Journal of Gastroenterology

, Volume 45, Issue 2, pp 171–178

Gallstones increase the prevalence of Barrett’s esophagus

Authors

  • Juntaro Matsuzaki
    • Division of Gastroenterology and Hepatology, Department of Internal MedicineKeio University School of Medicine
    • Division of Gastroenterology and Hepatology, Department of Internal MedicineKeio University School of Medicine
  • Keiko Asakura
    • Department of Preventive Medicine and Public HealthKeio University School of Medicine
  • Yoshimasa Saito
    • Division of Gastroenterology and Hepatology, Department of Internal MedicineKeio University School of Medicine
  • Kenro Hirata
    • Division of Gastroenterology and Hepatology, Department of Internal MedicineKeio University School of Medicine
  • Toru Takebayashi
    • Department of Preventive Medicine and Public HealthKeio University School of Medicine
  • Toshifumi Hibi
    • Division of Gastroenterology and Hepatology, Department of Internal MedicineKeio University School of Medicine
Original Article—Alimentary Tract

DOI: 10.1007/s00535-009-0153-4

Cite this article as:
Matsuzaki, J., Suzuki, H., Asakura, K. et al. J Gastroenterol (2010) 45: 171. doi:10.1007/s00535-009-0153-4
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Abstract

Purpose

Bile and acid exposures are thought to be major risk factors for Barrett’s esophagus in Western countries. The association of gallstones with Barrett’s esophagus has not been fully evaluated. The present study was designed as a case-control study for determining the possible factors associated with endoscopically suspected esophageal metaplasia (ESEM), defined as an endoscopic finding suggestive of Barrett’s esophagus, in Japanese patients.

Methods

A total of 528 patients with ESEM were allocated to the case group, while 528 age- and gender-matched patients without ESEM were allocated to the control group. Findings on esophagogastroduodenoscopy and clinical background factors were compared using a multivariate logistic regression model.

Results

The presence of gallstones and hiatus hernia and the severity of gastric mucosal atrophy were independently associated with the presence of ESEM [odds ratio (OR) 1.67, 95% confidence interval (CI) 1.03–2.69; OR 2.75, 95% CI 1.75–4.33; OR 1.25, 95% CI 1.01–5.6, respectively]. Compared with subjects with neither gastric corpus atrophy nor gallstones, although subjects with gallstones alone were not associated with the presence of ESEM (OR 1.59, 95% CI 0.87–2.92), having both gastric corpus atrophy and gallstones was strongly associated with the presence of ESEM (OR 2.94, 95% CI 1.40–6.17).

Conclusions

The presence of gallstones was independently associated with the presence of ESEM in the Japanese outpatient population, suggesting a causal association of distal esophageal bile exposure with the development of ESEM. Further studies are needed to confirm our findings in cases with histologically confirmed Barrett’s esophagus.

Keywords

Barrett’s esophagusESEMGallstoneGastric mucosal atrophy

Introduction

The incidence of esophageal adenocarcinoma is rising more rapidly than that of any other malignancy in Western countries [13]. Esophageal adenocarcinoma remains highly lethal, with a 5-year survival rate of less than 15% [4, 5]. In most patients, esophageal adenocarcinoma arises from its premalignant precursor lesion, Barrett’s esophagus (BE) [6]. BE is a transformation of the esophageal squamous epithelium into gastric metaplasia or specialized intestinal metaplasia [7]. Investigating the risk factors of BE was important to clarify the cause of BE and esophageal adenocarcinoma.

BEs are classically attributed to reflux of the acid component of gastric content into the esophagus. Meanwhile, a number of observation support the concept that bile reflux, as occurs in duodeno-gastro-esophageal reflux (DGER), also contributes to the development of BE [811]. Izbeki et al. [12] reported that prevalence of gallstone disease was increased and gallbladder motility was impaired in patients with BE. Since microscopic cholesterol crystals are regularly washed out of the gallbladder if its contractions are effective enough, impaired motility of the gallbladder is one of the factors contributing to the development of gallstones [13]. Gallbladder dysfunction or nonfunction is closely associated with the efficiency of continuous bile flow into the duodenum and the occurrence of duodeno-gastric reflux [14, 15]. Therefore, the formation of gallstones has been considered to be associated with duodeno-gastric reflux [16].

According to the Montreal definitions, the term endoscopically suspected esophageal metaplasia (ESEM) is used for an endoscopic finding consistent with BE that awaits histological evaluation [7]. The prevalence of long-segment ESEM, where the length of the circumferential ESEM is more than 3 cm, has been estimated to be 0.2–0.4%, while that of short segment ESEM, where the length of the circumferential ESEM is less than 3 cm, has been estimated to be 6.0–20.6% in Japan [17, 18]. To diagnose for BE, an intensive biopsy protocol of four quadrant biopsies, taken at 1–2 cm intervals, for all patients with ESEM has been recommended [19, 20]. Although histological confirmations are needed to clarify the risk factors for BE, lower esophageal adenocarcinoma is still a rare disease in Japan, and biopsies from sites of ESEM are not routinely obtained at the screening EGD due to cost, risk and complexity. Since the presence of ESEM is a prerequisite condition for the development of BE [21], risk factors for ESEM also extend to BE and esophageal adenocarcinoma.

Several risk factors for BE are reported, such as gastro-esophageal reflux symptoms, hiatus hernia, aging, male gender, obesity, alcohol and tobacco use [2227]. However, it is unknown whether the presence of gallstones is an independent risk factor for BE. Therefore, the authors performed a multivariate analysis on the relationship between ESEM and gallstones.

Methods

Study population

The authors conducted a hospital-based age- and gender-matched case control study on 4945 patients (2854 male, 2091 female; mean age, 62.6 years; range 13–94 years) who underwent esophagogastroduodenoscopy (EGD) at Keio University Hospital between November 2007 and April 2008. A total of 538 patients were diagnosed as having ESEM (10.8%). We reviewed the medical records and the digital photo image files of the EGD patients. Patients in whom the esophagogastric junction (EGJ) had been resected in a previous operation, such as total gastrectomy, proximal gastrectomy or esophagectomy, and those who had undergone endoscopic mucosal resection (EMR) or endoscopic variceal ligation (EVL) in the esophagus were excluded. Patients who had undergone distal gastrectomy were not excluded. In addition, patients for whom the EGJ was not recorded in the photo image files of EGD were also excluded. Then patients were excluded among 538 patients with ESEM; 528 patients (356 men and 172 women; mean age, 65.3 years; range 20–87 years) with ESEM were allocated to the case group, while 528 age- and gender-matched (frequency matching) patients without ESEM were allocated to the control group. When the control patients were selected, the medical records and EGD photo images of those patients were also reviewed, and patients who met the exclusion criteria were excluded (Fig. 1). Characteristics of the subjects are shown in Table 1. The study was performed in accordance with the Declaration of Helsinki.
https://static-content.springer.com/image/art%3A10.1007%2Fs00535-009-0153-4/MediaObjects/535_2009_153_Fig1_HTML.gif
Fig. 1

Diagram of the case control study. Among 4945 patients who underwent esophagogastroduodenoscopy (EGD) at Keio University Hospital between November 2007 and April 2008, there were 538 patients with endoscopically suspected esophageal metaplasia (ESEM), defined as an endoscopic finding suggestive of BE, and 4407 patients without ESEM. Among 538 subjects with ESEM, 10 subjects were excluded by the exclusion criteria, and 528 subjects were allocated to the case groups. Then among 4407 subjects without ESEM, 528 subjects were allocated to the control groups. These 1056 cases and controls were reviewed according to the medical records and EGD films, and it was confirmed that these did not meet the exclusion criteria

Table 1

Characteristics of subjects with or without ESEM

 

ESEM (+) cases (n = 528)

ESEM (−) controls (n = 528)

Age

 Mean ± SD (years)

65.3 ± 12.3

65.3 ± 12.3

  20–29

6 (1.1%)

6 (1.1%)

  30–39

16 (3.0%)

16 (3.0%)

  40–49

34 (6.4%)

34 (6.4%)

  50–59

91 (17.2%)

91 (17.2%)

  60–69

148 (28.0%)

148 (28.0%)

  70–79

189 (35.8%)

189 (35.8%)

  80–89

44 (8.3%)

44 (8.3%)

Gender

 Male

356 (67.4%)

356 (67.4%)

 Female

172 (32.6%)

172 (32.6%)

Hiatus hernia

 Presence

444 (84.1%)

327 (61.9%)

 Absence

84 (15.9%)

201 (38.1%)

Reflux esophagitis

 None

492 (93.2%)

508 (96.2%)

 Grade A

16 (3.0%)

11 (2.1%)

 Grade B

18 (3.4%)

6 (1.1%)

 Grade C

1 (0.2%)

3 (0.6%)

 Grade D

1 (0.2%)

0 (0%)

Gastric mucosal atrophy

 None

104 (19.7%)

104 (19.7%)

 Mild

228 (43.2%)

268 (50.8%)

 Moderate

154 (29.2%)

129 (24.4%)

 Severe

42 (8.0%)

27 (5.1%)

Clinical background factorsa [no./total no. (%)]

 Alcohol

139/371 (37.5%)

129/361 (35.7%)

 Smoking

171/374 (45.7%)

158/367 (43.1%)

 H. pylori

105/149 (70.5%)

83/112 (74.1%)

 Obesity

78/295 (26.4%)

64/315 (20.3%)

 BMI ± SD (kg/m2)

22.6 ± 4.0

22.4 ± 3.5

 Hypertension

176/343 (51.3%)

149/307 (48.5%)

 Diabetes

73/386 (18.9%)

64/367 (17.4%)

 Dyslipidemia

120/210 (57.1%)

120/201 (59.7%)

 Gallstones

85/371 (22.9%)

64/392 (16.3%)

ESEM endoscopically suspected esophageal metaplasia; BMI body mass index

aPart of the information about the clinical background could not be collected from the subjects’ medical records; therefore, total numbers of collected data for each factor were indicated in the clinical background section

Assessment by endoscopy

The presence/absence of ESEM and hiatus hernia was determined, and gastric mucosal atrophy and reflux esophagitis were graded retrospectively by three gastrointestinal endoscopists according to the criteria listed below.

ESEM

The presence/absence of ESEM was examined in the lower portion of the esophagus, including the EGJ, during inflation of the esophagus. The EGJ was defined as the oral side end of the fold continuous with the gastric lumen [28], as well as the anal side end of the palisade vessel, because the veins in the lower part of the esophagus were distributed uniformly, running parallel and longitudinally in the lamina propria [21, 29]. The squamo-columnar junction (SCJ) was defined by a clear change in the color of the mucosa. ESEM was defined as the area between the SCJ and the EGJ [21]. Most patients were evaluated for the presence/absence of ESEM using the anal side end of the lower esophageal palisade vessel, since such a definition of the EGJ was more suitable for the retrospective evaluation.

Gastric mucosal atrophy

The severity of gastric mucosal atrophy was assessed endoscopically by the Kimura–Takemoto classification of the atrophic pattern [21, 30, 31]. This classification divides the severity of gastric mucosal atrophy into seven types (C-0, C-1, C-2, C-3, O-1, O-2 and O-3) according to the location of the atrophic border as detected by endoscopy as follows: C-0, absence of atrophy; C-1, pyloric mucosal atrophy; C-2, atrophy extending over the lesser curvature of the lower third of the stomach; C-3, the atrophy extending over the lesser curvature of the middle third of the stomach; O-1, border of the atrophy between the lesser curvature and anterior wall of the stomach; O-2, atrophy within the limits of the anterior wall of the stomach; O-3, atrophic area extending from the anterior wall to the major curvature of the stomach. Using this classification, the severity of the gastric mucosal atrophy was divided into four grades: none (C-0), mild (C-1 and C-2), moderate (C-3 and O-1) and severe (O-2 and O-3).

Hiatus hernia

The presence/absence of hiatus hernia was examined by the valvular appearance of the cardia visualized from below using the retroflexed endoscope during gastric inflation [32].

Reflux esophagitis

Reflux esophagitis was defined as the presence of gross mucosal injury, ranging from red longitudinal streaks with associated friability to erosion or ulceration in the distal esophagus or breakage in the lower portion of the esophagus. The severity of reflux esophagitis was graded according to the Los Angeles classification [33].

Clinical background factors

The alcohol consumption status, smoking status and the presence/absence of H. pylori infection, obesity, hypertension, diabetes mellitus, dyslipidemia and gallstones were determined from the medical records. The alcohol consumption status was defined as a positive/negative history of daily alcohol consumption. The smoking status was defined as a positive/negative history of smoking cigarettes. The presence of H. pylori infection was defined as a history of H. pylori infection, including both pre- and post-eradication. The presence of H. pylori infection was detected by serological test, 13C-urea breath test, culture or histology of the gastric mucosal biopsy specimen. Obesity was defined as a body mass index of more than 25 kg/m2. Hypertension was defined as systolic blood pressure of over 140 mmHg and/or diastolic blood pressure of over 90 mmHg, or a history of use of antihypertensive drugs for the treatment of hypertension. Diabetes mellitus was defined as a serum hemoglobin A1c (HbA1c) value of over 6.5% or a history of use of antidiabetic agents. Dyslipidemia was defined as a serum level of low-density lipoprotein cholesterol (LDL-C) of over 140 mg/dl, high-density lipoprotein cholesterol (HDL-C) of under 40 mg/dl, a fasting triglyceride level of over 150 mg/dl or a history of use of lipid-lowering agents. The presence/absence of gallstones was determined by abdominal CT or ultrasonography. The presence/absence of gallstones of patients who had received cholecystectomy was determined by the previous record of abdominal CT or ultrasonography before cholecystectomy.

Statistical analyses

The associations of endoscopic findings or clinical background factors with the presence of ESEM were evaluated by a logistic regression model with adjustment for age and gender. Trends of association of the severity of reflux esophagitis and gastric mucosal atrophy with the presence of ESEM were evaluated by a logistic regression model that assigned scores to the level of the independent variable. The multivariate logistic regression model was conducted with adjustment for age, gender, hiatus hernia, reflux esophagitis, gastric mucosal atrophy, obesity and gallstones. All of the statistical analysis was performed using STATA 9.1 (Stata Corporation, College Station, TX). A two-sided p value of <0.05 was considered statistically significant.

Results

Association between endoscopic findings and ESEM

Among 528 subjects with ESEM, 64 subjects (12.1%) were diagnosed to have long segment ESEM, and 464 subjects (87.9%) were diagnosed to have short segment ESEM. According to the age- and gender-adjusted analysis, a strong association was detected between the presence of hiatus hernia and that of ESEM [odds ratio (OR) 3.40, 95% confidence interval (CI) 2.52–4.58]. The presence of grade B-D reflux esophagitis was significantly associated with the presence of ESEM (OR 2.31, 95% CI 1.04–5.14). Reflux esophagitis of greater severity grades was also significantly associated with the presence of ESEM (p = 0.02). In addition, gastric mucosal atrophy of greater severity grades was also significantly associated with the presence of ESEM (p = 0.04) (Table 2).
Table 2

Results for logistic regression analysis

 

ESEM (+) case no./total no. (%)

ESEM (−) control no./total no. (%)

Age- and gender-adjusted analysis

Multivariate analysisa

Odds ratio (95% CI)

p value

Odds ratio (95% CI)

p value

Hiatus hernia

444/528 (84.1%)

327/528 (61.9%)

3.40 (2.52–4.58)***

<0.001

2.75 (1.75–4.33)***

<0.001

Reflux esophagitis

 Grade A

16/528 (3.0%)

11/528 (2.1%)

1.51 (0.69–3.29)

 

0.94 (0.27–3.22)

 

 Grade B–D

20/528 (3.8%)

9/528 (1.7%)

2.31 (1.04–5.14)*

0.02 (trend)*

1.83 (0.51–6.61)

0.43 (trend)

Gastric mucosal atrophy

 Mild

228/528 (43.2%)

268/528 (50.8%)

0.86 (0.62–1.19)

 

0.92 (0.56–1.51)

 

 Moderate

154/528 (29.1%)

129/528 (24.4%)

1.22 (0.85–1.77)

 

1.56 (0.90–2.71)

 

 Severe

42/528 (8.0%)

27/528 (5.1%)

1.60 (0.91–2.81)

0.04 (trend)*

1.67 (0.78–3.61)

0.04 (trend)*

Alcohol

139/371 (37.5%)

129/361 (35.7%)

1.04 (0.74–1.46)

0.82

  

Smoking

171/374 (45.7%)

158/367 (43.1%)

1.09 (0.79–1.51)

0.59

  

H. pylori

105/149 (70.5%)

83/112 (74.1%)

0.83 (0.48–1.45)

0.52

  

Obesity

78/295 (26.4%)

64/315 (20.3%)

1.43 (0.98–2.10)

0.06

1.20 (0.77–1.89)

0.42

Hypertension

176/343 (51.3%)

149/307 (48.5%)

1.19 (0.86–1.64)

0.30

  

Diabetes

73/386 (18.9%)

64/367 (17.4%)

1.11 (0.76–1.62)

0.58

  

Dyslipidemia

120/210 (57.1%)

120/201 (59.7%)

0.97 (0.65–1.44)

0.86

  

Gallstones

85/371 (22.9%)

64/392 (16.3%)

1.56 (1.09–2.25)*

0.02

1.67 (1.03–2.69)*

0.04

ESEM endoscopically suspected esophageal metaplasia; CI confidence interval

p < 0.1

p < 0.05

*** p < 0.001

aAdjustment for age, gender, hiatus hernia, reflux esophagitis, gastric mucosal atrophy, obesity and gallstones

Association between clinical background factors and ESEM

All of the clinical background factors of the subjects could not be determined from the medical records. Therefore, the associations between the clinical background factors and the presence of ESEM were analyzed using partial subjects whose background could be determined. All of the determined rates of the background factors were not different between cases and controls. Among these background factors, only the presence of gallstones was significantly associated with that of ESEM (OR 1.56, 95% CI 1.09–2.25). The presence of obesity was possibly associated with that of ESEM (OR 1.43, 95% CI 0.98–2.10, p = 0.06) (Table 2).

Multivariate analysis for endoscopic findings, obesity, gallstones and ESEM

The age- and gender-adjusted analysis showed that the presence of hiatus hernia, gallstones and obesity, and the severity of reflux esophagitis and gastric mucosal atrophy were associated with ESEM. Therefore, the authors analyzed the association of these factors with the presence of ESEM by a multivariate logistic regression model (Table 2). The presence of hiatus hernia, gallstones and the severity of gastric mucosal atrophy were independently associated with the presence of ESEM.

Association of gastric mucosal atrophy and gallstones and ESEM

According to the Kimura–Takemoto classification, the presence of gastric corpus atrophy means moderate/severe gastric mucosal atrophy. The absence of gastric corpus atrophy means no/mild gastric mucosal atrophy. To assess the relationship among the presence of gastric corpus atrophy, gallstones and ESEM, the present subjects were re-allocated into four groups: subjects with neither gastric corpus atrophy nor gallstones, subjects with gastric corpus atrophy alone, subjects with gallstones alone, and subjects with both gastric corpus atrophy and gallstones. The associations of these four groups with the presence of ESEM were analyzed using a multivariate logistic regression model with adjustment for age, gender, hiatus hernia, reflux esophagitis, obesity and the three factors gastric corpus atrophy alone, gallstones alone, and both gastric corpus atrophy and gallstones (Table 3).
Table 3

Association of gastric mucosal atrophy and gallstones with ESEM

 

ESEM (+) cases

ESEM (−) controls

Odds ratio (95% CI)a

p value

No./total no. (%)

No./total no. (%)

Factor 1: gastric corpus atrophy (+)b, gallstone (−)

104/371 (28.0%)

96/392 (24.5%)

1.63 (1.03–2.57)*

0.04

Factor 2: gastric corpus atrophy (−)c, gallstone (+)

45/371 (12.1%)

44/392 (11.2%)

1.59 (0.87–2.92)

0.13

Factor 3: gastric corpus atrophy (+)b, gallstone (+)

40/371 (10.8%)

20/392 (5.1%)

2.94 (1.40–6.17)**

0.004

ESEM endoscopically suspected esophageal metaplasia; CI confidence interval

* p < 0.05

** p < 0.01

aResult of a multivariate logistic regression model with adjustment for age, gender, hiatus hernia, reflux esophagitis, obesity, factor 1, factor 2 and factor 3

bThe grade of gastric mucosal atrophy was moderate or severe

cThe grade of gastric mucosal atrophy was none or mild

Although the group with gallstones alone was not associated with the presence of ESEM (OR 1.59, 95% CI 0.87–2.92), the group with both gastric corpus atrophy and gallstones was strongly associated with the presence of ESEM (OR 2.94, 95% CI 1.40–6.17). The group with gastric corpus atrophy alone was also associated with the presence of ESEM (OR 1.63, 95% CI 1.03–2.57).

Discussion

The result of the present case control study showed that the presence of gallstones, hiatus hernia and the severity of gastric mucosal atrophy were independently associated with the presence of ESEM. It has been suggested that both gallstones and previous cholecystectomy contribute to the occurrence of duodeno-gastric reflux [16, 3439]. The underlying mechanism is thought to be a dysfunction of the antroduodenal motor unit that favors the reflux of duodenal contents into the stomach [37]. According to the large population-based study, a moderately increased risk for esophageal adenocarcinoma following cholecystectomy was observed (OR 1.3, p < 0.05) [40]. In the present study, independent association of the presence of gallstones with that of ESEM was shown, suggesting that the duodeno-gastric bile reflux plays an important role in the development of ESEM, although the association of previous cholecystectomy with the presence of ESEM was not directly examined.

The present study also showed that the presence of hiatus hernia was associated with that of ESEM. Previous studies have shown a strong association of hiatus hernia with BE [4143], suggesting the occurrence of gastro-esophageal reflux in hiatus hernia. On the other hand, the multivariate analysis revealed the severity of reflux esophagitis was not independently associated with the presence of ESEM. This result was consistent with that of the recent Korean study [24], which showed that 77.7% of BE patients did not have reflux esophagitis.

The association of the presence of H. pylori infection or the severity of gastric mucosal atrophy with the presence of ESEM was still controversial [41, 44, 45]. In general, many studies have shown that H. pylori infection and gastric mucosal atrophy are inversely associated with BE [25, 46]. However, the result of the present study suggested a positive association of the severity of gastric mucosal atrophy with the presence of ESEM, and the presence of H. pylori infection was not associated with the presence of ESEM. H. pylori-induced corpus atrophy reduces gastric acid secretion and the distal esophageal acid exposure [47], whereas gastric pH leads to bile precipitation in the stomach [48, 49]. Gastric acid would prevent gastro-esophageal bile reflux by precipitating bile, while gastric mucosal atrophy with low acid would accelerate the esophageal exposure of bile. In addition, duodeno-gastric bile reflux has been demonstrated to be associated with the development of intestinal metaplasia in the stomach as well as in the lower esophagus [5052] (Fig. 2). Patients with BE have been shown to have bile-related gastritis [53, 54]. Table 3 shows that the presence of both gastric corpus atrophy and gallstones was associated with that of ESEM more strongly than the presence of gallstones alone, suggesting the acceleration of DGER by the combination with gastric corpus atrophy. In line with this, in a population of patients with a high prevalence of H. pylori infection like the Japanese population, gastric corpus atrophy may reflect an abnormal gastric exposure to bile and lead to an abnormal esophageal exposure to bile. Since most of the cases with ESEM in the present study had short segment ESEM, the disease of the present patients might be milder than that of the enrolled patients in the previous Western studies. The positive association of gastric mucosal atrophy with ESEM suggests that the esophageal bile reflux is more important than acid reflux in the early stage of BE.
https://static-content.springer.com/image/art%3A10.1007%2Fs00535-009-0153-4/MediaObjects/535_2009_153_Fig2_HTML.gif
Fig. 2

The role of bile and gastric mucosal atrophy in the development of Barrett’s esophagus. Bile might play a main role in the development of Barrett’s esophagus. Lower esophageal bile exposure was caused by duodeno-gastro-esophageal reflux (DGER). Gallbladder dysfunction, which leads to the development of gallstones, is closely associated with the efficiency of continuous bile flow into the duodenum and the occurrence of DGER. This could be the reason why the presence of gallstones was associated with the presence of ESEM. On the other hand, DGER also caused gastric intestinal metaplasia and mucosal atrophy. In addition, gastric mucosal atrophy with low acid could enhance esophageal exposure to bile, which precipitates in the stomach with normal acidity

Although obesity is known to be associated with BE [55, 56], the multivariate analysis to investigate the association of gallstones and obesity with BE has not yet been reported. The result of the present study revealed that the presence of obesity was not an independent risk factor for ESEM, which means that the presence of obesity was confounding variable. Recent studies suggested that low plasma adiponectin is associated with the development of BE [26, 57]. On the other hand, low plasma adiponectin is thought to be also associated with the development of gallstones [58, 59]. In addition, obesity is known to increase the prevalence of hiatus hernia [60, 61]. Therefore, obesity may confound hiatus hernia or gallstones.

In conclusion, not only the presence of hiatus hernia, but also the presence of gallstones and the severity of gastric mucosal atrophy appear to be risk factors in the presence of ESEM in the Japanese outpatient population. The injurious potential of gallstones complications might be exacerbated by the presence of gastric corpus atrophy with low acid. These results suggest a causal association of distal esophageal bile exposure with the development of ESEM, which could be enhanced by severe gastric atrophy.

Acknowledgment

This study was supported by Graduate School Doctoral Student Aid Program, Keio University (to J.M.), Grant-in-Aid for Exploratory Research from the Japan Society for the Promotion of Science (JSPS) (19659057, to H.S.) and Keio Gijuku Academic Development Fund (to H.S.). The authors thank Prof. Nimish Vakil, University of Wisconsin Medical School, for his valuable instructions and suggestions for this report.

Copyright information

© Springer 2009