Elly C. Klinkenberg-Knol

Atrophic Gastritis and Helicobacter pylori Infection in Patients with Reflux Esophagitis Treated with Omeprazole or Fundoplication

BACKGROUND Helicobacter pylori infection plays an important part in the development of atrophic gastritis and intestinal metaplasia, conditions that predispose patients gastric cancer. Profound suppression of gastric acid is associated with increased severity of gastritis caused by H. pylori, but it is not known whether acid suppression increases the risk of atrophic gastritis. METHODS We studied patients from two separate cohorts who were being treated for reflux esophagitis: 72 patients treated with fundoplication in Sweden and 105 treated with omeprazole (20 to 40 mg once daily) in the Netherlands. In both cohorts, the patients were followed for an average of five years (range, three to eight). After fundoplication, the patients did not receive acid-suppressive therapy. The presence of H. pylori was assessed at the first visit by histologic evaluation in the fundoplication group and by histologic and serologic evaluation in the omeprazole group. The patients were not treated for H. pylori infection. Before treatment and during follow-up, the patients underwent repeated gastroscopy, with biopsy sampling for histologic evaluation. RESULTS Among the patients treated with fundoplication, atrophic gastritis did not develop in any of the 31 who were infected with H. pylori at base line or the 41 who were not infected; 1 patient infected with H. pylori had atrophic gastritis before treatment that persisted after treatment. Among the patients treated with omeprazole, none of whom had atrophic gastritis at base line, atrophic gastritis developed in 18 of the 59 infected with H. pylori(P<0.001) and 2 of the 46 who were not infected (P=0.62). CONCLUSIONS Patients with reflux esophagitis and H. pylori infection who are treated with omeprazole are at increased risk of atrophic gastritis.

Long-term omeprazole treatment in resistant gastroesophageal reflux disease: Efficacy, safety, and influence on gastric mucosa

BACKGROUND & AIMS The efficacy and safety of long-term acid suppression remains a subject for debate. We report data from patients with refractory reflux esophagitis who were undergoing maintenance therapy with >/=20 mg omeprazole daily for a mean period of 6.5 years (range, 1.4-11.2 years). METHODS Patients with severe reflux esophagitis resistant to long-term therapy with H(2)-receptor antagonists and who were not eligible for surgery were evaluated at least annually for endoscopic relapse and histological changes in the gastric corpus. RESULTS In 230 patients (mean age, 63 years at entry; 36% were >/=70 years), there were 158 relapses of esophagitis during 1490 treatment years (1 per 9.4 years), with no significant difference in relapse rates between Helicobacter pylori-positive and -negative patients. All patients rehealed during continued therapy with omeprazole at the same or higher dose. The annual incidence of gastric corpus mucosal atrophy was 4.7% and 0.7% in H. pylori-positive and -negative patients, respectively, which was mainly observed in elderly patients who had moderate/severe gastritis at entry. In patients with baseline moderate/severe gastritis, the incidences were similar: 7.9% and 8.4%, respectively. Corpus intestinal metaplasia was rare, and no dysplasia or neoplasms were observed. The adverse event profile was as might be expected from this elderly group of patients. CONCLUSIONS Long-term omeprazole therapy (up to 11 years) is highly effective and safe for control of reflux esophagitis.

Long-Term Treatment with Omeprazole for Refractory Reflux Esophagitis: Efficacy and Safety

Omeprazole, a substituted benzimidazole, diminishes gastric acid secretion profoundly and continuously by selectively inhibiting the proton pump (H+/KATPase) in the secretory membrane of the parietal cell [1]. In several studies, omeprazole, in doses ranging from 20 to 60 mg/d, was found to be superior to 150 to 300 mg of ranitidine twice daily [2-8] and to 400 mg of cimetidine once daily [9] in the short-term treatment of reflux esophagitis. However, after therapy was stopped, reflux esophagitis rapidly recurred in most cases [5, 6]. The primary advantage of proton pump inhibitors over all other antireflux therapies is their specific efficacy in patients with severe, refractory reflux disease, nonhealing Barrett ulcers, or peptic strictures [10-22]. Omeprazole is approved only for short-term use in the United States but is approved in other countries, such as the Netherlands, United Kingdom, Belgium, and Brasil, for long-term treatment of reflux esophagitis. Most clinical experience has been gained outside rigorously controlled clinical trials. In the Netherlands, a protocol of omeprazole to treat patients with refractory reflux disease was started in 1985. We report the results of omeprazole to treat patients for as long as 64 months. Methods Patients This open, compassionate-use study started in November 1985; our analysis includes all data collected to March 1991. It was conducted in 7 referral centers in the Netherlands. From November 1985 to January 1989, all patients with erosive reflux esophagitis diagnosed with endoscopy and no response to treatment with H2-receptor antagonists (cimetidine, 800 to 2000 mg/d; ranitidine, 600 to 900 mg/d; or famotidine, 80 to 120 mg/d) for at least 3 months before the start of the study were selected for the study. All eligible patients (n = 91) participated. Pre-entry severity of esophagitis was classified endoscopically as grade II (noncircumferential erosions), grade III (circumferential erosions or ulceration), or grade IV (erosions, ulceration plus deep ulcer or stricture) according to the classification of Savary and Miller [23]. We classified patients with Barrett esophagus according to the grade of esophagitis proximal to the Barrett epithelium. We defined healing of reflux esophagitis as absence of mucosal defects. Thirty-two patients had Barrett esophagus in combination with esophagitis. Twenty-five patients previously had antireflux surgery (Nissen fundoplication or hiatoplasty). Nine patients had been hospitalized for esophageal bleeding. Twenty-eight patients needed repeated dilatations before and during the initial healing phase. All patients were given 40 mg of omeprazole once daily for 4 to 16 weeks, until endoscopic examinations showed that the esophagitis was healed. In 5 patients, the healing dose of omeprazole was continued as a maintenance dose for reasons specified later. We did follow-up examinations every 3 months in the first year of maintenance therapy and thereafter at 6-month intervals. We interviewed patients to determine recurrence of symptoms (heartburn, regurgitation, and dysphagia) and adverse events. In addition, upper gastrointestinal endoscopy was done, including fundic biopsies, and a fasting blood sample was obtained for routine laboratory screening and serum gastrin tests. In patients with endoscopic relapse, we increased the dose of omeprazole by 20 mg. From 1990, patients received endoscopic examinations and laboratory tests annually. Serum gastrin was measured by a previously described sensitive and specific radioimmunoassay [24]. We considered 100 ng/L the upper limit of normal for fasting serum gastrin. At endoscopy, two or three biopsy specimens were obtained from the gastric corpus mucosa approximately 10 cm below the cardia along the greater curvature. The biopsy specimens were coded, fixed in neutral formalin, and embedded in paraffin. Deparaffinized 5-msections were stained with hematoxylin and eosin to assess the overall tissue structure. Adjacent sections were also stained with Sevier-Munger silver for argyrophil endocrine cells [25]. Of the six endocrine cell types in gastric corpus mucosa, 50% [26] or more [25] are composed of enterochromaffin-like cells, which are distinctly positive with Sevier-Munger silver stain. Serotonin-producing argentaffin enterochromaffin cells, composing a minor part (10% to 20%), and a minute number of somatostatin D1 cells are also argyrophilic, whereas the remaining endocrine cell types are negative [26]. We classified chronic gastritis as subatrophic or atrophic when at least 30% gland atrophy was evident, corresponding to both preatrophic and atrophic gastritis [27]. We classified the remaining cases of chronic gastritis as nonatrophic, thereby including superficial and interstitial gastritis and also mild subatrophic or atrophic changes. The endocrine cell changes were evaluated according to the classification of Solcia and associates [26]. The qualitative analysis of all corpus biopsy specimens was done blindly (by N. Havu, MD, Department of Pathology, Safety Assessment, AB Astra, Sodertalje, Sweden). Statistical Analysis We analyzed differences in serum gastrin level between the various time intervals for statistical significance using the Wilcoxon signed-rank test [28]. To compare percentages, we used Fisher exact tests. To compare the degree of enterochromaffin-like cell hyperplasia and gastritis at first and last biopsy, we used the McNemar test. This test considers all patients with changes but disregards those with unchanged classification of hyperplasia and gastritis, respectively. We estimated percentages of patients still in remission using the life-table method. Results are expressed as medians and ranges unless otherwise indicated. The protocol was approved by the ethics committee of the Free University Hospital. All eligible patients gave informed consent. Results Of the 91 patients entering the study, esophagitis healed in 58 (64%) after 4 weeks of treatment with 40 mg of omeprazole; it healed in 16 (18%) after 8 weeks and in 12 (13%) after 12 weeks. Four patients (4%) were healed only after acute treatment was extended to 16 weeks. One patient only healed after the dose of omeprazole was increased to 60 mg daily. These 5 patients continued to receive 40 mg of omeprazole as a maintenance dose. The time to healing for patients with Barrett esophagus and esophagitis was the same as for other patients, although prestudy endoscopic examination showed that patients with Barrett esophagus had more severe reflux esophagitis (63% grade IV esophagitis compared with 27% in the other patients). The median observation time during maintenance treatment was 48 months (range, 24 to 64 months). Drop-outs Four patients dropped out of the study. Three patients died: One died of postsurgical complications after a hip fracture 48 months after the start of maintenance treatment; one with known multiple myeloma died of related infectious complications after 36 months of maintenance therapy; and one died of pancreatic carcinoma that was diagnosed at autopsy after 42 months of therapy with omeprazole. One patient was lost to follow-up because of emigration. Clinical Evaluation All 91 patients were followed for at least 36 months: 67 patients for 48 months and 27 for 60 months or more. Symptomatic and endoscopic relapse of esophagitis occurred in 47% (95% CI, 36% to 58%) of the 86 patients receiving maintenance treatment with 20 mg of omeprazole daily (Figure 1). All patients with relapses healed within 3 months of increasing the daily dose of omeprazole by 20 mg daily (Figure 2). Seven of those 40 patients (18%; CI, 7% to 33%), who had already had a relapse, had another relapse after a mean follow-up period of 24 months (range, 9 to 36 months) and were successfully treated with a further dose increment to 60 mg daily for a mean duration of 36 months (range, 6 to 39 months). Attempts to decrease the dose after rehealing resulted in rapid relapse, as evidenced by symptoms and endoscopic examination. During the maintenance period, peptic strictures did not occur. We diagnosed Barrett esophagus by pre-entry endoscopic examination in 32 patients. During the follow-up period, we observed no regression or disappearance of Barrett epithelium. However, Barrett epithelium did not progress during the entire observation period. The relapse rate in patients with previous antireflux surgery was 40% (16 of 25 patients), which was similar to that for the whole group. Although most patients remained asymptomatic during maintenance treatment, 7 of the 91 (8%) patients reported occasional mild heartburn. Figure 1. Remission rates (%) in 86 patients with reflux esophagitis during maintenance treatment with 20 mg of omeprazole once daily during 60 months of follow-up (life-table method. Figure 2. Cumulative remission rates with dose adjustments required to maintain remission in 91 patients with reflux esophagitis during maintenance treatment with omeprazole. Effect on Fasting Serum Gastrin Levels In the initial healing phase, median fasting serum gastrin levels increased from 60 ng/L before study and during treatment with an H2-receptor antagonist to 162 ng/L during treatment with omeprazole (P<0.01). Thereafter, gastrin levels did not change significantly during maintenance treatment (Figure 3). For example, the mean of the paired differences in gastrin levels in 63 patients between 12 and 36 months of treatment was 109.73 ng/L, which was not significant (P = 0.1; CI, 247.31 to 27.85 ng/L). We detected no relation between the dose of omeprazole in the maintenance period and the serum gastrin level. Figure 3. Distribution of fasting serum gastrin levels (all measured individual values) during maintenance treatment with omeprazole. Ten of the 91 patients showed very high serum gastrin levels (at least two recordings of more than 500 ng/L during the follow-up period), with the highest recording being 3867 ng/L (Tabl

Endoscopic regression of Barrett's oesophagus during omeprazole treatment; a randomised double blind study

BACKGROUND Barrett’s oesophagus, columnar metaplasia of the epithelium, is a premalignant condition with a 50–100-fold increased risk of cancer. The condition is caused by chronic gastro-oesophageal reflux. Regression of metaplasia may decrease the cancer risk. AIMS To determine whether elimination of acid gastro-oesophageal reflux induces a regression of metaplastic epithelium. METHODS Sixty eight patients with acid reflux and proven Barrett’s oesophagus were included in a prospective, randomised, double blind study with parallel groups, and were treated with profound acid secretion suppression with omeprazole 40 mg twice daily, or with mild acid secretion suppression with ranitidine 150 mg twice daily, for 24 months. Endoscopy was performed at 0, 3, 9, 15, and 24 months with measurement of length and surface area of Barrett’s oesophagus; pH-metry was performed at 0 and 3 months. Per protocol analysis was performed on 26 patients treated with omeprazole, and 27 patients treated with ranitidine. RESULTS Omeprazole reduced reflux to 0.1%, ranitidine to 9.4% per 24 hours. Symptoms were ameliorated in both groups. There was a small, but statistically significant regression of Barrett’s oesophagus in the omeprazole group, both in length and in area. No change was observed in the ranitidine group. The difference between the regression in the omeprazole and ranitidine group was statistically significant for the area of Barrett’s oesophagus (p=0.02), and showed a trend in the same direction for the length of Barrett’s oesophagus (p=0.06). CONCLUSIONS Profound suppression of acid secretion, leading to elimination of acid reflux, induces partial regression of Barrett’s oesophagus.

Cure of Helicobacter pylori infection in patients with reflux oesophagitis treated with long term omeprazole reverses gastritis without exacerbation of reflux disease: results of a randomised controlled trial

Background:Helicobacter pylori gastritis may progress to glandular atrophy and intestinal metaplasia, conditions that predispose to gastric cancer. Profound suppression of gastric acid is associated with increased severity of H pylori gastritis. This prospective randomised study aimed to investigate whether H pylori eradication can influence gastritis and its sequelae during long term omeprazole therapy for gastro-oesophageal reflux disease (GORD). Methods: A total of 231 H pylori positive GORD patients who had been treated for ⩾12 months with omeprazole maintenance therapy (OM) were randomised to either continuation of OM (OM only; n = 120) or OM plus a one week course of omeprazole, amoxycillin, and clarithromycin (OM triple; n = 111). Endoscopy with standardised biopsy sampling as well as symptom evaluation were performed at baseline and after one and two years. Gastritis was assessed according to the Sydney classification system for activity, inflammation, atrophy, intestinal metaplasia, and H pylori density. Results: Corpus gastritis activity at entry was moderate or severe in 50% and 55% of the OM only and OM triple groups, respectively. In the OM triple group, H pylori was eradicated in 90 (88%) patients, and activity and inflammation decreased substantially in both the antrum and corpus (p<0.001, baseline v two years). Atrophic gastritis also improved in the corpus (p<0.001) but not in the antrum. In the 83 OM only patients with continuing infection, there was no change in antral and corpus gastritis activity or atrophy, but inflammation increased (p<0.01). H pylori eradication did not alter the dose of omeprazole required, or reflux symptoms. Conclusions: Most H pylori positive GORD patients have a corpus predominant pangastritis during omeprazole maintenance therapy. Eradication of H pylori eliminates gastric mucosal inflammation and induces regression of corpus glandular atrophy. H pylori eradication did not worsen reflux disease or lead to a need for increased omeprazole maintenance dose. We therefore recommend eradication of H pylori in GORD patients receiving long term acid suppression.

Effect of Helicobacter pylori eradication on chronic gastritis during omeprazole therapy.

BACKGROUND We have previously observed that profound acid suppressive therapy inHelicobacter pylori positive patients with gastro-oesophageal reflux disease is associated with increased corpus inflammation and accelerated development of atrophic gastritis. AIM To investigate ifH pylori eradication at the start of acid suppressive therapy prevents the development of these histological changes. PATIENTS/METHODS In a prospective randomised case control study, patients with reflux oesophagitis were treated with omeprazole 40 mg once daily for 12 months. H pylori positive patients were randomised to additional double blind treatment with omeprazole 20 mg, amoxicillin 1000 mg and clarithromycin 500 mg twice daily or placebo for one week. Biopsy sampling for histology, scored according to the updated Sydney classification, and culture were performed at baseline, and at three and 12 months. RESULTS In the persistently H pylori positive group (n=24), active inflammation increased in the corpus and decreased in the antrum during therapy (p=0.032 and p=0.002, respectively). In contrast, in theH pylori positive group that becameH pylori negative as a result of treatment (n=33), active and chronic inflammation in both the corpus and antrum decreased (p⩽0.0001). The decrease in active and chronic inflammation in the corpus differed significantly compared with the persistentlyH pylori positive group (both p=0.001). For atrophy scores, no significant differences were observed betweenH pylori eradicated and persistentlyH pylori positive patients within one year of follow up. No changes were observed in the H pylori negative control group (n=26). CONCLUSIONS H pylori eradication prevents the increase in corpus gastritis associated with profound acid suppressive therapy. Longer follow up is needed to determine if H pylori eradication prevents the development of atrophic gastritis.

Helicobacter pylori and the efficacy of omeprazole therapy for gastroesophageal reflux disease

OBJECTIVE:Helicobacter pylori infection may affect gastric acid output and intragastric pH. In patients with an insufficient lower esophageal sphincter, this effect may theoretically influence the severity of reflux disease, as well as the efficacy of acid suppressive therapy. To evaluate whether the H. pylori status of patients with gastroesophageal reflux disease (GERD) affects the severity of disease and the efficacy of omeprazole therapy to maintain disease remission, we conducted this study.METHODS:Patients with GERD were prospectively studied by upper gastrointestinal endoscopy with biopsy sampling for histology and H. pylori culture before start of treatment and at annual follow-up. At endoscopy, esophagitis was graded according to the criteria of Savary-Miller, and the presence of Barretts esophagus, hiatal herniation, or other abnormalities was recorded. Omeprazole was started at an initial dose of 20 mg daily; the dose was adjusted based on symptoms and the endoscopical findings.RESULTS:One hundred thirty-seven GERD patients were included and followed up for a mean 56.6 months; 49 (36%) of them were infected with H. pylori. H. pylori-infected and -uninfected patients did not differ with respect to age (60 ± 13 vs 61 ± 14 yr, p= 0.65) or duration of follow-up (54 ± 30 vs 58 ± 31 months, p= 0.12). H. pylori-negative patients tended to present with more severe esophagitis at baseline (median Savary-Miller score 3 vs 2, p= 0.06) and had a higher prevalence of Barretts esophagus (39/88 vs 10/49, p= 0.006). However, no difference was found with respect to the dose of omeprazole needed for maintained relief of symptoms and endoscopical signs of esophagitis (median 40 mg in both groups, p= 0.35).CONCLUSIONS:H. pylori-negative GERD patients have a higher prevalence of Barretts esophagus, but do not need a higher dose of omeprazole to maintain symptomatic and endoscopical disease remission.

The development of atrophic gastritis—Helicobacter pylori and the effects of acid suppressive therapy

Helicobacter pylori is uniquely adapted to survival in the strongly acidic gastric lumen. In vitro, both acid and certain acid suppressors affect bacterial growth. In vivo, there is little evidence that acid suppressors have any effect on bacterial survival. In contrast, decrease of acid secretion quickly leads to a spreading of the bacterial infection throughout the body and fundus of the stomach, which is accompanied by an increase of the associated gastritis.

Percutaneous endoscopic gastrostomy: Complications and suggestions to avoid them

Objectives Percutaneous endoscopic gastrostomy (PEG) tubes have become an excellent alternative for the long-term management of patients with proximal obstructions of the gastrointestinal tract. However, their use has limitations and can be associated with serious complications. We therefore studied the frequency and severity of complications related to the use of PEG tubes in our clinic. Design All adults (aged 18 years and above) in whom a PEG tube was placed between January 1 1994 and January 1 1999 at the Free University Hospital in Amsterdam were included in this study. In initial cases, the indication and procedure were individually judged according to a liberal protocol. However, after several major complications, a strict procedure protocol was implemented in September 1996. Results During the study period, 263 PEG tubes were placed in 254 patients with head and neck cancer (n = 183; 70%), neurological disorders (n = 52; 20%) or severe upper gastrointestinal motility disorders (n = 28; 11%). In period I, 167 PEG tubes were placed and in period II, 96 PEG tubes were inserted. Patients were followed for a median 111 days. Minor complications occurred in 13% of the patients. Major complications occurred in 8% of the patients. In period I, the percentage of major complications was higher than in period II (9.5% versus 6%). Conclusion PEG tube placement is a safe procedure when performed according to strict guidelines. By doing so, PEG tubes allow optimal feeding for prolonged periods with the occasional need for replacement of the tube. PEG tubes should not be introduced in acutely ill patients, patients with a short life expectancy and preferably not to patients with severe coughing.

Effect of short- and long-term treatment with omeprazole on the absorption and serum levels of cobalamin

Aims: To evaluate absorption of protein‐bound and unbound cyanocobalamin before and during treatment with omeprazole, and cobalamin levels in patients on long‐term treatment with omeprazole.