Zollinger-Ellison syndrome can be the initial endocrine manifestation in patients with multiple endocrine neoplasia-type I.

PURPOSE: To determine whether patients with multiple endocrine neoplasia type I (MEN-I) can initially present with Zollinger-Ellison syndrome (ZES), and to learn whether ZES exhibits any distinguishing features when it occurs as a first manifestation of MEN-I. PATIENTS AND METHODS: Sixty patients who had been referred to a clinical research center with ZES were examined by cohort analysis. Twenty-eight had MEN-I and 32 did not. In patients with MEN-I, we analyzed the temporal relationships between the clinical and biochemical manifestations of ZES and the other endocrinopathies associated with the neoplasia. To determine whether patients who had ZES as a first manifestation of MEN-I (n = 8) had any distinguishing clinical characteristics, we compared them to a cohort of patients with established sporadic ZES (n = 32) matched for age, sex, and time since the onset of symptoms consistent with ZES. RESULTS: Of the 28 patients with ZES and MEN-I, 11 initially presented with ZES and hyperparathyroidism (HP) and 1 with evidence only for pituitary disease. Eight patients (29%) presented with features of ZES and developed clinical and biochemical evidence for HP later, while the same number developed these 2 endocrinopathies in the opposite order. In whichever order ZES and HP occurred, the time from the diagnosis of the first to the diagnosis of the second was similar. It ranged from 9 to 177 months in patients who presented with ZES first, and from 12 to 264 months in patients who presented with HP first. At the time of initial diagnosis, the patients who presented with ZES as a manifestation of MEN-I had no distinguishing ZES-related symptoms, biochemical assays, or tumor imaging results compared to the cohort of patients who had the syndrome sporadically. CONCLUSION: Patients with MEN-I can initially present with a symptomatic pancreatic endocrine tumor syndrome without any other disease manifestations. In patients with ZES and MEN-I, up to one third may present with ZES without evidence of any other endocrinopathy. Consequently, patients with presumed sporadic ZES should undergo continual biochemical screening for other endocrinopathies characteristic of MEN-I and, in the future, genetic studies for the MEN-I gene.

Prospective study of the need for long-term antisecretory therapy in patients with Zollinger-Ellison syndrome following successful curative gastrinoma resection.

A long-term cure is now possible in more than 30% of selected patients with Zollinger-Ellison syndrome who undergo gastrinoma resection. The need, however, for continued gastric acid antisecretory therapy in these patients remains controversial. The current study was designed to determine whether post-operative antisecretory therapy is needed in patients who have undergone successful gastrinoma resection and, if so, to attempt to define criteria with which to identify patients who require therapy. Twenty-eight consecutive patients who had previously undergone curative gastrinoma resection were prospectively studied. When antisecretory therapy was discontinued, 43% (12/28) of these patients developed gastro-oesophageal reflux, diarrhoea, acid-peptic symptoms or endoscopic evidence of acid-peptic disease within 2 weeks and were deemed to have failed a trial of antisecretory drug withdrawal. The remaining 57% (16/28) of patients who successfully discontinued antisecretory therapy were followed for a mean time of 31 months after withdrawal of therapy. Analysis of acid output studies pre-operatively, as well as at the time of drug withdrawal, demonstrated that patients who were unable to discontinue antisecretory therapy exhibited higher pre-operative maximal acid output values and higher basal acid output values at the time of attempted drug withdrawal than patients who were able to discontinue therapy. Despite these findings, there was significant overlap in acid output values between groups so that it was not possible to define specific acid output criteria for successful drug withdrawal. Pre-operative clinical characteristics, such as the presence or absence of gastro-esophageal reflux or acid-peptic disease, or post-operative laboratory values, such as the fasting serum gastrin level, did not correlate with the ability to discontinue antisecretory therapy. We conclude that following successful curative gastrinoma resection, 40% of patients still require antisecretory therapy and that both symptom evaluation as well as upper endoscopy should be used to guide attempted drug withdrawal. Although patients who are not able to discontinue therapy have significantly higher acid output measurements than those who are able to discontinue therapy, neither acid output criteria nor any other laboratory or clinical characteristics are able to predict the need for continued antisecretory therapy in these patients.

Control of gastric acid hypersecretion in the management of patients with Zollinger-Ellison syndrome.

During the last 5 years important advances have occurred in the control of gastric acid hypersecretion in Zollinger-Ellison syndrome (ZES). The increased availability of potent gastric acid antisecretory agents such as histamine H2-receptor antagonists and more recently the H+K(+)-ATPase inhibitors such as omeprazole and lansoprazole have made it possible to medically control acid secretion in all patients. Increased understanding of the variation in antisecretory drug dosage between individual patients has led to identification of criteria to ensure effective antisecretory control and to the recognition of subgroups of patients who require special monitoring. Effective regimens for parenteral antisecretory control during surgery have been established. The importance of parathyroidectomy in patients with multiple endocrine neoplasia type I with ZES and the possible usefulness of highly selective vagotomy have been investigated. We review here the new data that led to increased understanding in each of these areas from our studies and studies by others.

Fine needle aspiration cytology of submucosal nodules in patients with Zollinger-Ellison syndrome.

Submucosal nodules are often encountered during investigations of the upper gastrointestinal (GI) tract. This is particularly true in diseases resulting in chronic hypergastrinemia, such as Zollinger-Ellison syndrome (ZES), in which submucosal gastric and duodenal lesions can occur. Forceps biopsy of submucosal lesions often yields only normal mucosa; however, fine needle aspiration cytology (FNAC) has recently been described as having high diagnostic accuracy for submucosal tumors. Therefore, we prospectively studied the use of FNAC in 43 patients with ZES. Overall, 33% of patients with ZES had nodules. In patients with the sporadic form of ZES, submucosal nodules were found in 18%, whereas submucosal nodules were found in 80% of patients who had ZES in conjunction with multiple endocrine neoplasia type I (MEN-I). FNAC identified 11/12 (92%) of the neuroendocrine tumors, and identified another 8/9 as non-neuroendocrine. Jumbo forceps biopsy was performed on 18 nodules and diagnosed one neuroendocrine tumor. Subsequently, 11 of these nodules were found to possess neuroendocrine tumor; thus only 1/11 (9%) neuroendocrine tumors removed were accurately identified by jumbo forceps biopsy. Of the first 14 nodules, sufficient tissue was left after biopsy to permit snare polypectomy on 12 nodules. Four nodules were found to contain neuroendocrine tumor. Snare polypectomy resulted in a duodenal perforation that required surgery in one patient, and thus was not performed on the final seven nodules.(ABSTRACT TRUNCATED AT 250 WORDS)

Currently used doses of omeprazole in Zollinger-Ellison syndrome are too high.

The efficacy of omeprazole increases during the first few days of administration, suggesting that long-term maintenance dose requirements in patients with Zollinger-Ellison syndrome may be lower than those initially established by upward titration. Long-term maintenance doses of omeprazole were prospectively reduced in 37 patients who had been taking omeprazole for 22 +/- 4 months. Successful reduction was defined as reduction to 20 mg once or twice daily with an absence of symptoms, endoscopy without evidence of active acid-peptic disease, and a gastric acid output of < 10 mEq/h. Sixty-eight percent of patients (25/37) were successfully reduced to 20 mg of omeprazole once (18/24) or twice daily (7/13). Ninety-five percent of patients (20/21) without multiple endocrine neoplasia type I, severe gastroesophageal reflux disease, or previous partial gastrectomy had safe reductions of doses. It is concluded that the currently used omeprazole maintenance doses in patients with Zollinger-Ellison syndrome are too high and advocated that the initial dose still be established by acute daily upward titration followed by gradual reduction once control of acid output has been achieved.

Esophageal function and occurrence of Barrett's esophagus in Zollinger-Ellison syndrome.

Manifestations of esophageal disease are present in up to 60% of patients with Zollinger-Ellison syndrome (ZES), although esophageal function has been studied in only a few patients and the prevalence of Barrett's mucosa is unknown in these patients. It is unclear whether the high prevalence of esophageal disease is related to gastric acid hypersecretion alone or to abnormalities of esophageal motility or lower esophageal sphincter (LES) function in addition. To address these issues in the present study esophageal function was evaluated prospectively in 92 consecutive patients with ZES (66 with active disease, 26 disease-free after curative resection) seen during a 1-year period after controlling acid hypersecretion. In the patients with active disease the mean basal acid output (BAO) was 33 +/- 3.0 mEq/h, the maximal acid output (MAO) was 56 +/- 4.0 mEg/h, fasting serum gastrin was 8,736 +/- 4,813 pg/ml and duration of disease prior to study was 12.5 +/- 2.0 years. At the time of manometry, gastric acid secretion was controlled in all patients and no patient had evidence of gastroesophageal reflux disease at upper gastrointestinal endoscopy. Esophageal manometry revealed normal motility in 85% of patients. Eleven percent had low LES pressures, and only 1% of patients had an elevated LES pressure. The frequency of Barrett's mucosa (3%) was similar to that found in the general population but much less than that reported in patients with idiopathic GERD. No correlation was noted between LES pressures or manometric abnormalities and the fasting serum gastrin, BAO, MAO or the presence or absence of multiple endocrine neoplasia type I or previous vagotomy. Esophageal manometric results and LES pressure were similar in disease-free patients and those with active ZES. In conclusion, these results suggest that hypergastrinemia or other disease-specific abnormalities are not contributing to the high incidence of esophageal disease in patients with ZES because esophageal function in patients with ZES is similar to normals. Specifically, motility disorders in patients with ZES occur in similar frequency to normals, and LES pressure is normal in most patients. Despite the high levels of acid secretion and prominence of symptoms, the occurrence of Barrett's mucosa was uncommon (3%) raising the possibility of additional protective mechanisms in patients with ZES.

Assessment and prediction of long-term cure in patients with the Zollinger-Ellison syndrome: the best approach.

OBJECTIVE: To identify the best method for determining freedom from disease after gastrinoma resection and for predicting long-term disease-free status in patients with the Zollinger-Ellison syndrome. DESIGN: Prospective study in consecutive patients. SETTING: Referral-based clinical research center. PATIENTS: Eighty-one consecutive patients with the Zollinger-Ellison syndrome who underwent surgical exploration for gastrinoma resection. INTERVENTION: Patients were evaluated after gastrinoma resection, before discharge, 3 to 6 months after surgery, and yearly thereafter. Evaluation included secretin provocative testing and fasting serum gastrin determinations. Follow-up examinations after the initial postoperative evaluations included a clinical assessment, acid secretion studies, a calcium provocative test, and various imaging studies. MEASUREMENTS AND MAIN RESULTS: Most patients (96%) had gastrinomas. Freedom from disease was defined by improved symptoms, reduced acid output and antisecretory drug requirements, and a normal gastrin level, normal imaging studies, and negative gastrin provocative studies. Fifty-two percent of patients (n = 42) were disease-free immediately after surgery, 44% at 3 to 6 months, 42% at 1 year, and 35% by 5 years (mean follow-up, 39 months). The secretin provocative test was the first test to become positive in 45% of patients with a recurrence, the serum gastrin determination was the first test to become positive in 36%, and both tests became positive at the same time in 18%. No recurrence was first detected by imaging studies or by calcium provocative testing. Fasting serum gastrin levels and secretin provocative test results at different postoperative times can be used to predict the probability of a patient remaining disease free at 3 years. Patients with a normal gastrin level and a normal secretin provocative test immediately after surgery had a 3-year disease-free probability of 75%, and normal results on both tests at 6 months, 1 year, and 2 years yielded respective probabilities of 88%, 95%, and 100%. CONCLUSIONS: Both the secretin provocative test and fasting serum gastrin determination are necessary for the early diagnosis of cases of recurrent disease after gastrinoma resection. The calcium provocative test and imaging studies do not detect any recurrences first. Fasting serum gastrin determinations and secretin provocative testing at different postoperative times can be used to predict the probability of a patient remaining disease free at 3 years.

An evaluation of human recombinant alpha interferon in patients with metastatic gastrinoma.

BACKGROUND: Metastatic gastrinoma is becoming increasingly recognized in patients with Zollinger-Ellison Syndrome. The mean 5-year survival of these patients is < 20%. Chemotherapeutic regimens are of limited benefit. The aim of this study was to evaluate the use of interferon in these patients because a preliminary report suggested it might be effective. METHODS: The efficacy and toxicity of interferon was assessed in 13 consecutive Zollinger-Ellison syndrome patients with liver metastases. Patients were treated with human recombinant alpha interferon (5 million IU, subcutaneously [SC]) daily and followed up at 3-month intervals with multiple imaging studies. At each follow-up, toxicity of therapy was assessed and fasting serum gastrin concentrations were obtained. RESULTS: No patient showed a reduction in tumor size at any follow-up. One patient died after 2 months. At 6 months, six patients (46%) had stable tumor size in the liver, although new bone metastases developed in one patient. Three patients showed stable disease for up to 21 months. Changes in serum gastrin correlated with tumor response at 6 months. All patients developed some side effects of therapy. Thirty-one percent required dose reduction, and one patient (8%) had to have interferon therapy interrupted briefly. CONCLUSIONS: These results fail to define a therapeutic role for interferon in the treatment of metastatic gastrinoma.