Stephan G. M. Meuwissen

Long-term sequelae of Helicobacter pylori gastritis.

Chronic Helicobacter pylori gastritis has been put forward as a risk factor for development of gastric mucosal atrophy and gastric cancer. The purpose of our study was to investigate the long-term effects of H pylori gastritis on the gastric mucosa. We prospectively studied 49 subjects negative for H pylori and 58 positive subjects for a mean follow-up of 11.5 years (range 10-13 years). Serum samples were obtained at the initial and follow-up visits for determination of H pylori IgG antibodies. Gastroscopies with biopsy sampling were done in all patients at both visits. Biopsy specimens were used for assessment of H pylori infection and histology. Development of atrophic gastritis and intestinal metaplasia occurred in 2 (4%) uninfected and 16 (28%) infected subjects. Regression of atrophy was noted in 4 (7%) infected subjects. Development of atrophic gastritis and intestinal metaplasia was significantly associated with H pylori infection (p = 0.0014; odds ratio 9.0, 95% CI 1.9-41.3). The proportion of atrophic gastritis in the study population showed an annual increase of 1.15% (0.5-1.8%). We conclude that H pylori infection is a significant risk factor for development of atrophic gastritis and intestinal metaplasia. Our findings support strongly the causative role of this infection in gastric carcinogenesis.

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 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

Quantification of Bacteria Adherent to Gastrointestinal Mucosa by Real-Time PCR

ABSTRACT The use of real-time quantitative PCR (5′ nuclease PCR assay) as a tool to study the gastrointestinal microflora that adheres to the colonic mucosa was evaluated. We developed primers and probes based on the 16S ribosomal DNA gene sequences for the detection of Escherichia coli and Bacteroides vulgatus. DNA was isolated from pure cultures and from gut biopsy specimens and quantified by the 5′ nuclease PCR assay. The assay showed a very high sensitivity: as little as 1 CFU of E. coli and 9 CFU of B. vulgatus could be detected. The specificities of the primer-probe combinations were evaluated with samples that were spiked with the species most closely related to E. coli and B. vulgatus and with eight other gut microflora species. Mucosal samples spiked with known amounts of E. coli or B. vulgatus DNA showed no PCR inhibition. We conclude that the 5′ nuclease PCR assay may be a useful alternative to conventional culture techniques to study the actual in vivo composition of a complex microbial community like the gut microflora.

Seroconversion for Helicobacter pylori

The prevalence of Helicobacter pylori antibodies increases with age, but it is unknown whether this is due to a constant rate of infection in different age groups, or whether most infection occurs in childhood. Follow-up data on infection rates and the course of infection in an untreated population are scarce. We measured H pylori IgG antibody concentrations in patients who were seen at our endoscopy unit between 1979 and 1983. 115 of 164 eligible patients (70%) participated in the study. H pylori IgG antibody concentrations were measured in two serum samples taken with a mean interval of 11.5 years. 56 patients tested positive at the first visit. During follow-up, 2 patients became infected (annual infection rate 0.30%, 95% Cl 0.04-1.08%). Evidence of infection disappeared in 6 patients: after gastric surgery in 3 and due to an unknown cause in the remaining 3 patients. A non-significant decrease of infection was shown in different age cohorts during follow-up. Antibody concentrations did not increase with age. These results strongly support the concept of dominant infection rates in childhood. Elimination of infection may occur in a few patients without eradication therapy.

Endosonographic Evidence of Persistence of Crohn’s Disease-Associated Fistulas After Infliximab Treatment, Irrespective of Clinical Response

PURPOSE: Infliximab has been reported to improve fistulizing Crohn’s disease. Moreover, prompt healing of mucosal ulcers has been described. Whether fistulas disappear or remainders of fistulas persist is unknown. This study documents fistulous tracts before and after infliximab therapy by means of hydrogen peroxide-enhanced endosonography METHODS: Eight patients with perianal, vaginal, or perineal fistulas were treated with a triplet of infliximab 5 mg/kg infusions. At baseline, and at Week 4 after the last infusion, fistulas were documented by local inspection, digital examination, and hydrogen peroxide-enhanced anal or vaginal endosonography. RESULTS: Patients with vaginal or perineal fistulas did not respond clinically to therapy, whereas patients with perianal fistulas improved considerably. However, in all patents remainders of fistulous tracts were demonstrated by endosonographic techniques. CONCLUSIONS: Short-term treatment of Crohn’s disease-associated fistulas with infliximab does not induce disappearance of fistulous tracts, irrespective of therapeutic response.

Effect of Oral Omeprazole on Serum Gastrin and Serum Pepsinogen I Levels

Fasting and meal-stimulated serum gastrin and serum pepsinogen I levels were determined in 8 healthy volunteers before, during, and after administration of 30 mg of omeprazole daily for 14 days. Fasting levels and the integrated increment of serum gastrin were significantly increased after 7 and 14 days of treatment with omeprazole, but not after a single dose. Fasting levels measured 2, 4, 7, 14, and 21 days after stopping treatment with omeprazole and the integrated increment of serum gastrin determined 7 and 14 days after discontinuation of omeprazole were not significantly different from pretreatment levels. Fasting serum pepsinogen I levels increased progressively during omeprazole treatment. This increase was significant after 7 and 14 days of treatment and 2 and 4 days after discontinuing omeprazole. These levels were not significantly different from pretreatment levels 7, 14, and 21 days after omeprazole treatment. Serum pepsinogen I did not significantly change after the test meal. It is concluded that fasting and meal-stimulated serum gastrin levels and fasting serum pepsinogen I levels increase significantly during treatment with 30 mg of omeprazole daily for 14 days, but after stopping treatment there is a rapid return to pretreatment levels.

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.

Clinical significance of pepsinogen A isozymogens, serum pepsinogen A and C levels, and serum gastrin levels

Gastric mucosal pepsinogen A phenotype, serum pepsinogen A level, serum pepsinogen C level, serum pepsinogen A/pepsinogen C ratio, and serum gastrin level were evaluated as potential markers for gastric cancer or its precursors in 19 healthy volunteers and 341 patients from the gastroscopy program. Gastric cancer, atrophic gastritis, and intestinal metaplasia of the stomach were associated with pepsinogen A phenotypes, characterized by an intense fraction 5, and with a low serum pepsinogen A level (<25 μg/l), a low serum pepsinogen A/pepsinogen C ration (<1.5), and a high serum gastrin level (> 79 ng/l). The specificity of pepsinogen A phenotypes with an intense fraction 5 for gastric cancer or its precursors was 95.1% with a sensitivity of 20.4%. The sensitivity and specificity of the noninvasive tests were evaluated with the receiver operating characteristic. For clinical purposes, a serum pepsinogen A/pepsinogen C ration less than 1.8 is the most suitable test, with a sensitivity of 74% and a specificity of 76% for gastric cancer or its precursors, with a reference population of patients with benign gastric disorders. However, the sensitivity and specificity of the single or combined tests are too low for population screening purposes. Cancer 59:952‐958, 1987.

Pharmacological Management of Gastro-Oesophageal Reflux Disease

SummaryGastro-oesophageal reflux disease (GORD) ranges from episodic symptomatic reflux without oesophagitis to severe oesophageal mucosal damage, such as Barrett’s metaplasia or peptic stricture. The multifactorial pathogenesis of GORD prevents medical cure of the disease. GORD is a chronic disease with a high tendency to relapse, requiring a long term treatment strategy in practically all patients. Complete healing of all mucosal lesions is not necessarily the aim of treatment in all patients. In milder forms of reflux disease, symptom relief is the most important goal.Many patients with mild GORD do well on symptomatic self-care with antacids and/or alginate. In addition, lifestyle changes should be advised to all patients: these improve symptoms and enhance the efficacy of therapy.In the acute treatment of GORD the prokinetic drug cisapride has been shown to be effective in relieving symptoms and healing grade I to II oesophagitis. Cisapride decreases symptomatic and endoscopic relapse in patients with mild GORD.Histamine H2-receptor antagonists are effective in relieving reflux symptoms in about 50% of patients, but with regard to healing, H2-antagonists appear to be mainly effective in grades I and II and not in higher grades of oesophagitis. Maintenance treatment with H2-antagonists is mainly symptomatically effective in patients with mild GORD.Proton pump inhibitors (PPIs) provide significantly higher healing rates of reflux oesophagitis than H2-antagonists, even in the more severe cases of oesophagitis and Barrett’s ulcers. PPIs are also effective in patients with oesophagitis refractory to treatment with H2-antagonists. PPIs have become the drugs of first choice in healing of all patients with more severe forms of reflux oesophagitis, and increasingly also for patients with milder forms of oesophagitis, certainly those who fail to respond to other drugs. In maintenance treatment of GORD, PPIs are the most effective drugs, offering the possibility of keeping nearly all patients in remission with adjusted doses. Current patient data of up to 5 years indicate the safety of this strategy for this period, but the exact consequences of strong acid inhibition over a longer period still have to be clarified. At present, all but a few patients with GORD can be managed adequately by medical therapy.