Long-term Omeprazole Treatment Research Articles

Blockade of aryl hydrocarbon receptor restricts omeprazole-induced chronic kidney disease.

Chronic kidney disease (CKD) is the 16th leading cause of mortality worldwide. Clinical studies have raised that long-term use of omeprazole (OME) is associated with the morbidity of CKD. OME is commonly used in clinical practice to treat peptic ulcers and gastroesophageal reflux disease. However, the mechanism underlying renal failure following OME treatment remains mostly unknown and the rodent model of OME-induced CKD is yet to be established. We described the process of renal injury after exposure to OME in mice; the early renal injury markers were increased in renal tubular epithelial cells (RTECs). And after long-term OME treatment, the OME-induced CKD mice model was established. Herein, aryl hydrocarbon receptor (AHR) translocation appeared after exposure to OME in HK-2 cells. Then for both in vivo and in vitro, we found that Ahr-knockout (KO) and AHR small interfering RNA (siRNA) substantially alleviated the OME-induced renal function impairment and tubular cell damage. Furthermore, our data demonstrate that antagonists of AHR and CYP1A1 could attenuate OME-induced tubular cell impairment in HK-2 cells. Taken together, these data indicate that OME induces CKD through the activation of the AHR-CYP axis in RTECs. Our findings suggest that blocking the AHR-CYP1A1 pathway acts as a potential strategy for the treatment of CKD caused by OME. KEY MESSAGES: We provide an omeprazole-induced chronic kidney disease (CKD) mice model. AHR activation and translocation process was involved in renal tubular damage and promoted the occurrence of CKD. The process of omeprazole nephrotoxicity can be ameliorated by blockade of the AHR-CYP1A1 axis.

Long-Term Administration of Omeprazole-Induced Hypergastrinemia and Changed Glucose Homeostasis and Expression of Metabolism-Related Genes.

PPIs, or proton pump inhibitors, are the most widely prescribed drugs. There is a debate regarding the relationship between long-term PPI use and the risk of type 2 diabetes mellitus (T2DM). A potential connection between T2DM and PPIs could be an elevated gastrin concentration. This study is aimed at investigating the long-term effects of PPI omeprazole (OZ) on glucose homeostasis and pancreatic gene expression profile in mice. Healthy adult male BALB/c mice were randomly divided into three equal groups (n = 10 in each one): (1) experimental mice that received OZ 20 mg/kg; (2) control mice that received 30 μl saline per os; (3) intact mice without any interventions. Mice were treated for 30 weeks. Glucose homeostasis was investigated by fasting blood glucose level, oral glucose tolerance test (GTT), insulin tolerance test (ITT), and basal insulin resistance (HOMA-IR). Serum gastrin and insulin concentration were determined by ELISA. Expressions of Sirt1, Pparg, Nfκb1 (p105), Nfe2l2, Cxcl5, Smad3, H2a.z, and H3f3b were measured by RT-PCR. The ROC analysis revealed an increase in fasting blood glucose levels in OZ-treated mice in comparison with control and intact groups during the 30-week experiment. A slight but statistically significant increase in glucose tolerance and insulin sensitivity was observed in OZ-treated mice within 30 weeks of the experiment. The mice treated with OZ exhibited significant increases in serum insulin and gastrin levels, accompanied by a rise in the HOMA-IR level. These animals had a statistically significant increase in Sirt1, Pparg, and Cxcl5 mRNA expression. There were no differences in β-cell numbers between groups. Long-term OZ treatment induced hypergastrin- and hyperinsulinemia and increased expression of Sirt1, Pparg, and Cxcl5 in mouse pancreatic tissues accompanied by specific changes in glucose metabolism. The mechanism of omeprazole-induced Cxcl5 mRNA expression and its association with pancreatic cancer risk should be investigated.

Neuropsychological assessment after long-term omeprazole treatment

Recent studies suggest that Omeprazole, a widely used treatment for gastric acid-related disorders, may have a significant effect on human cognition. However, there is no consensus on the matter. Though some studies suggest the drug is associated with an increased risk of cognitive decline, memory impairment, and dementia, this issue has not been sufficiently studied. Therefore, the goal of this study was to investigate the cognitive impairments associated with long-term Omeprazole treatment, with a focus on memory, attention, and executive functions. Additionally, we sought to verify whether the duration of treatment was associated with the magnitude of the associated cognitive impairments. The sample consisted of 30 participants of both genders treated with Omeprazole (experimental group) and 30 participants who did not use the drug (control group). The cognitive assessment battery: Verbal Fluency, Rey Auditory-Verbal Learning, Attention Assessment Battery, Five Digit Test, Hayling Test, and NEUPSILIN Subtest. The groups were compared using Student’s T-tests, and the association between treatment duration and cognitive performance was examined using Pearson’s coefficients. The results showed significant group differences in verbal fluency, short-term episodic memory, selective attention, and executive functions. The duration of Omeprazole treatment was also positively associated with the magnitude of cognitive impairment.

The clinical research on long-term low-dose omeprazole treatment of chronic obstructive pulmonary disease in acute attack

Objective To explore the clinical efficacy of the long-term low-dose application of omeprazole for the treatment of chronic obstructive pulmonary disease (COPD) with stability stage, and observe its safety. Methods From July 2013 to August 2014, 126 stabilization patients in Dajiang East Hospital of Hangzhou with COPD were selected, and they were randomly divided into Proton pump inhibitor (PPI) therapy group and the control group by random number table method, with 63 cases in each group.The control group patients were given routine therapy, PPI treatment group treated with omeprazole 20mg, one time/day, oral, treatment for 9 months, based on the control group. Frequency of upper respiratory tract infection and the number of COPD exacerbations of the two groups during and after one year treatment were mainly observed, and the adverse reaction of the two groups during the treatment were also observed. Results The frequency of upper respiratory tract infection and the number of COPD exacerbations results of the PPI treatment group during and after one year treatment were (2.04±0.33)times, (2.31±0.50)times and (0.98±0.39)times, (2.26±0.42)times, respectively, which were lower than those of the control group[(2.90±0.31)times, (3.24±0.47)times and (2.41±0.34)times and (3.19±0.38)times], the differences were statistically significant (t=9.33, 9.68, 10.41, 9.19, all P 0.05). Conclusion The low-dose omeprazole treatment of chronic obstructive pulmonary disease patients can significantly reduce the frequency of upper respiratory tract infection, COPD exacerbations times and the hospital time, and has good security, which has good security. Key words: Pulmonary disease, chronic obstructive; Omeprazole; Comparative study

Development of Pancreatic Acinar Cell Metaplasia After Successful Administration of Omeprazole for 6 Months in Rats

Long-term use of proton pump inhibitors (PPIs) has been reported to worsen corpus atrophic gastritis in patients with Helicobacter pylori infection. On the other hand, PPIs have been associated with fundic gland-type gastric polyps and various histological changes. In the present study, we attempted to establish a protocol for omeprazole (OPZ) administration to rats over a longer period and examined the morphological changes in the gastric mucosa after administration of OPZ for 6 months. A total of 34 Wistar rats (8 weeks old) were used. In a preliminary experiment to determine the appropriate dose of OPZ, the rats had ad libitum access to food containing different doses of OPZ for 1 month. We found an approximate dose of 100 mg/kg body weight/day of OPZ to be most suitable from the point of view of intragastric pH, body weight, and serum gastrin level. In the experiment proper, rats were divided into two groups, either control or OPZ diets, and morphological changes in the gastric mucosa in each group were then examined by hematoxylin and eosin and immunohistochemical staining with alpha-amylase, trypsin, and chromogranin A. Multiple vacuolar degeneration of parietal cells and numerous small mucous cells were evident at 1 month after treatment with OPZ. At 6 months after treatment with OPZ, cystic degeneration and acinar-cell-like cells containing red granules positive for alpha-amylase and trypsin and negative for chromogranin A were detected in the OPZ rats. The serum gastrin level in the OPZ group was significantly higher than that in the control group. We have established a protocol for long-term administration of OPZ in rats that is a useful model for analyzing morphological changes after long-term PPI therapy. Long-term OPZ treatment causes hypergastrinemia and pancreatic acinar cell metaplasia in this animal model.

Rebamipide Contributes to Reducing Adverse Effects of Long-Term Administration of Omeprazole in Rats

Proton pump inhibitors (PPIs) have become of great importance for the treatment of peptic ulcer disease and gastroesophageal reflux disease. However, these drugs have several adverse effects, including worsening of corpus atrophic gastritis in patients with H. pylori infection, various histological changes including fundic gland-type polyps, inhibition of glycoprotein production, and hypergastrinemia. On the other hand, it has been reported that rebamipide, a gastroprotective drug, has the potential to increase mucous secretion and basically regulate physiological defensive functions aimed to maintain tissue integrity. In this study, we attempted to clarify whether rebamipide improves morphological changes and hypergastrinemia after administration of omeprazole (OPZ) for 1 year in rats. Eight-week-old male Wistar rats were used. Rats were divided into four groups according to diet as follows: 100 mg/kg body weight OPZ group, 100 mg/kg body weight OPZ and 30 mg/kg body weight rebamipide (OPZ + trebanipide group), 30 mg/kg body weight rebamipide, and normal diet (CRF-1). Morphological changes in gastric mucosa in all groups were studied using hematoxylin and eosin staining, periodic acid-Schiff staining, and immunohistochemical staining for alpha-amylase. Serum gastrin level and basal acid secretion were also examined. In the OPZ group, cystic degenerations with amorphous eosinophilic contents, decreased mucous secretion, decreased chief cells, and development of pancreatic acinar cell metaplasia were detected. However, in the OPZ+rebamipide group, these morphological changes were significantly milder than in the OPZ group. Serum gastrin level and basal acid secretion in the OPZ group increased significantly compared to those in the control group. But these factors in the OPZ+rebamipide group were almost normalized (similar to those of control animals). In conclusion, long-term OPZ treatment causes various morphological changes, hypergastrinemia, and basal acid hypersecretion. The present results suggest that rebamipide contributes to reducing these adverse effects caused by long-term OPZ treatment in rats.

Impact of Helicobacter pylori eradication on the anti‐secretory efficacy of lansoprazole in gastroesophageal reflux disease patients

Helicobacter pylori eradication was recommended for the prevention of atrophic gastritis in gastroesophageal reflux disease (GERD) patients on long-term omeprazole treatment. It has been also shown that the treatment with proton pump inhibitors produces lower intragastric pH after H. pylori eradication in subjects with peptic ulcer and healthy individuals. The aim of the present study was to test the hypothesis of whether the efficacy of lansoprazole is reduced after the eradication of H. pylori in GERD patients with peptic esophagitis. Eight-hour intragastric pH recordings were performed before and after an 8-day course of lansoprazole (30 mg once daily) in 10 H. pylori-positive male patients with reflux esophagitis and were repeated after the H. pylori eradication. Intragastric acidity was measured by using an antimony electrode placed 10 cm below the cardia. Baseline median preprandial, post-prandial, total intragastric pH and the percentage of time with pH < 3 were not different before and after H. pylori eradication without lansoprazole treatment. During lansoprazole treatment, median post-prandial intragastric pH was lower (4 vs 2.7; P < 0.05) and the percentage of time with pH < 3 was longer (3.4%vs 41.8%; P < 0.05) after H. pylori eradication. Median total intragastric pH tended to be lower after eradication but no difference was found in preprandial median pH. In patients with reflux esophagitis treated with lansoprazole, intragastric pH increased significantly when H. pylori was present, especially in the post-prandial period, whereas baseline pH remained unchanged after H. pylori eradication.

Long-term omeprazole and esomeprazole treatment does not significantly increase gastric epithelial cell proliferation and epithelial growth factor receptor expression and has no effect on apoptosis and p53 expression

To study the effect of proton pump inhibitor (PPI) treatment on patients with reflux esophagitis and its in vivo effect on apoptosis, p53- and epidermal growth factor receptor (EGFR) expression. After informed consent was obtained, gastric biopsies of the antrum were taken from patients with reflux oesophagitis prior to and after 6 mo of 20 mg omeprazole (n = 14) or 40 mg esomeprazole (n = 12) therapy. Patients did not take any other medications known to affect the gastric mucosa. All patients were Helicobacter pylori negative as confirmed by rapid urease test and histology, respectively. Cell proliferation, apoptosis, EGFR, and p53 expression were measured by immunohistochemical techniques. At least 600 glandular epithelial cells were encountered and results were expressed as percentage of total cells counted. Was considered statistically significant. Although there was a trend towards increase of cell proliferation and EGFR expression both in omeprazole and esomeprazole treated group, the difference was not statistically significant. Neither apoptosis nor p53 expression was affected. Long-term PPI treatment does not significantly increase gastric epithelial cell proliferation and EGFR expression and has no effect on apoptosis and p53 expression.

Long-term omeprazole and esomeprazole treatment does not significantly increase gastric epithelial cell proliferation and EGFR expression and has no effect on apoptosis and p53 expression

Long-term omeprazole and esomeprazole treatment does not significantly increase gastric epithelial cell proliferation and EGFR expression and has no effect on apoptosis and p53 expression

Effect of long-term omeprazole treatment on antral G and D cells in children.

Long-term omeprazole therapy is associated with hypergastrinemia. In the antrum, gastrin secretion from G cells is inhibited in a paracrine manner by somatostatin secreted from D cells. Omeprazole may alter the ratio of G to D cells; however, there are limited data concerning such an effect in humans and none in children. The authors studied the effect of long-term omeprazole therapy on antral G- and D-cell numbers in children. Six children received omeprazole for 4 to 7 years for erosive reflux esophagitis. Endoscopic antral biopsy specimens obtained at baseline and at 1, 4, and 7 years of omeprazole administration were immunostained to assess G and D cell numbers per antral gland. The G- and D-cell numbers were also assessed in an age-matched control group consisting of 24 healthy children from six different age groups. The mean G-cell number per unit area showed a significant increase at 4 years (85 +/- 5.7 years) and at 7 years (89 +/- 6.8 years) on omeprazole compared with baseline (56 +/- 4.8 years) ( P < 0.01). D-cell numbers did not change. The ratio of G to D cells increased progressively, and the change from baseline was significant at 7 years taking omeprazole ( P < 0.02). In the control group, G- and D-cell numbers did not differ significantly within the six age groups. Long-term omeprazole therapy is associated with a significant increase in G-cell numbers and in the ratio of G to D cells in children. These changes reflect the effect of omeprazole because there was no change in these parameters in the age-matched control group.

Intragastric volatile N-nitrosamines, nitrite, pH, and Helicobacter pylori during long-term treatment with omeprazole

Background & Aims: This study evaluated the effect of long-term gastric acid suppressive therapy with omeprazole on intragastric levels of carcinogenic N-nitrosamines and related parameters. Methods: Forty-five patients on long-term omeprazole medication (mean, 35 months) and 13 healthy subjects without medication participated. Volatile N-nitrosamines were determined in gastric juice and urine. Intragastric pH, nitrite, nitrate, and H. pylori status were determined. DNA isolated from gastric biopsy specimens was analyzed for precarcinogenic alkyl-DNA adducts. Results: The intragastric pH in patients was significantly higher compared with controls (P = 0.0001). Gastric nitrite levels in patients were nonsignificantly higher. There was no difference in total levels of intragastric volatile N-nitrosamines between patients and controls, however, urinary N-nitrosodimethylamine excretion was higher in patients (P = 0.001). On omeprazole, Helicobacter pylori–positive vs.–negative patients had a nonsignificantly higher intragastric nitrite level and higher urinary N-nitrosodimethylamine excretion. No alkyl-DNA adducts could be detected in gastric epithelium. Conclusions: Increased intragastric pH caused by long-term treatment with omeprazole does not result in increased intragastric levels of nitrite and volatile N-nitrosamines. The significantly higher urinary N-nitrosamine excretion implies the risk of increased endogenous formation of N-nitrosamines during long-term omeprazole treatment. This risk may be higher in H. pylori–positive patients.GASTROENTEROLOGY 2001;121:517-525

Long-term Omeprazole Treatment Suppresses Body Weight Gain and Bone Mineralization in Young Male Rats

Background: The stomach is rich in endocrine cells, including those producing ghrelin, which is thought to play a role in the control of body growth. Omeprazole treatment is associated with hypergastrinaemia, resulting in growth of the oxyntic mucosa in general and the enterochromaffin-like (ECL) cells in particular. In the present study, we examined the effects of long-term omeprazole treatment on young male rats with respect to body growth and stomach. Methods: Male rats (24 days old) were treated with omeprazole (400 µmol/kg/day) or vehicle for 77 days. The body weight was recorded twice per week. At sacrifice, dual-energy X-ray absorptiometry (DXA) was used to assess total bone area, bone mineral content (BMC), bone mineral density (BMD) and body composition (fat and lean body mass). The lengths of the spine and the femur were recorded. The plasma concentrations of gastrin and histamine were determined by radioimmunoassays. The endocrine cells of the stomach were examined by immunocytochemistry. Results: The body weight gain was suppressed by omeprazole treatment. The bone area, BMC and BMD were reduced, while the lengths of the spine and the femur and the body composition were unchanged. Omeprazole-induced hypergastrinaemia was associated with enlargement of the oxyntic area and with hyperplasia of ECL cells but not of A-like cells and D cells. In contrast, the enterchromaffin (EC) cell density in the antrum was reduced. Conclusions: Omeprazole treatment of young male rats reduces body weight and bone mass gain. The densities of ECL cells in the oxyntic mucosa was increased and of the EC cells in the antral mucosa reduced.

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. GASTROENTEROLOGY 2000;118:661-669

Eradication of Helicobacter pylori Compared with Long-Term Acid Suppression in Duodenal Ulcer Disease: A Randomized Trial with 2-Year Follow-up

Background: Trials evaluating long-term management of duodenal ulcer disease have mainly been focused on recurrence of ulcers, disregarding effects on dyspeptic and reflux symptoms. Profound acid inhibition with a proton pump inhibitor is the gold standard therapy in acid-related diseases. We aimed to compare the symptomatic effects of eradication therapy with those of long-term omeprazole treatment in a design with periods both with and without acid inhibition. Methods: Patients with active duodenal ulcer were randomized either to omeprazole, 20 mg twice daily until healing, followed by omeprazole, 20 mg/day for 1 year, or to eradication therapy (metronidazole, amoxicillin, and omeprazole for 2 weeks) followed by placebo for 1 year. All patients were followed up passively for an additional year. Clinical controls were performed every 2 months the 1st year (maintenance phase) and every 6 months during the passive follow-up phase. The study was multicentric and double-blind. The primary end-point was discontinuation of treatment, irrespective of reason. Results: Two hundred and seventy-six patients were randomized (139 in the eradication treatment group). In the maintenance phase there were no differences in the reporting of dyspeptic symptoms or in premature withdrawal. In the passive follow-up phase only five patients in the eradication therapy group discontinued owing to relapse of dyspeptic symptoms or ulcer, compared with 51 patients initially randomized to long-term omeprazole. There were no differences in reflux symptoms or in the development of reflux oesophagitis. Conclusions: Eradication therapy and long-term omeprazole are equally effective in controlling dyspeptic symptoms and reflux in duodenal ulcer patients with healed ulcers. One-quarter of the duodenal ulcer patients who start eradication therapy continue to be symptomatic or fail therapy for other reasons over a 2-year period. Eradication therapy does not increase the risk of reflux in ulcer patients.

Effect of Long-Term Gastric Acid Suppressive Therapy on Serum Vitamin B 12 Levels in Patients with Zollinger-Ellison Syndrome

Background and aims: Long-term treatment with H +-K +-adenotriphosphatase (ATPase) inhibitors, such as omeprazole or lansoprazole, for severe gastroesophageal reflux disease is now widely used. Whether such treatment will result in vitamin B 12 deficiency is controversial. We studied whether long-term treatment with omeprazole alters serum vitamin B 12 levels in patients with Zollinger-Ellison syndrome. Methods: In 131 consecutive patients treated with either omeprazole (n = 111) or histamine H 2-receptor antagonists (n = 20), serum vitamin B 12 and folate levels and complete blood counts were determined after acid secretion had been controlled for at least 6 months. These studies were repeated yearly. Serum vitamin B 12 and folate levels were correlated with the type of antisecretory drug and the extent of inhibition of acid secretion. Results: The mean duration of omeprazole treatment was 4.5 years, and for H 2-receptor antagonists 10 years. Vitamin B 12 levels, but not serum folate levels or any hematological parameter, were significantly ( P = 0.03) lower in patients treated with omeprazole, especially those with omeprazole-induced sustained hyposecretion ( P = 0.0014) or complete achlorhydria ( P <0.0001). In 68 patients with two determinations at least 5 years apart, vitamin B 12 levels decreased significantly (30%; P = 0.001) only in patients rendered achlorhydric. The duration of omeprazole treatment was inversely correlated with vitamin B 12 levels ( P = 0.013), but not folate levels. Eight patients (6%) developed subnormal B 12 levels during follow-up. Conclusions: Long-term omeprazole treatment leads to significant decreases in serum vitamin B 12 but not folate levels. These results suggest patients with Zollinger-Ellison syndrome treated with H +-K +-ATPase inhibitors should have serum vitamin B 12 levels monitored. Furthermore, these results raise the possibility that other patients treated chronically with H +-K +-ATPase inhibitors may develop B 12 deficiency.

Effects of Long-Term Omeprazole Treatment on Adult Rat Gastric Mucosa - Enhancement of the Epithelial Cell Proliferation and Suppression of Its Differentiation

Effects of long-term omeprazole treatment on the process of epithelial cell proliferation and differentiation in the adult rat gastric mucosa were investigated. Animals were treated with omeprazole (25 mg/kg body weight/day) for 28 days to induce anacidity in the stomach. The treatment induced a marked decrease in the number of chief cells in the gastric mucosa and at the same time an increase in that of immature pepsinogen-producing cells expressing class III mucin. This was accompanied by a decrease to 60% and 10% of the control values in the mucosal levels of pepsinogen and its mRNA, respectively. Moreover, the expression of cathepsin E in surface mucous cells was reduced. Cell proliferation studies revealed that the rate of bromodeoxyuridine-labeled cells was increased by omeprazole. The above-described changes were reversed by cessation of the treatment and they were not caused by the omeprazole-treatment at a dose which does not induce anacidity in the stomach. These results suggest that long-term omeprazole treatment reversibly increases the epithelial cell proliferation and suppresses its differentiation in the adult rat gastric mucosa probably by altering the acidic environment specific for the stomach.

Diagnostic value of serum pepsinogen C in patients with raised serum concentrations of pepsinogen A.

Hypopepsinogenaemia A is often found in patients with gastric atrophy and gastric surgery. In these conditions serum pepsinogen C provides additional diagnostic information, especially when expressed as pepsinogen A:C ratio. Hyperpepsinogenaemia A has been shown in patients with duodenal ulcer disease, Zollinger-Ellison syndrome, hypertrophic gastropathy, chronic renal failure, and during omeprazole treatment. As patients with hyperpepsinogenaemia A often overlap in symptoms, endoscopical findings, and serum gastrin values, this study has evaluated whether measurement of serum pepsinogen C in subjects with hyperpepsinogenaemia A can help in differentiating clinical conditions. Serum concentrations of pepsinogen A and C were measured in serologically Helicobacter pylori negative blood transfusion donors (127) as reference population, and in patients with Zollinger-Ellison syndrome (24), duodenal ulcer (50), hypertrophic gastropathy (5), and chronic renal failure (50), and also in reflux oesophagitis patients on longterm omeprazole treatment (28). A low pepsinogen A:C ratio was found in all patients with hypertrophic gastropathy. A pepsinogen A:C ratio above the critical value of 4.7 was found in 14 (70.0%) of the Zollinger-Ellison patients, two (9.5%) of the duodenal ulcer patients, 11 (25.6%) of the patients with chronic renal failure, and in one (7.1%) of the patients receiving longterm omeprazole treatment. In fact, all but three hyperpepsinogenaemia A patients with a pepsinogen A:C ratio greater than 4.7 and normal renal function had the Zollinger-Ellison syndrome. In patients with hyperpepsinogenaemia A, a low pepsinogen A:C ratio may point to hypertrophic gastropathy, while a pepsinogen A:C ratio greater than 4.7 is suggestive for the Zollinger-Ellison syndrome.

Gastric endocrine cell evolution in patients with Zollinger-Ellison syndrome

Evolution of gastrinoma tumoral mass, fasting serum gastrin concentrations, and gastric endocrine cells has been analyzed in 21 patients with the Zollinger-Ellison syndrome committed to long-term omeprazole treatment (up to 7.75 years, median 37 months). Gastrinoma growth was seen in eight patients. Significant increase in serum gastrin was only observed in the group of patients with gastrinoma growth. Fundic argyrophil cell densities were correlated with serum gastrin (r' = 0.68, P = 0.002). Argyrophil and antral gastrin cell densities significantly increased during the survey, but increases were greater in the group with gastrinoma growth (respectively, +136% and +131%) than in the other group (respectively, +34% and +43%). Progression in the degree of argyrophil cell hyperplasia, noted qualitatively, was observed in 11 patients. Fundic carcinoids developed in three of these 11 patients, all three having multiple endocrine neoplasia type 1 (MEN 1). Positive linear individual correlations (r > or = 0.85) between argyrophil cell densities and corresponding durations of omeprazole treatment were found in nine of the 10 patients studied at least three times and who had a clear-cut increase in those cell densities. Thus, increase in serum gastrin and fundic argyrophil cell densities appeared closely associated with gastrinoma growth; however, duration of drug-induced hypochlorhydria may also affect cell proliferation.

Gastric Endocrine Cells and Gastritis in Patients Receiving Long-Term Omeprazole Treatment

Both argyrophil endocrine cells and gastritis were investigated in 2,120 biopsies of gastric corpus mucosa from 443 out of 448 patients receiving long-term (for periods ranging from several months to 4 years) omeprazole treatment. None of the patients showed neoplasia or dysplasia, either endocrine or non-endocrine. In 123 out of 443 patients (27.8%), endocrine hyperplasia of diffuse (9.3%), linear (4.1%) or micronodular (14.4%) type was detected either before or at some time during treatment. Chronic atrophic gastritis was found in 45 (10.2%) patients, 60% of whom also showed micronodular hyperplasia. In patients with chronic atrophic gastritis, micronodular hyperplasia occurred in 49% of 96 biopsies, compared with 6% of 1,083 biopsies from patients with non-atrophic chronic gastritis and 2% of 941 biopsies from patients with no evidence of gastritis. In 202 patients treated with omeprazole for at least 330 days, the incidence of micronodular hyperplasia increased from 2.5% at the first biopsy to 10.4% at the final biopsy, while the incidence of chronic atrophic gastritis increased from 1.0% to 13.0%. The present and parallel studies suggest that progression of gastritis is inherent in the natural history of acid-related diseases, while endocrine cell changes are mostly secondary to gastritis-related gland atrophy and have no tumorigenic potential.

Acid suppression in the long-term treatment of peptic stricture and Barrett's oesophagus.

Peptic stricture and Barrett's oesophagus are not only the major, but also the most common, complications of gastro-oesophageal reflux disease. The clinical problems that these manifestations present are highly significant, and in patients with peptic stricture the resultant dysphagia can be a major disability that causes nutritional problems. Dilation of a stricture exposes the patient to a small, but significant, risk of oesophageal perforation. Barrett's oesophagus per se rarely causes morbidity, but carries a significant risk of developing oesophageal carcinoma, with its attendant morbidity and mortality. Successful anti-reflux surgery for peptic stricture and Barrett's oesophagus effectively abolishes pathological oesophageal acid exposure and provides the best indicator of the potential benefits that may be obtained from treatment with acid-inhibitory drugs. The reported experience clearly indicates that successful anti-reflux surgery results in resolution of peptic stricture following initial dilation, concomitant with persistent control of oesophageal acid exposure. In patients with Barrett's oesophagus, healing of oesophagitis is well documented after successful surgery, but it is unclear whether the Barrett's epithelium progresses or regresses significantly in all but a minority of patients. It is now established that acid pump inhibition can reduce pathological oesophageal acid exposure as effectively as successful anti-reflux surgery. In a minority of patients, however, omeprazole, 40 or 60 mg daily, divided into two doses, is necessary to achieve this effect. This is particularly true for patients with the more severe forms of disease, in whom peptic stricture and Barrett's oesophagus are most prevalent. Results indicate that peptic stricture can resolve during effective gastric acid inhibition with omeprazole, and results from controlled trials on the management of these patients with omeprazole are awaited. Similarly, there are reports of regression of Barrett's oesophagus during omeprazole therapy, but the completeness and predictability of any such effect have not yet been adequately evaluated. There is sufficient experience from long-term omeprazole treatment of gastro-oesophageal reflux disease to indicate that maintenance of a satisfactory response of peptic stricture or Barrett's oesophagus depends upon continued effective gastric acid inhibition.