Correlation between Helicobacter pylori infection and reflux esophagitis: still an ongoing debate

Context The vast majority of pathologies in the oesophagus, stomach and duodenum are related to either H. pylori infection or gastro-oesophageal reflux disease (GERD). Both conditions affect a large proportion of the population and they may occur either independently or concomitantly. The question of whether the two conditions are mutually exclusive, synergistic, or simply independent is an issue that was raised several years ago and is a matter of ongoing debate. Aim We aimed to determine the correlation between gastric Helicobacter colonization and grossly and histologically proven reflux esophagitis. Settings and design This work was designed as a descriptive cross-sectional study. Patients and methods The study was conducted on 50 patients, five women and 45 men, aged 19–79 years (mean: 35.3 years). The inclusion criterion was having a history of symptoms suggestive of GERD. The cases were chosen from among outpatients and inpatients undergoing diagnostic endoscopic study at the endoscopy unit. The main presenting complaints were GERD symptoms, dyspepsia and postprandial epigastric pain. All cases were subjected to thorough history taking regarding the details and nature of the presenting complaint, special habits including caffeine consumption, smoking, and intake of medications such as antacids and H2 blockers, complete physical examination and upper endoscopy. Detailed description of upper endoscopic examination was reported, including the grade of esophagitis according to Savary–Miller classification. Three groups of biopsies were taken from each case: the first set from the lower end of the oesophagus and the two other sets from the gastric antrum. The oesophageal biopsies and one set of gastric biopsies were examined histologically after being processed. The second gastric biopsy set was used for direct detection of H. pylori using the rapid urease test (Campylobacter-like organism test). The rapid urease test offers a sensitivity of 80–99% and a specificity of 92–100% in untreated patients when compared with histology as the gold standard in the diagnosis of H. pylori infection. Statistical analysis Data were statistically described in terms of frequencies (number of cases) and percentages and compared using the χ2-test. The exact test was used when the expected frequency was less than 5. Results On using the rapid urease enzyme test there were 44 (88%) positive cases and six (12%) negative cases for H. pylori. By direct histopathologic examination there were 32 (64%) positive cases and 18 (36%) negative cases for H. pylori. There was no statistically significant correlation between gastric colonization with H. pylori and reflux esophagitis diagnosed grossly and histopathologically. Conclusion The study showed no statistically significant correlation between H. pylori infection and the presence of reflux esophagitis.


Introduction
Helicobacter pylori infection and gastro-oesophageal reflux disease (GERD) account for most upper gastrointestinal pathologies with a wide spectrum of clinical manifestations.
The interplay of both conditions is complex, in part intriguing, and has become a matter of debate because of conflicting results.
The geographical location, genetic background, ethnicity, gastric location of the infection and bacterial virulence might be strong contributors to the heterogeneity of results in different studies [1].
H. pylori, previously named Campylobacter pyloridis, is a Gram-negative, microaerophilic bacterium colonizing the stomach. It was identified in 1982 by Marshall and Warren [2].
GERD is a common condition with a variety of clinical manifestations and potentially serious complications.
The role of H. pylori infection in GERD has received attention only recently. However, the evidence for an association between H. pylori and GERD is still absent [3].
The objective of this study is to determine the relationship between gastric Helicobacter colonization and histologically proven esophagitis.

Patients and methods
The study was conducted on 50 patients, five women and 45 men, aged 19-79 years (mean: 35.3 years). The inclusion criterion was having a history of symptoms suggestive of GERD. The study protocol was approved by the research ethical committee.
Written consent was obtained from all participants.
The cases were chosen from among outpatients and inpatients undergoing diagnostic endoscopic study at the endoscopy unit. The main presenting complaints were GERD symptoms, dyspepsia and postprandial epigastric pain.
All cases were subjected to thorough history taking regarding the details and nature of the presenting complaint, special habits including caffeine consumption, smoking, and intake of medications such as antacids and H2 blockers, complete physical examination and upper endoscopy.
Detailed description of upper endoscopic examination was reported, including the grade of esophagitis according to Savary-Miller classification [4].
Three groups of biopsies were taken from each case: the first set from the lower end of the oesophagus and the other two sets from the gastric antrum. The oesophageal biopsies and one set of gastric biopsies were examined histologically after being processed.
The second gastric biopsy set was used for direct detection of H. pylori using the rapid urease test [Campylobacter-like organism (CLO) test]. The rapid urease test offers a sensitivity of 80-99% and a specificity of 92-100% in untreated patients when compared with histology as the gold standard in the diagnosis of H. pylori infection [5].
Graded variables in the pathology report included the density of H. pylori organisms; inflammation, activity, mucosal atrophy and intestinal metaplasia were reported and graded according to the Sydney system [6].
Each variable was divided into three grades (mild, moderate and severe), and the presence of mononuclear cells was evaluated as well.
H. pylori are visible using haemotoxylin and eosin staining but are more easily demonstrated by Giemsa stain. Detection of two or three bacteria per section, if they are absolutely typical of H. pylori, is sufficient for diagnosis [7].
Esophagitis is diagnosed by the presence of intraepithelial leucocytes (lymphocytes, neutrophils, eosinophils) and or basal cell hyperplasia. All histological specimens were assessed by a single pathologist who was blinded to the diagnosis of patients.
Data were statistically described in terms of frequencies (number of cases) and percentages and compared using the χ 2 -test. Exact test was used when the expected frequency was less than 5.
Accuracy was represented bysensitivity, specificity, positive predictive value, negative predictive value and overall accuracy. P values less than 0.05 were considered statistically significant.
All statistical calculations were carried out using IBM Statistical Package for the Social Sciences (SPSS; IBM Corp, Armonk, New York, USA) release 22 for Microsoft Windows.
There was no statistically significant correlation between gastric colonization with H. pylori and reflux esophagitis diagnosed grossly and histopathologically (Tables 1  and 2).
The cases in which the CLO test was positive while the biopsy was negative might be attributed to the following: (1) Patients were under treatment with antibiotics.
(2) The biopsy site was not colonized by H. pylori.
(3) Other H. pylori-like organisms may give a falsepositive urease enzyme test result.

Discussion
The incidence of H. pylori infection in patients with GERD varies widely in the literature − from 30 to 90% − and is ∼35% in most series. This heterogeneity among studies may be due to the geographical location of the studies and the virulence of H. pylori strains involved [8].
Despite the large number of published studies, the pathophysiological inter-relation between GERD and H. pylori remains controversial.
The pathophysiology of GERD is multifactorial. Although no single factor has been isolated as the cause of GERD, a negative association between the prevalence of H. pylori and the severity of GERD, including Barrett's oesophagus, has been demonstrated in epidemiological studies.
There is considerable heterogeneity among studies, resulting in different conclusions. There are data suggesting a protecting role of H. pylori (HP) in GERD, other data suggest an aggravating role, and many studies support a mere coexistence of the two conditions [9].
At present, the relationship between H. pylori and GERD is not yet well established, and in the medical literature it is possible to find a variety of reports.
Whereas some authors find a close relationship between both conditions, others do not report any relationship between them, and finally other groups of authors maintain that this micro-organism has even a protective effect against GERD [10].
It has also been postulated that not only the presence of H. pylori but also the virulence of each genotype and the anatomic location of the infection with H. pylori is important for protection from GERD and its complications. Thus, it has been demonstrated that patients infected by CagApositive genotypes, which are more virulent, have a lower probability of suffering from GERD and its complications, probably due to a greater degree of atrophic gastritis and hypochlorhydria [1,[11][12][13].
The most widespread opinion now is that there is no consistent relationship between GERD and H. pylori infection, although an impact on certain subgroups of patients cannot be entirely ruled out [14].
The aim of our present study is to determine the correlation between gastric colonization with H.  pylori and grossly and histologically documented reflux esophagitis.
The study was conducted on 50 patients and it was found that 44 (88%) cases were positive for H. pylori as per the rapid urease (CLO) test and 32 (64%) cases were positive using direct histopathological examination of gastric biopsies.
There was no statistically significant correlation between esophagitis diagnosed grossly or pathologically with pathologically documented H. pylori gastritis.
The results of our study in which we did not find a significant correlation between gastric colonization with H. pylori and reflux esophagitis are in accordance with many studies that addressed the same issue.
They concluded that the presence of H. pylori has no impact on oesophageal motility, lower oesophageal sphincter pressure, or gastro-oesophageal reflux [15].
The clinical, endoscopic, manometric and pH-metric data in the study of Grande et al. [14] show no significant role of H. pylori infection in the development of GERD or in the pathogenesis of reflux esophagitis.
Kuipers et al. [16] conducted a study on 231 patients to investigate whether H. pylori eradication can influence gastritis and its sequelae during long-term omeprazole therapy for GERD.
They found that most H. pylori-positive GORD patients have a corpus predominant pangastritis during omeprazole maintenance therapy. Eradication of H. pylori eliminated gastric mucosal inflammation and induced regression of corpus glandular atrophy.
H. pylori eradication did not worsen reflux disease, nor did it lead to a need for increased omeprazole maintenance dose. Accordingly, they recommended eradication of H. pylori in GORD patients receiving long-term acid suppression [16].
Hong and Kim in 2015 in their meta-analysis concluded a negative association between the prevalence of H. pylori and the severity of GERD.
Their explanation was that in patients with East Asian CagA-positive strains, acid injury may be minimized by hypochlorhydria from pangastritis and gastric atrophy. Additionally, host genetic factors may affect the development of GERD [1].
A large-scale prospective cohort study in Korea showed that H. pylori infection had a strong negative association with reflux esophagitis and that eradication of H. pylori increased the risk for reflux esophagitis [17].
Wu et al. [18] conducted a double-blinded placebocontrolled randomized study on 236 patients to investigate the effects of H. pylori eradication on treating GERD patients.
Their final conclusion showed that H. pylori eradication rendered the control of reflux disease more difficult. However, balancing the risk for gastric carcinogenesis and peptic ulcer formation against the need for higher doses of acid suppressive therapy for symptom control, they recommended H. pylori eradication before long-term PPI therapy [18].
Awad et al. [19] studied 37 patients with GERD (78% HP-positive) using ambulatory 24-h oesophageal pH-metry and manometry. There was no difference in the manometric findings between HP-positive and HP-negative groups but the HP-positive patients had a lower acid exposure tendency.
This may suggest a protective role of HP in the pathogenesis of GERD [19].
A recent study explored this debate from a different perspective through the hypothesis of altered motility induced by H. pylori infection. That study aimed to explore the effects of H. pylori infection on both motilin and ghrolin.
The study concluded that H. pylori infection is neither protective nor harmful with respect to gastrooesophageal reflux and neither ghrelin nor motilin levels were associated with gastro-oesophageal reflux. Neither gastrin, ghrelin, or motilin levels were affected by H. pylori infection. There is an inverse association between gastrin and ghrelin levels after H. pylori eradication [11].
Perhaps the importance of finding an answer to the debate on the relation between H. pylori infection and reflux esophagitis is the conclusion of Iijima et al. [20], who addressed the importance of eradicating HP by stating that eradication will suppress gastric inflammation and inhibit gastric mucosal atrophy, which would subsequently stop the progression to intestinal metaplasia and development of gastric cancer.
In their study, Iijima et al. [20] noticed that reflux esophagitis occurred in ∼10% of Japanese patients undergoing eradication therapy.
Accordingly, the fact that eradication-induced reflux esophagitis could increase the long-term risk for Barrett's oesophagus and oesophageal adenocarcinoma should also be considered in the Japanese population.
They recommended appropriate treatment with proton pump inhibitors for patients undergoing eradication therapy in clinical practice.

Conclusion
Our study did not show a correlation between H. pylori infection and presence of GERD. Accordingly, it can be assumed that infection with H. pylori is not related to the pathogenesis of GERD.However, it needs to be emphasized that as there are multiple factors determining the complex interaction between H. pylori and reflux esophagitis, and bearing in mind that geographical location and ethnicity as well as genetic factors are strong contributors to the heterogeneity of results in different studies, and as no large-scale study has addressed this complex interaction in the Egyptian population, no solid conclusions can be drawn from the initial results of our study because of the small sample size, and further prospective nationwide large-scale studies are needed.
Another reason for the need to conduct large-scale studies in Egypt addressing the complex inter-relation between H. pylori infection and GERD are the recent epidemiologic data in western countries that documented that the prevalence of GERD and oesophageal adenocarcinoma has increased as the prevalence of H. pylori has decreased.
According to these epidemiologic findings in western countries it is believed that eradicating H. pylori might provoke reflux esophagitis with its consequences, namely Barrett's oesophagus and subsequent development of oesophageal adenocarcinoma [21].
Accordingly, wide-scale studies need to be conducted in Egypt for follow-up of cases after eradicating H. pylori infection and to determine whether or not reflux will increase, because if such a hypothesis is correct in the Egyptian population it means that all patients in whom H. pylori had been eradicated need to be followed up closely.

Financial support and sponsorship
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Conflicts of interest
There are no conflicts of interest.