Replacement of oral proton pump inhibitors with intravenous pantoprazole to effectively control gastric acid hypersecretion in patients with Zollinger-Ellison syndrome

OBJECTIVES: In patients with Zollinger-Ellison syndrome (ZES) or other conditions requiring oral doses of proton pump inhibitors, it frequently becomes necessary to use parenterally administered gastric acid inhibitors. However, i.v. histamine-2 receptor antagonists are not effective at usual doses and lose their effectiveness because of tachyphlaxis. With the approval in the United States of i.v. pantoprazole, a substituted benzimidazole available in i.v. formulation, it will become possible to acutely manage gastric acid secretion in the acute care setting of a hospital. This study was developed to monitor the safety and establish the efficacy of i.v. pantoprazole as an alternative to oral proton pump inhibitors for the control of gastric acid hypersecretion in patients with ZES. METHODS: The efficacy of replacing oral PPI therapy with i.v. pantoprazole was evaluated in 14 ZES patients. After study enrollment, patients taking their current doses of oral PPI (omeprazole or lansoprazole) were switched to pantoprazole i.v. for 6 days during an 8-day inpatient period in the clinical research center. Effective control was defined as an acid output (AO) of < 10 mEq/h (< 5 mEq/h in patients with prior gastric acid-reducing surgery). RESULTS: The mean age of the 14 patients enrolled in the study was 52.4 yr (range = 38-67). Mean basal AO was 0.55 +/- 0.32 mEq/h and mean fasting gastrin was 1089 pg/ml (range = 36-3720). Four patients were also diagnosed with the multiple endocrine neoplasia type I syndrome, nine were male, and two had previously undergone acid-reducing surgery. Before study enrollment, gastric acid hypersecretion was controlled in nine of 14 patients with omeprazole (20-200 mg daily) and five of 14 with lansoprazole (30-210 mg daily). In the oral phase of the study all patients had adequate control of gastric acid secretion, with a mean AO of 0.55 +/- 0.32 mEq/h (mean +/- SEM). Thereafter, 80 mg of i.v. pantoprazole was administered b.i.d. for 7 days by a brief (15 min) infusion and the dose was titrated upward to a predetermined maximum of 240 mg/24 h to control AO. A dose of 80 mg b.i.d. of i.v. pantoprazole controlled AO in 13 of 14 of the patients (93%) for the duration of the study (p > 0.05 compared to baseline values for all timepoints). One sporadic ZES patient (oral control value = 0.65 mEq/h on 100 mg of omeprazole b.i.d. p.o.) was not controlled with 80 mg of i.v. pantoprazole b.i.d. and dosage was titrated upward to 120 mg b.i.d. after day 2. CONCLUSIONS: There were no serious adverse events observed. Intravenous pantoprazole provides gastric acid secretory control that is equivalent to the acid suppression observed with oral proton pump inhibitors. Most ZES patients (93%) maintained effective control of AO previously established with oral PPIs when switched to 80 mg of i.v. pantoprazole b.i.d.; however, for difficult-to-control patients, doses > 80 mg b.i.d. may be required.     

Intravenous pantoprazole rapidly controls gastric acid hypersecretion in patients with Zollinger-Ellison syndrome

BACKGROUND & AIMS: Parenteral control of gastric acid hypersecretion in conditions such as Zollinger-Ellison syndrome (ZES) or idiopathic gastric acid hypersecretion is necessary perioperatively or when oral medications cannot be taken for other reasons (e.g., during chemotherapy, acute upper gastrointestinal bleeding, or in intensive care unit settings). METHODS: We evaluated the efficacy and safety of 15-minute infusions of the proton pump inhibitor pantoprazole (80-120 mg every 8-12 hours) in controlling acid output for up to 7 days. Effective control was defined as acid output >10 milliequivalents per hour (mEq/h) (<5 mEq/h in patients with prior acid-reducing surgery) for 24 hours. RESULTS: The 21 patients enrolled had a mean age of 51.9 years (range, 29-75) and a mean disease duration of 8.1 years (range, <0.5-21); 13 were male, 7 had multiple endocrine neoplasia syndrome type I, 4 had undergone acid-reducing surgery, 2 had received chemotherapy, and 13 had undergone gastrinoma resections without cure. Basal acid output (mean +/- SD) was 40.2 +/- 27.9 mEq/h (range, 11.2-117.9). In all patients, acid output was controlled within the first hour (mean onset of effective control, 41 minutes) after an initial 80-mg intravenous pantoprazole dose. Pantoprazole, 80 mg every 12 hours, was effective in 17 of 21 patients (81%) for up to 7 days. Four patients required upward dose titration, 2 required 120 mg pantoprazole every 12 hours, and 2 required 80 mg every 8 hours. At study end, acid output remained controlled for 6 hours beyond the next expected dose in 71% of patients (n = 15); mean acid output increased to 4.0 mEq/h (range, 0-9.7). No serious or unexpected adverse events were observed. CONCLUSIONS: Intravenous pantoprazole, 160-240 mg/day administered in divided doses by 15-minute infusion, rapidly and effectively controlled acid output within 1 hour and maintained control for up to 7 days in all ZES patients.     

Sensitivity, specificity and predictive values of the secretin infusion test in the diagnosis of gastrinoma

From 1974 to 1981, 55 patients, 18 with Zollinger-Ellison syndrome (ZES) histologically confirmed and 37 patients with duodenal ulcer (DU) without pylorostenosis were followed for a minimal period of 5 years. The diagnostic values of a) basal acid output (BAO mEq/h); b) 60 min acid output after secretin infusion, 3 CU-GIH/kg, (MAO-SE mEq/h); c) basal serum gastrin (BSG pg/ml: mean of 4 gastrin determinations) and d) serum gastrin after secretin (SG-SE pg/ml: mean of 4 gastrin determinations during secretin infusion) were calculated. Cut off point values of 100 p. 100 specificity (i. e. no DU patient reached these values) with a positive predictive value of 100 p. 100 (i. e. probability for gastrinoma when this cut off point was attained) were BAO greater than 26 mEq/h, MAO-SE greater than 18 mEq/h, BSG greater than 221 pg/ml, SG-SE greater than 186 pg/ml. The sensitivities of these parameters (i. e. percent of ZES which reached the given cut off point) were respectively (p. 100): 39, 78, 72 and 94. Ranking these parameters according to their own discriminative value expressed by R2 (square correlation coefficient) gave SG-SE, R2 = 0.559; BSG, R2 = 0.508; MAO-SE, R2 = 0.456; BAO, R2 = 0.414. The most discriminative association of 2 variables was SG-SE and MAO-SE (R2 = 0.650). Association of SG-SE, MAO-SE and BAO or BSG (or BAO and BSG) did not increase significantly the discrimination between ZES and DU (R2 = 0.672).     

Effects of curative gastrinoma resection on gastric secretory function and antisecretory drug requirement in the Zollinger-Ellison syndrome.

The chronic hypergastrinemia in diseases such as the Zollinger-Ellison syndrome has trophic effects on the gastric mucosa, causing increased parietal cell mass reflected by increased maximal acid output (MAO) and basal acid output (BAO). The time course for the development of these gastric changes in humans is unknown, and controversy exists regarding whether reversal of the hypergastrinemia results in rapid normalization of gastric secretory function. To address these uncertainties, gastric secretory function was prospectively evaluated in 20 patients with the Zollinger-Ellison syndrome undergoing successful curative resection of gastrinoma. Each patient had gastric acid measurements, imaging studies, fasting serum gastrin and secretin provocative testing preoperatively, postoperatively at 3-6 months, and yearly thereafter. Preoperative mean BAO was 39 mEq/h, MAO 56 mEq/h, BAO-MAO ratio 0.73, and fasting gastrin output 1020 pg/mL. All patients were evaluated at 6 months, 17 at 1 year, 15 at 2 years, 13 at 3 years, and 9 at 4 years. By 3-6 months, MAO decreased by 50% in men (mean, 30 mEq/h) and by 35% in women (mean, 29 mEq/h) and then remained relatively unchanged for up to 4 years. Before surgery, 14 of 20 patients (70%) had an elevated MAO, whereas 4 years after resection, none of 9 patients had elevated levels. By 3-6 months, BAO decreased by 75% and remained unchanged for up to 4 years. At 3-6 months, 56% of patients were mild hypersecretors and 67% remained hypersecretors up to 4 years. Preoperatively, the BAO-MAO ratio was elevated in 16 of 20 patients (80%); postoperatively, only 5 of 18 patients (28%) at 3-6 months, 2 of 15 (13%) at 1 year, and 2 of 10 (20%) at 4 years continued to have elevated ratios. Preoperatively, the mean ranitidine dose was 1597 mg/day, whereas after surgery the mean dose was 535 mg/day at 3-6 months and approximately 300 mg/day at 1-4 years with 8 patients requiring no antisecretory drug. These results show that the trophic effects of chronic hypergastrinemia are, in general, rapidly reversible with a 50% decrease in MAO within 3-6 months of cure. Similarly, BAO decreased by 75% within 3-6 months. Despite these decreases, careful monitoring of acid secretion is required after reversal of the chronic hypergastrinemia in diseases such as the Zollinger-Ellison syndrome, because 55% of patients at 3-6 months and up to 67% at 4 years continue to remain mild hypersecretors and require low doses of antisecretory drugs.     

Diagnosis of the Zollinger-Ellison syndrome. I: Significance of anamnestic,clinical and laboratory examinations

The authors describe the diagnostic algorithm of Zollinger-Ellison's syndrome which proved useful in the diagnosis of 73 patients with a confirmed diagnosis. They evaluate the diagnostic validity of anamnestic and clinical data, of different examination methods and compare them with experience assembled abroad. For the diagnosis of sporadic gastrinomas the onset of the disease after the age of 40 years is important, the development of serious peptic complications (haemorrhage F-70%, M-59%, perforation M-54%, F-47%) and the presence of watery diarrhoea (41%). As to laboratory parameters they rely on high BAO values (96% > 15 mmol H+/hour and 100% > 5 mmol H+ after gastric resection. Less important is the examination of basal serum gastrin (almost 30% patients have normal or liminal values of BSG--empirically set at 100-150 pg. ml-1). The authors draw attention to the fact that patients with ZES after gastric resections may have BSG values lower than 100 pg/ml (12%). A positive secretin test has a higher validity (rise of SG by 150-200 pg. ml-1 above basal values) positive in 82.2% patients, liminally positive in 11% and negative in 6.3% patients. An even higher diagnostic value was possessed by a BAO/MAO index higher than 0.6 which was positive in 93.4% patients. At present it is not used as pentagastrin is not available. Every year they diagnose 4-6 new cases of ZES which with regard to the number of inhabitants (5 million) places Slovakia along with Denmark and Sweden among the countries with the highest detection rate (0.8-1.2 ZES cases/1 million per year).     

Serum gastrin in Zollinger-Ellison syndrome: II. Prospective study of gastrin provocative testing in 293 patients from the National Institutes of Health and comparison with 537 cases from the literature. evaluation of diagnostic criteria, proposal of new criteria, and correlations with clinical and tumoral features

In two-thirds of patients with Zollinger-Ellison syndrome (ZES), fasting serum gastrin (FSG) levels overlap with values seen in other conditions. In these patients, gastrin provocative tests are needed to establish the diagnosis of ZES. Whereas numerous gastrin provocative tests have been proposed, only the secretin, calcium, and meal tests are widely used today. Many studies have analyzed gastrin provocative test results in ZES, but they are limited by small patient numbers and methodologic differences. To address this issue, we report the results of a prospective National Institutes of Health (NIH) study of gastrin provocative tests in 293 patients with ZES and compare these data with those from 537 ZES and 462 non-ZES patients from the literature. In 97%-99% of gastrinoma patients, an increase in serum gastrin post secretin (Delta secretin) or post calcium (Delta calcium) occurred. In NIH ZES patients with <10-fold increase in FSG, the sensitivity/specificity of the widely used criteria were as follows: Delta secretin > or =200 pg/mL (83%/100%), Delta secretin >50% (86%/93%), Delta calcium > or =395 pg/mL (54%/100%), and Delta calcium >50% (78%/83%). A systematic analysis of the sensitivity and specificity of other possible criteria for a positive secretin or calcium test allowed us to identify a new criterion for secretin testing (Delta > or =120 pg/mL) with the highest sensitivity/specificity (94%/100%) and to confirm the commonly used criterion for calcium tests (Delta > or =395 pg/mL) (62%/100%). This analysis further showed that the secretin test was more sensitive than the calcium test (94% vs. 62%).Our results suggest that secretin stimulation should be used as the first-line provocative test because of its greater sensitivity and simplicity and lack of side effects. In ZES patients with a negative secretin test, 38%-50% have a positive calcium test. Therefore the calcium test should be considered in patients with a strong clinical suspicion of ZES but a negative secretin test. Furthermore, we found that some clinical (diarrhea, duration of medical treatment), laboratory (basal acid output), and tumoral (size, extent) characteristics correlate with the serum gastrin increase post secretin and post calcium. However, using the proposed criteria, the result of these provocative tests (that is, positive or negative) is minimally influenced by these factors, so secretin and calcium provocative tests are reliable in patients with different clinical, laboratory, and tumor characteristics. A systematic analysis of meal testing showed that 54%-77% of ZES patients have a <50% postprandial serum gastrin increase. However, 9%-20% of ZES patients had a >100% increase post meal, causing significant overlap with antral syndromes. Furthermore, we could not confirm the usefulness of meal tests for localization of duodenal gastrinomas. We conclude that the secretin test is a crucial element in the diagnosis of most ZES patients, the calcium test may be useful in selected patients, but the meal test is not helpful in the management of ZES. For secretin testing, the criterion with the highest sensitivity and specificity is an increase of > or =120 pg/mL, which should replace other criteria commonly used today.     

Gastric acid and pancreatic polypeptide responses to modified sham feeding: indication of an increased basal vagal tone in a subgroup of duodenal ulcer patients.

The effect of sham feeding upon gastric acid secretion and pancreatic polypeptide release was investigated in 28 patients with duodenal ulcer in order to evaluate whether high basal vagal activity is the cause of basal acid hypersecretion in patients with duodenal ulcer and basal secretion higher than 30% of their peak acid output. The patients were divided into two groups based on the ratio of basal/pentagastrin stimulated peak acid output (BAO/PAO) was higher or lower than 0.30: group A n = 19 (BAO/PAO less than or equal to 0.30) and group B n = 9 (BAO/PAO greater than 0.30). Gastric acid response to sham feeding (SAO) was significantly higher than basal level in group A (SAO: 11.4 mEq/h (2.5-20.1) vs BAO: 5.2 mEq/h (0.8-22.9), p less than 0.01, median (range)) while in group B the acid secretion did not increase with sham feeding (SAO: 9.6 mEq/h (4.5-13.6) vs BAO: 8.8 mEq/h (6.3-13.8) ns, median (range)). A negative correlation (r= -0.6118226, p less than 0.01) was found between acid increase expressed as basal subtracted sham feeding response (SAO-BAO) and BAO/PAO ratio of the entire group of duodenal ulcer patients (n = 28) suggesting that the greater is basal acid secretory capacity the smaller is acid increase in response to residual vagal activation. Pancreatic polypeptide response to sham feeding was higher in group A than in group B but no correlation (r = 0.20, n = 28) nor individual covariation was found between acid and pancreatic polypeptide secretions during vagal stimulation. sham feeding did not change serum gastrin. It is concluded that an increased vagal stimulation seems to be the cause of basal hypersecretion in a subgroup of patients with duodenal ulcer. The lact of correlation between the pancreatic polypeptide and acid responses to vagal stimulation interferes with the reliability of pancreatic polypeptide as indicator of vagal tone on gastric parietal cells.     

Serum gastrin in Zollinger-Ellison syndrome: I. Prospective study of fasting serum gastrin in 309 patients from the National Institutes of Health and comparison with 2229 cases from the literature

The assessment of fasting serum gastrin (FSG) is essential for the diagnosis and management of patients with the Zollinger-Ellison syndrome (ZES). Although many studies have analyzed FSG levels in patients with gastrinoma, limited information has resulted from these studies because of their small size, different methodologies, and lack of correlations of FSG levels with clinical, laboratory, or tumor features in ZES patients. To address this issue, we report the results of a prospective National Institutes of Health (NIH) study of 309 patients with ZES and compare our results with those of 2229 ZES patients in 513 small series and case reports in the literature. In the NIH and literature ZES patients, normal FSG values were uncommon (0.3%-3%), as were very high FSG levels >100-fold normal (4.9%-9%). Two-thirds of gastrinoma patients had FSG values <10-fold normal that overlap with gastrin levels seen in more common conditions, like Helicobacter pylori infection or antral G-cell hyperplasia/hyperfunction. In these patients, FSG levels are not diagnostic of ZES, and gastrin provocative tests are needed to establish the diagnosis. Most clinical variables (multiple endocrine neoplasia type 1 status, presence or absence of the most common symptoms, prior medical treatment) are not correlated with FSG levels, while a good correlation of FSG values was found with other clinical features (prior gastric surgery, diarrhea, duration from onset to diagnosis). Increasing basal acid output, but not maximal acid output correlated closely with increasing FSG. Numerous tumoral features correlated with the magnitude of FSG in our study, including tumor location (pancreatic > duodenal), primary size (larger > smaller) and extent (liver metastases > local disease). In conclusion, this detailed analysis of FSG in a large number of patients with ZES allowed us to identify important clinical guidelines that should contribute to improved diagnosis and management of patients with ZES.     

A Prospective Study of Gastric Acid Analysis and Esophageal Acid Exposure in Patients with Gastroesophageal Reflux Refractory to Medical Therapy

A number of factors have been proposed to account for the lack of response to medical therapy in patients with gastroesophageal reflux; however, no controlled studies are available in the literature. The goal of this study was to determine possible causes of medical refractoriness in patients with gastroesophageal reflux. Gastric acid output and esophageal acid exposure were measured in patients who continue to have reflux symptoms despite aggressive antisecretory therapy. In addition, an upper endoscopy was also performed in each patient. Patients with a drug-controlled acid output < 1 mEq/hr and a supine total esophageal pH < 4 for less than 1.7% of the time measured were considered responsive to therapy; on the other hand, those with a drug-controlled gastric acid output > 1 mEq/hr and a supine esophageal pH < 4 for more than 1.7% of the time measured were considered resistant to therapy. Twenty -four patients met the inclusion criteria (13 male and 11 female; mean age, 52). Drug-controlled gastric acid output was more than 1 mEq/hr in 25% of patients and less than 1 mEq/hr in the remainder. Of those patients with a gastric acid output of less than 1 mEq/hr (18 patients), 8(44%) had a supine esophageal pH < 4 for more than 1.7% of the time, suggesting that factors other than gastroesophageal reflux likely contributed to their reflux-like symptoms. Acid suppression appears adequate in the majority of patients with gastroesophageal reflux refractory to medical therapy. The exact cause of persistent reflux-like symptoms in patients who fail medical treatment is uncertain but may be related to non-acid-related factors such as esophageal hypersensitivity to physiologic reflux, increased intake of air resulting in aerophagia, or other factors such as bile reflux.     

Prospective study of the standard meal provocative test in Zollinger-Ellison syndrome

PURPOSE: The purpose of this work was to evaluate the proposed usefulness of a standard meal-stimulated gastrin provocative test in: (1) distinguishing Zollinger-Ellison syndrome (ZES) from antral syndromes; (2) localizing duodenal gastrinomas; or (3) suggesting that patients with multiple endocrine neoplasia type I (MEN-I) may have an increased incidence of antral syndromes. PATIENTS AND METHODS: Seventy-four consecutive patients with ZES referred to the National Institutes of Health were studied prospectively. The extent and location of gastrinomas, acid secretory studies, and the presence or absence of MEN-I were determined and correlated with the results of the gastrin response to standard meal provocative testing. RESULTS: For patients with fasting serum gastrin levels less than 1,000 pg/mL (n = 43), only 44% had a less than 50% increase over the pre-meal value, which is reported to be the typical response in ZES, and 40% had a 50% to 99% increase. Furthermore 16% had a 100% or greater increase, 9% a 150% or greater increase, and 5% a 200% or greater increase, which overlaps with values reported to be characteristic of 98%, 92%, and 46% of patients with antral syndromes. Results did not differ for patients with or without MEN-I, depend on the extent of the gastrinoma (duodenal versus pancreatic gastrinomas), the presence of previous gastric surgery or type of gastric surgery, or for patients with fasting serum gastrin concentrations greater than or equal to 1,000 pg/mL or less than 1,000 pg/mL. studies of four patients before and after resection of the gastrinoma, who prior to surgery had a greater than 100% increase in gastrin secretion after the meal, demonstrated that all patients had a less than 100% increase postoperatively even though no gastric resection was done. CONCLUSIONS: Approximately half of the patients with ZES have a greater than 50% increase in serum gastrin concentration following a standard test meal and one fifth have a 100% or greater increase. Therefore, they cannot be distinguished on this basis from patients with antral syndromes. The increased serum gastrin level after the meal in these patients with ZES appears to be due to the gastrinoma. Furthermore, the current study provides no evidence for the proposals that antral syndromes are more common in patients with MEN-I, that gastric surgery affects the meal response in patients with gastrinomas, or that the meal test is useful in localizing duodenal gastrinomas.     

The Effect of Intragastric Ammonia Production on Titratable Gastric Acid Output in Helicobacter pylori-Infected Patients with Chronic Gastritis

The purpose of this study was to assess whether intragastric neutralization of HCl by ammonia in Helicobacter pylori-infected patients could meaningfully affect the titratable acid output as a measure of gastric acid secretion in a relation to the severity of infection. In 79 patients with different degrees of Helicobacter pylori infection and chronic gastritis, the basal acid output (BAO) and maximal acid output (MAO) after pentagastrin (6 μg/kg s.c.) was estimated. Cl⁻ and NH₄⁺ contents in these fractions were also assayed. H⁺/Cl⁻ ratio in the MAO fraction was diminished in markedly infected patients (68.1 ± 3.9%, vs 84.1 ± 3.3% in noninfected patients; P < 0.005). Ammonium content was maximal in patients with marked infection (0.912 ± 0.086 vs 0.149 ± 0.034 mmol/hr in MAO [P < 0.001] and 0.475 ± 0.063 vs 0.105 ± 0.016 mmol/hr in BAO of noninfected patients [P < 0.001]), with intermediate values in mild and moderate infection. The NH₄⁺/(H⁺ + NH₄⁺) ratio reached 27.01 ± 7.34% in the BAO of moderately infected patients, vs 10.22 ± 3.81% in noninfected patients (P = 0.05), and 7.25 ± 1.06% in the MAO of markedly infected patients, vs 1.14 ± 0.33% in noninfected patients (P < 0.001). The intragastric ammonia production affects the titratable acid output in Helicobacter pylori-infected patients dependent on the severity of infection. Therefore this factor should be taken into consideration in the evaluation of gastric secretory function in Helicobacter pylori-infected patients. This study was supported by Medical University of Bialystok Grant 514 928.     

The effect of vagotomy and antrectomy on serum pepsinogens I and II

Ninety-seven consecutive patients with gastric surgery for peptic ulcer were studied; 86 had duodenal ulcer (DU), and 11 gastric ulcer (GU). DU patients were surgically treated by proximal vagotomy, proximal vagotomy and pyloroplasty, truncal vagotomy and pyloroplasty, or truncal vagotomy and antrectomy. All GU patients were operated on by the Billroth I method. Serum pepsinogen I(S-PG I), serum pepsinogen II (S-PG II), basal acid output (BAO), and maximal acid output (MAO) were determined before and 3 months and 1 year after the operation. The mean preoperative S-PG I concentration in DU patients (154 +/- 7 micrograms/l; mean +/- SE) was significantly higher than that (97 +/- 9 micrograms/l) in GU patients (p less than 0.001). A significant decrease in the mean S-PG I concentration in DU patients was seen 3 months (92 +/- 6 micrograms/l) and 1 year (66 +/- 4 micrograms/l) after the operation (p less than 0.001). This change did not depend on the type of vagotomy. However, this decrease was not seen in all individual patients as it was in BAO values. Moreover, the mean BAO decrease was much greater at 3 months (7% of the preoperative value) and 1 year (23%) after the operation than the respective decrease in S-PG I concentration. There was also no correlation between S-PG I and acid output (BAO and MAO) before and after the operation. In GU patients the decrease in mean S-PG I value after the Billroth I operation was smaller than in DU patients after vagotomy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Oral pantoprazole for acid suppression in the treatment of patients with Zollinger-Ellison syndrome.

BACKGROUND: The management of patients with gastric acid hypersecretion due to gastrinoma, usually recognized as Zollinger-Ellison syndrome (ZES), was radically changed 10 years ago by the use of proton pump inhibitors. Surgical treatment now concentrates on tumour excision, and in the majority of patients, gastrectomy is no longer required to prevent complications of acid hypersecretion that can be managed pharmacologically. AIMS: To verify the ability of pantoprazole to control gastric acid hypersecretion and the clinical effects of acid hypersecretion in seven patients with documented ZES. METHODS: Pantoprazole was administered at an initial dose of 80 mg daily for seven days before basal acid output (BAO) was measured at 08:00, ie, 1 h before the next dose of pantoprazole was normally ingested. A lower (40 mg) or higher (120 mg or more) dose of pantoprazole was then used to keep the BAO in the therapeutic range (between 0.1 and 10 mmol/h) and to control clinical symptoms such as acid-related pain or diarrhea. RESULTS: BAO and clinical symptoms were controlled with pantoprazole 40 mg daily in one patient, 80 mg daily in two patients, 120 mg daily in three patients and 160 mg daily in one patient. CONCLUSIONS: Pantoprazole was able to control acid hypersecretion in ZES patients when administered in doses between 40 and 160 mg daily. An initial dose of 120 mg given before further titration of the drug regimen appears to be a reasonable therapeutic strategy.     

Zollinger-Ellison syndrome. Clinical presentation in 261 patients

We prospectively evaluated the initial presenting symptoms in 261 patients with Zollinger-Ellison syndrome (ZES) over a 25-year period. Twenty-two percent of the patients had multiple endocrine neoplasia-type 1 (MEN-1) with ZES. Mean age at onset was 41.1 +/- 0.7 years, with MEN-1 patients presenting at a younger age than those with sporadic ZES (p < 0.0001). Three percent of the patients had onset of the disease < age 20 years, and 7% > 60 years. A mean delay to diagnosis of 5.2 +/- 0.4 years occurred in all patients. A shorter duration of symptoms was noted in female patients and in patients with liver metastases. Abdominal pain and diarrhea were the most common symptoms, present in 75% and 73% of patients, respectively. Heartburn and weight loss, which were uncommonly reported in early series, were present in 44% and 17% of patients, respectively. Gastrointestinal bleeding was the initial presentation in a quarter of the patients. Patients rarely presented with only 1 symptom (11%); pain and diarrhea was the most frequent combination, occurring in 55% of patients. An important presenting sign that should suggest ZES is prominent gastric body folds, which were noted on endoscopy in 94% of patients; however, esophageal stricture and duodenal or pyloric scarring, reported in numerous case reports, were noted in only 4%-10%. Patients with MEN-1 presented less frequently with pain and bleeding and more frequently with nephrolithiasis. Comparing the clinical presentation before the introduction of histamine H2-receptor antagonists (pre-1980, n = 36), after the introduction of histamine H2-receptor antagonists (1981-1989, n = 118), and after the introduction of proton pump inhibitors (PPIs) (> 1990, n = 106) demonstrates no change in age of onset; delay in diagnosis; frequency of pain, diarrhea, weight loss; or frequency of complications of severe peptic disease (bleeding, perforations, esophageal strictures, pyloric scarring). Since the introduction of histamine H2-receptor antagonists, fewer patients had a previous history of gastric acid-reducing surgery or total gastrectomy. Only 1 patient evaluated after 1980 had a total gastrectomy, and this was done in 1977. The location of the primary tumor in general had a minimal effect on the clinical presentation, causing no effect on the age at presentation, delay in diagnosis, frequency of nephrolithiasis, or severity of disease (strictures, perforations, peptic ulcers, pyloric scarring). Disease extent had a minimal effect on symptoms, with only bleeding being more frequent in patients with localized disease. Patients with advanced disease presented at a later age and with a shorter disease history (p = 0.001), were less likely to have MEN-1 (p = 0.0087), and tended to have diarrhea more frequently (p = 0.079). A correct diagnosis of ZES was made by the referring physician initially in only 3% of the patients. The most common misdiagnosis made were idiopathic peptic ulcer disease (71%), idiopathic gastroesophageal reflux disease (GERD) (7%), and chronic idiopathic diarrhea (7%). Other less common misdiagnosis were Crohn disease (2%) and various diarrhea diseases (celiac sprue [3%], irritable bowel syndrome [3%], infectious diarrhea [2%], and lactose intolerance [1%]). Other medical disorders were present in 55% of all patients; patients with sporadic disease had fewer other medical disorders than patients with MEN-1 (45% versus 90%, p < 0.00001). Hyperparathyroidism and a previous history of kidney stones were significantly more frequent in patients with MEN-1 than in those with sporadic ZES. Pulmonary disorders and other malignancies were also more common in patients with MEN-1. These results demonstrate that abdominal pain, diarrhea, and heartburn are the most common presenting symptoms in ZES and that heartburn and diarrhea are more common than previously reported. The presence of weight loss especially with abdominal pain, diarrhea, or heartburn is an important clue suggesting the presence of gastrinoma. The presence of prominent gastric body folds, a clinical sign that has not been appreciated, is another important clue to the diagnosis of ZES. Patients with MEN-1 presented at an earlier age; however, in general, the initial symptoms were similar to patients without MEN-1. Gastrinoma extent and location have minimal effects on the clinical presentation. Overall, neither the introduction of successful antisecretory therapy nor widespread publication about ZES, attempting to increase awareness, has shortened the delay in diagnosis or reduced the incidence of patients presenting with peptic complications. The introduction of successful antisecretory therapy, however, has dramatically decreased the rate of surgery in controlling the acid secretion and likely led to patients presenting with less severe symptoms and fewer complications. (ABSTRACT TRUNCATED)     

Effect of 1 week's administration of prednisone on gastric acid secretion and liberation of gastrin in healthy humans

In a double-blind, randomized study we examined the effects of an oral administration of prednisone (60 mg/day for 6 days) or placebo on gastric acid output basally (BAO), in response to peptone meals 1%, 2%, 4% and 8%, 500 ml each) and to pentagastrin 6 micrograms/kg s.c. to determine maximal acid output, MAO) and on plasma gastrin levels in 14 healthy volunteers. Gastric acid output was measured by intragastric titration (pH 5.5). For gastrin determination we used a specific radioimmunoassay. Experiments were performed one day (day 0) before giving the drugs and one day (day 7) and one month (day 30) after finishing the treatment. Both groups were comparable in their gastric acid responses on day 0. Six days treatment with prednisone did not significantly alter BAO, MAO and the gastric acid response to peptone and pentagastrin. Also, one month after finishing the treatment there were no significant differences in gastric acid output. Both groups had similar plasma gastrin levels on each day. Prednisone did not significantly alter plasma gastrin levels. We conclude that a six-day treatment with prednisone does not alter BAO, MAO and gastric secretory responses to peptone nor release of gastrin in healthy human volunteers.     

Monthly variation in frequency of active duodenal ulcer and maximal acid output

The frequency of duodenal ulcer has been reported to vary seasonally. It is not known whether gastric acid secretion of patients with this condition has similar seasonal variation. During 1981–85, 1864 patients (mean age 38.0 years, s.d. = 24.2, males comprising 67.1%) with newly diagnosed active duodenal ulcer were documented endoscopically. Of these 626 patients (mean age 38.5 years, s.d. = 15.0, males comprising 71.4%) agreed to have their basal acid output (BAO) and pentagastrin-stimulated maximal acid output (MAO) measured. Time series analysis using the frequency domain approach identified that the monthly frequencies of duodenal ulcer over the 5-year period occurred in cycles of 12 months. Multiple comparison using Duncan's procedure identified the occurrence of a significant peak in November and December. MAO varied significantly ( P < 0.04) with season with two peaks, one occurring in February and another in July. Month-adjusted MAO was significantly higher ( P < 0.001) in male than in female patients. BAO showed no significant variation by month. It is concluded that active duodenal ulceration and MAO manifest significant variation by month, but their peaks do not coincide, indicating that acidity is unlikely to be a major factor responsible for the frequency of duodenal ulcer peaking in winter. These results also suggest that it is advisable to adjust for seasonal variation when MAO is compared among groups of duodenal ulcer patients.     

Abnormal pancreatic polypeptide release by secretin infusion in Zollinger-Ellison syndrome

In 28 patients with the Zollinger-Ellison syndrome (ZES), 26 studied before and two after tumor excision, and in 26 age-matched control patients with duodenal ulcer (DU), plasma pancreatic polypeptide and serum gastrin concentrations were studied before, during, and after infusion of pure secretin (3 CU/kg/hr). In 21 ZES patients, gastric acid output was simultaneously studied. Fasting pancreatic polypeptide concentrations were over 300 pmol/liter in five of 26 gastrinomas. In DU, secretin caused a nonsignificant increase in plasma pancreatic polypeptide concentration and markedly decreased gastric acid output. In ZES, however, it resulted in a marked increase of both plasma pancreatic polypeptide concentration and gastric acid output. Basal and post secretin pancreatic polypeptide concentrations showed no correlation with gastric acid output, serum gastrin levels, or the age of the subjects, in DU patients as well as in ZES. These concentrations were not different in ZES patients who had a vagotomy compared to nonvagotomized ZES patients. Furthermore, the pancreatic polypeptide response to intravenous secretin was abolished by gastrinoma excision.A portion of this work has appeared in abstract form (Gastroenterology 82:1161, 1982) and was presented at the Annual Meeting of the American Gastroenterological Association, Chicago (Illinois), on May 18, 1982.     

Use of omeprazole in patients with Zollinger-Ellison syndrome

Omeprazole, a substituted benzimidazole, has been shown to be a potent inhibitor of gastric acid secretion in patients with Zollinger-Ellison syndrome (ZES). We review our experience, as well as the published data on 210 patients with ZES who have required omeprazole for control of gastric acid hypersecretion over the past seven years. The dose of omeprazole required in individual patients ranged from 10 to 180 mg/24 hr with 20-60% requiring a split dosage regimen. Omeprazole was effective in approximately 99% of the patients over a period ranging from 0.5 to 54 months. Twenty-four percent of patients required an increase in omeprazole dose, while 26% required a decrease in dose. Adverse effects attributable to omeprazole were reported in 2% of patients, and in all cases, they were mild (ie, rash, constipation, headache). There was no effect of omeprazole on serum gastrin concentration or on gastric endocrine cells in three studies. Although one patient with multiple endocrine neoplasia, type-I syndrome (MEN-I) in this series developed a gastric carcinoid while taking omeprazole, evidence is presented that suggests the presence of MEN-I per se may be important in determining the development of gastric carcinoid in patients with ZES. It is concluded that omeprazole is safe and effective in patients with ZES, and in these patients, it is the drug of choice for the management of gastric acid hypersecretion. However, yearly assessment is indicated to clearly evaluate the long-term risk of gastric carcinoid as well as therapy directed at the gastrinoma itself.     

幽门螺杆菌相关性萎缩性胃炎酸分泌与杆菌定植的关系

目的研究胃酸分泌和粘膜萎缩对胃体和胃窦幽门螺杆菌（ Hp）定植的影响。方法将 95例 Hp阳性的慢性萎缩性胃炎患者分组。组一：胃窦中度萎缩伴胃体轻、中或重度萎缩性胃炎;组二：胃体轻度萎缩伴胃窦轻、中或重度萎缩性胃炎。分别测定基础酸分泌、最大酸分泌和胃泌素, Warthin-Starry染色诊断 Hp,同一组织诊断萎缩并分度。内因子抗体阳性者除外。结果组一中胃窦萎缩固定不变的各组之间,酸分泌显著降低组胃窦部 Hp定植率显著降低（ P< 0.05）;组一中胃体萎缩中度与重度组比较,最大酸分泌差异无统计学意义 (P >0.05),胃体重度萎缩组 Hp定植率较中度萎缩组明显低下 (P< 0.05)。组二中胃体萎缩固定不变的各组之间,酸分泌显著降低组胃体 Hp定植率显著降低 (P< 0.05);组二中胃窦萎缩中度与重度组比较,基础酸、最大酸分泌差异无统计学意义 (P >0.05),胃窦重度萎缩组 Hp定植率较中度萎缩组明显低下（ P< 0.05）。结论慢性萎缩性胃炎的低酸和萎缩明显影响胃窦、体部 Hp的定植,两种影响因素既独立又互补。     

Maintenance oral pantoprazole therapy is effective for patients with Zollinger-Ellison syndrome and idiopathic hypersecretion

OBJECTIVE: Maintenance proton pump inhibitor (PPI) therapy is effective for gastric acid hypersecretory states, although data with pantoprazole are limited. The aim of this study was to evaluate the safety and efficacy of long term p.o. pantoprazole in individuals with hypersecretion. METHODS: All subjects had Zollinger-Ellison syndrome or idiopathic hypersecretion. Baseline acid output was measured in the presence of prior maintenance antisecretory therapy before pantoprazole exposure. The starting dose was 40 mg b.i.d. in most cases, and the dose was adjusted to document control within the first 2 wk of therapy. The maximal allowable dose was 240 mg daily. Acid output was measured on day 28 and then quarterly from month 3. The primary efficacy endpoint was documented control of acid secretion at 6 months, i.e., acid output in the last 1 h before the next dose of therapy of <10 mEq/h (<5 mEq/h in subjects with prior acid-reducing surgery). RESULTS: A total of 26 subjects had Zollinger-Ellison syndrome (six with multiple endocrine neoplasia syndrome type 1) and nine had idiopathic hypersecretion. Pre-enrollment therapy included omeprazole in 27 subjects and lansoprazole in eight, and 82.4% of subjects were controlled on their prior regimens. With upward dose titration, acid output was controlled in all subjects by day 10 and in all but two (6%) at the 6-month time point. Median acid secretion on therapy at 6 months was <2 mEq/h (mean 2.2 mEq/h; range 0-10.5 mEq/h) at a dose of 40 mg b.i.d. for 24 subjects, 80 mg b.i.d. for seven subjects, and 120 mg b.i.d. for two subjects. During the course of the study, five subjects required doses of 240 mg daily. Pantoprazole was generally well tolerated. No cases of anterior optic ischemic neuropathy occurred. Five subjects died during follow-up, all because of events unrelated to the study drug. CONCLUSIONS: Maintenance p.o. pantoprazole therapy at a dose of 80-240 mg/day in divided doses was both effective and generally well tolerated for patients with Zollinger-Ellison syndrome and idiopathic hypersecretion.