Patients with Multiple Endocrine Neoplasia Type 1 with Gastrinomas ...

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The Journal of Clinical Endocrinology & Metabolism 91(1):204 –212 Copyright © 2006 by The Endocrine Society doi: 10.1210/jc.2005-1349

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 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).

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.

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.

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. (J Clin Endocrinol Metab 91: 204 –212, 2006)

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.

G

ASTRINOMAS ARE THE most common, symptomatic pancreatic endocrine tumor (PET) in multiple endocrine neoplasia type 1 (MEN1) (1–3). 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– 8). Unlike patients with sporadic ZES, most MEN1/ZES patients cannot be cured (3, 5, 6, 9 –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 (17–21) and can result in important complications that can be life threatening (20 –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 (23–25). 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 –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 pa-

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. JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community.

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Hoffmann et al. • MEN1/ZES and Esophageal Disease

tients, 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 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– 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

J Clin Endocrinol Metab, January 2006, 91(1):204 –212

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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 (ⱖ3 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 pullthrough 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 ␹2 test or Fisher’s exact test. P ⬍ 0.05 was considered significant. All continuous variables are expressed in mean ⫾ sem.

Results

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 1). 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 1). 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 1). There was no significant difference in other demographic features, clinical or treatment aspects, tumor extent, or acid secretory rates (Table 1). 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 2). 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 2), occurring in 14 of 80 MEN1/ZES patients (18%) and seven patients (3%) with sporadic ZES (P ⬍ 0.00001) (Table 2). 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 2). One MEN1 patient developed esophageal adenocarcinoma, whereas in the sporadic ZES group, no patients developed this cancer (Fig. 1). The adenocarcinoma was found at the time of surveillance for highgrade dysplasia and led to the patient’s death. Peptic stric-

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

MEN1 present

MEN1 absent

Total

Total Male gender Race Caucasian Non-Caucasian Age (yr) Age of onset of ZESa Age at first NIH visit Duration (yr) Onset to Dx Onset to last follow-up at NIH Symptoms Esophageal symptoms Pain Diarrhea Bleeding Ulcer history Duration of antisecretory treatment (yr) Total treatment PPI treatment H2-antagonist treatment No treatment PPI dose (mg/d)b Initial Last dose NIH H2-antagonist dose (mg/d)c Acid secretion (mEq/h)d BAO MAO Fasting gastrin level (pg/ml) Mean Median Acid-reducing surgery Attempted gastrinoma surgerye PET extent Localizedf Metastasized to liver

80 (27) 33 (43)

215 (73) 129 (60)

295 162 (55)

64 (80) 16 (20)

170 (79) 45 (21)

234 (79) 61 (21)

NS NS

33.4 ⫾ 1.0 41.8 ⫾ 1.2

43.2 ⫾ 0.8 49.9 ⫾ 0.7

40.5 ⫾ 0.7 47.5 ⫾ 0.6

⬍0.0001 ⬍0.001

5.7 ⫾ 0.7 19.0 ⫾ 1.0

5.8 ⫾ 0.5 16.5 ⫾ 0.7

5.8 ⫾ 0.4 17.2 ⫾ 0.6

NS NS

47 (59) 58 (73) 58 (73) 16 (20) 45 (56)

110 (51) 171 (80) 163 (76) 60 (28) 159 (74)

157 (53) 229 (78) (75) 76 (26) 204 (69)

NS NS NS NS 0.0035

⫾ ⫾ ⫾ ⫾

0.4 0.3 0.3 0.3

NS NS 0.007 NS

14.2 9.7 7.2 4.0

⫾ ⫾ ⫾ ⫾

0.9 0.5 0.7 0.6

12.6 8.9 5.2 4.4

⫾ ⫾ ⫾ ⫾

0.5 0.4 0.4 0.4

13.0 9.1 5.7 4.3

P

0.0041

67.4 ⫾ 4.1 73.8 ⫾ 5.1 1649 ⫾ 254

65.1 ⫾ 2.5 58.5 ⫾ 2.7 2331 ⫾ 162

65.7 ⫾ 2.1 62.6 ⫾ 2.5 2175 ⫾ 139

NS 0.004 0.006

44.0 ⫾ 3.8 55.2 ⫾ 4.6

44.0 ⫾ 1.6 61.7 ⫾ 2.2

44.0 ⫾ 1.6 60.4 ⫾ 2.0

NS NS

6538 ⫾ 2047 835 14 (18) 53 (66)

4154 ⫾ 1299 626 31 (14) 163 (76)

4797 ⫾ 1097 647 45 (15) 216 (73)

NS NS NS

56 (70) 24 (30)

160 (74) 55 (26)

216 (73) 79 (27)

NS NS

Data are expressed as mean ⫾ SEM or number (percent). Percentage is the percent of the patients with the indicated MEN1 status with the indicated characteristic. Dx, Diagnosis; Tx, therapy; NS, not significant; H2-antagonist, histamine H2-antagonist. a Onset of ZES was determined as first time of continuous symptoms compatible with gastric acid hypersecretion as described in Patients and Methods. b Initial is the dose of the first PPI received and last is the dose of PPI the patient received at last NIH follow-up. c H2-antagonist dose was expressed as the ranitidine-equivalent dose calculated as described previously (61). d BAO and MAO values at initial NIH evaluation in patients without prior gastric acid-reducing surgery (66 MEN1, 187 no MEN1). e Acid-reducing surgery includes 11 patients with total gastrectomy, 16 patients with vagotomy/pyloroplasty, and 22 patients with Billroth I or II. f Localized refers to absence of liver or distant metastases determined as described in Patients and Methods.

ture of the esophagus was 3-fold higher in MEN1/ZES (15 vs. 5%, P ⫽ 0.0027) (Table 2). 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 2).

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 3). 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 ⫽



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

MEN1 present

MEN1 absent

No. of patients Esophageal symptoms Heartburn Any Daily Dysphagia Reflux surgery previouslya Endoscopic findings Barrett’s present (total) ⬍3 cm ⱖ3 cm Dysplasia Low grade High grade Adenocarcinoma Stricture Present Length (cm) Stricture or Barrett’s present Esophagitis Hiatal hernia Present Size (cm) Age (yr) Barrett’s found Stricture found Manometric findingsb LES pressure (mm Hg) LES motility normal

80 (27)

215 (73)

295

Total

P

46 (58) 20 (25) 7 (9) 2 (3)

110 (51) 27 (13) 7 (3) 6 (3)

156 (53) 47 (16) 14 (5) 8 (3)

14 (18) 8 (13) 5 (6) 3 (4) 1 (1) 2 (3) 1 (1)

7 (3) 2 (1) 5 (2) 1 (0.5) 1 (0.5) 0 (0) 0 (0)

21 (7) 10 (3) 11 (4) 4 (1) 2 (0.7) 2 (0.7) 1 (0.3)

⬍0.00001 NS NS 0.030 NS NS NS

12 (15) 2.8 ⫾ 0.37 22 (28) 26 (32)

10 (5) 3.0 ⫾ 0.7 15 (7) 63 (29)

22 (8) 3.0 ⫾ 0.4 37 (13) 89 (30)

0.0027 NS ⬍0.00001 NS

27 (34) 1.8 ⫾ 0.2

72 (33) 2.0 ⫾ 0.1

99 (34) 2.0 ⫾ 0.1

NS NS

45.3 ⫾ 2.5 50.3 ⫾ 3.3

51.2 ⫾ 2.3 56.1 ⫾ 3.5

47.3 ⫾ 1.9 52.9 ⫾ 2.3

NS NS

17.9 ⫾ 1.5 (100%)

20.0 ⫾ 0.8 (100%)

19.6 ⫾ 0.7 (100%)

NS NS

NS 0.0096 0.049 NS

Data are expressed as mean ⫾ SE or number (percent). Percentage is the percent of the patients with the indicated MEN1 status with the indicated characteristic. NS, Not significant. a Referring to patients that had reflux surgery performed before initial visit to NIH. b Data from esophageal manometry from 89 patients (15 with MEN1, 74 without MEN1), of which all had normal esophagus motility findings.

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 3). 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 4). 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 4) as well as more frequently having heartburn (P ⬍ 0.00001), dysphagia (P ⬍ 0.00001), or esophagitis (P ⬍ 0.0001) (Table 4). Neither other endoscopic findings (hiatal hernia, pyloric scarring) nor LES pressure differed between patients either with or without Barrett’s esophagus/stricture (Table 4). Other clinical, laboratory, tumoral features, or treatment aspects did not differ in MEN1/ ZES patients either with or without Barrett’s or stricture (Table 4). Discussion

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% (1–3, 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 –21, 27–29, 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

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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.

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



209

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

No. of patients Age at onset MEN1 (yr)a Duration (yr) Onset to Dx of MEN1b Onset of MEN1 to last follow-up Duration of MEN1 at first NIH visit MEN1 onset to ZES Dx MEN1 featuresc HPT Pituitary Adrenal Carcinoidd Other PETe MEN1 course HPT development HPT prior to first NIH visit (yr)f Duration of HPT at first NIH visit Renal colic present PTX PTX performed Age at first PTX No. of PTXs Gastrinoma resection MEN1 presenting features ZES HPT Pituitary disease Asymptomaticg Othere HPT/ZES relationshiph HPT prior to ZES ZES prior to HPT Family history of MEN1

Barrett’s or stricture present

22 (28) 30.0 ⫾ 2.4 10.7 24.9 13.9 12.4

⫾ ⫾ ⫾ ⫾

1.7 2.7 2.3 2.3

Barrett’s or stricture absent

58 (73) 27.8 ⫾ 1.2 8.9 24.0 13.6 10.4

⫾ ⫾ ⫾ ⫾

1.1 1.4 1.3 1.0

Total

P

80 28.4 ⫾ 1.1

NS

⫾ ⫾ ⫾ ⫾

NS NS NS NS

9.4 24.3 13.7 10.9

0.9 1.2 1.1 0.9

21 (95) 13 (95) 12 (60) 8 (40) 2 (10)

58 (100) 36 (62) 27 (47) 22 (38) 4 (7)

79 (99) 49 (61) 39 (49) 30 (38) 6 (8)

NS NS NS NS NS

14 (70) 8.6 ⫾ 2.4 11 (55)

51 (88) 10.6 ⫾ 1.2 37 (64)

65 (81) 10.0 ⫾ 1.1 48 (60)

0.018 NS NS

17 (85) 38.8 ⫾ 3.2 1.6 ⫾ 0.3 15 (75)

58 (100) 35.5 ⫾ 1.3 1.9 ⫾ 0.1 38 (66)

75 (94) 36.2 ⫾ 1.3 1.8 ⫾ 0.1 53 (66)

0.0011 NS NS NS

11 (55) 7 (35) 1 (5) 2 (10) 1 (5)

19 (33) 29 (50) 4 (7) 5 (9) 1 (2)

30 (38) 36 (45) 5 (6) 7 (9) 2 (3)

NS NS NS NS NS

10 (50) 11 (55) 12 (60)

41 (77) 17 (30) 44 (76)

51 (64) 28 (35) 56 (70)

0.034 NS NS

Data are expressed as mean ⫾ SEM or number (percent). HPT, Hyperparathyroidism; PTX, parathyroidectomy; Dx, diagnosis. a Determined as the time of the first clinical manifestation of MEN1 or its biochemical detection in asymptomatic patients as described in Patients and Methods. b Time of diagnosis was the first time a patient was informed by a physician to have MEN1. c MEN1 feature that a given patient manifested at any time during the study. d Carcinoid tumor included gastric, bronchial, and thymic carcinoids. e Other PET includes five patients with insulinoma, one patient with insulinoma and carcinoid syndrome, and one patient with glucagonoma. f HPT manifested by renal colic or detected biochemically in asymptomatic patients prior to the first NIH visit. Patients that developed HPT after first evaluation at NIH are not included in this analysis. g Asymptomatic refers to patients in which MEN1 was detected biochemically. h Refers to whether HPT was manifested before ZES or vice versa, as described in Patients and Methods.

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.

210



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

No. of patients Male gender Caucasian Age onset of ZES (yr) Onset to Dx of ZES (yr) Heartburn Any Daily Dysphagia Ulcer history Endoscopic findings Hiatal hernia Present Size (cm) Esophagitis Pyloric scarring LES pressure (mm Hg)a Reflux surgery previously Attempted gastrinoma resection Liver metastases present Acid-reducing surgeryb Duration of antisecretory Tx (yr) Total Tx PPI Tx H2-Antagonist Tx No Tx Onset ZES to first PPI Tx (yr) PPI dose (mg/d)a H2-Antagonist dose (mg/d)a Acid secretion (mEq/h)a BAO MAO Fasting gastrin levels (pg/ml)

Barrett’s present

Barrett’s absent

Stricture present

Stricture absent

Barrett’s/stricture present

Barrett’s/stricture absent

14 (18) 9 (64) 10 (71) 31.5 ⫾ 2.3 9.9 ⫾ 2.2c

66 (82) 24 (36) 54 (82) 33.8 ⫾ 1.2 4.8 ⫾ 0.7

12 (15) 7 (58) 9 (75) 39.3 ⫾ 2.5c 6.4 ⫾ 1.9

68 (85) 26 (38) 55 (81) 32.4 ⫾ 1.1 5.6 ⫾ 6.1

22 (28) 13 (59)c 17 (77) 34.1 ⫾ 2.0 7.7 ⫾ 1.6

58 (72) 20 (34) 47 (81) 33.1 ⫾ 1.2 4.9 ⫾ 0.7

14 (100)e 8 (57)d 2 (14) 11 (79)

32 (48) 12 (18) 5 (8) 34 (52)

9 (75) 11 (92)g 6 (50)g 8 (67)

37 (54) 9 (13) 1 (1) 37 (54)

19 (86)e 15 (68)g 6 (27)d 16 (73)

27 (47) 5 (9) 1 (2) 29 (50)

6 (43) 3.2 ⫾ 0.6c 11 (79)g 3 (21) 20 ⫾ 0.0 2 (14)c 9 (64) 4 (29) 4 (29)

21 (32) 1.4 ⫾ 0.2 15 (23) 6 (9) 17.6 ⫾ 1.8 0 (0) 44 (67) 20 (30) 10 (15)

6 (50) 2.2 ⫾ 0.7 10 (83)f 1 (8) 20 ⫾ 0.0 1 (8) 9 (75) 6 (50) 3 (25)

21 (31) 1.7 ⫾ 0.3 16 (24) 8 (12) 17.8 ⫾ 1.6 1 (1) 44 (65) 18 (26) 11 (16)

10 (45) 2.5 ⫾ 0.5c 17 (77)g 3 (14) 20.0 ⫾ 0.0 2 (9) 15 (68) 8 (36) 5 (23)

17 (29) 1.4 ⫾ 0.2 9 (16) 6 (10) 17.6 ⫾ 1.8 0 (0) 38 (66) 16 (28) 9 (16)

13.7 8.1 6.2 5.5 10.4 100 1362

⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾

2.1 1.4 1.9 1.4 2.1 20.6 564

51.3 ⫾ 8.4 61.6 ⫾ 14.0 3632 ⫾ 1797

14.4 10.1 7.4 3.7 8.3 99.3 1737

⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾

1.0 0.6 0.8 0.7 0.9 5.0 294

42.4 ⫾ 4.3 54.9 ⫾ 5.0 7164 ⫾ 2457

15.3 10.5 7.0 4.2 8.3 97.8 1050

⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾

2.5 1.5 2.2 1.2 2.3 13.5 253

53.9 ⫾ 9.6 48.8 ⫾ 17.7 2935 ⫾ 1172

14.0 9.6 7.2 4.0 8.7 93.9 1768

⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾

0.9 0.6 0.8 0.7 0.9 6.3 301

42.7 ⫾ 4.2 56.6 ⫾ 4.9 7183 ⫾ 2400

14.7 9.3 7.5 4.5 9.5 101.3 1357

⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾

1.8 1.1 1.6 1.0 1.6 12.8 422

55.4 ⫾ 6.5c 63.3 ⫾ 11.5 3514 ⫾ 1270

14.1 9.9 7.1 3.8 8.3 91.0 1779

⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾

1.0 0.6 0.8 0.8 1.0 5.2 324

40.1 ⫾ 4.5 53.9 ⫾ 5.1 7705 ⫾ 2788

Data are expressed as mean ⫾ SEM or number (percent). Dx, Diagnosis; Tx, therapy. a See Table 1 and 2 legends. b Acid-reducing surgery in patients with MEN1 included Billroth I/II operations, seven total gastrectomies and five vagotomies/pylorotomies. Compared to Barrett’s or stricture absent: c P ⬍ 0.05; d P ⬍ 0.01; e P ⬍ 0.001; f P ⬍ 0.0001; g P ⬍ 0.00001.

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 es-

sential 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. Acknowledgments Received June 16, 2005. Accepted October 18, 2005. 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: [email protected]. The authors have no conflict of interest.


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