De novo erosive esophagitis in duodenal ulcer patients related to pre-existing reflux symptoms , smoking , and patient age , but not to Helicobacter pylori eradication : a one-year follow-up study

Introduction Epidemiological data demonstrate clear trends of the increasing prevalence of gastroesophageal refl ux disease (GERD) in different parts of the world (1, 2) as well as GERD-associated precancerous Barrett’s esophagus and adenocarcinoma of the lower esophagus in Western countries (3–6). Several studies have shown that H. pylori eradication could provoke or worsen nonerosive GERD and erosive esophagitis (7–9). On the contrary, some other studies, however, have not confi rmed the provocation of GERD by the eradication of H. pylori or even revealed a relief of refl ux symptoms after the cure of H. pylori infection (10–12). Some other patient-associated factors, such as gender, overweight, use of alcohol, smoking, were also analyzed and implicated to predispose the development of GERD (13).


Introduction
Epidemiological data demonstrate clear trends of the increasing prevalence of gastroesophageal refl ux disease (GERD) in different parts of the world (1,2) as well as GERD-associated precancerous Barrett's esophagus and adenocarcinoma of the lower esophagus in Western countries (3)(4)(5)(6).Several studies have shown that H. pylori eradication could provoke or worsen nonerosive GERD and erosive esophagitis (7)(8)(9).On the contrary, some other studies, however, have not confi rmed the provocation of GERD by the eradication of H. pylori or even revealed a relief of refl ux symptoms after the cure of H. pylori infection (10)(11)(12).Some other patient-associated factors, such as gender, overweight, use of alcohol, smoking, were also analyzed and implicated to predispose the development of GERD (13).
Erosive esophagitis is a quite common fi nding in duodenal ulcer (DU) patients (14), and it is still not clear whether H. pylori may play role in the pathogenesis of pathological gastroesophageal refl ux, or other factors are more important in the development of GERD in DU patients (15).
Therefore, we carried out a one-year follow-up study of DU patients without erosive esophagitis with the aim to elucidate the role of H. pylori eradication and other factors in the development of erosive GERD.

Patients and methods
One hundred eighty-three consecutive H. pyloripositive DU patients who underwent endoscopy in our department were enrolled into the study.Patients with concomitant erosive esophagitis both at entrance and in the anamnesis were excluded from the study as well as patients with a recent use of nonsteroidal anti-infl ammatory drugs (NSAIDs), proton pump inhibitors, antibiotics, or bismuth compounds and with any severe accompanying diseases.One hundred forty-two (77.6%) patients were included in the treatment group and assigned to one of the following eradication regimens: i) RAM (ranitidine, 300 mg b.Gastroscopy was performed at the beginning of the study, 6-8 weeks and 12 months later or earlier if DU relapse was suspected.Hiatal hernia was defi ned endoscopically as a distance of more than 2 cm from the esophagogastric junction to the diaphragmatic impingement. Endoscopic refl ux-esophagitis was defi ned and quantifi ed according to the Savary-Miller classification: grade I, erythematous or erythemato-exudative erosion (alone or multiple), which can cover several folds (as long as they are not confl uent); grade II, confl uent but not circumferential erosion; grade III, circumferential erosive and exudative lesions; grade IV: a) chronic lesions (ulcer, stenosis, enbrachyesophagus cylindric cell epithelialization) with active infl ammation; b) cicatricial stage (stenosis, brachyesophagus, cylindrical cell epithelialization without active infl ammation) (16,17).
Before each endoscopy, patients were asked to indicate the frequency of heartburn and regurgitation and the impact of these symptoms on everyday activities.Patients with typical refl ux symptoms (heartburn and/or acid regurgitation) at least twice a week were considered as patients with concomitant nonerosive GERD (Genval consensus) (18).
During endoscopy, 3 biopsy specimens from the antrum and 3 from the corpus were obtained for urease testing and histological examination.H. pylori infection was diagnosed by the rapid urease test and histology.Histological evaluation of biopsies from the antrum and corpus of the stomach were performed according to the Sydney system ( 19) by a single pathologist who was blinded to any clinical and demographic data.If the results of at least one of the tests were positive, H. pylori positivity was established.Final H. pylori status was established during examination 12 months later or during the ulcer relapse.The latter was considered when peptic ulcer was confi rmed on endoscopy 12 months later or earlier if symptoms reoccurred.
The obtained data were analyzed and compared using χ 2 or Student's t test.Logistic regression analysis was also applied.Values of P<0.05 were considered signifi cant.
The study was approved by the Ethics Committee of Kaunas University of Medicine, and written informed consent was obtained from each patient.

Results
Of the 183 patients studied, 150 completed the follow-up study: 119 patients in the eradication group and 31 in the control group.Thirty-three (18%) patients dropped out and did not fi nish the follow-up.Patients in the eradication and control groups did not differ statistically signifi cantly regarding gender, mean age, history of peptic ulcer, and smoking at the beginning of the study.Follow-up time for all patients was 11.0±2.6 months on the average; for those who did not relapse, 11.9±1.6 months; and for those who relapsed, 8.4±3.2 months.
Final assessment of H. pylori infection after months or at DU relapse endoscopy revealed that (58.8%) patients from the eradication group were successfully cured from H. pylori; in 49 (41.2%)patients, treatment of H. pylori was unsuccessful.All of the 31 control patients remained H. pylori-positive.
Erosive esophagitis During the last endoscopy, erosive esophagitis was found in 19 (12.7%) of 150 patients.Grade I esophagitis was found in 17 cases and grade II in cases.Eight (11.4%) of the 70 successfully eradicated patients, 9 (18.4%) of the 49 unsuccessfully treated patients, and 2 (6.5%) of the 31 control patients developed esophagitis (P>0.05among groups).

Evaluation of histological gastritis
The baseline histological characteristics of gastritis between patients in whom esophagitis developed and did not develop are compared in Table 1.No statistically signifi cant differences were found.

Factors predicting the development of erosive esophagitis
Comparison of baseline demographic and clinical data between patients who developed erosive esophagitis and who did not develop is presented in Table 2. Signifi cant differences were established regarding the mean age, smoking status, and pres-ence of nonerosive GERD at baseline.Referring to age median, the patients were divided into 2 groups: aged up to 43 years and more than 43 years.Esophagitis was reported in 15 (20%) of the 75 patients aged up to 43 years and in 4 (5.3%) of the 75 patients aged more than 43 years (P<0.01).

Discussion
During the last decade, a number of studies addressed the issue of the development of GERD after H. pylori eradication.Studies were carried out in different subgroups (DU, GERD, functional dyspepsia) of patients (11)(12)(13)(20)(21)(22)(23)(24), and results obtained were controversial.Labenz et al. reported a signifi cant increase in the incidence of erosive esophagitis during three years in H. pylori-eradicated vs. noneradicated DU patients (7).Other authors like McColl et al. could not prove that H. pylori eradication did not provoke development of GERD in DU patients (11).The analysis of 8 double-blind prospective trials of H. pylori therapy in a total of 1165 patients with DU added further support to the theory that eradication of H. pylori in DU patients does not worsen GERD and may improve symptoms Laimas Jonaitis, Juozas Kupčinskas, Gediminas Kiudelis, Limas Kupčinskas  (24).Similar conclusions were drawn in a systematic review, which found no evidence that H. pylori eradication in patients with DU might provoke refl ux esophagitis (25).Pathophysiologically, most of the DU cases are associated with antrum-predominant H. pylori gastritis with increased gastric acid secretion; therefore, such patients might be at increased risk for developing GERD and DU, and both conditions might improve after H. pylori eradication (11).In our series, DU was associated with an antral predominant pattern of gastritis, and the prevalence of gastric atrophy was low; therefore, we could not expect the increased acid secretion after eradication.However, it has been reported that in DU patients after the cure of H. pylori infection, erosive esophagitis occurs in up to 30% of cases (14,26,27).Our study was focused on investigation of risk factors predisposing the development de novo erosive esophagitis in DU patients after eradication.The peculiarity of our study was that we have had a control group, which was not infl uenced at all by the treatment with antibiotics, probably with no suppression of H. pylori.We have achieved a 58.8%rate of H. pylori eradication in our study.This could be explained by the use of H2-receptor antagonistbased eradication regimens instead of proton pomp inhibitors by about half of study patients.H2-receptor antagonist-based eradication schemes were widely used in Lithuania until 2001.Our study confi rmed the absence of any infl uence of H. pylori eradication on the occurrence of erosive esophagitis in DU patients; therefore, we could suppose that the development of erosive esophagitis might be related to other factors.
GERD is a multifactorial disease, and hiatus hernia, older age, increased body mass index, consumption of wine and coffee were reported as predictors of the development of GERD (28)(29)(30)(31)(32)(33).The presence of nonerosive GERD could be also a factor predisposing the development of erosive esophagitis (34).These factors could be different in separate patients' groups and in different geographical areas (32,35,36).Our study revealed that in DU patients after eradication therapy, the development of de novo refl ux esophagitis was related to pre-existing refl ux symptoms, smoking, and patient's age.Contrarily to some other authors (9,26,37), we have not found the association between hiatal hernia and de novo erosive esophagitis.It could be related to the fact that hiatal hernia was not very frequent fi nding among our relatively "young" patients' cohort.
Results of our study reveled that the risk factors for occurrence of erosive esophagitis after HP eradication in DU patients are similar to those established for development of GERD in general population (33,38).We have found that DU patients with 3 major risk factors (age more than 43 years, nonerosive GERD, and smoking) have a quite big chance to develop erosive esophagitis in the nearest future (OR, 18.50; P<0.001).

Conclusion
H. pylori eradication did not infl uence the incidence of erosive esophagitis in patients with duodenal ulcer during a one-year follow-up period.Other factors such as pre-existing nonerosive GERD, smoking, and older age are important for the development of de novo erosive esophagitis.

Table 1 .
Histological features of gastritis in duodenal ulcer patients at the baseline in relation to the development of erosive esophagitis during the 1-year follow-up

Table 2 .
Comparison of baseline demographic and clinical variables between patients with and without erosive esophagitis at the end of study