫾
0.96, p ⬍ 0.01 by Mann-Whitney U test). HP ⫽ Helicobacter pylori.
However, it has been also reported that esophagitis was
found only one of 12 patients with basal acid output of ⬍0.1
mEq/h, suggesting that decreased gastric acid secretion may
work for preventing the development of reflux esophagitis.
It is generally accepted that old individuals are more
liable to have reflux esophagitis (8, 9). The primary reason
is considered to be an increase in the esophagogastric dysfunction, a protection system of gastric acid regurgitation,
with advancing age (21, 22). The morbidity rates of atrophic
gastritis are higher in Japanese than in Western persons (10,
11). The most likely explanation for the prevalence of atrophic gastritis in Japan is the higher incidence of H. pylori
infection in older individuals compared with those in Western countries (11). How, then, can we account for the fact
that the prevalence of reflux esophagitis increases in this
older population, which is more likely to show atrophic
gastritis with hypoacidity, probably due to long-standing
Helicobacter infection?
Concerning the question, the results of this study clearly
demonstrated that the prevalence of H. pylori infection was
AJG – December, 1999
H. pylori Infection Inhibits Reflux Esophagitis
3471
Figure 3. A: The serum pepsinogen I/II ratio was significantly higher in the patients with reflux esophagitis than in the controls (4.74 ⫾
1.66 vs 3.19 ⫾ 1.65, p ⬍ 0.0001, Mann-Whitney U test). B: The pepsinogen I/II ratio was not different between the patients with and
without reflux esophagitis, compared in the H. pylori-negative cases, but it was significantly higher in the patients with reflux esophagitis
than in those without it when compared in the H. pylori-positive cases (3.73 ⫾ 1.58 vs 2.48 ⫾ 1.00, p ⬍ 0.0001, Mann-Whitney U test).
PG ⫽ pepsinogen; HP ⫽ Helicobacter pylori.
significantly lower in the patients with reflux esophagitis
than the age-matched control subjects who did not have
reflux esophagitis. Several controlled studies have been
performed on this issue, but the results are conflicting. Some
have reported that no difference was found in the prevalence
of H. pylori infection between the patients with esophagitis
and the control subjects who did not have any upper gastrointestinal tract lesions (23, 24), whereas others have reported that the prevalence was significantly lower in the
patients with esophagitis than the control subjects (25, 26).
The discordance might be caused by the different prevalence of H. pylori infection in control subjects according to
the respective studies. The prevalence of H. pylori infection
in control subjects in the present study was higher (72.0%)
than that of previous studies in Western countries, but was
equivalent to that reported in Japan (11).
Werdmuller et al. reported that the incidence of H. pylori
infection is significantly lower in patients with esophagitis
than in control subjects, but they concluded that H. pylori
does not play either a direct or an indirect role in the
pathogenesis of reflux esophagitis because it did not correlate with the severity of esophagitis (25). However, the
authors did not evaluate the grade of atrophic gastritis in
their patients with esophagitis or in the reference group. As
shown in the present study, the severity of atrophic gastritis,
as assessed by the updated Sydney system, and by the serum
pepsinogen I/II ratio was milder in the reflux esophagitis
group than in the control group. Moreover, even if the object
was limited to the patients with H. pylori infection, the
severity of atrophic gastritis was significantly milder in the
patients with reflux esophagitis than in those without it.
These data suggest that, in Japan, the majority of patients
with reflux esophagitis do not have H. pylori infection or
atrophic gastritis. In addition, even in the limited group of
patients with H. pylori infection, reflux esophagitis tended
to appear in those patients with milder atrophic gastritis.
Therefore, it is possible that H. pylori infection may be a
negative factor for the development of reflux esophagitis by
causing atrophic gastritis and concomitant decrease in gastric acid secretion. Because no difference was found in the
degree of atrophic gastritis estimated by histology and pepsinogen I/II ratio between the patients with reflux esophagitis and those without it when examined in the H. pylorinegative group, some factors other than the hypoacidity due
to atrophic gastritis (such as esophagogastric dysfunction)
may be more important for the development of reflux esophagitis in this group.
Asaka et al. have reported that the prevalence of H. pylori
infection in Japan increases with advancing age (11). The
incidence increases approximately 1%/yr for persons who
were born after 1950, whereas it is high (70 – 80%) and
relatively constant for those who were born before 1950.
The decrease in the prevalence of H. pylori due to the
Westernized life style in Japan will eventually lead to re-
3472
Koike et al.
duced frequency of atrophic gastritis (11). Although the
incidence of reflux esophagitis in Japan is, at present, less
than that in Western countries, our data predict that decrease
in the prevalence of H. pylori in future may ultimately result
in an increased incidence of reflux esophagitis even in our
country.
In summary, the present study clearly demonstrated that,
in Japan, the prevalence of H. pylori infection and the
degree of atrophic gastritis were significantly lower in the
patients with reflux esophagitis than in control subjects.
Thus, H. pylori infection may be a factor in suppressing the
development of reflux esophagitis through the induction of
atrophic gastritis.
AJG – Vol. 94, No. 12, 1999
11.
12.
13.
14.
15.
Reprint requests and correspondence: Tomoyuki Koike, M.D.,
The Third Department of Internal Medicine, Tohoku University
School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi
980-8574, Japan.
Received Dec. 31, 1998; accepted June 23, 1999.
16.
17.
REFERENCES
1. Dodds WJ, Dent J, Hogan WJ, et al. Mechanisms of gastroenterologeal reflux in patients with reflux esophagitis. N Engl
J Med 1982;307:1547–52.
2. Dent J, Holloway RH, Toouli J, et al. Mechanisms of lower
oesophageal sphincter incompetence in patients with symptomatic gastroesophageal reflux. Gut 1988;29:1020 – 8.
3. Kahrilas PJ, Dodds WJ, Hogan WJ, et al. Esophageal peristaltic dysfunction in peptic esophagitis. Gastroenterology 1986;
91:897–904.
4. Antaridis G, Snape WJ, Cohen S. Clinical and manometric
findings in benign peptic strictures of the esophagus. Dig Dis
Sci 1979;24:858 – 61.
5. Klinkenberg-Knol EC, Jansen JM, Festen HP, et al. Doubleblind multicentre comparison of omeprazole and ranitidine in
the treatment of reflux oesophagitits. Lancet 1987;1:349 –51.
6. Hetzel DJ, Dent J, Reed WD, et al. Healing and relapse of
severe peptic esophagitis after treatment with omeprazole.
Gastroenterology 1988;95:903–12.
7. Vantrappen G, Rutgeerts L, Schurmans P, et al. Omeprazole
(40 mg) is superior to ranitidine in short-term treatment of
ulcerative reflux esophagitis. Dig Dis Sci 1988;33:523–9.
8. Stoker DL, Williams JG, Leicestor DG, et al. Oesophagitis—A five year review. Gut 1988;29:A1450.
9. Collen MJ, Abdulian JD, Chen YK. Gastroesophageal reflux
disease in the elderly: More severe disease that requires aggressive therapy. Am J Gastroenterol 1995;90:1053–7.
10. Kimura K. Chronological transition of the fundic-pyloric bor-
18.
19.
20.
21.
22.
23.
24.
25.
26.
der determined by stepwise biopsy of the lesser and greater
curvatures of the stomach. Gastroenterology 1972;63:584 –92.
Asaka M, Kimura T, Kudo M, et al. Relationship of Helicobacter pylori to serum pepsinogen in an asymptomatic Japanese population. Gastroenterology 1992;102:760 – 6.
Kohli Y, Kato T, Iwaki M, et al. Endoscopic diagnosis of
Helicobacter pylori distribution in gastric mucosa of patients
with chronic gastritis. Eur J Gastroenterol Hepatol 1993;5:
127–31.
Armstrong D, Bennett JR, Blum AL, et al. The endoscopic
assessment of esophagitis: A progress report on observer
agreement. Gastroenterology 1996;111:85–92.
Dixon MF, Genta RM, Yardley JH, et al. The updated Sydney
system. International workshop on the histopathology of gastritis. Am J Surg Pathol 1996;20:1161– 81.
Samloff IM, Varis K, Ihamaki T, et al. Relationships among
serum pepsinogen I, serum pepsinogen II, and gastric mucosal
histology. A study in relatives of patients with pernicious
anemia. Gastroenterology 1982;83:204 –9.
Miki K, Ichinose M, Shimizu A. Serum pepsinogens as a
screening test of extensive chronic gastritis. Gastroenterol Jpn
1987;22:133– 41.
Ichinose M, Miki K, Furihata C, et al. Radioimmunoassay of
serum group I and group II pepsinogens in normal controls and
patients with various disorders. Clin Chim Acta 1982;126:
183–91.
Allison PR. Reflux esophagitis, sliding hiatal hernia and the
anatomy of repair. Surg Gynecol Obstet 1951;92:419 –31.
Stanciu C, Bennett JR. Oesophageal acid clearing: One factor
in the production of reflux oesophagitis. Gut 1974;15:852–7.
Hirschowitz BI. A clinical analysis, with appropriate controls
of gastric acid and pepsin secretion in clinical esophagitis.
Gastroenterology 1991;101:1149 –58.
Hollis JB, Castell DO. Esophageal function in elderly man. A
new look at “presbyesophagus”. Ann Intern Med 1974;80:
371– 4.
Mandelstam P, Lieber A. Cineradiographic evaluation of the
esophagus in normal adults. A study of 146 subjects ranging in
age from 21 to 90 years. Gastroenterology 1970;58:32–9.
Newton M, Bryan R, Bumham WR, et al. Evaluation of
Helicobacter pylori in reflux oesophagitis and Barrett’s oesophagus. Gut 1997;40:9 –13.
Hackelsberger A, Schultze V, Gunther T, et al. The prevalence
of Helicobacter pylori gastritis in patients with reflux
oesophagitis: A case-control study. Eur J Gastroenterol Hepatol 1998;10:465– 8.
Werdmuller BF, Loffeld RJ. Helicobacter pylori infection has
no role in the pathogenesis of reflux esophagitis. Dig Dis Sci
1997;42:103–5.
Varanasi RV, Fantry GT, Wilson KT. Decreased prevalence of
Helicobacter pylori infection in gastroesophageal reflux disease. Helicobacter 1998;3:188 –94.