== The mean BAO and MAO preoperatively and, at the indicated times, postoperatively are shown for each of the three postoperative acid secretory categories as defined inFigure legend 1. CGA (P=0.009) and 24-hr urinary N-MIAA (P=0.0038) == Conclusions == Postcurative-resection, gastric hypersecretion persists long-term (mean-8 yrs) in 62% of patients and in 28% it is extreme, despite normogastrinemia. No preoperative variable except BAO correlates with postresection hypersecretion. The persistent increased ECL-cell extent postcurative resection suggests prolonged hypergastrinemia can lead to changes in ECL-cells that are MDNCF either irreversible in humans or sustained by unknown mechanisms BS-181 hydrochloride not involving hypergastrinemia and which can result in hypersecretion, in a proportion of which it can be extreme. Whether similar findings may occur in patients with idiopathic GERD treated for prolonged periods (>10 years) with PPIs, at present is unknown. Keywords:Zollinger-Ellison syndrome, gastrinoma, acid secretion, proton pump inhibitors, ECL cells == Introduction == Zollinger-Ellison syndrome (ZES) is caused by gastric acid hypersecretion due to the ectopic release of gastrin from a neuroendocrine tumor (i.e. gastrinoma)[1,2]. Because the diagnosis is often delayed, patients have hypergastrinemia for >48 years prior to surgical exploration for cure and many, postoperatively for life, because <40% are cured postresection long-term [3]. This prolonged hypergastrinemia not only results in marked increases in acid secretion, it also has profound trophic effects on the gastric mucosal cells causing an increase in BS-181 hydrochloride parietal cell mass, gastric mucosal thickness and gastric enterochromaffin-like cells [ECL cells] [2,48]. Therefore, ZES has been proposed to be an excellent natural model to study the chronic effects of hypergastrinemia in man, as well as a possible natural model to investigate the effects of the rapid reversal of chronic hypergastrinemia in man, by studying those ZES patients who are successfully, surgically cured [8,9]. Both of the above areas are receiving increasing attention because of the increasing BS-181 hydrochloride number of patients with gastro-esophageal reflux disease (GERD) chronically taking proton pump inhibitors (PPI), with 80100% developing hypergastrinemia, including a significant percent in a range seen in ZES patients [913]. Whereas numerous studies have shown that such treatment is safe and effective short term (<5 years) [8,14,15], the long-term consequences of such treatment are still largely unknown. The importance of the changes is that ECL-cell hyperplasia can progress to gastric carcinoids [11,16,17], which can occasionally be malignant [18]. The ECL and parietal cell hyperplasia can lead to gastric hypersecretion after stopping antisecretory treatment (rebound hypersecretion) which can make it difficult to wean patients with GERD off of PPIs [11,1922]. A recent study reports even healthy, asymptomatic individuals treated for only an 8-week period with PPIs, can develop dyspeptic symptoms when the PPIs are stopped [23]. Whereas the possible development of gastric carcinoid tumors in both animals and humans [4,5,8,11,24] with chronic long-term gastric antisecretory treatment has been extensively studied; in humans much less information is available on rebound hypersecretion and few long term studies on the effects of rapid reversal of chronic hypergastrinemia, such as after stopping chronic PPI treatment [11,19,20,22]. Previous studies show approximately 3040% of ZES patients are cured long-term [3,25] and in proportion; mild gastric acid hypersecretion may persist [26]. However, neither the possible mechanisms leading to this latter finding are known or have been studied, nor is it known if similar results might be seen in GERD patients treated for very prolonged periods >10 years). Studying the gastric acid secretion following curative resection of the gastrinoma could serve as a natural model for acid secretory changes that might occur after withdrawal of prolonged treatment with PPIs and may provide an insight into the mechanisms that are involved. To address these questions we studied gastric acid secretion in 50 ZES patients who underwent curative gastrinoma resection and attempted to define factors that may be associated with gastric acid hypersecretion postcurative resection in these patients. == METHODS == All patients with ZES referred to the National Institutes of Health were considered for the current study. These patients are included in the prospective study of ZES approved by the Clinical Research Committee of the National Institute of Diabetes and Digestive and Kidney Diseases. To be eligible for participation in the present study, patients needed to fulfill the following criteria: 1) have an established diagnosis of ZES as previously defined [27]; 2) agree to undergo exploratory laparotomy for possible cure; 3) be eligible for curative surgery as previously defined [3,25]; 4) have no medical contraindications to surgery; 5) have no medical illness limiting life expectancy; and 6) agree to long term follow-up including an assessment of disease-free status, gastric acid secretory status and ECL-cell activity. The diagnosis of ZES was.
