Helicobacter pylori infection is associated with milder gastro-oesophageal reflux disease
Transcript of Helicobacter pylori infection is associated with milder gastro-oesophageal reflux disease
Helicobacter pylori infection is associated with mildergastro-oesophageal re¯ux disease
J . C. Y. WU, J. J . Y. SUNG, F. K. L. CHAN, J. Y. L. CHING, A. C. W. NG, M. Y. Y. GO,
S. K. H. WONG*, E. K. W. NG* & S. C. S. CHUNG*
Departments of Medicine & Therapeutics and *Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong
Accepted for publication 13 November 1999
INTRODUCTION
The relationship between Helicobacter pylori and gastro-
oesophageal re¯ux disease (GERD) has been a subject of
great dispute in recent years. The last few decades has
witnessed a gradually decreasing prevalence of H. pylori
infection in the West and a dramatic rise in incidence of
adenocarcinoma of the oesophagus and cardia.1±3
Provocative data from Labenz et al. suggest that era-
dication of H. pylori in patients with duodenal ulcer
leads to the development of re¯ux oesophagitis.4 In
Asia, where H. pylori is very prevalent, GERD is
relatively uncommon. We have previously reported
that the prevalence of H. pylori infection in GERD is
signi®cantly lower than in the asymptomatic Chinese
population.5 Recent studies have reported that GERD in
the Chinese population is generally less severe and
complications such as Barrett's oesophagus are rare.6±9
All these observations point to the potential protective
effects of H. pylori against the development of GERD. In
our study, however, up to one-third of GERD patients in
the Chinese population were infected with H. pylori.5
SUMMARY
Background: We have previously demonstrated a nega-
tive relationship between the prevalence of Helicobacter
pylori and gastro-oesophageal re¯ux disease (GERD).
Aim: To study the effects of H. pylori infection on the
severity of GERD.
Methods: Ethnic Chinese patients with frequent heart-
burn and/or endoscopic oesophagitis were studied.
Endoscopic examination was performed to assess the
severity of oesophagitis (modi®ed Savary±Miller grad-
ing) and the presence of hiatus hernia. Biopsies were
taken for rapid urease testing and con®rmation of
Barrett's oesophagus. Risk factors which may affect the
severity of oesophagitis (age, sex, smoking, drinking,
diabetes mellitus, hiatus hernia, H. pylori status and
body mass index) were evaluated by a multiple regres-
sion model. The cagA status of H. pylori infected GERD
and age-and-sex matched controls were determined by
Western blot. Age-and-sex matched non-re¯ux patients
were recruited as controls for comparison.
Results: Two hundred and twenty-®ve patients with
GERD were studied, of whom 77 (34%) were infected
with H. pylori. Oesophagitis and Barrett's oesophagus
were found in 140 patients (62%) and six patients (3%),
respectively. H. pylori infected patients had signi®cantly
less severe oesophagitis compared to the uninfected
group (P � 0.022). All patients with Barrett's oesopha-
gus were uninfected. Factors that predicted severe
oesophagitis included age over 60 years (P < 0.001)
and hiatus hernia (P < 0.001). H. pylori infection was
the only factor that showed a negative correlation with
severe oesophagitis (P � 0.011). The prevalence of the
cagA positive strain in endoscopy-negative GERD, ero-
sive oesophagitis and control subjects was 70, 76 and
78%, respectively (P � 0.75).
Conclusions: H. pylori infection is associated with milder
GERD.
Correspondence to: Prof. J. J. Y. Sung, Department of Medicine & Thera-
peutics, Prince of Wales Hospital, Shatin, Hong Kong.E-mail: [email protected]
Aliment Pharmacol Ther 2000; 14: 427±432.
Ó 2000 Blackwell Science Ltd 427
Whether H. pylori still plays a protective role in these
GERD patients is unknown.
In the midst of the controversy over H. pylori and
GERD, Vicari et al. reported that cagA positive H. pylori
was extremely rare in patients with severe GERD
complications such as Barrett's oesophagus and adeno-
carcinoma of the oesophagus.10 This intriguing study
suggests that infection by different strains of H. pylori
may explain the different clinical outcome of the
patients.
We hypothesized that H. pylori infection, especially
with cagA positive strains, protects GERD patients from
developing severe oesophagitis and complications. In
this study, we evaluated the contribution of H. pylori
infection, among other factors, on the severity of
oesophagitis in patients suffering from GERD. The
prevalence of cagA positive H. pylori in GERD patients
was also compared to those without the disease.
PATIENTS AND METHODS
Consecutive ethnic Chinese patients with GERD were
recruited prospectively. All patients had either (i)
weekly attacks of heartburn and acid re¯ux as their
chief complaint in the past 6 months, which improved
on acid suppressive therapy, or (ii) endoscopic con®r-
mation of erosive oesophagitis. Exclusion criteria
included current or past history of peptic ulcer disease,
previous gastric surgery or anti-Helicobacter therapy,
and the use of proton pump inhibitors, NSAIDs, steroids
or tetracycline in the past 4 weeks. Demographic details
of the GERD patients were recorded, including age, sex,
smoking and drinking habits, tea and coffee consump-
tion, body mass index, and concurrent medical condi-
tions including hypertension and diabetes mellitus. All
recruited patients underwent an endoscopic examina-
tion to assess the severity of re¯ux oesophagitis,
presence of hiatus hernia and to exclude coexisting
peptic ulcers. H. pylori status was determined by rapid
urease test and histology with biopsies taken from the
antrum and the corpus. Oesophageal biopsies were also
taken if the endoscopic appearance suggested Barrett's
oesophagus. The severity of re¯ux oesophagitis was
evaluated using the modi®ed Savary±Miller grading
system11 by a single endoscopist (JCYW), who reviewed
video tape of the endoscopic examinations without
knowing the H. pylori status of the patient. In this
study, grade 1 oesophagitis was de®ned as the presence
of single or isolated erosion(s) on one mucosal fold;
grade 2 as non-circumferential erosions on more than
one mucosal fold with or without con¯uence; grade 3 as
oesophagitis circumferential erosions and grade 4 as
presence of stricture or ulcer. Mild oesophagitis was
de®ned as Savary±Miller grades 1±2 and severe oeso-
phagitis as grades 3±4 or Barrett's oesophagus.
For GERD patients with H. pylori infection, a blood
sample was obtained to determine cagA by the Western
blot technique (Helico Blot 2.0; Genelab, Singapore).
Age- and sex-matched non-re¯ux controls with H. pylori
infection were recruited for cagA serology. These were
patients undergoing endoscopy for various indications
other than re¯ux symptoms and oesophagitis. Exclusion
criteria for the recruitment of GERD patients were also
applied in these control subjects. H. pylori infected
patients with mild or severe GERD and control subjects
were compared for the prevalence of cagA positive
strains.
Statistical analysis
Risk factors that may affect the severity of oesophagitis,
including age, sex, smoking, alcohol consumption,
coffee or tea intake, asthma, diabetes mellitus, hyper-
tension, hiatus hernia, H. pylori infection, and body
mass index (BMI) were evaluated using univariate
analysis followed by multiple regression analysis. A
standardized regression coef®cient estimated for each
independent variable was tested for signi®cance by two-
tailed t-test (SPSS 7.5). The relative proportion of the
contribution by each variable was expressed as a
standardized regression coef®cient (b). The Mann±
Whitney U-test was used to compare the severity of
oesophagitis between H. pylori infected and non-infec-
ted GERD patients. The prevalence of cagA positive
H. pylori in endoscopy-negative GERD, erosive oesoph-
agitis and non-re¯ux controls was compared by
chi-squared test. Two-tailed P-values of less than 0.05
were regarded as statistically signi®cant.
RESULTS
From September 1997 to April 1999, 283 consecutive
patients were diagnosed to have GERD at the Prince of
Wales Hospital. Fifty-eight patients were excluded from
the study for the following reasons: coexisting peptic
ulcers (30), previous gastric surgery (7), refusal of
endoscopy (2), infective oesophagitis (5: herpes 2,
candida 3), pill oesophagitis (3), recent use of proton
428 J. C. Y. WU et al.
Ó 2000 Blackwell Science Ltd, Aliment Pharmacol Ther 14, 427±432
pump inhibitors (2), NSAID or steroid use (5) and
previous H. pylori eradication (4). Two hundred and
twenty-®ve patients were recruited to the study. The
mean age of this group was 56.8 � 18.9 years and 107
patients (48%) were male. Mean body mass index was
23.6 � 3.0 with 41 patients (18%) considered to be
overweight (BMI > 25). Chronic smoking and drinking
habits were documented in 35 (16%) and 26 (12%)
patients, respectively (Table 1).
Of these 225 patients, erosive oesophagitis was
documented by endoscopy in 140 (62%). The remain-
ing 85 (38%) patients had typical re¯ux symptoms but
no observable oesophagitis on endoscopy. There were
63 patients (28%) with grade 1 oesophagitis, 40
patients (18%) with grade 2, 22 (10%) with grade 3
and 15 (7%) with grade 4. All cases with grade 4
oesophagitis had an oesophageal ulcer but none of them
had a peptic stricture. Barrett's oesophagus with
histologically proven specialized intestinal metaplasia
was found in six (3%) patients. Of these six patients, one
had long segment Barrett's oesophagus and four had
short segment Barrett's oesophagus (de®ned as involve-
ment of < 3 cm above the Z-line). One patient with
dysphagia and odynophagia in addition to heartburn
was recruited for endoscopy and was subsequently
diagnosed as having adenocarcinoma of the oesophag-
ogastric junction.
Seventy-seven (34%) GERD patients were con®rmed to
have H. pylori infection. Of these, 33 (43%) had non-
erosive GERD, 38 (49%) had mild (grade 1 and 2)
oesophagitis, whereas six (8%) had severe (grade 3 and
4) oesophagitis. Of the uninfected patients, 52 (35%)
had non-erosive GERD, 65 (44%) had mild oesophagitis
and 31 (22%) had severe disease. None of the patients
with Barrett's oesophagus or the single patient with
adenocarcinoma of the oesophagogastric junction was
infected by H. pylori. As a whole, H. pylori infected
GERD patients had signi®cantly less severe re¯ux
disease compared to non-infected patients (Mann±
Whitney U-test, P � 0.022) (Table 1, Figure 1). Pre-
valence of H. pylori infection in patients with severe
oesophagitis (16%) was also signi®cantly lower than
non-erosive GERD (39%, P � 0.017, v2-test) and mild
oesophagitis (37%, P � 0.027, v2-test) (Table 2).
Table 1. Patient characteristics of
H. pylori-positive and negative GERD
patients
H. pylori-positive H. pylori-negative P-value
Number of patients 77 148
Mean age (s.d.) 54.6 � 17.5 58.7 � 18.7 0.115
Male (%) 35 (45.5) 72 (48.6) 0.649
Hiatus hernia (%) 41 (53.2) 83 (56.1) 0.685
Diabetes mellitus (%) 6 (7.8) 16 (10.8) 0.47
Smoking (%) 16 (20.8) 19 (12.8) 0.296
Overweight (%) 18 (23.4) 23 (15.5) 0.149
Severity of GERD (%)
Non-erosive 33 (42.9) 52 (35.1)
Grade 1 and 2 38 (49.4) 65 (43.9) 0.022
Grade 3 and 4 6 (7.8) 31 (21.9)
Figure 1. Spectrum of GERD in H. pylori-
positive and negative patients.
H. PYLORI INFECTION IS ASSOCIATED WITH MILDER GERD 429
Ó 2000 Blackwell Science Ltd, Aliment Pharmacol Ther 14, 427±432
Patients were classi®ed into three different age groups:
young (< 40 years), middle (40±60 years) and old
(> 60 years). Thirty per cent (30 out of 100) of the
old patients had severe (grade 3 and 4) oesophagitis
compared to 9% (7 out of 75) in the middle age group
and none in the young group with the same degree of
oesophagitis (Table 3). The youngest patient diagnosed
to have Barrett's oesophagus was 58 and other patients
were over 60. Hiatus hernia was found in 124 (55%)
patients and this endoscopic ®nding showed a strong
association with severe re¯ux disease. Of 37 patients
with severe oesophagitis (grade 3 and 4), 36 (97%) had
hiatus hernia. Hiatus hernia was also found in all but
one patient with Barrett's oesophagus. Prevalence of
hiatus hernia increased with age and it was signi®cantly
more prevalent in the oldest group (> 60 years old)
than in the middle and young age groups (Table 3).
Using univariate analysis, the variables that predicted
severe oesophagitis included age > 60 years (b � 0.285,
P < 0.001) and presence of hiatus hernia (b � 0.429,
P < 0.001). H. pylori infection was the only independ-
ent variable that showed a negative correlation with the
severity of oesophagitis (b � ± 0.14, P � 0.011). The
correlation between the severity of oesophagitis and
these three independent variables remained signi®cant
using multiple regression analysis (Table 4).
From May 1998 to April 1999, sera had been collected
from 48 consecutive H. pylori infected GERD patients for
determination of cagA status. Of these patients, 23
(48%) had endoscopy-negative GERD and 25 (52%) had
erosive oesophagitis. Fifty-eight age- and sex-matched
non-re¯ux patients were studied as a control. They
underwent endoscopy for indications including anaemia
(19), irritable bowel syndrome (18), achalasia (2) and
non-ulcer dyspepsia (19). The prevalence of the cagA
positive strain in erosive oesophagitis, endoscopy-neg-
ative GERD and control patients was 76, 70 and 78%,
respectively (Table 2). There was no signi®cant differ-
Table 2. Prevalence of H. pylori infection and cagA positivity in patients with different degrees of GERD
Non-erosive
GERD
Grade 1 and 2
oesophagitis
Grade 3 and 4
oesophagitis
Barrett's
oesophagus
Number of patients 85 103 37 6
Prevalence of H. pylori infection (%) 33 (39) 38 (37) 6 (16) 0 (0)
Prevalence of cagA + strain (%) 70 76 75 Ð
18±40 > 40±60 > 60 P-value
Number of patients 50 75 100
Prevalence of H. pylori infection (%) 18 (36) 29 (38.7) 30 (30) 0.47
Prevalence of hiatus hernia (%) 18 (36) 30 (40) 76 (76) < 0.001
Table 3. Prevalence of H. pylori infection
and hiatus hernia in different age
groups
Variable
Standardized
regression
coef®cient (b) P-value
Mean age 56.8 � 18.9 0.285 < 0.001
Sex M 107 (47.6%) ±0.29 0.61
F 118 (52.4%)
Smoking 35 (15.6%) 0.04 0.78
Alcohol 26 (11.6%) 0.037 0.79
Diabetes mellitus 22 (9.8%) ±0.02 0.72
Overweight (BMI > 25) 41 (18.2%) ±0.039 0.469
Body mass index (kg/m2) 23.6 � 3.0
Hiatus hernia 124 (55.1%) 0.429 < 0.001
H. pylori infection 77 (34.2%) ±0.14 0.011
Table 4. Demography of GERD patients
and standardized regression coef®cient of
each variable
430 J. C. Y. WU et al.
Ó 2000 Blackwell Science Ltd, Aliment Pharmacol Ther 14, 427±432
ence in the prevalence of cagA+ strain between the three
groups of patients (P � 0.75).
DISCUSSION
Although epidemiological data suggest that H. pylori
infection protects against the development of GERD, up
to one-third of patients with con®rmed GERD are still
infected by the bacterium. In a recent study from the
Netherlands, Schenk et al. reported milder oesophagitis
among H. pylori-infected GERD patients when compared
to non-infected patients,12 but the difference in severity
of the disease did not reach statistical signi®cance.
While observer bias cannot be excluded in their study,
the strong negative association between H. pylori infec-
tion and Barrett's oesophagus is beyond doubt. One of
the possible mechanisms of the protective effect of
H. pylori infection is related to acid suppression as a
result of corpus gastritis. Recovery of acid secretion in
patients with severe corpus gastritis after eradication of
H. pylori may result in unmasking symptoms of acid
re¯ux.13 As cagA positive strains are considered to be
more virulent and induce more severe corpus gastritis,
acid suppression is likely to be more profound in
patients infected by this H. pylori strain.14±16 Recent
studies reported that in H. pylori-infected GERD pa-
tients, cagA negative strains are more commonly found
among those with complications.10, 17 In Asia, how-
ever, the signi®cance of cagA positive strains is unclear.
Most studies from Asian countries have failed to con®rm
a strong association between cagA positive strains and
peptic ulcer disease or gastric cancers.18
To avoid inter-observer variation and bias in assessing
the severity of oesophagitis, our study was designed so
that all cases were assessed by a single endoscopist who
viewed video tape of the endoscopic examination
without knowing the H. pylori status of the patients.
In this study, 62% of patients showed evidence of
erosive oesophagitis. This high prevalence of re¯ux
oesophagitis re¯ects the stringent criteria for the
diagnosis of GERD in our study. Whilst the majority of
patients in this series had endoscopic lesions, severe
oesophagitis (grade 3 and 4) and Barrett's oesophagus
were relatively uncommon (16.3 and 2.7%, respec-
tively) compared to Western studies.19±21 As one would
expect, advanced age and the presence of hiatus hernia
were strongly associated with more severe re¯ux
disease. On the other hand, body mass, diabetes, and
smoking and drinking habits did not affect the outcome.
H. pylori infection is the only factor that showed a
negative correlation with the severity of oesophagitis in
this study. The absence of H. pylori in all patients with
Barrett's oesophagus and adenocarcinoma of the oeso-
phagogastric junction further supports a protective role
of H. pylori against severe re¯ux disease.
Vicari et al. studied the relationship between cagA
positive H. pylori and GERD complications in a high-risk
population, who reported a predominance of cagA
negative strain among severe and complicated GERD
patients.10 Unlike Vicari's study, we studied a Chinese
population with a low prevalence of GERD and its
complications, and a high prevalence of H. pylori
infection. Our study showed that in the Chinese
population, the cagA positive strain is highly prevalent
in both controls (77.6%) and GERD patients (72.9%),
which mainly consists of mild to moderate oesophagitis.
Milder oesophagitis in H. pylori infected GERD patients
can be explained by the high prevalence of cagA positive
strain. This ®nding also suggests that the high preva-
lence of cagA positive H. pylori in Chinese patients may
contribute to a lower prevalence of GERD, Barrett's
oesophagus and adenocarcinoma of the oesophagus.
Despite the high prevalence of cagA positive strain, we
postulate that H. pylori gastritis may still be less severe
in GERD patients, which can only decrease the severity
but cannot completely protect the development of
GERD.22 A comparative study of H. pylori gastritis
patterns between GERD patients and non-re¯ux controls
is therefore mandatory.
In conclusion, H. pylori infection ameliorates the sever-
ity of disease in patients with GERD. The high prevalence
of cagA positive H. pylori may contribute to a lower
prevalence and milder GERD in the Chinese population.
ACKNOWLEDGEMENTS
This work was supported by a grant (CUHK 4260/98M)
from the Research Grant Committee of Hong Kong.
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