Gastric Secretion in Zollinger-Ellison Syndrome
2001; Wolters Kluwer; Volume: 80; Issue: 3 Linguagem: Inglês
10.1097/00005792-200105000-00005
ISSN1536-5964
AutoresPraveen K. Roy, David Venzon, Kathryn Feigenbaum, Pamela D. Koviack, Showkat Bashir, Jeremiah V. Ojeaburu, Fathia Gibril, Robert T. Jensen,
Tópico(s)Fibroblast Growth Factor Research
ResumoIntroduction Abbreviations used in this article: BAC, basal acid H+ concentration, BAC/MAC, ratio of basal and maximal acid H+ concentration, BAO, basal acid output, CT, computed tomographic scan, MAC, maximal acid H+ concentration, MAO, maximal acid output, MEN1, multiple endocrine neoplasia-type 1, MRI, magnetic resonance imaging, NIH, National Institutes of Health, PPI, proton pump inhibitor, ZES, Zollinger-Ellison syndrome Since the initial description of Zollinger-Ellison syndrome (ZES) in 1955 (314), this disorder has been characterized by the presence of severe gastric acid hypersecretion and refractory peptic ulcer disease treatable only by total gastrectomy due to a non-beta islet cell tumor (75,132,133). Later it was demonstrated the tumor ectopically releases gastrin (that is, it is a gastrinoma) and the hypergastrinemia is responsible for the gastric acid hypersecretion (108,109,132,133,176). In the early descriptions of ZES by Zollinger, Ellison, and others, it was reported that gastric acid hypersecretion was a cardinal feature of this syndrome, with gastric outputs of several liters over a 12-hour period, associated with high concentrations of acid (100 mEq/L) (74,75,314,317). In fact, after the initial description of ZES, gastric acid secretory studies were the method of choice for the diagnosis of ZES (5,75,139,158,223,229,314). After gastrin was determined to be the causative hormone in ZES and it was shown that hypergastrinemia was present in almost all cases of ZES, assessment of fasting gastrin levels or performance of gastrin provocative tests became the initial study that led to the diagnosis of ZES in most patients (93,124,133,134,176,177,195,226,275,307). Currently, a number of factors continue to make assessing gastric acid secretion 1 of the requirements for the diagnosis of ZES (131,133,171,184,190,307). Gastric secretory testing is the only unequivocal means to distinguish physiologic from pathologic causes of hypergastrinemia (51,131,133,184,190,307). The current importance of gastric secretory testing is further increased because hypergastrinemia secondary to non-ZES causes (such as potent acid suppressant medications) is now common (144,148,233). In 60% of patients with ZES, fasting gastrin levels overlap with those in patients with other causes of gastric hypersecretion and hypergastrinemia (93,133). In these patients secretin provocative testing is the most commonly used study to determine whether ZES may be present (63,93,151,177). Unfortunately, secretin provocative tests can be negative in a significant proportion of patients with ZES—as high as 50% in some studies (53,93,154,273). Furthermore, recently it has not been possible to obtain secretin for gastrin provocative testing. Therefore, in patients with negative secretin provocative tests or no secretin testing, the level of the gastric hypersecretion combined with the presence of hypergastrinemia is increasingly important for the diagnosis of ZES. Despite its importance in the diagnosis of ZES, previous studies on gastric acid hypersecretion in this disorder provide limited information for a number of reasons. Most studies evaluating the sensitivity of the various proposed gastric acid secretory criteria for the diagnosis of ZES were done a number of years ago and may have significant limitations in regard to patients today. Most studies were performed before the full clinical spectrum of ZES was appreciated and established criteria were developed for its diagnosis. Therefore, in many of these older studies, patients without established ZES were included, or conversely, some cases that would be diagnosed as ZES today were not included. Patients were not categorized as to whether multiple endocrine neoplasia-type 1 (MEN1) was present or not, and whether gastric acid-reducing surgery had been performed and the type of procedure performed, each of which could affect the gastric acid secretory rate (128,131,133,175,190,216). Furthermore, it was not apparent in most studies that adequate hydration or metabolic and electrolyte balance was established during the time the gastric acid secretory rate was determined, which could affect the results. Finally, because in the older studies most patients presented with advanced disease with complications of ZES (74,75,314) and no effective gastric antisecretory drugs were available, gastric acid secretory rates were usually measured in acutely ill patients with peptic ulcer complications, which also could affect the results. The result of these factors is that in almost all series studying gastric acid secretion in patients with ZES, only small numbers of patients were included. Therefore, while the specificity of various proposed acid secretory criteria for the diagnosis of ZES has been studied extensively in patients with idiopathic peptic ulcer disease, relatively few patients with ZES were studied to determine the sensitivity of the various proposed criteria. Furthermore, because of the limited numbers of patients studied, there are no studies that have evaluated possible correlations between the various presenting symptoms and signs, primary tumor location, tumor extent, and tumor size with the magnitude of the gastric acid hypersecretion. This is potentially clinically important because the magnitude of gastric acid hypersecretion is reported to vary widely in different patients (5,22,38,74,118,149,154,158,165,179,185,242,250,254,285,291,292,299,303); however, the factors contributing to this variation are unknown. Twenty-five years ago a protocol to study prospectively the natural history, diagnosis, pathogenesis, and treatment of gastrinoma was initiated at the National Institutes of Health (NIH) (Bethesda, MD). The results of this prospective study of gastric acid hypersecretion in 235 consecutive patients with ZES are analyzed in this report and compared with results of 984 patients from 182 different reports in the literature. The specific aims of this study were 1) to correlate the presenting clinical symptoms and signs with the results of the gastric acid secretory studies to gain insight into the principal causative factors; 2) to evaluate the sensitivity of the various proposed gastric acid secretory criteria for the diagnosis of ZES; 3) to study the variability in gastric acid secretion and determine whether the duration of the testing could be shortened; and 4) to identify new gastric acid secretory criteria that would be useful to diagnose ZES or to differentiate it from idiopathic peptic ulcer disease. Case Reports Case 1 A 50-year-old woman with a 12-year history of epigastric pain, heartburn, and diarrhea had been diagnosed as having idiopathic peptic ulcer disease at the onset of her symptoms and was started on histamine H2-receptor antagonists with partial relief of symptoms. Helicobacter pylori testing was repeatedly negative. Whenever she stopped the histamine H2-receptor antagonist, peptic ulcer symptoms with diarrhea would recur within 2 months. On 1 such occasion 5 years before referral to the NIH, an upper gastrointestinal endoscopy demonstrated a solitary duodenal ulcer (Figure 1) typical of idiopathic peptic ulcer disease. Due to refractory peptic disease a Billroth II resection with vagotomy was performed. Peptic ulcer disease recurred postoperatively and she was placed on omeprazole, which led to resolution of the symptoms. Three years before admission to the NIH, fasting gastrin levels while taking omeprazole were elevated at 250 pg/mL (normal < 150 pg/mL). Four days after stopping omeprazole, gastric secretory testing showed basal acid output (BAO) of 15 mEq/hr (pH = 1.9) (normal < 5 mEq/hr), basal volume of 150 mL/hr, and fasting gastrin level of 190 pg/mL (normal < 150 pg/mL). Evaluation at the NIH revealed an elevated fasting gastrin level of 240 pg/mL (normal < 200 pg/mL) off all gastric antisecretory medications (that is, omeprazole for 2 weeks and ranitidine for 2 days). No secretin was available so secretin provocative testing could not be done to establish the diagnosis. Gastric acid secretory studies revealed BAO of 32 mEq/hr, maximal acid output (MAO) of 45 mEq/hr, basal gastric pH of 0.8, and basal gastric volume of 190 mL/hr. The BAO/MAO ratio was 0.71 and the basal and maximal acid H+ concentration (BAC/MAC) ratio was 0.9. Tumor imaging studies revealed a possible 1.5-cm duodenal primary tumor. At surgery a 1.2-cm duodenal neuroendocrine tumor was surgically resected which stained positive for gastrin and chromogranin A.Fig. 1: Upper gastrointestinal endoscopy showing a single duodenal ulcer (Case 1) in a patient with abdominal pain, heartburn, and diarrhea due to ZES. Only a single duodenal ulcer, which is typical of that seen in idiopathic peptic ulcer disease, was seen in this patient. Up to 70%(170) of patients with ZES present with a typical duodenal ulcer; therefore, the diagnosis will be suggested more frequently by the history (that is, diarrhea with ulcer disease), the refractory nature of the disease, the hypergastrinemia, and the gastric secretory results, than by atypical locations of the peptic ulcer.Comment: This patient's disease continued to be misdiagnosed as idiopathic peptic ulcer disease partially because of the typical appearance of a single duodenal ulcer (see Figure 1). Up to 70% of patients with ZES in some series initially have only a typical solitary duodenal ulcer at presentation (134). The refractory nature of the peptic ulcer disease, presence of diarrhea with peptic ulcer disease, and peptic ulcer disease without H. pylori present should have suggested the diagnosis of ZES. This case emphasizes the value of gastric secretory testing in suggesting the diagnosis of ZES. The basal acid level of 15 mEq/hr post acid-reducing surgery found in this patient before referral is seen in 73% of patients with ZES with previous gastric acid-reducing surgery in our studies and is reported to have a specificity of 100% in this situation (191). This measurement, together with the high basal gastric volume of 150 mL/hr, which has a specificity of 95% and sensitivity of 87% in our study in patients with previous gastric acid-reducing surgery, combined with the continuing mild hypergastrinemia in the presence of an acid gastric pH, should have strongly suggested the diagnosis of ZES. At the NIH this patient had a fasting gastric pH of ≤2.0 which occurs in 100% of ZES patients, BAO >5 mEq/hr (sensitivity 81%–100%), BAC/MAC ratio ≥0.6 (sensitivity 89%–93%), and gastric volume >140 mL/hr (sensitivity 43%–87%), all strongly supporting the diagnosis of ZES. This case illustrates that gastric secretory criteria can support the diagnosis of ZES, especially when secretin provocative gastrin testing is not available. Case 2 A 60-year-old man presented with a 2-year history of abdominal pain and abdominal cramping. There was no associated weight loss. An esophagogastro-duodenoscopy was normal without prominent gastric folds; however, fasting gastrin levels were 1,000 pg/mL on 2 occasions (normal < 200 pg/mL). An abdominal computed tomography (CT) scan showed a possible pancreatic head lesion. Secretin abdominal angiogram revealed a blush in the gastroduodenal artery with a 1.3-fold increase in the gastrin gradient in this vessel. He was started on oral ranitidine therapy with some improvement of his symptoms. He was subsequently referred to a surgeon for abdominal exploration for a possible gastrinoma. When a repeat fasting gastrin level was found to be elevated at 980 pg/mL and the fasting gastric fluid pH was 3.5, he was referred to the NIH for a second opinion before the surgical procedure. At the NIH, he was noted to have persistent hypergastrinemia (1,400–4,000 pg/mL). On gastric acid secretory studies both BAO and MAO were 0 mEq/hr (pH = 7.0), indicating he was achlorhydric. Antiparietal antibodies and anti-intrinsic factor antibodies were positive. No H. pylori was seen on histology or found by CLO testing. Pale, atrophic-appearing gastric mucosa in the gastric body was present on endoscopy (Figure 2, top panel) and biopsies were consistent with chronic atrophic gastritis. Vitamin B12 levels were decreased to 99 pg/mL (normal > 165 pg/mL). Conventional imaging studies (CT scan and magnetic resonance imaging [MRI] of abdomen) and somatostatin receptor scintigraphy were negative. A diagnosis of pernicious anemia was made. Vitamin B12 supplementation was started. On follow-up serum vitamin B12 increased to the normal range and the patient remained free of gastrointestinal symptoms except for occasional episodes of cramping with constipation thought due to irritable bowel syndrome.Fig. 2: Upper gastrointestinal endoscopy result in a patient with hypergastrinemia due to atrophic gastritis (top panel) (Case 2), a healthy subject (middle panel), and a patient with ZES (bottom panel). Case 2 (top panel) reinforces the essential role of gastric acid secretory testing in evaluating the finding of fasting hypergastrinemia and preventing an inappropriate diagnosis of ZES. In this patient an inappropriate exploratory laparotomy was only just prevented by gastric secretory testing. However, the upper gastrointestinal endoscopic result (top panel) should have suggested that the true diagnosis was not ZES. Prominent gastric folds (bottom panel) are found in 94% of patients with ZES and are lacking in patients with pernicious anemia (top panel), and are usually absent in healthy subjects (middle panel).Comment: This case illustrates the misdiagnoses that can occur when fasting hypergastrinemia is detected and gastric acid secretory studies are not used. Without gastric acid secretory testing it is frequently not possible to determine whether the fasting hypergastrinemia is physiologic or due to pathologic causes. In achlorhydric subjects, gastrin provocative tests may give misleading results (84,97). Furthermore, in patients without ZES, gastrinoma localization studies can give false-positive results, as illustrated by this case (97). The results in the present study and a literature review of 984 cases demonstrate that 100% of patients with ZES have a fasting gastric pH ≤2.0; therefore, the finding of a fasting gastric pH of 3.5 in this patient should have excluded a diagnosis of ZES. Another important clue to the correct diagnosis missed in this patient was the lack of prominent folds on upper gastrointestinal endoscopy, which are present in 94% of patients with ZES (Figure 2, middle and bottom panels) (246). This case illustrates the importance of gastric acid secretory testing and of having established criteria for the diagnosis of ZES. Case 3 A 64-year-old woman with a 10-year history of heartburn and diarrhea and recent onset of vomiting and dysphagia was referred to the NIH for evaluation for possible ZES. Before referral the patient was diagnosed as having idiopathic gastroesophageal reflux disease and treated intermittently with histamine H2-receptor antagonists. Whenever the histamine H2-receptor antagonists were stopped the symptoms recurred. Two months before referral the patient was found to have an elevated fasting gastrin of 600 pg/mL (normal < 100 pg/mL). Upper gastrointestinal endoscopy showed severe erosive esophagitis, a possible small esophageal stricture, and pyloric scarring with minimal gastric stasis. During this time she developed severe vomiting, which was not controlled by anti-emetics. A nasogastric tube was inserted and a fasting gastric pH of 1.0 was found with BAO of 18 mEq/hr (normal < 10 mEq/hr). A secretin provocative test was reported as negative. Because of persistent vomiting, the nasogastric tube was left in for 1 week before referral to the NIH, and during part of this time no nasogastric suction or parenteral gastric antisecretory drugs were given. At the NIH, the mean fasting gastrin level was 843 pg/mL, BAO was 62 mEq/hr, MAO was 80 mEq/hr (normal < 30 mEq/hr), fasting basal gastric pH was 0.95, and basal gastric output was 310 mL/hr. An upper gastrointestinal endoscopy barium study revealed a long, benign-appearing distal esophageal stricture (Figure 3). Tumor imaging studies demonstrated possible metastatic liver disease, and metastatic gastrinoma was established by percutaneous liver biopsy. Parenteral ranitidine (2 mg/kg per hr) controlled gastric acid secretion to 2 mEq/hr, and the esophageal stricture was treated with esophageal dilators. Upper gastrointestinal endoscopy demonstrated gastric distension and minimal pyloric narrowing with a small duodenal ulcer. Subsequent treatment with omeprazole and periodic esophageal dilations controlled all symptoms.Fig. 3: Upper gastrointestinal barium X-ray study demonstrating a long esophageal stricture and proximal esophageal dilation in a patient with ZES (Case 3). Because of the failure to interpret the gastric secretory results properly and to realize that a significant proportion of patients with ZES can have nondiagnostic secretin tests (up to 54% in some studies) (53,93,154,273), the diagnosis of ZES in this patient was delayed. The delay may have contributed to the diagnosis being established only after liver metastases were present and the inappropriate treatment of the gastric acid hypersecretion that resulted in the long esophageal stricture.Comment: This patient had a long delay in the diagnosis of ZES, which was diagnosed only after the gastrinoma had metastasized to the liver. The failure to establish the diagnosis of ZES also resulted in inadequate gastric antisecretory treatment, which led to the development of a long esophageal stricture (see Figure 3). The ZES diagnosis was missed because it was not appreciated that a significant proportion of patients with ZES (53,93,273) (up to 50% of patients in 1 study [154]) have negative secretin tests (93), and the gastric secretory tests were not interpreted correctly. In the present study and a literature review of 689 patients with ZES without previous acid-reducing surgery, 91% had BAO ≥18 mEq/hr and 77%–86% had basal volume >200 mL, with specificities of 96% and 95%, respectively; therefore, these acid secretory results could have led to the correct diagnosis when combined with the fasting hypergastrinemia. Materials and Methods All patients admitted to the NIH with a diagnosis of ZES over a 25-year period (1974–1999) were eligible for the study. The only exclusion criteria were patients who had previously undergone a total gastrectomy or could not have secretory testing for any reason (such as patients with advanced ulcer disease or a complication, for whom it was unsafe to stop gastric antisecretory medications). The present study is part of the ongoing prospective study of patients with ZES at the NIH since 1974 as approved by the Clinical Research Committee of the National Institute of Diabetes and Digestive and Kidney Diseases. Diagnostic criteria for ZES were similar to previously described criteria (88) and included the following: the presence of basal gastric fluid with a pH ≤3.5; the presence of an elevated fasting serum gastrin level; positive provocative testing with secretin (an increase of >200 pg/mL postinjection) or with calcium (an increase >395 pg/mL) (93); positive histologic confirmation of gastrinoma; or a combination of these criteria. Diagnostic criteria for MEN1 included ZES plus either a family history of MEN1 or evidence of hyperparathyroidism, pituitary disease, or adrenal disease as previously described (16,128,219). Serum gastrin levels were determined by Bioscience Laboratories (New York, NY) until 1994 and subsequently by Mayo Clinic Laboratories (Rochester, MN). All samples were diluted as necessary to give values on the midportion of the standard curve as described previously (42,88,93). Secretin testing was performed using an intravenous bolus injection (2 g/kg body weight) of Secretin-Kabi (Ferring AB, Malmo, Sweden) and the results analyzed as described previously. A >200 pg/mL increase over the preinjection values was a positive result, as defined previously (93). The calcium provocative test was performed as described previously (93) with calcium gluconate (10%) (5 mg calcium/kg per hr) given by continuous intravenous infusion for 3 hours. A >395 pg/mL increase over the average of the preinjection values was considered a positive response, as defined previously (93,274). On admission to the NIH all patients had a detailed history and physical examination as described previously (246). Briefly, in the history, particular attention was paid to the initial clinical symptoms of ZES, a history of endocrinopathies, and a family history of endocrinopathies or multiple endocrine neoplasia. All patients also had laboratory evaluations including complete blood count, urinalysis, fasting serum gastrin concentration, tumor imaging studies, biochemistry studies including liver function tests, and an upper gastrointestinal endoscopy. Conventional imaging studies (ultrasound [161], CT scan with contrast [297], and MRI [231,281]) were performed to assess tumor location, size, and extent, as described previously (219,222,312). If the tumor location or extent was unclear, selective abdominal angiography was performed (172). Since 1994, all patients underwent initially and then yearly somatostatin receptor scintigraphy using 6 mCi of [111In-DTPA-dPhe1]octreotide with spot views, whole body views, and with single photon emission CT imaging at 4 hours and 24 hours postinjection (98,282). Based on the results of the imaging studies and surgical exploration when it was performed, patients were stratified into those with localized disease without liver metastases and those with liver metastases. Liver metastases were established by biopsy in all patients (279,302,312). Surgical exploration was performed in all patients with ZES without MEN1, without diffuse liver metastases or an illness limiting life expectancy, as described previously (n = 129) (1,90,219). Exploratory laparotomy also was performed in patients with ZES with MEN1 (n = 30) with an imagable lesion >3 cm, who did not have diffuse liver metastases or an associated illness limiting life expectancy, as described previously (162,219). At exploration all patients had a standard extensive search for a gastrinoma (1,162,219,276). Briefly, the following was performed beginning with palpation after an extended Kocher maneuver: intraoperative endoscopic transillumination of the duodenum (94), intraoperative ultrasound with a 10 MHz real time transducer (217,218), and a 3-cm longitudinal duodenotomy was made which was centered on the anterolateral surface of the descending duodenum (since 1987) (218,276). To analyze the effect of primary tumor location, patients were divided into those who had only a duodenal primary; those who had only a pancreatic primary; those who had both a duodenal and pancreatic primary; those who had a lymph node primary; those who had a primary in another nonduodenal, nonpancreatic, nonlymph node location; and those who had a primary tumor in an unknown location. A primary tumor of the lymph node was defined as occurring in a patient who was disease-free (normal fasting gastrin, negative provocative test, and negative imaging [88]) after resection of only a lymph node gastrinoma as described previously (7,219). Other nonduodenal-pancreatic-lymph node primary locations were defined as occurring in patients who were disease-free after resection of a gastrinoma from these sites (219,309). Computed tomography or MRI of the sella turcica and determinations of serum prolactin, calcium, and parathyroid hormone concentrations (using both an assay for the intact parathyroid hormone molecule and an antibody directed against the midportion of parathyroid hormone) were performed to determine if associated MEN1 was present, as described previously (16,219). During upper gastrointestinal endoscopy the presence of prominent gastric folds as well as esophageal strictures, pyloric or duodenal scarring, and any mucosal lesions was carefully noted (246). Prominent gastric folds were defined as gastric body folds that appeared more prominent to the endoscopist than normal and that persisted on complete inflation of the stomach with air during endoscopy (246). Gastric acid secretion was measured for each patient when off all antisecretory medication as previously described (88,183,239). Before measuring BAO or MAO, patients were not treated with anticholinergic agents for at least 3 days, oral anti-histamine H2- receptor antagonists for at least 30 hours, and proton pump inhibitors (PPIs) for at least 2 weeks, and all intravenous histamine H2-receptor antagonist infusions were stopped for at least 12 hours (183). Briefly, after an overnight fast a nasogastric tube was passed. Tube placement was checked by infusing 50 mL of fluid and verifying that >90% was recovered. The first 15-minute aliquot was discarded. Subsequently, gastric fluid was collected by continuous aspiration for 1 hour in 15-minute samples. After measuring the volume and recording the undiluted pH, samples were titrated to pH 7 with 0.01 N NaOH. Results were expressed in milliequivalents (mEq) of acid per hour and mEq per 15-minute sample. MAO was determined for each patient when off all antisecretory medication with either Histolog (1.5 mg/kg intramuscularly; Eli Lilly, Indianapolis, IN) or pentagastrin (6 μ/kg subcutaneously; Ayerst Laboratories, New York, NY) as described above for the determination of basal secretion after stimulating gastric acid secretion (183,232). Similar to BAO, 15-minute aliquots were collected, the volume and the pH of each recorded, an aliquot titrated separately to pH 7.0 with 0.01 N NaOH, and results were expressed as mEq of acid per hour, mEq per 15-minute aliquot, and the volume in mL per hour and per 15-minute sample. Before the gastric analysis, urinary specific gravity was determined; if it was >1.015, patients were hydrated with intravenous fluids and then the gastric analysis was performed. Literature review of acid secretory results in patients with ZES To compare our results with gastric secretory results previously reported in patients with ZES, we attempted to identify all published cases of ZES that included gastric secretory results. For literature published after 1966, MEDLINE (National Library of Medicine, Bethesda, MD) was used to search using the keywords gastrinoma, Zollinger-Ellison syndrome, acid secretion, and pancreatic endocrine tumor. The bibliographies of all papers were reviewed to identify papers published before 1966 as well as reports not referenced in MEDLINE. All cases were reviewed and classified as to whether gastric acid secretory testing had been performed, and the BAO and MAO data were entered into an Excel spreadsheet, which was used for all analyses involving data from the literature. Statistical analysis Statistical analysis was performed using the Student t test for paired and unpaired values, the Mann-Whitney U test, McNemar test, the Fisher exact test, chi-square, and ANOVA. For a post hoc test the Bonferroni/Dunn test was used. Values of p < 0.05 were considered significant. All continuous variables are reported as mean ± SEM. Results General characteristics of patients in the study Over the 25 years of this prospective study, 261 patients with ZES were evaluated at the NIH. Of these, 235 were eligible for the study. Of the 26 patients excluded, 10 patients had had a total gastrectomy before evaluation at the NIH and thus gastric acid secretory studies could not be performed. In 16 other patients gastric acid secretory studies were not done because it was deemed unsafe to stop the antisecretory drugs long enough to meet the criteria for time of discontinuation before a gastric analysis. Of the 235 patients entered into the study, 30 (13%) had undergone acid-reducing surgery before evaluation at the NIH, including primarily vagotomy and pyloroplasty (15 patients) and Billroth resections (Table 1). Fifty-one patients (22%) met the criteria for MEN1 at the time of admission at the NIH; the percentage was not significantly different in patients with or without previous gastric acid-reducing surgery (see Table 1). There was a slight male predominance, and the percentage of males without or with prior gastric acid-reducing surgery (57% versus 63%, p = 0.51) did not differ. The mean age at onset of disease was 40.8 ± 0.8 years with no difference between patients without and with prior gastric acid-reducing surgery (p = 0.13). Race had no effect on the presence or absence of prior gastric acid-reducing surgery; in each group, most patients (78%–80%) were white, followed by 17%–18% black patients, and <5% Hispanic or Asian patients. The mean duration of disease from onset to diagnosis for all patients was 5.4 ± 0.4 years with significantly longer disease duration in patients with prior gastric acid-reducing surgery (6.6 ± 1.3 yr versus 5.2 ± 0.4 yr, p = 0.035) (see Table 1). Patients were evaluated at the NIH an average of 1.5 yr after the diagnosis of ZES was made, with no difference between the 2 groups of patients (p = 0.56). Almost a third of patients with no prior gastric acid-reducing surgery had prior abdominal surgery for other non-gastric surgical indications, which was lower in proportion than the half of the patients with prior gastric acid-reducing surgery who had prior non-gastric related surgery (p = 0.0l98) (see Table 1). All patients with prior gastric acid-reducing surgery were taking a gastric antisecretory medication before evaluation at the NIH, compared with 96% of patients with no prior gastric acid-reducing surgery. In patients with no prior gastric acid-reducing surgery, 32% had taken a PPI before their initial evaluation at the NIH, which did not differ significantly (p = 0.68) from the patients with prior gastric acid-reducing surgery (23%). For all patients, 86% had taken a
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