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


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



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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Helicobacter pylori infection is associated with milder gastro-oesophageal reflux disease