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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Subjects and methods
  5. Subjects
  6. Endoscopy
  7. Eradication therapy
  8. Symptoms and medications
  9. Results
  10. Patients
  11. Change of reflux oesophagitis grading
  12. Presence of gastro-oesophageal reflux symptoms
  13. Presence of medications
  14. Discussion
  15. Acknowledgements
  16. References

Background:  Development of reflux oesophagitis after Helicobacter pylori eradication therapy has been reported, but the prognosis is not well known.

Aim:  To evaluate the prognosis of patients with reflux oesophagitis that developed after eradication therapy by long-term observation.

Methods:  Forty-five patients who developed reflux oesophagitis after successful H. pylori eradication therapy were followed up prospectively. All 45 patients were followed up by endoscopy more than 3 years after onset of reflux oesophagitis (3-year follow-up group) and nine were followed up more than 5 years after onset (5-year follow-up group). Endoscopic observations were performed yearly or when upper gastrointestinal symptoms recurred. Reflux oesophagitis was graded according to the Los Angeles Classification System. Presence of gastro-oesophageal reflux symptoms and medication of proton pump inhibitors, H2-blockers or prokinetics were investigated at final endoscopy.

Results:  All patients were classified as grade A or B at initial endoscopy. At final observation, the grade of reflux oesophagitis improved in 35/45 (78.8%) patients from the 3-year follow-up group and 7/9 (78.8%) patients from the 5-year follow-up group. Reflux oesophagitis progressed from grade A to B in only four (8.9%) patients from the 3-year follow-up group and in no patients in the 5-year follow-up group. No patient progressed to grade C or D. Gastro-oesophageal reflux symptoms were seen in 12 patients (26.7%) from the 3-year follow-up group and four patients (44.4%) from the 5-year follow-up group. Among them, medication was needed continuously in only six (13.3%) and two (22.2%) patients, respectively.

Conclusions:  Reflux oesophagitis, which develops after H. pylori eradication therapy, rarely becomes a long-term clinical problem among patients who complete therapy successfully.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Subjects and methods
  5. Subjects
  6. Endoscopy
  7. Eradication therapy
  8. Symptoms and medications
  9. Results
  10. Patients
  11. Change of reflux oesophagitis grading
  12. Presence of gastro-oesophageal reflux symptoms
  13. Presence of medications
  14. Discussion
  15. Acknowledgements
  16. References

It is clear that eradication therapy for Helicobacter pylori prevents ulcer recurrence in patients with peptic ulcer diseases and those undergoing treatment for lymphoma of mucosa-associated lymphoid tissue (MALToma).1–5 Moreover, it appears that this therapy is effective in the prevention of gastric cancer and as a treatment for non-ulcer dyspepsia.6–9 We recently reported that eradication therapy improves atrophic gastritis and intestinal metaplasia.10

Although H. pylori eradication therapy has several merits, it can also cause problems, which occur after eradication. Reflux oesophagitis is one of them. Several studies have reported the development of reflux oesophagitis after eradication therapy, with most cases presenting as mild oesophagitis at the time of occurrence.11, 12 The long-term prognosis of this type of reflux oesophagitis has not been reported. Reflux oesophagitis can ultimately progress to oesophageal complications such as deep ulceration, stricture formation and the development of Barrett's mucosa.13 Recent studies have also pointed out that oesophageal adenocarcinoma arises from Barrett's mucosa in patients with reflux oesophagitis.14–16 In this prospective study, we evaluated by long-term observation the prognosis of patients with reflux oesophagitis that developed after eradication therapy.

Subjects

  1. Top of page
  2. Summary
  3. Introduction
  4. Subjects and methods
  5. Subjects
  6. Endoscopy
  7. Eradication therapy
  8. Symptoms and medications
  9. Results
  10. Patients
  11. Change of reflux oesophagitis grading
  12. Presence of gastro-oesophageal reflux symptoms
  13. Presence of medications
  14. Discussion
  15. Acknowledgements
  16. References

Six hundred and twenty patients underwent H. pylori eradication therapy from May 1994 to December 1997 at Hiroshima University Hospital and Hiroshima Mitsubishi Hospital. Four hundred and fifty-eight (73.9%) patients were considered to have achieved successful eradication (intention-to-treat analysis) 1 month after therapy. Seventy-two of 458 (15.7%) patients, having a history of neither endoscopic reflux oesophagitis nor therapy of reflux oesophagitis, developed endoscopic reflux oesophagitis during 3 years after the eradication therapy. Among them, 45 patients [male/female (M/F) 42/3, mean age 51.2 years] were prospectively studied. We also confirmed that they also had no history of gastrectomy and did not take proton-pump inhibitors or H2-blockers during the 4 weeks before initial baseline endoscopy. Before the eradication therapy, H. pylori infection was confirmed by the rapid urease test (CLO test; Delta West Ltd, Bentley, Australia), by histological examination and by measurement of serum anti-H. pylori immunoglobulin-γ(IgG) antibodies (Pyloristat kit; Whittaker Bioproducts, Inc., Walkersville, MD). Patients were defined as H. pylori-positive if all tests were positive. After eradication therapy, no patient received anti-secretory drugs or prokinetics until reflux oesophagitis was observed by endoscopy. After the development of reflux oesophagitis, patients could remain under follow-up care prospectively, even if they received medications for gastro-oesophageal reflux symptoms or other abdominal symptoms. Informed consent to enrol in the prospective study was obtained from each patient.

Endoscopy

  1. Top of page
  2. Summary
  3. Introduction
  4. Subjects and methods
  5. Subjects
  6. Endoscopy
  7. Eradication therapy
  8. Symptoms and medications
  9. Results
  10. Patients
  11. Change of reflux oesophagitis grading
  12. Presence of gastro-oesophageal reflux symptoms
  13. Presence of medications
  14. Discussion
  15. Acknowledgements
  16. References

Patients underwent endoscopy before eradication, at 4 weeks after eradication therapy, at 1-year intervals and when symptoms (gastro-oesophageal reflux symptoms or other abdominal symptoms) occurred that required further treatment. The presence of endoscopic reflux oesophagitis was noted, and photos were taken for evaluation of severity. Reflux oesophagitis was graded from A to D according to the Los Angeles Classification System by one of three skilled physicians (A.S., K.H. or N.M.).17 When a mucosal break was not seen endoscopically, we defined the reflux oesophagitis as grade O. We also investigated the presence of hiatal hernia at initial endoscopy. After inspection of the oesophagus, stomach and proximal duodenum, the stomach was inflated with air, and the size of the hiatal hernia (if present) was measured using the endoscope.12 The length of hiatal hernia was measured as the distance from the oesophago-gastric junction to the diaphragm. A hiatal hernia was diagnosed when this length was greater than 2 cm. At each endoscopic examination, gastric biopsy specimens were taken for rapid urease test and histological examination by Giemsa staining.

Eradication therapy

  1. Top of page
  2. Summary
  3. Introduction
  4. Subjects and methods
  5. Subjects
  6. Endoscopy
  7. Eradication therapy
  8. Symptoms and medications
  9. Results
  10. Patients
  11. Change of reflux oesophagitis grading
  12. Presence of gastro-oesophageal reflux symptoms
  13. Presence of medications
  14. Discussion
  15. Acknowledgements
  16. References

After initial endoscopic examination, patients were treated with omeprazole (20 mg b.d.) and amoxicillin (1000 mg b.d.) for 3 weeks or omeprazole (20 mg b.d.), amoxicillin (750 mg b.d.) and clarithromycin (200 mg t.d.s.) for 1 week. The success of eradication was confirmed by rapid urease test, histological examination and the 13C-urea breath test.18 The results of all tests were negative in all patients at 4 weeks after treatment completion.

Symptoms and medications

  1. Top of page
  2. Summary
  3. Introduction
  4. Subjects and methods
  5. Subjects
  6. Endoscopy
  7. Eradication therapy
  8. Symptoms and medications
  9. Results
  10. Patients
  11. Change of reflux oesophagitis grading
  12. Presence of gastro-oesophageal reflux symptoms
  13. Presence of medications
  14. Discussion
  15. Acknowledgements
  16. References

We also investigated symptoms and medications in the study patients at the time of their final endoscopy. The presence of gastro-oesophageal reflux symptoms (heartburn, dysphagia, regurgitation and chest pain) was sought. Epigastralgia is a pain in the epigastric region. In this study, the meaning of this term also included burning in the epigastric region.19, 20 We defined symptomatic status as the presence of symptoms at least once a week.21 Patients could be treated with proton-pump inhibitors, H2-blockers or prokinetics for gastro-oesophageal reflux symptoms whenever needed. We investigated medications that patients had been receiving for more than 2 weeks at the time of the final endoscopy by interview, questionnaire or information from the patient's chart.

Patients

  1. Top of page
  2. Summary
  3. Introduction
  4. Subjects and methods
  5. Subjects
  6. Endoscopy
  7. Eradication therapy
  8. Symptoms and medications
  9. Results
  10. Patients
  11. Change of reflux oesophagitis grading
  12. Presence of gastro-oesophageal reflux symptoms
  13. Presence of medications
  14. Discussion
  15. Acknowledgements
  16. References

All 45 patients were followed up by endoscopy for at least 3 years after onset of reflux oesophagitis (3-year follow-up group). Within this group, nine patients were followed up for a further 2-year period (5-year follow-up group). Gender, mean age, endoscopic diagnosis and mean follow-up period in each group are summarized in Table 1.

Table 1.  Clinical features of both reflux oesophagitis follow-up groups
 3-year follow-up group5-year follow-up group
Gender (M/F)42/39/0
Age (years) (mean ± s.e.)51.2 ± 1.354.2 ± 2.6
Disease
 Gastric ulcer133
 Duodenal ulcer152
 Gastroduodenal ulcer52
Gastritis122
Follow-up period (years)4.29 ± 0.125.42 ± 0.14

Change of reflux oesophagitis grading

  1. Top of page
  2. Summary
  3. Introduction
  4. Subjects and methods
  5. Subjects
  6. Endoscopy
  7. Eradication therapy
  8. Symptoms and medications
  9. Results
  10. Patients
  11. Change of reflux oesophagitis grading
  12. Presence of gastro-oesophageal reflux symptoms
  13. Presence of medications
  14. Discussion
  15. Acknowledgements
  16. References

In the 3-year follow-up group, 35 patients were classified as grade A at initial endoscopy. In 26 of 35 patients, oesophagitis disappeared (grade O) at final endoscopy. The reflux oesophagitis grade did not change in five patients. In four patients, reflux oesophagitis progressed from grade A to B, but no patient showed reflux oesophagitis progression to grade C or D. Among the 10 patients whose reflux oesophagitis was classified as grade B at initial endoscopy, oesophagitis disappeared in four patients and improved to grade A in five patients at final endoscopy. One patient did not change reflux oesophagitis grades, and reflux oesophagitis did not progress to grade C or D in any patient (Table 2A).

Table 2.  Change of reflux oesophagitis grading in 3- and 5-year follow-up groups
Reflux oesophagitis grade (number of patients)
At initial observationAt final observation
(A) 3-year follow-up group
Grade A (35)Grade O (26)
Grade A (5)
Grade B (4)
Grade B (10)Grade O (4)
Grade A (5)
Grade B (1)
(B) 5-year follow-up group
Grade A (7)Grade O (5)
Grade A (2)
Grade B (2)Grade O (2)

Seven patients were classified as grade A at initial endoscopy among the 5-year follow-up group. Among them, five patients' oesophagitis disappeared at final endoscopy. Reflux oesophagitis grade did not change in two patients. No patient's reflux oesophagitis progressed to grade B, C or D. In two patients whose reflux oesophagitis was classified as grade B at initial endoscopy, oesophagitis disappeared and improved to grade O at final endoscopy (Table 2B).

The percentage of patients whose oesophagitis disappeared or improved was 78.8% (35/45) in the 3-year follow-up group and 78.8% (7/9) in the 5-year follow-up group. The percentage of patients whose oesophagitis progressed was only 8.9% (4/45) in the 3-year follow-up group and zero in 5-year follow-up group. We compared the difference in reflux oesophagitis prognoses with clinical diagnoses, but there was no difference between them (Table 3). Hiatal hernia was seen in 17 patients (37.8%) of the 3-year follow-up group at initial endoscopy. All four patients whose oesophagitis progressed from grade A to B had hiatal hernia. There was a significant difference in the rate of hiatal hernia between these four patients and others (P = 0.016). We did not observe the development of Barrett's mucosa or adenocarcinoma among any patient on endoscopic observation.

Table 3.  Change of reflux oesophagitis grading from reflux oesophagitis inception to final observation by clinical diagnoses
Prognosis of RENumber of patients
Gastric ulcer (n = 13)Duodenal ulcer (n = 15)GDU (n = 5)Gastritis (n = 12)
  1. RE, reflux oesophagitis; GDU, gastroduodenal ulcer.

Improved11 (84.6%)11 (73.3%)3 (60.0%)10 (83.3%)
Unchanged1 (7.7%)2 (13.3%)2 (40.0%)1 (8.3%)
Progressed1 (7.7%)2 (13.3%)0 (0%)1 (8.3%)

Presence of gastro-oesophageal reflux symptoms

  1. Top of page
  2. Summary
  3. Introduction
  4. Subjects and methods
  5. Subjects
  6. Endoscopy
  7. Eradication therapy
  8. Symptoms and medications
  9. Results
  10. Patients
  11. Change of reflux oesophagitis grading
  12. Presence of gastro-oesophageal reflux symptoms
  13. Presence of medications
  14. Discussion
  15. Acknowledgements
  16. References

In the 3-year follow-up group, 12 patients (26.7%) had gastro-oesophageal reflux symptoms at final endoscopy (two had both heartburn and epigastralgia, seven had heartburn, two had epigastralgia, and one had regurgitation). In the 5-year follow-up group, four patients (44.4%) had gastro-oesophageal reflux symptoms at last endoscopy (Table 4). No patient complained of dysphagia or chest pain.

Table 4.  Gastro-oesophageal reflux symptoms, medications and grade of reflux oesophagitis at final observation in the 3- and 5-year follow-up groups
PatientSymptomsMedicationsRE grade
  1. –, No symptom or no medication; PPI, proton-pump inhibitor.

  2. Patients 2, 3, 11 and 12 in the 3-year follow-up group are patients 1, 2, 3 and 4 in the 5-year follow-up group, respectively.

3-year follow-up group
 1Heartburn + epigastralgiaH2-blockerO
 2Heartburn + epigastralgiaA
 3HeartburnPPI + prokineticsO
 4HeartburnPPIA
 5HeartburnA
 6HeartburnA
 7HeartburnO
 8HeartburnB
 9HeartburnB
10EpigastralgiaH2-blockerB
11EpigastralgiaO
12RegurgitationH2-blockerO
13H2-blockerO
5-year follow-up group
1Heartburn + epigastralgiaA
2HeartburnPPI + prokineticsO
3EpigastralgiaO
4RegurgitationH2-blockerO

Presence of medications

  1. Top of page
  2. Summary
  3. Introduction
  4. Subjects and methods
  5. Subjects
  6. Endoscopy
  7. Eradication therapy
  8. Symptoms and medications
  9. Results
  10. Patients
  11. Change of reflux oesophagitis grading
  12. Presence of gastro-oesophageal reflux symptoms
  13. Presence of medications
  14. Discussion
  15. Acknowledgements
  16. References

Medications taken at the time of final endoscopy are also shown in Table 4. There were six patients (13.3%) in the 3-year follow-up group and two patients (22.2%) in the 5-year follow-up group who were taking proton-pump inhibitors, H2-blockers or prokinetics for more than 2 weeks.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Subjects and methods
  5. Subjects
  6. Endoscopy
  7. Eradication therapy
  8. Symptoms and medications
  9. Results
  10. Patients
  11. Change of reflux oesophagitis grading
  12. Presence of gastro-oesophageal reflux symptoms
  13. Presence of medications
  14. Discussion
  15. Acknowledgements
  16. References

To our knowledge, this is the first prospective study to estimate the long-term prognosis of reflux oesophagitis developed after H. pylori eradication therapy. After 3–5 years of observation, most cases of oesophagitis improved, and few patients had gastro-oesophageal symptoms needing medication.

Reflux oesophagitis development after eradication of H. pylori was first reported by Schutze et al.22 and was noticed more often after Labenz et al. showed that reflux oesophagitis developed in 13% of successfully eradicated patients with duodenal ulcers.10 Our recent study also showed that reflux oesophagitis developed after eradication therapy in 36 of 210 (17%) patients, and most patients had mild reflux oesophagitis (grade A or B according to the Los Angeles Classification System).16 In this study we followed up these mild cases of oesophagitis for more than 3 years and evaluated the prognosis of reflux oesophagitis after H. pylori eradication. Most cases of oesophagitis improved at final endoscopy in both the 3- and 5-year follow-up groups, and we saw the progression of reflux oesophagitis from grade A to B in few patients. Our recent study that assessed the natural course of mild reflux oesophagitis (grade A or B) showed that 29.5% of patients had no further episodes of reflux oesophagitis (grade O) and 11.5% of patients progressed to more severe forms of reflux oesophagitis (grade C or D).20 In the present study, 30 of 45 patients (66.7%) showed an improvement of reflux oesophagitis (from grade A or B to O) in the 3-year follow-up group and no patient's oesophagitis progressed to grade C or D. Comparing these results, we found that mild reflux oesophagitis which occurred after H. pylori eradication therapy differs from naturally occurring mild reflux oesophagitis in prognosis and does not progress to severe oesophagitis during long-term observation. However, in the 3-year follow-up group, four patients were treated with proton-pump inhibitor or H2-blocker and showed an improvement of reflux oesophagitis (grade O) at final endoscopy (patients 1, 3, 12 and 13 in Table 4). Their oesophagitis might be unchanged or progress without medications, but they were a fraction of all patients.

Alteration of acid secretion in the stomach is one of the mechanisms that improves cases of reflux oesophagitis that developed after eradication. Gastric acid secretion is known to decrease by corpus gastritis and atrophy derived from H. pylori infection and to recover to normal or almost normal levels after successful eradication.23–28 Iijima et al. reported that gastric acid secretion in H. pylori-positive patients with gastric ulcer was lower than that in H. pylori-negative controls before eradication therapy. They also showed that acid secretion increased 1 month after treatment; this was followed by a slight decrease at 7 months.29 Therefore, healing of gastritis and increased acid secretion might cause the development of reflux oesophagitis in patients with corpus gastritis or gastric ulcers at an early stage after eradication therapy. Then slowly decreasing acid secretion might contribute to the improvement of mild oesophagitis without the use of any medication.

On the other hand, high gastric acid secretion is observed in patients with duodenal ulcers, and it decreases gradually after H. pylori eradication therapy.29–31 Therefore, the change in acid secretion is not enough by itself to explain the occurrence of reflux oesophagitis. In this study, differences in prognoses were not seen when compared between clinical diagnoses. Therefore factors which influence gastric acid secretion regardless of clinical diagnosis should be discussed. Interleukin-1β is known to be a potent inhibitor of gastric acid secretion in patients infected with H. pylori.32 Decrease of Interleukin-1β by eradication therapy might contribute to rapidly increasing acid secretion and development of reflux oesophagitis, and interleukin-1-β polymorphism33 might influence the prognosis of reflux oesophagitis developing after eradication therapy.

Our recent study also showed that risk factors for progression of mild reflux oesophagitis were increased age, female gender, the presence of symptoms at initial diagnosis by endoscopy, presence of a hiatal hernia, absence of atrophic gastritis and absence of H. pylori infection.20 In this previous study, most patients were younger men (in their 40s or 50s) who did not have gastro-oesophageal reflux symptoms at initial endoscopy. All patients had also been infected with H. pylori and were observed for atrophic change in their gastric mucosa. Patient background was one of the reasons for a prognosis different from the prognosis expected for patients with a natural history of mild reflux oesophagitis. Hiatal hernia is also a risk factor for reflux oesophagitis development after H. pylori eradication therapy.12 In the current study, the rate of hiatal hernia was significantly higher in patients with reflux oesophagitis progression than in other patients. We think that hiatal hernia is an important factor in the progression of reflux oesophagitis regardless of H. pylori infection and eradication.

Patients showed good prognoses not only in reflux oesophagitis grading changes but also in the lessening of symptoms and need for medication. At final endoscopy, 12 patients (26.7%) had gastro-oesophageal reflux symptoms, and six patients (13.3%) were using proton-pump inhibitors, H2-blockers or prokinetics medications in the 3-year follow-up group. Because the incidence of reflux oesophagitis after H. pylori eradication is 10–20%,11, 12 these results suggest that only 2–4% of patients have gastro-oesophageal reflux symptoms and that only 1–2% of patients require medication among all successfully eradicated patients.

In conclusion, it is rare for reflux oesophagitis which develops after H. pylori eradication therapy to become severe and cause long-term gastro-oesophageal reflux symptoms. However, we have not studied the prognosis of patients without endoscopic evidence of oesophagitis but who have developed gastro-oesophageal reflux symptoms after eradication therapy. Further study also needs to be done on the development of Barrett's mucosa, which may be a cause of oesophageal adenocarcinomas.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Subjects and methods
  5. Subjects
  6. Endoscopy
  7. Eradication therapy
  8. Symptoms and medications
  9. Results
  10. Patients
  11. Change of reflux oesophagitis grading
  12. Presence of gastro-oesophageal reflux symptoms
  13. Presence of medications
  14. Discussion
  15. Acknowledgements
  16. References
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