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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-1349
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 1 204-212
Copyright © 2006 by The Endocrine Society

Patients with Multiple Endocrine Neoplasia Type 1 with Gastrinomas Have an Increased Risk of Severe Esophageal Disease Including Stricture and the Premalignant Condition, Barrett’s Esophagus

K. Martin Hoffmann, Fathia Gibril, Laurence K. Entsuah, Jose Serrano and Robert T. Jensen

Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1804

Address all correspondence and requests for reprints to: Dr. R. T. Jensen, Digestive National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases/Digestive Diseases Branch, Building 10, Room 9C-103, 10 Center Drive MSC 1804, Bethesda, Maryland 20892-1804. E-mail: robertj{at}bdg10.niddk.nih.gov.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Multiple endocrine neoplasia type 1 (MEN1) patients frequently develop Zollinger-Ellison syndrome (MEN1/ZES). Although esophageal reflux symptoms are common in these patients, little is known about long-term occurrence of severe peptic esophageal disease including strictures and Barrett’s esophagus (BE).

Objective: The objective of the study was to prospectively analyze the frequency of severe peptic esophageal disease in ZES patients with and without MEN1.

Setting: The study was conducted at a tertiary care research center.

Patients: Two hundred ninety-five patients (80 = MEN1/ZES, 215 = sporadic ZES) participated in a prospective study.

Interventions and Outcome Measures: Assessment of MEN1, acid hypersecretion, upper gastrointestinal endoscopy/biopsies, and tumor status were measured initially and at each follow-up. Esophageal manometry was performed in 89 patients. Frequency and type of esophageal disease were correlated with clinical/laboratory/tumoral features of ZES/MEN1.

Results: In MEN1/ZES patients, esophageal stricture was 3-fold higher, BE 5-fold higher, and dysplasia 8-fold higher, and one patient died of esophageal adenocarcinoma. Esophageal symptoms were more frequent or severe in MEN1/ZES, but known risk factors for severe esophageal disease and ZES-specific features did not differ between MEN1/ZES and sporadic ZES. In MEN1/ZES, the onset of ZES was 10 yr earlier, and H2-antagonists were used longer and at lower doses. MEN1/ZES patients with esophageal disease differed from those without in that ZES diagnosis was delayed longer, esophageal symptoms were more frequent or severe, hiatal hernias were more frequent, esophagitis or pyloric scarring was more common, basal acid output was higher, and hyperparathyroidism was underdiagnosed.

Conclusions: This study shows that MEN1/ZES patients have a higher incidence of severe esophageal disease including the premalignant condition BE and identifies factors important for their pathogenesis that need to be incorporated into their long-term treatment.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
GASTRINOMAS ARE THE most common, symptomatic pancreatic endocrine tumor (PET) in multiple endocrine neoplasia type 1 (MEN1) (1, 2, 3). Gastrinomas are increasingly determining the long-term survival in MEN1 (3). The presence of gastrinomas present two management problems including Zollinger-Ellison syndrome (ZES) with gastric acid hypersecretion leading to peptic complications as well as growth of the gastrinoma (2, 3, 4, 5, 6, 7, 8). Unlike patients with sporadic ZES, most MEN1/ZES patients cannot be cured (3, 5, 6, 9, 10, 11) and face life-long acid hypersecretion and the possible consequences of gastrinoma growth. In MEN1/ZES, treatment of the acid hypersecretion is frequently complicated by hypercalcemia due to hyperparathyroidism (HPT), which affects acid secretory rates, sensitivity to antisecretory drugs, and gastroesophageal motility (3, 10, 12, 13). Whereas there are numerous studies in MEN1/ZES on the natural history of the gastrinoma and the possible effect of surgery (5, 9, 14, 15) as well as on advances in the acute treatment of acid hypersecretion preventing morbidity/mortality due to peptic complications (3, 16), there is little information on the long-term effects of gastric acid hypersecretion.

The chronic effects of acid hypersecretion on the esophagus are frequently the most difficult to treat (17, 18, 19, 20, 21) and can result in important complications that can be life threatening (20, 21, 22). Chronic acid hypersecretion increases the occurrence and severity of gastroesophageal reflux disease (GERD), which can lead to not only the development of esophageal strictures but also the premalignant condition, Barrett’s esophagus, which is associated with an increased risk of esophageal adenocarcinoma (23, 24, 25). There are isolated reports of esophageal strictures and Barrett’s disease, as well as esophageal adenocarcinoma, in ZES patients with and without MEN1 (8, 17, 19, 20, 22, 26, 27, 28, 29). Recent studies report significant differences in clinical, laboratory, and natural history of ZES as well as gastrinoma behavior between ZES patients with or without MEN1 (3, 8). However, whether development of severe peptic esophageal disease is more frequent in MEN1/ZES, compared with sporadic ZES patients, is presently unknown. To address this question, in this study we analyzed the frequency and characteristics of severe esophageal disease in ZES patients with or without MEN1 in patients followed up in a large prospective study.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients and general methods

This study is part of the ongoing prospective study of patients with ZES since 1974 at the National Institutes of Health (NIH) and approved by the Clinical Research Committee of the National Institute of Diabetes and Digestive and Kidney Diseases, NIH. Three hundred nine consecutive patients with ZES with or without MEN1 were considered for the present study (89 with MEN1/ZES).

The diagnosis of ZES was established (2, 30) by determining fasting serum gastrin levels and basal (BAO) and maximal acid output (MAO) and performing secretin and calcium provocative tests (30). The diagnostic criteria for MEN1 in a patient with ZES have been described previously (2, 31) and included a family history compatible with MEN1 or a combination of clinical and biochemical evidence of primary HPT, pituitary disease, and positive genetic testing for MEN1 with ZES.

Specific protocol

Eligibility for the current study was determined by the presence of ZES, consent for upper gastrointestinal (UGI) endoscopy and follow-up studies. A total of 295 of the eligible 309 patients were included. Fourteen patients (five sporadic ZES, nine MEN1/ZES) were not entered because they did not complete the required studies. At an initial NIH visit, a detailed medical history with emphasis on UGI symptoms and symptoms compatible with MEN1 was taken (2, 8, 31). The onset of MEN1 was the time of the first clinical manifestation of MEN1 or the time MEN1 was detected by biochemical screening (2). Time of HPT onset was the time of first biochemical evidence of hypercalcemia; detection of elevated PTH; or, if none of these tests was performed, first renal colic (2). At the initial NIH evaluation, imaging studies (computed tomography scan, magnetic resonance imaging scan, sonography) were performed to assess tumor location/extent (32, 33). If results were unclear, selective abdominal angiography was performed (34). Since 1994 patients underwent somatostatin receptor scintigraphy (32, 35, 36). All patients underwent a detailed evaluation to determine the possible presence and extent of MEN1 involvement (2, 4, 31, 35, 37). Briefly, this included a review of the personal and family history for MEN1-related symptoms, laboratory studies to assess the possible presence of hormonal overactivity (parathyroid, pituitary, adrenal, pancreas), and imaging/endoscopy studies for possible tumors/adenomas (35, 37). Gastric carcinoids were detected endoscopically and confirmed by histological examination (38). Thymic and bronchial carcinoids were detected by computed tomography, somatostatin receptor scintigraphy, and/or magnetic resonance imaging scans and confirmed by thoracotomy (2, 35). Patients without MEN1, advanced liver metastases, or severe concomitant medical conditions underwent surgery for attempted cure (5, 9). Patients with MEN1/ZES had surgery only if tumor size was larger than 2.5 cm (5, 9, 39).

At the initial visit, acid secretory studies (BAO, MAO) were performed off antisecretory medications (2, 7). Acid hypersecretion was controlled by histamine H2-receptor antagonists (before 1985) (40, 41) or proton pump inhibitors (PPIs) since 1995 (16). Sufficient drug was given to reduce acid hypersecretion to less than 10 mEq/h in the hour before the next dose of medication or less than 5 mEq/h in patients with previous gastric surgery/severe GERD (17, 41, 42, 43).

After the initial evaluation, patients underwent regular evaluations (1–3 yr) including imaging studies, assessments of disease status or MEN1 abnormalities, UGI endoscopy, and acid control (2, 5, 9, 35, 38, 44). UGI endoscopy was performed using a videoscope (GIF100 endoscope; Olympus America, Inc., Melville, NY) (since 1990) and before 1990 using Olympus 2T or Fujinon (Wayne, NJ) FP endoscopes (38, 43, 45). Patients underwent esophageal biopsies if there was macroscopic evidence of columnar-lined esophagus. Barrett’s esophagus was diagnosed as abnormal-appearing esophageal mucosa proximal to the gastroesophageal junction, with intestinal metaplasia confirmed histologically (45, 46). Intestinal metaplasia was defined by the presence of columnar epithelium with a villiform surface, mucous glands, and goblet cells. The length of the Barrett’s segment was measured as described previously (47) and was stratified into long segment (≥3 cm) and short segment (<3 cm) (46). To search for dysplastic mucosa in patients with possible Barrett’s, four quadrant biopsies were performed at intervals of 1 cm until normal-appearing mucosa was reached. Dysplastic Barrett’s esophagus was graded as low grade or high grade (24). Esophagitis was diagnosed and graded endoscopically and defined as the presence of erythema, erosion, or ulceration in the tubular esophagus (45, 48, 49).

Lower esophageal sphincter (LES) pressure measurements were performed in 89 patients using an MMS 100 (Narco Bio-Systems, Houston, TX) with a standard 8-port, water-perfused catheter and slow pull-through method as described previously (45). Esophageal motility was determined to be normal in the absence of achalasia, hypotensive or hypertensive LES, and diffuse esophageal spasms (45).

Statistical analysis

Analysis was performed using the Mann-Whitney U test and the {chi}2 test or Fisher’s exact test. P < 0.05 was considered significant. All continuous variables are expressed in mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Eighty patients (27%) had ZES/MEN1, whereas 215 (73%) had sporadic ZES. Similar to other large series of ZES patients with or without MEN1 (2, 3, 8), the majority were Caucasian. There was a delay in diagnosis of the ZES of 6 yr, and the most common presenting symptoms of ZES were abdominal pain and diarrhea. The mean BAO value was more than four times elevated, the fasting serum gastrin level was more than 6-fold increased, and the majority of patients (70–75%) had localized disease at presentation (Table 1Go). Patients with MEN1/ZES differed from patients with sporadic ZES in showing a female predominance (P = 0.0041), being younger at both the age of onset of ZES and their first NIH visit (P < 0.001), having a longer duration of treatment with H2-receptor antagonists (P = 0.007), and having been treated with a lower mean H2-receptor antagonist dosage (P = 0.006) at presentation at NIH (Table 1Go). Although the PPI dose did not differ significantly at the initial presentation between the two groups, MEN1/ZES patients required significantly higher PPI doses at follow-up (P = 0.004) (Table 1Go). There was no significant difference in other demographic features, clinical or treatment aspects, tumor extent, or acid secretory rates (Table 1Go).


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  		TABLE 1. Demographic and clinical characteristics of patients studied with ZES with or without MEN1

 
Whereas an equal percentage of patients with MEN1/ZES or sporadic ZES gave a history of any heartburn during the previous month (58 vs. 51%), daily occurrence was almost twice as frequent in MEN1/ZES patients (P = 0.0096) (Table 2Go). Furthermore, dysphagia was three times more frequent in MEN1/ZES patients (P = 0.049). Barrett’s esophagus was more than five times more frequent in MEN1/ZES (Table 2Go), occurring in 14 of 80 MEN1/ZES patients (18%) and seven patients (3%) with sporadic ZES (P < 0.00001) (Table 2Go). Short-segment Barrett’s was more frequent than long-segment Barrett’s in patients with MEN1/ZES. Dysplasia occurred in three patients (4%) in the MEN1/ZES group, which was greater (P = 0.03) than the 0.5% of patients with sporadic ZES with dysplasia (Table 2Go). One MEN1 patient developed esophageal adenocarcinoma, whereas in the sporadic ZES group, no patients developed this cancer (Fig. 1Go). The adenocarcinoma was found at the time of surveillance for high-grade dysplasia and led to the patient’s death. Peptic stricture of the esophagus was 3-fold higher in MEN1/ZES (15 vs. 5%, P = 0.0027) (Table 2Go). The stricture length or the age at stricture diagnosis did not differ between the two groups of ZES patients. Either esophageal stricture or Barrett’s esophagus was four times as frequent in patients with MEN1/ZES (28 vs. 7%, P < 0.00001). At UGI endoscopy there was no difference in the frequency/length of hiatal hernias or the frequency of esophagitis between the two groups of ZES patients. During follow-up gastric antisecretory drug doses were increased to control GERD symptoms and acid hypersecretion as described previously (17, 18, 45), resulting in a decrease of the frequency of esophagitis to less than 1% of patients during follow-up. However, the frequency of Barrett’s did not change. A subset of 89 patients underwent esophageal manometry. All of these patients had normal motility, and there was no difference in LES pressures between sporadic ZES and MEN1/ZES patients (Table 2Go).


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  		TABLE 2. Comparison of esophageal findings of patients with ZES with or without MEN1 syndrome

 


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  		FIG. 1. Esophageal endoscopic findings in two MEN1/ZES1 patients presenting at different stages of Barrett’s disease. Upper panel, Mucosal changes characteristic for long-segment Barrett’s esophagus. Normal squamous esophageal epithelium is replaced by metaplastic epithelium (arrow). Diagnosis was established by verifying intestinal columnar metaplasia histologically without dysplasia. Lower panel, Irregular polypoid lesions occurring within a section of Barrett’s esophagus (arrows). Histological examination showed Barrett’s esophagus with high-grade dysplasia and the presence of invasive adenocarcinoma of the esophagus. T, Tumor.

 
In MEN1/ZES patients, there was a mean delay of 10 yr from the onset of MEN1 symptoms to diagnosis. All but one patient (99%) had HPT in addition to ZES, with 61% having pituitary disease, 49% adrenal disease, and 38% other carcinoid tumors. All but four patients underwent a parathyroidectomy at a mean age of 36.2 yr (Table 3Go). In almost 40% of the patients, symptoms due to ZES were the initial manifestation of MEN1, which is similar to results in some (2, 31) but not other series (2). Except for MEN1 features related to HPT, none of the MEN1-related characteristics differed between MEN1/ZES patients with or without Barrett’s esophagus and/or stricture. Aspects of HPT differed in MEN1/ZES patients with or without esophageal disease in a number of ways. First, fewer patients with MEN1/ZES in the Barrett’s/stricture group had HPT diagnosed before the first NIH visit (P = 0.018). Second, there were fewer parathyroidectomies performed in the Barrett’s/stricture group (P = 0.0011). Third, fewer MEN1/ZES patients in the Barrett’s/stricture group had HPT diagnosed before the diagnosis of ZES (P = 0.034) (Table 3Go).


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  		TABLE 3. Comparison of features in MEN1/ZES patients with or without Barrett’s and/or stricture

 
The MEN1/ZES patients with Barrett’s/stricture more frequently were male (P = 0.041) and had heartburn (P < 0.001), dysphagia (P = 0.0014), larger hiatal hernias (P = 0.037), esophagitis (P < 0.00001), and had a higher BAO (P = 0.03) (Table 4Go). Patients with Barrett’s esophagus with MEN1/ZES had twice as long a delay in diagnosis of ZES than those without Barrett’s with MEN1/ZES (P = 0.018) and more frequently had heartburn (P < 0.01) and a larger hiatal hernia (P = 0.043) and previously had antireflux surgery (P = 0.029). MEN1/ZES patients with esophageal stricture were older (P = 0.033) at the time of onset of ZES than MEN1/ZES patients without stricture (Table 4Go) as well as more frequently having heartburn (P < 0.00001), dysphagia (P < 0.00001), or esophagitis (P < 0.0001) (Table 4Go). Neither other endoscopic findings (hiatal hernia, pyloric scarring) nor LES pressure differed between patients either with or without Barrett’s esophagus/stricture (Table 4Go). Other clinical, laboratory, tumoral features, or treatment aspects did not differ in MEN1/ZES patients either with or without Barrett’s or stricture (Table 4Go).


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  		TABLE 4. Comparison of clinical and laboratory features in patients with MEN1/ZES with or without Barrett’s or esophageal stricture

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
In the present study, we compared esophageal disease in ZES patients with or without MEN1. Patients with MEN1 develop PETs (38–100%), parathyroid hyperplasia (83–100%), pituitary adenomas (18–65%), adrenal adenomas (11–37%), skin tumors (64–88%) (1), smooth muscle and central nervous system tumors (1, 37), and carcinoids (bronchial/gastric/thymic) (1, 2, 35, 38, 50). The most common functional PET is gastrinomas, occurring in 21–70% (1, 2, 3, 9, 14). In the past, complications from the acid hypersecretion were a major cause of death in MEN1/ZES patients (3). However, with the development of effective antisecretory medications, its acute life-threatening complications can be controlled (3). In MEN1/ZES patients, one area that has not been studied and could have a long-term effect on morbidity/mortality is the possible complications of chronic acid hypersecretion, especially on producing esophageal disease. Chronic acid exposure of the esophagus is an important causative factor of peptic-related esophageal disease including esophagitis; strictures; and the premalignant condition, Barrett’s esophagus (1, 24, 47, 48, 51). One study in ZES reported a low prevalence of Barrett’s disease (45); however, few MEN1/ZES patients were included. Numerous studies show MEN1/ZES patients differ from sporadic ZES patients in many features of ZES (3, 6, 8). There are a number of case reports of patients with MEN1/ZES developing esophageal disease due to peptic disease including Barrett’s and strictures (8, 17, 19, 20, 21, 27, 28, 29, 52, 53); however, the frequency of these complications as well as whether MEN1/ZES patients are at increased risk are unknown. Therefore, in this study we assessed the occurrence and severity of severe esophageal disease in a group of patients prospectively followed up with MEN1/ZES or sporadic ZES.

A number of our findings support the conclusion that severe esophageal disease is more frequent in MEN1/ZES than in patients with sporadic ZES. First, esophageal strictures were three times more common in MEN1/ZES patients. Second, Barrett’s esophagus was six times as frequent in MEN1/ZES patients. Third, dysplasia in Barrett’s esophagus, a condition that is associated with a 30- to 60-fold increased risk of developing esophageal adenocarcinoma (23, 24), occurred more frequently in MEN1/ZES patients. This fact was also highlighted by one patient with MEN1/ZES who developed high-grade dysplasia with Barrett’s and died from an esophageal adenocarcinoma, whereas in the 215 patients with sporadic ZES no patient developed cancer. Fourth, MEN1/ZES patients more frequently had daily heartburn and dysphagia. Whereas each of the above findings support the conclusion that peptic esophageal disease was more severe in patients with MEN1/ZES, it could be argued that our finding of a similar frequency of esophagitis in patients with MEN1/ZES or sporadic ZES is not consistent with this conclusion. However, a previous study (45) in ZES patients at NIH did not show a positive correlation between GERD symptom severity and the degree of esophagitis at the initial NIH evaluation. This likely occurred because to evaluate acid secretion during their NIH initial visit (6, 7, 45), most patients (>90%) were receiving antisecretory treatment at the time of the NIH endoscopic evaluation, which was different from the regimen the patient was maintained on before referral. Therefore, the frequency and severity of the esophagitis found at NIH were primarily determined by the adequacy of this antisecretory treatment and did not reflect the result of the antisecretory regimen the patient was maintained on before referral (17).

In patients without MEN1 or ZES, various clinical (presence/severity/duration of heartburn) (47, 48, 54, 55), demographic (race, gender, age) (47, 56, 57), anatomical (presence/size of hiatal hernia) (54, 55, 58, 59), and manometric (LES basal pressure, motility abnormalities) (51, 55, 60) factors are associated with an increased occurrence and/or severity of Barrett’s esophagus. Furthermore, in ZES (7), adequacy of acid treatment could be an important variable (17). We found that patients with MEN1/ZES had a higher frequency of severe heartburn with twice as many having daily symptoms of GERD. Furthermore, ZES developed 10 yr earlier than in sporadic ZES patients. These results suggest a longer duration and severity of uncontrolled GERD was contributing to the increase in esophageal complications in MEN1/ZES patients. This increased occurrence of GERD symptoms was not due to greater acid secretory rates in MEN1/ZES patients. In terms of demographic factors, race was not an important factor in the development of Barrett’s/stricture in MEN1/ZES patients, in contrast to various studies that show a Caucasian predominance in patients without MEN1 or ZES (56, 57). Furthermore, female gender was more frequent in MEN1/ZES patients who had a higher rate of Barrett’s disease, which is the opposite of what is reported in studies of patients without MEN1 or ZES (47, 56, 57). For anatomical features frequently associated with the development of Barrett’s disease in patients without MEN1 or ZES (54, 55, 58, 59), neither the presence nor length of a hiatal hernia was different between MEN1/ZES and sporadic ZES patients. Similarly, manometrical features, which are frequently altered in patients without MEN1 or ZES with Barrett’s disease (51, 55, 60), were not different.

The above results show a marked difference in ZES patients in the importance of various clinical, demographic, anatomical, and manometric findings, compared with studies in patients without MEN1 or ZES, demonstrating that the important factors contributing to the development of Barrett’s disease in patients with MEN1/ZES and sporadic ZES are different from that of patients without MEN1 or ZES. Patients with MEN1/ZES received lower antisecretory drug doses of H2-receptor antagonists, whereas the mean PPI doses were comparable in both groups at initial presentation. Previous studies show that MEN1/ZES patients need higher doses of antisecretory drugs to control their acid hypersecretion (10, 18), suggesting that the MEN1/ZES patients were being undertreated with PPIs as well as H2-receptor antagonists. This conclusion is supported by a number of findings in our study. During the subsequent follow-up at NIH, the MEN1/ZES patients required significantly higher doses of PPIs to control their acid hypersecretion than patients with sporadic ZES. The increased frequency and severity of GERD symptoms in MEN1/ZES patients demonstrated they were more frequently receiving insufficient doses of antisecretory drugs. This is consistent with our finding that MEN1/ZES patients had a significantly longer period of time during the course of their ZES when they were treated exclusively with H2-receptor antagonists. H2-receptor antagonists have been shown to be suboptimal in acid control treatment, compared with PPIs in ZES patients (16, 41). ZES patients receiving histamine H2-receptor antagonists therefore likely had higher and more frequent acid exposure of the esophagus, compared with patients who received PPI therapy (17, 18).

Except for MEN1 features related to HPT, no feature of MEN1 differed between MEN1/ZES patients with or without esophageal disease. Significantly fewer patients with esophageal disease had a diagnosis of HPT before the first NIH visit, there were fewer parathyroidectomies performed in this group, and fewer patients had HPT diagnosed before the first symptoms of ZES, even though an equal percentage of both groups developed HPT. These results suggest that HPT was underdiagnosed and inadequately treated in a larger proportion of patients with MEN1/ZES who developed severe esophageal disease. It is known that hypercalcemia can interfere with antisecretory drug treatment by both increasing acid secretory rate and antisecretory drug resistance (3, 6, 10, 11) and can alter esophageal motility and decrease LES pressure (12, 13), which could contribute to increased esophageal reflux. Thus, the resulting higher serum calcium levels could have contributed to a higher incidence of acid-related esophageal disease in this group. The findings of a higher BAO, more severe GERD, and presence of more complications of peptic disease all support the conclusion that patients with MEN1/ZES with esophageal disease had greater acid secretory drive that was not as well controlled as in the patients with MEN1/ZES without esophageal disease. These results suggest that the degree of control of acid hypersecretion is the primary risk factor for the development of severe esophageal disease in MEN1/ZES patients.

In conclusion, we found a higher frequency of severe esophageal disease including the presence of the premalignant condition Barrett’s esophagus and strictures in ZES patients with MEN1, compared with patients with sporadic ZES. This is likely due to a combination of factors specific for the course of ZES in MEN1 patients including an onset of ZES that was 10 yr earlier in MEN1 patients and a number of factors leading to inadequate control of acid hypersecretion. These include a longer period of time in which MEN1/ZES patients were treated with histamine H2-antagonists; lower doses of some antisecretory drugs; and underdiagnosed HPT leading to undertreatment of the hypercalcemia due to the HPT, possibly resulting in a higher acid secretory drive in some MEN1/ZES patients.

These findings have important implications for the clinical management of MEN1 patients, especially those with ZES. First, in MEN1 patients, it is essential to diagnose ZES as early as possible so that gastric acid hypersecretion can be appropriately treated. Second, it is important to realize, as our study demonstrates, that inadequately controlled acid secretion over a long period of time in these patients increases the risk of developing advanced esophageal disease, including Barrett’s esophagus, and this can increase the possibility of adenocarcinoma of the esophagus. Third, it is essential to adequately treat the gastric acid hypersecretion in MEN1/ZES patients. This almost invariably requires the use of PPIs, frequently twice a day (18). Fourth, it needs to be realized that the presence of HPT makes acid secretory control more difficult. Therefore, antisecretory acid control needs to be carefully monitored. Fifth, adequate monitoring of acid secretory control requires both symptomatic assessment for GERD as well as regular assessment for control of acid hypersecretion. Symptomatic and acid secretory assessments are particularly important to control any GERD symptoms because studies in sporadic ZES patients (3, 17) show that higher doses of antisecretory drugs are frequently needed and that sufficient antisecretory drug to reduce acid secretion to less than 1 mEq/h may be needed to adequately control reflux disease in these patients.


   Footnotes
 
The authors have no conflict of interest.

First Published Online October 25, 2005

Abbreviations: BAO, Basal acid output; GERD, gastroesophageal reflux disease; HPT, hyperparathyroidism; LES, lower esophageal sphincter; MAO, maximal acid output; MEN1, multiple endocrine neoplasia type 1; PET, pancreatic endocrine tumor; PPI, proton pump inhibitor; UGI, upper gastrointestinal; ZES, Zollinger-Ellison syndrome.

Received June 16, 2005.

Accepted October 18, 2005.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Marx S, Spiegel AM, Skarulis MC, Doppman JL, Collins FS, Liotta LA 1998 Multiple endocrine neoplasia type 1: clinical and genetic topics. Ann Intern Med 129:484–494[Abstract/Free Full Text]
  2. Gibril F, Schumann M, Pace A, Jensen RT 2004 Multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome. A prospective study of 107 cases and comparison with 1009 patients from the literature. Medicine 83:43–83[CrossRef][Medline]
  3. Jensen RT 1998 Management of the Zollinger-Ellison syndrome in patients with multiple endocrine neoplasia type 1. J Intern Med 243:477–488[CrossRef][Medline]
  4. Gibril F, Venzon DJ, Ojeaburu JV, Bashir S, Jensen RT 2001 Prospective study of the natural history of gastrinoma in patients with MEN1: definition of an aggressive and a nonaggressive form. J Clin Endocrinol Metab 86:5282–5293[Abstract/Free Full Text]
  5. Norton JA, Alexander HR, Fraker DL, Venzon DJ, Gibril F, Jensen RT 2001 Comparison of surgical results in patients with advanced and limited disease with multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome. Ann Surg 234:495–506[CrossRef][Medline]
  6. Jensen RT 2001 Zollinger-Ellison syndrome. In: Doherty GM, Skogseid B, eds. Surgical endocrinology: clinical syndromes. Philadelphia: Lippincott, Williams, Wilkins; 291–344
  7. Roy P, Venzon DJ, Feigenbaum KM, Koviack PD, Bashir S, Ojeaburu JV, Gibril F, Jensen RT 2001 Gastric secretion in Zollinger-Ellison syndrome: correlation with clinical expression, tumor extent and role in diagnosis—a prospective NIH study of 235 patients and review of the literature in 984 cases. Medicine(Baltimore) 80:189–222[CrossRef][Medline]
  8. Roy P, Venzon DJ, Shojamanesh H, Abou-Saif A, Peghini P, Doppman JL, Gibril F, Jensen RT 2000 Zollinger-Ellison syndrome: clinical presentation in 261 patients. Medicine 79:379–411[Medline]
  9. Norton JA, Fraker DL, Alexander HR, Venzon DJ, Doppman JL, Serrano J, Goebel SU, Peghini PL, Roy PK, Gibril F, Jensen RT 1999 Surgery to cure the Zollinger-Ellison syndrome. N Engl J Med 341:635–644[Abstract/Free Full Text]
  10. Norton JA, Cornelius MJ, Doppman JL, Maton PN, Gardner JD, Jensen RT 1987 Effect of parathyroidectomy in patients with hyperparathyroidism, Zollinger-Ellison syndrome and multiple endocrine neoplasia type I: a prospective study. Surgery 102:958–966[Medline]
  11. McCarthy DM, Peikin SR, Lopatin RN, Long BW, Spiegel A, Marx S, Brennan M 1979 Hyperparathyroidism a reversible cause of cimetidine-resistant gastric hypersecretion. Br Med J 1:1765–1766[Medline]
  12. Danielides IC, Mellow MH 1978 Effect of acute hypercalcemia on human esophageal motility. Gastroenterology 75:1115–1119[Medline]
  13. Mowschenson PM, Rosenberg S, Pallota J, Silen W 1982 Effect of hyperparathyroidism and hypercalcemia on lower esophageal sphincter pressure. Am J Surg 143:36–39[Medline]
  14. Thompson NW 1998 Current concepts in the surgical management of multiple endocrine neoplasia type 1 pancreatic-duodenal disease. Results in the treatment of 40 patients with Zollinger-Ellison syndrome, hypoglycaemia or both. J Intern Med 243:495–500[Medline]
  15. Weber HC, Venzon DJ, Lin JT, Fishbein VA, Orbuch M, Strader DB, Gibril F, Metz DC, Fraker DL, Norton JA, Jensen RT 1995 Determinants of metastatic rate and survival in patients with Zollinger-Ellison syndrome: a prospective long-term study. Gastroenterology 108:1637–1649[CrossRef][Medline]
  16. Jensen RT 1999 Use of omeprazole and other proton pump inhibitors in the Zollinger-Ellison syndrome. In: Olbe L, ed. Milestones in drug therapy. Basel, Switzerland: Birkhauser Verlag AG Publishing Co.; 205–221
  17. Miller LS, Vinayek R, Frucht H, Gardner JD, Jensen RT, Maton PN 1990 Reflux esophagitis in patients with Zollinger-Ellison syndrome. Gastroenterology 98:341–346[Medline]
  18. Metz DC, Pisegna JR, Fishbeyn VA, Benya RV, Feigenbaum KM, Koviack PD, Jensen RT 1992 Currently used doses of omeprazole in Zollinger-Ellison syndrome are too high. Gastroenterology 103:1498–1508[Medline]
  19. Bondeson AG, Bondeson L, Thompson NW 1990 Stricture and perforation of the esophagus: overlooked threats in the Zollinger-Ellison syndrome. World J Surg 14:361–363[Medline]
  20. Kahn H, Waxman J 1992 Peripancreatic lymph node gastrinoma in a patient with Zollinger-Ellison syndrome. Mt Sinai J Med 59:425–428[Medline]
  21. Ng T, Maziak DE, Shamji FM 2001 Esophageal perforation: a rare complication of Zollinger-Ellison syndrome. Ann Thorac Surg 72:592–593[Abstract/Free Full Text]
  22. Symonds DA, Ramsey HE 1980 Adenocarcinoma arising in Barrett’s esophagus with Zollinger-Ellison syndrome. Am J Clin Pathol 73:823–826[Medline]
  23. Spechler SJ 2003 Esophageal complications of gastroesophageal reflux disease: presentation, diagnosis, management, and outcomes. Clin Cornerstone 5:41–48[Medline]
  24. Flejou JF 2005 Barrett’s oesophagus: from metaplasia to dysplasia and cancer. Gut 54(Suppl 1):i6–i12
  25. Richter JE 1999 Peptic strictures of the esophagus. Gastroenterol Clin North Am 28:875–891[Medline]
  26. Richter JE, Pandol SJ, Castell DO, McCarthy DM 1981 Gastroesophageal reflux disease in the Zollinger-Ellison syndrome. Ann Intern Med 95:37–43[Medline]
  27. Kark TR, Pindyck F, Sicular A 1983 Zollinger-Ellison syndrome with esophagitis and barrett mucosa. Am J Gastroenterol 78:611–614[Medline]
  28. Ramakrishnan T 1981 Zollinger-Ellison syndrome presenting as reflux esophagitis and stricture. J La State Med Soc 133:189–190[Medline]
  29. Smith HJ, Chapa HJ, Kilman WJ, Watkins WL 1979 Zollinger-Ellison syndrome presenting as esophageal stricture. Gastrointest Radiol 4:349–351[CrossRef][Medline]
  30. Fishbeyn VA, Norton JA, Benya RV, Pisegna JR, Venzon DJ, Metz DC, Jensen RT 1993 Assessment and prediction of long-term cure in patients with Zollinger-Ellison syndrome: the best approach. Ann Intern Med 119:199–206[Abstract/Free Full Text]
  31. Benya RV, Metz DC, Venzon DJ, Fishbeyn VA, Strader DB, Orbuch M, Jensen RT 1994 Zollinger-Ellison syndrome can be the initial endocrine manifestation in patients with multiple endocrine neoplasia-type 1. Am J Med 97:436–444[CrossRef][Medline]
  32. Termanini B, Gibril F, Reynolds JC, Doppman JL, Chen CC, Stewart CA, Sutliff VE, Jensen RT 1997 Value of somatostatin receptor scintigraphy: a prospective study in gastrinoma of its effect on clinical management. Gastroenterology 112:335–347[CrossRef][Medline]
  33. Frucht H, Doppman JL, Norton JA, Miller DL, Dwyer AJ, Frank JA, Vinayek R, Maton PN, Jensen RT 1989 Gastrinomas: comparison of MR imaging with CT, angiography and US. Radiology 171:713–717[Abstract/Free Full Text]
  34. Maton PN, Miller DL, Doppman JL, Collen MJ, Norton JA, Vinayek R, Slaff JI, Wank SA, Gardner JD, Jensen RT1987 Role of selective angiography in the management of Zollinger-Ellison syndrome. Gastroenterology 92:913–918
  35. Gibril F, Chen Y-J, Schrump DS, Vortmeyer A, Zhuang Z, Lubensky IA, Reynolds JC, Louie A, Entsuah LK, Huang K, Asgharian B, Jensen RT 2003 Prospective study of thymic carcinoids in patients with multiple endocrine neoplasia type 1. J Clin Endocrinol Metab 88:1066–1081[Abstract/Free Full Text]
  36. Gibril F, Reynolds JC, Chen CC, Yu F, Goebel SU, Serrano J, Doppman JL, Jensen RT 1999 Specificity of somatostatin receptor scintigraphy: a prospective study and the effects of false positive localizations on management in patients with gastrinomas. J Nucl Med 40:539–553[Abstract/Free Full Text]
  37. Asgharian B, Chen YJ, Patronas NJ, Peghini PL, Reynolds JC, Vortmeyer A, Zhuang Z, Venzon DJ, Gibril F, Jensen RT 2004 Meningiomas may be a component tumor of MEN1. Clin Cancer Res 10:869–880[Abstract/Free Full Text]
  38. Gibril F, Reynolds JC, Roy PK, Peghini PL, Doppman JL, Jensen RT 2000 Ability of somatostatin receptor scintigraphy to identify patients with localized gastric carcinoids: a prospective study. J Nucl Med 41:1646–1656[Abstract/Free Full Text]
  39. Sheppard BC, Norton JA, Doppman JL, Maton PN, Gardner JD, Jensen RT 1989 Management of islet cell tumors in patients with multiple endocrine neoplasia: a prospective study. Surgery 106:1108–1117[Medline]
  40. Collen MJ, Howard JM, McArthur KE, Raufman JP, Cornelius MJ, Ciarleglio CA, Gardner JD, Jensen RT 1984 Comparison of ranitidine and cimetidine in the treatment of gastric hypersecretion. Ann Intern Med 100:52–58[Medline]
  41. Raufman JP, Collins SM, Pandol SJ, Korman LY, Collen MJ, Cornelius MJ, Feld MK, McCarthy DM, Gardner JD, Jensen RT 1983 Reliability of symptoms in assessing control of gastric acid secretion in patients with Zollinger-Ellison syndrome. Gastroenterology 84:108–113[Medline]
  42. Maton PN, Frucht H, Vinayek R, Wank SA, Gardner JD, Jensen RT 1988 Medical management of patients with Zollinger-Ellison syndrome who have had previous gastric surgery: a prospective study. Gastroenterology 94:294–299[Medline]
  43. Maton PN, Vinayek R, Frucht H, McArthur KA, Miller LS, Saeed ZA, Gardner JD, Jensen RT 1989 Long-term efficacy and safety of omeprazole in patients with Zollinger-Ellison syndrome: a prospective study. Gastroenterology 97:827–836[Medline]
  44. Asgharian B, Turner ML, Gibril F, Entsuah LK, Serrano J, Jensen RT 2004 Cutaneous tumors in patients with MEN1 and gastrinomas: prospective study of frequency and development of criteria with high sensitivity and specificity. J Clin Endocrinol Metab 89:5328–5336[Abstract/Free Full Text]
  45. Strader DB, Benjamin S, Orbuch M, Lubensky TA, Gibril F, Weber C, Fishbeyn VA, Jensen RT, Metz DC 1995 Esophageal function and occurrence of Barrett’s esophagus in Zollinger-Ellison syndrome. Digestion 56:347–356[Medline]
  46. Sampliner RE 1998 Practice guidelines on the diagnosis, surveillance, and therapy of Barrett’s esophagus. the Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 93:1028–1032[CrossRef][Medline]
  47. Eloubeidi MA, Provenzale E 2001 Clinical and demographic predictors of Barrett’s esophagus among patients with gastroesophageal reflux disease: a multivariable analysis in veterans. J Clin Gastroenterol 33:306–309[Medline]
  48. Lieberman DA, Oehlke M, Helfand M 1997 Risk factors for Barrett’s esophagus in community-based practice. GORGE consortium. Gastroenterology Outcomes Research Group in Endoscopy. Am J Gastroenterol 92:1293–1297[Medline]
  49. Castell DO, Wu WC, Ott DJ 1985 Gastroesophageal reflux disease. Mount Kisco, NY: Futura; 1–324
  50. Sachithanandan N, Harle RA, Burgess JR 2005 Bronchopulmonary carcinoid in multiple endocrine neoplasia type 1. Cancer 103:509–515[Medline]
  51. Coenraad M, Masclee AA, Straathof JW, Ganesh S, Griffioen G, Lamers CB 1998 Is Barrett’s esophagus characterized by more pronounced acid reflux than severe esophagitis? Am J Gastroenterol 93:1068–1072[CrossRef][Medline]
  52. Hirschowitz BI, Simmons JL, Johnson LF, Mohnen J 2004 Risk factors for esophagitis in extreme acid hypersecretors with and without Zollinger-Ellison syndrome. Clin Gastroenterol Hepatol 2:220–229[Medline]
  53. Liu DH, Crastnopol P, Phillips W 1967 Perforation of a gastrojejunal ulcer into the pericardium. Arch Surg 94:294–298[Medline]
  54. Toruner M, Soykan I, Ensari A, Kuzu I, Yurdaydin C, Ozden A 2004 Barrett’s esophagus: prevalence and its relationship with dyspeptic symptoms. J Gastroenterol Hepatol 19:535–540[CrossRef][Medline]
  55. Csendes A, Smok G, Quiroz J, Burdiles P, Rojas J, Castro C, Henriquez A 2002 Clinical, endoscopic, and functional studies in 408 patients with Barrett’s esophagus, compared to 174 cases of intestinal metaplasia of the cardia. Am J Gastroenterol 97:554–560[Medline]
  56. Spechler SJ, Zeroogian JM, Antonioli DA, Wang HH, Goyal RK 1994 Prevalence of metaplasia at the gastro-oesophageal junction. Lancet 344:1533–1536[CrossRef][Medline]
  57. Weston AP, Sharma P, Mathur S, Banerjee S, Jafri AK, Cherian R, McGregor D, Hassanein RS, Hall M 2004 Risk stratification of Barrett’s esophagus: updated prospective multivariate analysis. Am J Gastroenterol 99:1657–1666[CrossRef][Medline]
  58. Wakelin DE, Al-Mutawa T, Wendel C, Green C, Garewal HS, Fass R 2003 A predictive model for length of Barrett’s esophagus with hiatal hernia length and duration of esophageal acid exposure. Gastrointest Endosc 58:350–355[Medline]
  59. Cameron AJ 1999 Barrett’s esophagus: prevalence and size of hiatal hernia. Am J Gastroenterol 94:2054–2059[CrossRef][Medline]
  60. Loughney T, Maydonovitch CL, Wong RK 1998 Esophageal manometry and ambulatory 24-hour pH monitoring in patients with short and long segment Barrett’s esophagus. Am J Gastroenterol 93:916–919[Medline]
  61. Howard JM, Chremos AN, Collen MJ, McArthur KE, Cherner JA, Maton PN, Ciarleglio CA, Cornelius MJ, Gardner JD, Jensen RT 1985 Famotidine, a new, potent, long-acting histamine H2-receptor antagonist: comparison with cimetidine and ranitidine in the treatment of Zollinger-Ellison syndrome. Gastroenterology 88:1026–1033[Medline]




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