Idiopathic gastric acid hypersecretion presenting as a diarrheal disorder and mimicking both Zollinger-Ellison syndrome and Crohn's disease

Many gastric acid hypersecretory states (basal acid output of greater than 15.0 mEq/h) exist for which the etiology is known, such as Zollinger-Ellison syndrome, systemic mastocytosis, antral exclusion, antral predominant Helicobacter pylori gastritis (antral G cell hyperplasia), chronic gastric outlet obstruction, short gut syndrome and basophilic leukemias. However, many hypersecretory patients have no identified etiology for their acid hypersecretion and are designated as idiopathic gastric acid hypersecretors with a basal acid output of greater than 10 mEq/h and a normal serum gastrin level. Because of the gastric acid hypersecretion these patients also commonly have an increased frequency of stools. Idiopathic gastric acid hypersecretion represents a known cause of gastric acid hypersecretion that is far more common than Zollinger-Ellison syndrome and it has a markedly different treatment regimen and natural history. We report a case of a patient with idiopathic gastric acid hypersecretion previously misdiagnosed as having Crohn's disease because of a presenting complaint of diarrhea and mimicking Zollinger-Ellison syndrome because her fasting serum gastrin level was elevated when incorrectly measured in the presence of antisecretory treatment.     

Helicobacter pylori infection

Summary The present report describes two patients with fasting hypergastrinemia, gastric acid hypersecretion, andHelicobacter pylori gastritis. Provocative testing for Zollinger-Ellison syndrome was negative and imaging studies did not demonstrate an intra-abdominal mass. Following eradication of theHelicobacter pylori infection, the fasting hypergastrinemia resolved in both patients and in one patient the gastric acid hypersecretion also resolved. The implications of this case on the differential diagnosis of Zollinger-Ellison syndrome are discussed.     

Idiopathic gastric acid hypersecretion

Many patients with acid-peptic disease have idiopathic gastric acid hypersecretion defined as a basal acid output >10.0 meq/hr; however, a significant proportion have basal acid outputs >15.0 meq/hr, which is within the range found in Zollinger-Ellison syndrome. Although idiopathic gastric acid hypersecretion is more common than Zollinger-Ellison syndrome, it is important that these two disorders be differentiated because of differences in treatment and natural history. In the present study, we compared 124 patients with idiopathic gastric acid hypersecretion and 137 patients with Zollinger-Ellison syndrome. There were no significant differences with regard to age at diagnosis, history of upper gastrointestinal hemorrhage, nausea, vomiting, and family history of duodenal ulcer and other acid-peptic disease. However, significant differences were observed between patients with idiopathic gastric acid hypersecretion and patients with Zollinger-Ellison syndrome with regard to percentage of males: 77% compared to 64% (P=0.008), mean serum gastrin: 60 pg/ml compared to 3679 pg/ml (normal <100 pg/ml) (P<0.001), mean basal acid output: 15.4 meq/hr compared to 47.0 meq/hr (P<0.001), mean age at onset of symptoms: 33 years compared to 41 years (P<0.001), mean duration of symptoms before diagnosis: 11 years compared to five years (P<0.001), percentage with abdominal pain: 67% compared to 82% (P=0.00004), percentage with diarrhea: 12% compared to 75% (P<0.000001), percentage with pyrosis: 58% compared to 40% (P=0.003), percentage with duodenal ulcer: 53% compared to 74% (P<0.000001), and percentage with esophagitis: 31% compared to 42% (P=0.0004). The differences in clinical features could be attributed to difference in mean basal acid output, and/or differences in levels of basal acid output used for diagnosis of idiopathic gastric acid hypersecretion (basal acid output >10.0 meq/hr) and Zollinger-Ellison syndrome (basal acid output >15.0 meq/hr). When 45 patients with idiopathic gastric acid hypersecretion and 39 patients with Zollinger-Ellison syndrome with basal acid outputs 15.1–30.0 meq/hr were compared, the main significant differences were with regard to mean serum gastrin: 69 pg/ml compared to 655 pg/ml (P<0.001), percentage of male gender: 82% compared to 62% (P=0.03), and percentage with diarrhea: 16% compared to 64% (P=0.000005). These results indicate that in general patients with idiopathic gastric acid hypersecretion and patients with Zollinger-Ellison syndrome often have similar clinical features that can be difficult to distinguish. However, the increased frequency of diarrhea and female gender should lead to a strong suspicion of Zollinger-Ellison syndrome, which can be distinguished in almost every case by measurement of serum gastrin.     

Prospective study of efficacy and safety of lansoprazole in Zollinger-Ellison syndrome

Lansoprazole, a new substituted benzimidazole H⁺, K⁺-ATPase inhibitor, profoundly inhibits gastric acid secretion and has potential use in the management of diseases such as Zollinger-Ellison syndrome (ZES). In the present study we evaluated the efficacy and safety of lansoprazole in controlling acid hypersecretion in 20 patients with ZES. The starting dose was 60 mg once daily. Control of acid hypersecretion was defined as the dose required to reduce acid secretion to <10 meq/hr in the last hour before the next dose. Doses were adjusted upwards until effective control was achieved. Patients not controlled with 120 mg once daily were placed on twice daily lansoprazole. Most patients (90%) required lansoprazole once daily. During long-term follow-up (mean 18.5 months), 25% of patients required upward dose adjustments and 25% of patients required twice daily lansoprazole. Following cessation of therapy, the mean time for gastric acid output to reach half basal acid output was 39.1 hr. Lansoprazole was well-tolerated without side effects. Clinical chemistry and hematological studies were unchanged, and no gastric carcinoids developed. These results demonstrate that lansoprazole is a safe and effective inhibitor of gastric acid hypersecretion in patients with Zollinger-Ellison syndrome. Because it has a long duration of action, lansoprazole can be used to control gastric acid hypersecretion in most patients with Zollinger-Ellison syndrome using a once daily dosing schedule.     

Marked hypergastrinemia in gastric outlet obstruction

We report a 45-year-old woman with chronic peptic ulcer disease and multiple episodes of bowel obstruction, who was admitted with gastric outlet obstruction. Because of gastric hypersecretion, a diagnosis of Zollinger-Ellison syndrome was suspected and an initial serum gastrin of 1,251 pg/ml supported this diagnosis. Subsequent evaluation failed to reveal a gastrinoma. A repeat serum gastrin level after 14 days of continuous nasogastric decompression was 43 pg/ml, suggesting that the initial hypergastrinemia was due to antral distention. It is important to consider the possibility of gastric outlet obstruction as a stimulus for serum gastrins in the range previously considered diagnostic for the Zollinger-Ellison syndrome.     

Proteinlosing gastropathy with gastric hypersecretion of acid (H+) and pepsin and hypergastrinemia. A case report.

A case with proteinlosing gastropathy with gastric hypersecretion of H+ and pepsin as well as hypergastrinemia is presented. Zollinger-Ellison syndrome was excluded by reduction in acid secretion and serum gastrin during the observation period as well as by the effect on gastric secretion and serum gastrin after injections of secretin and glucagon.     

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.     

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.     

Zollinger-Ellison syndrome. Recent advances in the management of the gastrinoma

Because of increasingly effective oral antisecretory agents, gastric acid hypersecretion is now able to be controlled in all patients with Zollinger-Ellison syndrome with the result that the natural history of the gastrinoma is becoming the major determinant of long-term survival. In this article recent advances in the management of the gastrinoma itself are reviewed, including results with new modalities such as intraoperative ultrasound, MRI, and selective gastrin sampling to localize gastrinoma in patients with Zollinger-Ellison syndrome, as well as recent results of the treatment of metastatic and localized gastrinomas.     

Misdiagnosis of the Zollinger-Ellison syndrome due to hyperlipidemia

Most authorities feel that diagnosis of the Zollinger-Ellison syndrome is established when the serum gastrin level is greater than 1000 pg/mL (1000 ng/L) in a patient with gastric acid hypersecretion and clinical manifestations consistent with the diagnosis. A patient with recurrent peptic ulcer disease is reported who was thought to have had the Zollinger-Ellison syndrome based on two serum gastrin level measurements greater than 1000 pg/mL (1000 ng/L). Subsequent evaluation revealed the gastrin elevation to be spurious because the sample was hyperlipidemic. Lipemic serum samples may yield falsely elevated serum gastrin determinations as determined by radioimmunoassay.     

Peptic ulcer perforation as the presentation of Zollinger-Ellison syndrome

We examined the characteristics of patients with Zollinger-Ellison syndrome who developed a perforation prior to diagnosis to determine whether any clinical features were useful markers of the syndrome. Of 160 patients with Zollinger-Ellison syndrome, perforation occurred prior to the diagnosis being made in 11 (7%). At surgery, perforations were found in the duodenum in six cases and in the jejunum in five. In no case was tumor identified at emergency surgery, and the diagnosis of Zollinger-Ellison syndrome was made only in the postoperative period when excessive gastric secretions were noted. Neither acid output nor serum gastrin concentration were useful predictors for perforation. The patients, six men and five women, were 27–61 years old (median 48) and one had MEN-1. Three patients had no symptoms prior to the perforation. The other eight had symptoms for 1–15 years, with diarrhea occurring in 45% of the cases. Following the diagnosis of Zollinger-Ellison syndrome, patients were given medication to control gastric acid hypersecretion. Eight patients remained well, but the three patients who had had a partial gastrectomy had a complicated course despite medical therapy. Although features of perforation in Zollinger-Ellison syndrome are not specific, jejunal perforation or perforation associated with a history of diarrhea is suggestive of the diagnosis. Serum gastrin should be measured in every case and a partial gastrectomy avoided.     

Clinical recovery owing to target parietal cell failure in a patient with Zollinger-Ellison syndrome.

A patient is presented with Zollinger-Ellison syndrome, in whom spontaneous disappearance of gastric hypersecretion and peptic ulcer disease occurred subsequent to an intercurrent illness causing acute nonspecific inflammation of the gastric mucosal lining. The dramatic clinical improvement after subsiding of the intercurrent illness was obviously linked to pronounced failure of the parietal cell mass for acid secretion and not to infarction of the gastrinoma because gastrin secretion by the tumor was unchanged.     

Zollinger-Ellison phenotype in the absence of hypergastrinemia and islet-cell tumor

Patients with the Zollinger-Ellison syndrome are characterized by islet-cell tumors, striking gastric acid hypersecretion, and peptic ulcer disease. They often experience severe abdominal pain, diarrhea, and gastrointestinal bleeding with potentially life-threatening consequences. It is a rare syndrome caused by nonbeta cell islet-cell tumors (gastrinomas) located in or in proximity to the pancreas. These tumors freely secrete gastrin, a peptide hormone that serves as a powerful stimulant of gastric acid secretion. Exuberant secretion of gastrin from the gastrinomas produces severe gastric acid hypersecretion that often leads to impressive peptic ulcer disease and the constellation of symptoms listed above. We describe a patient presenting with clinical manifestations characteristic of the ZES with strikingly elevated gastric acid secretion, multiple ulcers in the first and second portions of the duodenum and diarrhea, but in absence of islet-cell tumor and/or hypergastrinemia.     

Recent advances in the management of gastric acid hypersecretion in patients with Zollinger-Ellison syndrome

Several histamine H2 receptor antagonists and the H+,K(+)-ATPase inhibitor, omeprazole, have been shown to be capable of controlling gastric acid secretion safely and effectively in patients with Zollinger-Ellison syndrome. The relative merits of these agents are discussed, and their use in the acute and long-term control of acid hypersecretion and in special circumstances that require particular care are described. The surgical approaches to the control of acid secretion are described, and the current place of surgery in the management of acid hypersecretion is discussed.     

Reliability of symptoms in assessing control of gastric acid secretion in patients with Zollinger-Ellison syndrome

In the present study we explored whether the presence or absence of symptoms could provide a reliable way of assessing the adequacy of control of gastric secretion in patients with Zollinger-Ellison syndrome who were treated medically. Over a 5-yr period, 26 Zollinger-Ellison syndrome patients were entered into a prospective study which examined the presence or absence of symptoms that are associated with gastric hypersecretion, the presence of absence of upper gastrointestinal pathology, and the degree of control of gastric acid secretion. During their last admission, 15 of the 26 patients (58%) were symptomatic, but post-drug gastric acid secretion for the 2 h before the next dose of medication was not significantly different from that in asymptomatic patients. This lack of correlation between the presence or absence of symptoms and post-drug gastric acid secretion was evident for the group as a whole, as well as for 8 to 12 patients who underwent multiple admissions. Of 23 patients who underwent upper gastrointestinal endoscopy of x-ray, or both, on their last admission, 12 had pathology. Post-drug gastric acid secretion was less in patients without pathology than in those with pathology. Furthermore, in patients in whom post-drug gastric acid secretion was less than or equal to 10 mEq/h, the criterion of acceptable control used in this study, pathology did not occur. These findings demonstrate that the presence or absence of symptoms cannot be used to assess the adequacy of medical control of gastric acid secretion in patients with Zollinger-Ellison syndrome. In our opinion, maintenance of post-drug gastric acid secretion less than or equal to 10 mEq/h for the 2 h before the next dose of medication is an acceptable criterion for long-term control of gastric secretion in patients with Zollinger-Ellison syndrome.     

Current concepts on physiological control of gastric acid secretion. Clinical applications.

Gastric acid secretion by the parietal cell is a single digestive process involving a continuous interplay between nervous and hormonal stimuli. Gastric acid hypersecretion and hypergastrinemia may represent pathologic disturbance of the normal "gastric phase" of acid secretion (excluded antrum syndrome) or abnormal gastrin secretion from a nongastric source as in the Zollinger-Ellison syndrome. Diagnosis of these two syndromes preoperatively is dependent on immunoassay for serum gastrin. A fall in serum gastrin level after the injection of secretin will distinguish the excluded antrum syndrome from the Zollinger-Ellison syndrome. Which hormone or hormones cause the acid hyposecretion of the watery diarrhea hypokalemia achlorhydria syndrome is still uncertain. Potential candidates include secretin, glucagon (alone or combined with gastrin), vasoactive intestinal peptide and gastric inhibitory polypeptide. Secretin has undergone trials as therapy in peptic ulcer whereas glucagon is under investigation for the treatment of acute pancreatitis because of its dual actions as (1) an enterogastrone and (2) an inhibitor of pancreatic secretion.     

Development of sustained achlorhydria in a patient with the Zollinger-Ellison syndrome treated with omeprazole.

Spontaneous remission of gastric acid hypersecretion in the Zollinger-Ellison syndrome occurs rarely. This study shows the development of gastric secretory mucosal atrophy resulting in achlorhydria and loss of pepsin secretion in a 63-year-old woman with the Zollinger-Ellison syndrome. Reduced secretion began soon after starting treatment with omeprazole, and achlorhydria became complete 6 months later. The patient remains well with normal endoscopy results and is achlorhydric 4 years after the start of treatment and 34 months after stopping omeprazole. She was not colonized with Helicobacter pylori until 36 months after developing achlorhydria. Serum gastrin has increased from 1000 to between 5000 and 12,500 ng/L (pg/mL), was not suppressible by gastric acidification, and was not associated with G-cell hyperplasia. She also has a normal Schilling test and normal immunoglobulins, and lacks antibodies to parietal cells or H+, K(+)-ATPase. Moderate enterochromaffinlike cell hyperplasia is apparent for the first time on the latest biopsy sample.     

Failure of cimetidine in Zollinger-Ellison syndrome

Both the pharmacokinetics and the pharmacodynamics of cimetidine were investigated in three patients with Zollinger-Ellison syndrome, who were unresponsive to conventional dosing regimens. Doses employed in these patients ranged from 2400 to 5400 mg daily. The poor response to oral cimetidine, as measured by acid secretion and gastric pH, was associated with subtherapeutic and unreliable cimetidine serum concentrations. The response to intravenous cimetidine was only a transient suppression of gastric secretion. The failure of cimetidine to control gastric hypersecretion in these patients was attributed to both a diminished oral bioavailability and a decreased pharmacologic response to the drug.     

Famotidine, a new, potent, long-acting histamine H2-receptor antagonist: comparison with cimetidine and ranitidine in the treatment of Zollinger-Ellison syndrome

Famotidine, a new, potent, long-acting histamine H2-receptor antagonist was compared with cimetidine and ranitidine in 9 patients with Zollinger-Ellison syndrome. The mean minimum daily requirement of famotidine to control gastric acid hypersecretion was 0.24 g (range 0.08-0.48 g) compared with 2.1 g (range 0.6-3.6 g) for ranitidine and 7.8 g (range 1.2-13.2 g) for cimetidine. Equally potent doses of the three drugs had similar onsets of action, but the duration of action of famotidine was 30% longer than the duration of action of either ranitidine or cimetidine (p less than 0.05). Eight patients were treated for up to 9 mo (mean 6 mo) with good control of gastric acid hypersecretion and with no evidence of biochemical or hematologic toxicity. These studies demonstrate that famotidine is nine times more potent than ranitidine and 32 times more potent than cimetidine, has a longer duration of action than ranitidine or cimetidine, and is both safe and effective in the long-term therapy of Zollinger-Ellison syndrome.     

Intravenous omeprazole in patients with Zollinger-Ellison syndrome undergoing surgery

Twenty patients with Zollinger-Ellison syndrome who were undergoing surgery were studied prospectively to assess the efficacy and safety of IV omeprazole. During the preoperative period, in 19 of 20 patients, omeprazole 60 mg administered as an IV bolus every 12 hours inhibited acid output to less than 5 mEq/h measured in the last hour before the next dose of drug. In one patient, acid output was 25 mEq/h 12 hours after omeprazole, 60 mg, and increasing the dose to 100 mg every 12 hours reduced acid output to less than 5 mEq/h. During the operative and postoperative periods, IV omeprazole controlled gastric acid hypersecretion in all patients for up to 15 days. During this time, all patients received the dose determined preoperatively. No patient developed any clinical, hematological, or biochemical toxicity that could be attributed to omeprazole therapy during the preoperative or postoperative period. The present study demonstrates that omeprazole administered by IV bolus is safe and effective for controlling gastric acid hypersecretion. In contrast to IV histamine H2-receptor antagonists, IV omeprazole has the advantages of not requiring continuous infusion or postoperative dose adjustments. Intravenous omeprazole will become the drug of choice in patients with Zollinger-Ellison syndrome undergoing surgery.