Paolo L. Peghini

Ranitidine controls nocturnal gastric acid breakthrough on omeprazole: A controlled study in normal subjects

BACKGROUND & AIMS Proton pump inhibitors administered twice daily do not provide complete nocturnal acid suppression. Acid breakthrough, or decrease in intragastric pH to <4 for an hour or longer, occurs in three quarters of normal subjects and patients at night. We compared the effect of a third dose of omeprazole at bedtime with that of a dose of ranitidine at bedtime on residual nocturnal acid secretion in patients receiving omeprazole twice daily. METHODS Twelve volunteers underwent overnight intragastric pH monitoring after 7 days of treatment with omeprazole, 20 mg twice daily, followed by different treatment supplements at bedtime: placebo; additional omeprazole, 20 mg; ranitidine, 150 mg; and ranitidine, 300 mg. RESULTS Additional omeprazole at bedtime reduced the percentage of time with intragastric pH of <4 from 48% to 31% (P < 0.005) compared with omeprazole twice daily with placebo at bedtime. Ranitidine at bedtime reduced this parameter more, 5% with 150 mg and 6% with 300 mg (P <0.01 vs. omeprazole twice daily plus bedtime). Results for percentage of time with intragastric pH <3 were similar. Eleven subjects had acid breakthrough with placebo at bedtime; 7 with omeprazole at bedtime (P = NS); 4 with ranitidine, 150 mg at bedtime; and 3 with ranitidine, 300 mg at bedtime (P < 0. 05, ranitidine vs. placebo). CONCLUSIONS Bedtime ranitidine is more effective than bedtime omeprazole on residual nocturnal acid secretion in patients receiving omeprazole twice daily. This finding suggests that fasting breakthrough nocturnal acid secretion in patients receiving omeprazole twice daily is most likely histamine related.

Zollinger-Ellison syndrome. Clinical presentation in 261 patients.

We prospectively evaluated the initial presenting symptoms in 261 patients with Zollinger-Ellison syndrome (ZES) over a 25-year period. Twenty-two percent of the patients had multiple endocrine neoplasia-type 1 (MEN-1) with ZES. Mean age at onset was 41.1 +/- 0.7 years, with MEN-1 patients presenting at a younger age than those with sporadic ZES (p < 0.0001). Three percent of the patients had onset of the disease < age 20 years, and 7% > 60 years. A mean delay to diagnosis of 5.2 +/- 0.4 years occurred in all patients. A shorter duration of symptoms was noted in female patients and in patients with liver metastases. Abdominal pain and diarrhea were the most common symptoms, present in 75% and 73% of patients, respectively. Heartburn and weight loss, which were uncommonly reported in early series, were present in 44% and 17% of patients, respectively. Gastrointestinal bleeding was the initial presentation in a quarter of the patients. Patients rarely presented with only 1 symptom (11%); pain and diarrhea was the most frequent combination, occurring in 55% of patients. An important presenting sign that should suggest ZES is prominent gastric body folds, which were noted on endoscopy in 94% of patients; however, esophageal stricture and duodenal or pyloric scarring, reported in numerous case reports, were noted in only 4%-10%. Patients with MEN-1 presented less frequently with pain and bleeding and more frequently with nephrolithiasis. Comparing the clinical presentation before the introduction of histamine H2-receptor antagonists (pre-1980, n = 36), after the introduction of histamine H2-receptor antagonists (1981-1989, n = 118), and after the introduction of proton pump inhibitors (PPIs) (> 1990, n = 106) demonstrates no change in age of onset; delay in diagnosis; frequency of pain, diarrhea, weight loss; or frequency of complications of severe peptic disease (bleeding, perforations, esophageal strictures, pyloric scarring). Since the introduction of histamine H2-receptor antagonists, fewer patients had a previous history of gastric acid-reducing surgery or total gastrectomy. Only 1 patient evaluated after 1980 had a total gastrectomy, and this was done in 1977. The location of the primary tumor in general had a minimal effect on the clinical presentation, causing no effect on the age at presentation, delay in diagnosis, frequency of nephrolithiasis, or severity of disease (strictures, perforations, peptic ulcers, pyloric scarring). Disease extent had a minimal effect on symptoms, with only bleeding being more frequent in patients with localized disease. Patients with advanced disease presented at a later age and with a shorter disease history (p = 0.001), were less likely to have MEN-1 (p = 0.0087), and tended to have diarrhea more frequently (p = 0.079). A correct diagnosis of ZES was made by the referring physician initially in only 3% of the patients. The most common misdiagnosis made were idiopathic peptic ulcer disease (71%), idiopathic gastroesophageal reflux disease (GERD) (7%), and chronic idiopathic diarrhea (7%). Other less common misdiagnosis were Crohn disease (2%) and various diarrhea diseases (celiac sprue [3%], irritable bowel syndrome [3%], infectious diarrhea [2%], and lactose intolerance [1%]). Other medical disorders were present in 55% of all patients; patients with sporadic disease had fewer other medical disorders than patients with MEN-1 (45% versus 90%, p < 0.00001). Hyperparathyroidism and a previous history of kidney stones were significantly more frequent in patients with MEN-1 than in those with sporadic ZES. Pulmonary disorders and other malignancies were also more common in patients with MEN-1. These results demonstrate that abdominal pain, diarrhea, and heartburn are the most common presenting symptoms in ZES and that heartburn and diarrhea are more common than previously reported. The presence of weight loss especially with abdominal pain, diarrhea, or heartburn is an important clue suggesting the presence of gastrinoma. The presence of prominent gastric body folds, a clinical sign that has not been appreciated, is another important clue to the diagnosis of ZES. Patients with MEN-1 presented at an earlier age; however, in general, the initial symptoms were similar to patients without MEN-1. Gastrinoma extent and location have minimal effects on the clinical presentation. Overall, neither the introduction of successful antisecretory therapy nor widespread publication about ZES, attempting to increase awareness, has shortened the delay in diagnosis or reduced the incidence of patients presenting with peptic complications. The introduction of successful antisecretory therapy, however, has dramatically decreased the rate of surgery in controlling the acid secretion and likely led to patients presenting with less severe symptoms and fewer complications. (ABSTRACT TRUNCATED)

Meningiomas May Be a Component Tumor of Multiple Endocrine Neoplasia Type 1

Purpose: Recently, an increased incidence of some nonendocrine tumors are reported in patients with multiple endocrine neoplasia type 1 (MEN 1). There are rare reports of meningiomas and other central nervous system tumors in these patients, but it is unknown if they are more frequent or if allelic loss of the MEN1 gene is important in their pathogenesis. The aim of this study was to address these two latter questions. Experimental Design: Results from a prospective study of 74 MEN 1 patients with suspected/proven pancreatic endocrine tumors (PETs) were analyzed, as well as molecular studies performed on a resected meningioma. All patients had serial brain imaging studies (computed tomography, magnetic resonance imaging, and octreoscanning since 1994) and yearly studies evaluating MEN 1 involvement with a mean follow-up of 7.2 years. Results were compared with 185 patients with sporadic Zollinger-Ellison syndrome. Results: Six patients (8%) had meningiomas. Meningiomas were single and found late in the MEN 1 course (mean age = 51 years). Magnetic resonance imaging/computed tomography were more sensitive than octreoscanning. Their diagnosis averaged 18 years after the onset of hyperparathyroidism, 10–15 years after pituitary disease or PETs. Meningiomas were 11 times more frequent in patients with PETs with MEN 1 than without MEN 1 (P = 0.017). No clinical, laboratory, or MEN 1 feature distinguished patients with meningiomas. Meningiomas were asymptomatic and 60% showed no growth. A resected meningioma showed loss of heterozygosity at 11q13 and 1p, including at p73 and ARHI/NOEY2 locus, but not at the neurofibromatosis 2 gene locus. Conclusions: These results show meningiomas are not an infrequent occurrence in MEN 1, and loss of the function of the MEN1 gene product plays a role in their pathogenesis in these patients.

Prior Sensitization of Esophageal Mucosa by Acid Reflux Predisposes to Reflux-induced Chest Pain

Esophageal acid exposure is believed to be a major source of unexplained chest pain; but, individual episodes of reflux in pH study are not consistently associated with chest pain. Our aim was to discover whether prior sensitization of esophageal mucosa by acid reflux predisposes to reflux-induced chest pain. Ambulatory pH studies of patients referred to our laboratory from January 1991 to November 1996 with noncardiac chest pain was reviewed. We compared the frequency of esophageal acid exposure in the 30 minutes preceding chest pain episodes with a positive symptom/reflux association (+SRA) to reflux with the frequency of acid exposure in the 30 minutes preceding those chest pain episodes that were not associated with reflux negative symptom/reflux association (−SRA). We analyzed the time esophageal pH <4, symptom index (SI) defined as percentage of chest pain episodes associated with reflux in the preceding 5 minutes, and amount of reflux in the 30 minutes preceding each chest pain episode. Of 104 patients, 52 had chest pain during their pH study, 10 had high SI (≥50%), and 42 had low SI (<50%). Those with a high SI were significantly more likely to have an abnormal pH study (p = 0.015). Chest pain associated with reflux in proceeding 5 minutes (+SRA) was strongly associated (p < 0.002) with additional reflux episodes in the preceding 25-minute period. Chest pain related to reflux is associated with sensitization of the esophageal mucosa by prior reflux events.

Mucosal acid exposure sensitizes a subset of normal subjects to intra-oesophageal balloon distension.

Object: To assess the effect of acid infusion on the response of normal subjects to progressive intra-oesophageal balloon distension (IOBD). Methods: Twenty-one volunteers underwent slow IOBD. Subjects were asked to indicate the first perception of sensation (S1) and the onset of pain (S2), balloon volumes being recorded at both points. A 15-min infusion of 0.1 M HCl (8ml/min) was then instilled proximal to the balloon. Subjects were designated as acid-sensitive if they reported chest pain or heartburn during the acid infusion. Thereafter S1 and S2 were assessed again in the same manner. Results: Nine subjects were acid-sensitive, 12 were acid-insensitive. The subgroup of 12 acid-insensitive subjects had an increase of pain threshold after acid infusion (P<0.05), whereas the nine acid-sensitive subjects showed a decrease of pain threshold after acid infusion (P<0.05). No change of the threshold for sensation occurred in either of these groups after acid infusion. Conclusion: Individuals showing mucosal acid sensitivity have a lower threshold for mechanoreceptor stimulation after acid exposure.

CASE REPORT: Retained Gastric Antrum Syndrome

With the understanding of the role of H. pylori in causing peptic ulcer disease (PUD) and the development of potent gastric antisecretory drugs, the number of patients undergoing gastric acid-reducing surgery (vagotomy and drainage procedure, Billroth I and II resections) is decreasing rapidly (1). One of the welcome results of this decrease is that physicians see fewer patients with postgastrectomy problems. However, a negative aspect of this result is that they also are less familiar with treating such problems. Recurrent PUD after a Billroth II operation is uncommon (0.5–6%), but when it occurs it is a difficult management problem (1–3). It can be caused by an incomplete vagotomy, insufficient gastric resection, mechanical dysfunction of the stoma, the frequent use of aspirin or NSAIDS, incomplete excision of the gastric antrum from the detached duodenum (retained gastric antrum), or Zollinger-Ellison syndrome (ZES) (1–3). Even when gastric acid-reducing surgery with Billroth II resection was a frequent operation in the United States, retained gastric antrum (RGA) was an uncommon cause of recurrent postoperative ulcer (1–3). In the past this diagnosis was frequently not considered, resulting in delays of diagnosis longer than 20 years (4–8). With the decreasing frequency of gastric acid-reducing surgery and the decreased exposure most physicians will have to patients with recurrent ulcers postoperatively, it is likely in the future this diagnosis will be missed for an even longer period of time. This is unfortunate because this condition can cause repetitive ulceration with recurrent bleeding; however, if diagnosed, it is completely curable by surgical resection of the retained antrum. In this case report we describe a patient in whom the diagnosis of RGA was missed for 31 years and discuss techniques that are available that, if performed, will establish the diagnosis and lead to its cure.

Is the epidermal growth factor receptor (EGFR) overexpressed in gastrinomas

The EGFR is overexpressed in many tumors including pancreatic exocrine cancers. Whether it is overexpressed in pancreatic endocrine tumors (PETs) such as gastrinomas is unclear. In one report all gastrinomas expressed EGFR, whereas with other PETs EGFR was only rarely expressed. Because overexpression of EGFR is associated with poor prognosis in many tumors, and a proportion of gastrinomas are aggressive, the expression of EGFR may have prognostic significance. To address this question the following study was performed. Gastrinomas from 16 patients with Zollinger-Ellison syndrome were examined for EGFR expression and the expression was compared to the tumor growth. Competitive RT-PCR and immunohistochemistry were performed on 10 gastrinomas each. Paraffin-embedded sections were stained using 3 different monoclonal antibodies. Breast cancer specimens served as positive controls. mRNA levels were assessed by competitive RT-PCR with mRNA-specific primers. EGFR mRNA levels were normalized for b-actin mRNA levels and expressed as the ratio between the two. Pooled mRNA fractions from normal human pancreatic tissue were used as normal controls. Sixteen gastrinomas (6M, 10F), 14 sporadic tumors and 2 MEN-l associated gastrinomas were analyzed. The mean age of the patients was 43.6±0.4 yr [15.5-65.3). The mean fasting serum gastrin level was 5934±2018 pglml [404-26667]. The mean follow-up was 5.3±0.7 yr [0.9-11.2). Five patients had aggressive disease. All tumors expressed EGFR mRNA. The mean EGFRIb-actin ratio of the gastrinomas was lower than that of normal pancreatic tissue (0.0085±0.OO24 vs. 0.055±0.025). In none of the 10 gastrinomas did the ratio exceed that found in normal pancreas. The mean EGFRIb-actin ratio did not differ between aggressive (n=5) and benign (n=5) gastrinomas (0.040±0.035 vs. 0.0115±0.004). The EGFRIb-actin ratio did not differ between duodenal gastrinomas (n=5) and primary tumors in another location (n=4), (0.011±0.004 vs. 0.OO6±0.OO2). Immunostaining for EGFR was negative in each of the 10 tumors tested. The results show that the EGFR is expressed in all gastrinomas, however it is not overexpressed compared to normal pancreatic tissue. Furthermore its level of expression does not correlate with the aggressiveness of the tumor or with the primary location of the tumor, which has been shown to be an important determinant of metastatic potential. These results suggest that in contrast to exocrine pancreatic tumors, in PETs overexpression of EGFR is unlikely to be an important pathogenic process.