Diagnosis and management of Zollinger-Ellison syndrome in 2018.

Zollinger-Ellison syndrome (ZES) is a clinical syndrome characterized by gastric acid hypersecretion due to the ectopic secretion of gastrin by a gastrinoma, a neuroendocrine tumor (NET) which mostly develops in the duodenum and in the pancreas. This syndrome was first described by Zollinger and Ellison in 1964; if left untreated, ZES can lead to multiple complications mainly due to gastric hypersecretion and some patients can suffer from the complications of an advanced metastatic disease. Although its clinical features are considered typical, the diagnosis of ZES is often challenging for the clinician. A previous review was published in 2005 by our group, but in 12 years many things have changed: the diagnostic tools have been improved and many different therapeutical options are now available.

Weight Gain in Zollinger-Ellison Syndrome After Acid Suppression.

OBJECTIVES: Zollinger-Ellison syndrome (ZES) is characterized by hypergastrinemia and gastric acid hypersecretion resulting in peptic ulcer disease, diarrhea, and weight loss. Acid secretion can be controlled with medication, and biochemical cure is possible with surgery. Data on how these interventions affect patients' weight are lacking. We aimed to determine how medical and surgical acid control affects weight over time. METHODS: We performed a retrospective cohort study on 60 ZES patients. Acid control was achieved with appropriate-dose proton pump inhibitor (PPI) therapy. Surgery was performed for curative intent when appropriate. Weight change was assessed versus pre-acid control or immediate preoperative weights and expressed as absolute and percent change from baseline at 6, 12, 18, and 24 months. RESULTS: A total of 30 PPI-controlled patients and 20 surgery-controlled patients were analyzed. Weight gain was noted at all time points while on appropriate-dose PPI therapy (P < 0.005). Of patients who had surgery with curative intent, weight gain was noted at 12 months (7.9%, P = 0.013) and 18 months (7.1%, P = 0.007). There was a trend toward weight gain seen at all time points in the patients who were surgically cured. CONCLUSIONS: These data represent a novel description of weight gain after acid suppression in ZES.

[Evolution of clinical ideas about Zollinger-Ellison syndrome].

The paper gives the current views of the diagnosis and treatment of Zollinger-Ellison syndrome (ZES). It underlines the importance of including ZES in differential diagnosis in patient with frequently recurrent and standard-dose proton pump inhibitor therapy-resistant erosive and ulcerative lesions of the upper gastrointestinal tract. It provides the current stepwise algorithm for the diagnosis of the pathology in question. Relevant and promising treatments in patients with ZES are considered.

Mechanism of acid hypersecretion post curative gastrinoma resection.

BACKGROUND: Some patients with Zollinger-Ellison syndrome post curative gastrinoma resection continue to show gastric acid hypersecretion; however, the mechanism is unknown. AIM: The aim of this study was to prospectively study acid secretion following curative gastrinoma resection and analyze factors contributing in patients with Zollinger-Ellison syndrome. METHODS: Fifty patients cured post gastrinoma resection were studied with serial assessments of acid secretory status, cure status and ECL-cell status/activity (with serial biopsies, CgA, urinary N-MIAA). Correlative analysis was performed to determine predictive factors. RESULTS: Hypersecretion occurred in 31 patients (62%) and 14 had extreme-hypersecretion. There was an initial decline (3-6 months) in BAO/MAO, which then remained stable for eight years. Preoperative BAO correlated with the postoperative secretion, but not other clinical, tumoral, laboratory variables, the degree of postoperative acid suppression or type of antisecretory drug needed. Hypersecretors had greater postoperative ECL changes (P=0.005), serum CGA (P=0.009) and 24-h urinary N-MIAA (P=0.0038). CONCLUSIONS: Post curative resection, gastric hypersecretion persists long term (mean 8 years) 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 post curative resection suggests prolonged hypergastrinemia can lead to changes in ECL-cells that are either irreversible in humans or sustained by unknown mechanisms not involving fasting 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.

Costs and risks in the management of patients with gastric acid hypersecretion.

GOALS: To define both risks and costs of optimal care of patients with gastric acid hypersecretion. BACKGROUND: The management of Zollinger-Ellison syndrome and other gastric acid hypersecretory disorders remains challenging. The optimal strategy for follow-up including gastric acid analysis, laboratory studies, and endoscopy is unknown but important given the potential complications from uncontrolled acid secretion. STUDY: Over the last 18 years, patients with gastric acid hypersecretory disorders have been followed prospectively with gastric acid analysis and endoscopy titrating oral lansoprazole and evaluating for complications. Protocol driven charges were calculated using the most recent information available. RESULTS: After 1 year of treatment optimization, 19 of 67 patients had 43 relapses, (once only in 10 patients). Risk markers for relapse included: (1) antrectomy, 67% relapsed versus 21% in unoperated patients; (2) basal acid output >5 mmol/h (risk=5.17); and (3) poor compliance. On treatment, 79% of 58 intact patients (excluding antrectomy) were lesion-free; 11% had only 1 relapse. Thus 90% were well managed with optimized lansoprazole alone. Protocol driven charges exceeded $25,000 the first year and $7000 annually thereafter. CONCLUSIONS: Relapse is infrequent and generally mild with acid secreting status closely monitored. The ideal strategy to balance costs and testing awaits further study.

Gastric acid hypersecretory states: recent insights and advances.

Gastric acid hypersecretory states are characterized by basal hypersecretion of gastric acid and historically include disorders associated with hypergastrinemia, hyperhistaminemia, and those of unknown etiology. Although gastric acid secretion is infrequently measured, it is important to recognize the role of gastric hypersecretion in the symptoms of these disorders because they share several features of pathogenesis and treatment. In this article, recent important articles reporting insights into their diagnosis, pathogenesis, and treatment are reviewed. Particular attention is paid to Zollinger-Ellison syndrome, because it has the most extreme acid hypersecretion of this group of disorders and because numerous recent articles deal with various aspects of the diagnosis, molecular pathogenesis, and treatment of the gastrinoma itself or the acid hypersecretion. Two new hypersecretory disorders are reviewed: rebound acid hypersecretion after the use of proton pump inhibitors and acid hypersecretion with cysteamine treatment in children with cystinosis.

Treatment strategies for Zollinger-Ellison syndrome.

BACKGROUND: Zollinger-Ellison syndrome (ZES) is a rare disorder caused by tumor secretion of the hormone gastrin, which results in gastric acid hypersecretion and secondarily complicated peptic ulcer and diarrhea. Until the development of H(2)-receptor antagonists and later proton pump inhibitors (PPIs), the disease was virulent, often associated with ulcer-related mortality, and the mainstay of treatment was total gastrectomy. OBJECTIVE: To evaluate current approaches to diagnosis and therapy, focusing on the role of PPIs. METHODS: An extensive literature search through PubMed using the search term 'Zollinger-Ellison syndrome' from 1964 to the present was performed. Primary articles were identified, and pertinent articles obtained from the reference lists were also examined. RESULTS/CONCLUSIONS: The clinical manifestations of ZES are well described, but overlaps with other more common disorders delay diagnosis. The use of abdominal imaging with somatostatin receptor scintigraphy and endoscopic ultrasound has improved tumor staging. PPI therapy is remarkably effective in controlling gastric acid hypersecretion, thereby reducing morbidity and potential mortality of this syndrome. The dose of drug necessary to control symptoms is highly variable but, even when used in high doses for prolonged periods of time, the disease remained controlled with very few drug-related side effects.

Importance of gastrin in the pathogenesis and treatment of gastric tumors.

In addition to regulating acid secretion, the gastric antral hormone gastrin regulates several important cellular processes in the gastric epithelium including proliferation, apoptosis, migration, invasion, tissue remodelling and angiogenesis. Elevated serum concentrations of this hormone are caused by many conditions, particularly hypochlorhydria (as a result of autoimmune or Helicobacter pylori (H pylori)-induced chronic atrophic gastritis or acid suppressing drugs) and gastrin producing tumors (gastrinomas). There is now accumulating evidence that altered local and plasma concentrations of gastrin may play a role during the development of various gastric tumors. In the absence of H pylori infection, marked hypergastrinemia frequently results in the development of gastric enterochromaffin cell-like neuroendocrine tumors and surgery to remove the cause of hypergastrinemia may lead to tumor resolution in this condition. In animal models such as transgenic INS-GAS mice, hypergastrinemia has also been shown to act as a cofactor with Helicobacter infection during gastric adenocarcinoma development. However, it is currently unclear as to what extent gastrin also modulates human gastric adenocarcinoma development. Therapeutic approaches targeting hypergastrinemia, such as immunization with G17DT, have been evaluated for the treatment of gastric adenocarcinoma, with some promising results. Although the mild hypergastrinemia associated with proton pump inhibitor drug use has been shown to cause ECL-cell hyperplasia and to increase H pylori-induced gastric atrophy, there is currently no convincing evidence that this class of agents contributes towards the development of gastric neuroendocrine tumors or gastric adenocarcinomas in human subjects.

Zollinger-Ellison syndrome in 2006: concepts from a clinical point of view.

Zollinger-Ellison syndrome (ZES) is characterised by peptic ulcers of the upper gastrointestinal tract failing to heal despite maximal medical therapy, diarrhoea and marked gastric acid hypersecretion associated with a gastrin-secreting tumour (gastrinoma). ZES might be associated with multiple endocrine neoplasia type 1. The main diagnostic features are hypergastrinemia and acid hypersecretion. When these parameters give borderline results, provocation test (with secretin or calcium) may be required. To identify the localisation of gastrinoma several imaging techniques have been proposed. Somatostatin receptor scintigraphy is capable to localise the tumour in 80% of the cases and to identify it even in anatomic sites other than pancreas and duodenum. Endoscopic ultrasonography has a sensitivity as high as 79-93% and a specificity of 93%. The 2 main principal therapeutic strategies are to control both the gastric acid hypersecretion and the growth of the neoplasia. Proton pump inhibitors (PPIs) are the drugs of choice for patients with ZES. Furthermore, safety of PPIs in the maintenance therapy has been proven both in short- and in long-term studies. The best surgical treatment is excision of gastrinoma before metastatic spread has occurred. Somatostatin-analogues can reduce both gastric acid hypersecretion and serum gastrin levels. Moreover, they have an antiproliferative effect. Chemotherapy, interferon and embolisation are indicated in rapidly evolving tumours or in cases in which the tumoral symptoms cannot be treated by other approaches.

Gastric carcinoid tumors in multiple endocrine neoplasia-1 patients with Zollinger-Ellison syndrome can be symptomatic, demonstrate aggressive growth, and require surgical treatment.

BACKGROUND: Gastric carcinoid tumors occur in 15% to 50% of patients with multiple endocrine neoplasia-1/Zollinger-Ellison syndrome (MEN-1/ZES) but are thought to be benign. We report 5 patients with MEN-1/ZES with symptomatic, aggressive gastric carcinoid tumors that required surgical procedures. METHODS: This was a retrospective chart review. RESULTS: Each patient had MEN-1/ZES. Each patient had innumerable gastric carcinoid tumors with symptoms. The fasting gastrin level was 47,000 pg/mL (normal, <200 pg/mL); the basal acid output was 79 mEq/hr (n = 3), and the age at surgical exploration was 47 +/- 6 years, with a duration of MEN-1 of 21 +/- 3 years and of ZES of 15 +/- 2 years. All patients had elevated 5-HIAA or serotonin levels. Somatostatin receptor scintigraphy showed increased stomach uptake in 4 patients (80%). Four patients had a total gastrectomy; 4 patients had lymph node metastases removed, and 3 patients had liver metastases resected. One patient who did not have a total gastrectomy had liver carcinoid metastases. CONCLUSIONS: These results demonstrate that gastric carcinoid tumors in patients with longstanding MEN-1/ZES may be symptomatic, aggressive, and metastasize to the liver. With increased long-term medical treatment and life expectancy, these tumors will become an important determinant of survival.

Optimal treatment of Zollinger-Ellison syndrome and related conditions in elderly patients.

Zollinger-Ellison syndrome is characterised by refractory peptic ulcer disease, severe diarrhoea and gastric acid hypersecretion associated with an islet-cell tumour of the pancreas (gastrinoma). The true incidence and prevalence of this rare disease is unknown; in the US, the frequency is one per one million people and the age at presentation varies from 7 to 90 years. Zollinger-Ellison syndrome is sporadic in 62-80% of cases and in 20-38% of cases is associated with multiple endocrine neoplasia type 1 (MEN 1). The diagnosis of Zollinger-Ellison syndrome is certain when the plasma gastrin is >1000 pg/mL and the basal acid output is >15 mEq/h in patients with an intact stomach, >5 mEq/h in gastrectomised patients, or when this hypergastrinemia is associated with a pH <2. The treatment is based on control of gastric acid hypersecretion and of the malignant tumour and its possible metastases. Proton pump inhibitors are the most effective antisecretory drugs and can be administered in the elderly at high dosages without drug-related adverse effects. As an initial therapy, daily dosages of omeprazole 80-100 mg or pantoprazole 40-160 mg are employed. In long-term treatment the doses can be greatly reduced once effective control of the gastric output has been established. Intravenous proton pump inhibitors may be administered when patients cannot take oral therapy, particularly in acute conditions. All sporadic localised gastrinomas should be excised if possible. When liver metastases are also present, their debulking may improve symptoms and survival, and facilitate medical treatment. There is some controversy as to the surgical approach for gastrinomas associated with MEN 1. Somatostatin analogues can be useful in reducing gastric acid hypersecretion, serum gastrin and gastric enterochromaffin-like (ECL) cells and can thus contribute to treating the disease more effectively. Their antiproliferative effect can be used in treating liver metastases. Chemotherapy is not the therapy of choice in patients with gastrinomas and is indicated only in those with malignant progressive disease; interferon alpha, embolisation and chemoembolisation are not advisable for the elderly. The treatment of elderly Zollinger-Ellison syndrome patients, similarly to all elderly oncological patients, should be based on the use of comprehensive geriatric assessment. This will enable the clinician to define the functional status of the elderly person, to decide whether the patient can tolerate surgery and/or the stress of antineoplastic therapy, and finally, to determine whether this patient can tolerate an aggressive treatment for Zollinger-Ellison syndrome or whether the only possible choice is palliative relief of symptoms.

Case presentation of gastrinoma combined with gastric carcinoid with the longest survival record -- Zollinger-Ellison syndrome: pathophysiology, diagnosis and therapy.

BACKGROUND: Zollinger-Ellison syndrome is a very rare disease caused by tumor with gastrin producing cells accompanied by hypergastrinemia leading to gastric hypersecretion and peptic ulcers and their complications. CASE STUDY: Female case of gastrinoma (Zollinger-Ellison syndrome; Z-E) with a record of 38 yrs of survival. Acute gastro-duodenal ulcers started at 28 yr of age and Z-E was diagnosed by using gastrin assays. Basal and maximal acid outputs and ratio of basal/maximal outputs were away over normal limits. Because of ulcer recurrence and complications, patient was subjected to several gastric surgeries but refused total gastrectomy. She was also treated with many H2-receptor (R) antagonists and proton-pump inhibitors (PPI), each new drug being initially highly effective but then showing declining efficacy except when PPI, lansoprazole was used. The gastrin level rose in the course of disease from initial high value of 2000 pg/mL to the extreme 4500 ng/mL at present. During the last 2 yrs, metastasis mainly to liver developed and they were successfully treated by synthetic octapeptide derivative of somatostatin and, as a result, metastatis partly reduced and plasma gastrin drasticly decreased. Biopsy taken from liver metastasis showed the presence of typical gastrinoma cells with gastrin and chromogranin, while that from oxyntic mucosa revealed the ECL-cell hyperplasia with carcinoid tumors and unexpected gastric atrophy. CONCLUSIONS: This phenomenal case described in this article might be the new proven evidence needed by gastroenterologists to overturn the traditional treatment using total gastrectomy as a treatment of choice to the partial gastrectomy combined with proton pump inhibitors.

[Efficacy and safety of intravenously administered pantoprazole in the treatment of gastrinoma]. / Efficacia e sicurezza del pantoprazolo in somministrazione endovenosa nel trattamento del gastrinoma.

The efficacy and safety of the proton pump inhibitor pantoprazole (P) in patients with Zollinger-Ellison syndrome (ZES) is well documented. We treated 21 patients with ZES with intravenous P; 13 of these patients were treated surgically in advance. The effect of P was very rapid, with reduction of the acid output within 15 min and its normalization within 60 min. The control of gastric acid secretion was maintained for a mean of 10.9 hours after the infusion of P. We conclude that the use of intravenous P allows a safe and efficient control of the acid ipersecretion in patients with ZES.

Gastric secretion in Zollinger-Ellison syndrome. Correlation with clinical expression, tumor extent and role in diagnosis--a prospective NIH study of 235 patients and a review of 984 cases in the literature.

We prospectively studied 235 patients with Zollinger-Ellison syndrome (ZES) (205 without and 30 with prior acid-reducing surgery) and compared the results with 984 patients from 182 reports in the literature. The aims of the study were to evaluate the sensitivity of proposed acid secretory criteria for the diagnosis of ZES, propose new criteria, evaluate the variability and methodology of gastric secretory testing, and correlate the symptoms and signs of ZES, tumor extent, and primary tumor size and location with the degree of gastric acid hypersecretion. Multiple endocrine neoplasia-type 1 (MEN1) occurred in 22% of patients. The mean basal acid output (BAO) in patients without and with prior acid-reducing surgery was 41.2 +/- 1.7 mEq/hr (range, 1.6-118.3 mEq/hr) and 27.6 +/- 3.5 mEq/hr (range 5.9-102.9 mEq/hr), respectively. In patients with MEN1, those with female gender, Hispanic, or Asian race had lower BAOs. Diarrhea, esophageal stricture, and pyloric scarring were associated with a higher BAO. Neither other symptoms nor the tumor extent, primary tumor location, or size correlated with the magnitude of acid hypersecretion. ZES diagnosis was delayed a mean of 5.5 +/- 0.4 yr. Patients who were misdiagnosed as having either Crohn or celiac disease had higher BAOs. The sensitivities from our study and the literature review of the proposed BAO criteria for the diagnosis of ZES in patients without previous gastric acid-reducing surgery were 91% and 90% for BAO > or = 15 mEq/hr, 86% and 82% for BAO > or = 18 mEq/hr, 69% and 67% for BAO > 25 mEq/hr, and < 60% for BAO > 31 mEq/hr, respectively. The specificities of all the proposed BAO criteria were high. Both the criterion of BAO > or = 15 mEq/hr and BAO > or = 18 mEq/hr had good specificities and equal sensitivity. With prior acid-reducing surgery, the sensitivities in our study and from the literature review were 100% and 81% for BAO > or = 5 mEq/hr, 73% and 45% for BAO > 14.4 mEq/hr, and 37% and 31% for BAO > 19.2 mEq/hr, respectively. The reported mean specificity for the criterion of BAO > or = 5 mEq/hr was 85%, while it was 100% for the other 2 criteria. The maximal acid output (MAO) criterion of > 70 mEq/hr had sensitivities in the present National Institutes of Health (NIH) study and the literature review of 39% and 31%, respectively, and the criterion of MAO > 100 mEq/hr had a sensitivity of < 15% in patients with no prior acid-reducing surgery. The proposed criterion of BAO/MAO ratio > 0.6 had a low sensitivity. The proposed criterion of the ratio of basal and maximal acid H+ concentration (BAC/MAC ratio) > or = 0.6 had an excellent sensitivity-- > or = 89% in patients with or without previous acid-reducing surgery. The reported specificity for both the BAO/MAO criterion and the BAC/MAC criterion were similar, but BAC/MAC had a better sensitivity. Combination criteria of BAO generally did not improve sensitivity. The criterion of pH < or = 1 was met by only 27% of patients, and pH < or = 0.96 by 21% of patients with previous acid-reducing surgery. For patients with MEN1 with no prior acid-reducing surgery, the sensitivities were lower compared with patients with the sporadic form of ZES. The mean gastric volume in patients without prior acid-reducing surgery was 314 +/- 10 mL/hr and 247 +/- 25 mL/hr in patients with prior acid-reducing surgery. A basal volume criteria of > 160 mL/hr in patients without prior acid-reducing surgery occurred in > 86% of patients, and > 140 mL/hr in 87% of patients with prior acid-reducing surgery; these, thus, are neglected findings that have good sensitivities. Our analysis shows criteria based on MAO, pH, and BAO/MAO ratio do not have high sensitivities and thus are not useful. In patients without prior acid-reducing surgery, the criteria of BAO > or = 15 mEq/hr, BAC/MAC ratio > or = 0.6, and basal gastric volume > 160 mL/hr are useful for the diagnosis of ZES and have good specificities. In patients with prior acid-reducing surgery, the criteria of BAO > or = 5 mEq/hr, BAC/MAC ratio > or = 0.6, and basal gastric volume > 140 mL/hr have high sensitivities. In patients with sporadic ZES without acid-reducing surgery, the criterion of BAO > or = 18 mEq/hr is recommended as it has a similar sensitivity but higher specificity than the criterion of BAO > or = 15 mEq/hr. Only 1 patient in either data set (NIH or the literature) with or without previous acid-reducing surgery had a basal gastric pH > 2, therefore this finding essentially excludes the diagnosis of ZES. Gastric secretory measurements for 30 minutes, but not 15 minutes, give results comparable to those for a full hour. On the basis of these results, a number of gastric secretory criteria are proposed, including some for the first time, and alterations in methodology are proposed that should prove useful in the diagnosis of ZES.