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World J Gastrointest Endosc. Apr 16, 2011; 3(4): 71-77
Published online Apr 16, 2011. doi: 10.4253/wjge.v3.i4.71
Assessment of gastroesophageal reflux disease by serodiagnosis of Helicobacter pylori-related chronic gastritis stage
Shotaro Enomoto, Masashi Oka, Hiroshi Ohata, Chizu Mukoubayashi, Mika Watanabe, Kosaku Moribata, Yosuke Muraki, Naoki Shingaki, Hisanobu Deguchi, Kazuki Ueda, Izumi Inoue, Takao Maekita, Mikitaka Iguchi, Kimihiko Yanaoka, Hideyuki Tamai, Mitsuhiro Fujishiro, Osamu Mohara, Masao Ichinose
Shotaro Enomoto, Masashi Oka, Chizu Mukoubayashi, Mika Watanabe, Kosaku Moribata, Yosuke Muraki, Naoki Shingaki, Hisanobu Deguchi, Kazuki Ueda, Izumi Inoue, Takao Maekita, Mikitaka Iguchi, Kimihiko Yanaoka, Hideyuki Tamai, Masao Ichinose, Second Department of Internal Medicine, Wakayama Medical University, Wakayama 641-0012, Japan
Hiroshi Ohata, Osamu Mohara, Wakayama Wellness Foundation, Wakayama 640-8404, Japan
Mitsuhiro Fujishiro, Department of Endoscopy and Endoscopic Surgery, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan
Author contributions: Enomoto S carried out the data analyses and drafted the manuscript. Ohata H, Mukoubayashi C, Watanabe M, Deguchi H and Yanaoka K carried out endoscopic examinations of the study subjects. Moribata K, Muraki Y, Shingaki N, Ueda K, Inoue I, Maekita T, Iguchi M, Tamai H, Fujishiro M and Mohara O contributed to critical review of the article. Oka M and Ichinose M contributed to the conception and design of the study and also made a substantial contribution to data acquisition. All authors read and approved the final manuscript.
Correspondence to: Shotaro Enomoto, MD, PhD, Second Department of Internal Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama-city, Wakayama 641-0012, Japan. shoe@orion.ocn.ne.jp
Telephone: +81-73-447-1335 Fax: +81-73-445-3616
Received: December 14, 2010
Revised: February 23, 2011
Accepted: March 2, 2011
Published online: April 16, 2011

Abstract

AIM: To evaluate the association of Helicobacter pylori (H.pylori)-related chronic gastritis stage with upper gastrointestinal symptoms and gastroesophageal reflux disease (GERD).

METHODS: Subjects underwent upper gastrointestinal endoscopy, a questionnaire using a frequency scale for symptoms of GERD (FSSG), and measurements of serum H.pylori-antibody and pepsinogen (PG) levels. They were classified into the following 4 groups in terms of H.pylori-related chronic gastritis stage: Group A (n = 219), H.pylori(-)PG(-); Group B (n = 310), H.pylori(+)PG(-); Group C (n = 279), H.pylori(+)PG(+); and Group D (n = 17), H.pylori(-)PG(+).

RESULTS: Reflux esophagitis occurred in 30.6% of Group A, 14.5% of Group B, 6.8% of Group C, and 0% of Group D (P < 0.001). Scores for acid reflux symptoms decreased significantly with chronic gastritis stage (from Group A to D) (P < 0.05), while scores for dysmotility symptoms did not differ significantly. The prevalence of non-erosive reflux disease (NERD) did not differ among groups. However, in subjects with GERD, the prevalence of NERD tended to increase with chronic gastritis stage (P = 0.081).

CONCLUSION: Acid reflux symptoms and the prevalence of reflux esophagitis can be assessed by measuring both serum H.pylori-antibody and PG levels.

Key Words: Gastroesophageal reflux disease, Helicobacter pylori, Pepsinogen, Screening and diagnosis


  • Citation: Enomoto S, Oka M, Ohata H, Mukoubayashi C, Watanabe M, Moribata K, Muraki Y, Shingaki N, Deguchi H, Ueda K, Inoue I, Maekita T, Iguchi M, Yanaoka K, Tamai H, Fujishiro M, Mohara O, Ichinose M. Assessment of gastroesophageal reflux disease by serodiagnosis of Helicobacter pylori-related chronic gastritis stage. World J Gastrointest Endosc 2011; 3(4): 71-77
  • URL: https://www.wjgnet.com/1948-5190/full/v3/i4/71.htm
  • DOI: https://dx.doi.org/10.4253/wjge.v3.i4.71

INTRODUCTION

Gastroesophageal reflux disease (GERD) includes not only reflux esophagitis (RE) confirmed by upper gastrointestinal endoscopy, but also non-erosive reflux disease (NERD) characterized only by subjective symptoms, such as heartburn without RE. The Montreal definition was presented as the worldwide consensus on GERD in 2006[1] and is based mostly on subjective symptoms: “GERD is a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications”. According to this definition, GERD is further classified into esophageal syndrome and extraesophageal syndrome, and a wide variety of symptoms are present. Thus, closer examination of subjective symptoms is required in differentiating GERD from other organic digestive tract diseases.

Questionnaires are effective in ascertaining the subjective symptoms of GERD patients. Many GERD-specific questionnaires have been developed[2], including the questionnaire for the diagnosis of reflux diseases[3], which is the most widely used of these questionnaires around the world. In Japan, Kusano et al developed the frequency scale for symptoms of GERD (FSSG)[4], a scale that has been used for early diagnosis and therapy assessment. Of the 12 FSSG questions, 7 questions deal with acid reflux symptoms, and the remaining 5 questions deal with gastrointestinal dysmotility symptoms, allowing GERD to be assessed by symptom group[5]. Assessing upper gastrointestinal symptoms by broadly dividing them into two groups is not only useful for planning treatment strategy for GERD[6], but it is also important for objectively analyzing the disease state.

By measuring two serum parameters, the Helicobacter pylori (H.pylori) antibody (Ab) titer and the serum pepsinogen (PG) level as a screening test for extensive chronic atrophic gastritis (CAG)[7], we have graded H.pylori-related chronic gastritis into four stages from A to D: Group A, H.pylori-negative/PG-negative; Group B, H.pylori-positive/PG-negative; Group C, H.pylori-positive/PG-positive; and Group D, H.pylori-negative/PG-positive. Group A included H.pylori non-infected healthy subjects. Group B showed established H.pylori infection, but without CAG. Group C had CAG. Group D had severe intestinal metaplasia due to progression of CAG, but H.pylori had been spontaneously eliminated, representing so-called metaplastic gastritis. CAG advances from Ato B to C, and then to D. We have documented that the incidence of gastric cancer gradually increases with chronic gastritis progression[8,9,10]. This has enabled screening of high-risk patients for gastric cancer based on serodiagnosis. An inverse relationship has been reported between CAG and RE onset[11], and many studies have found that the incidence of H.pylori infection is lower in Japanese RE patients than in healthy individuals (control group)[12-14]. A study found that NERD is closely related to H.pylori infection and progression in gastric mucosal atrophy[15]. Moreover, one study found a negative correlation between GERD and the anti-H.pylori-Ab positive rate[16], while another study documented that H.pylori infection was unrelated to GERD and was neither an exacerbating factor nor a preventive factor[17]. To the best of our knowledge, no studies have used GERD-specific questionnaires to quantify acid reflux and gastrointestinal dysmotility symptoms and to closely examine the relationships between H.pylori-related chronic gastritis progression and upper gastrointestinal symptoms.

In routine clinical care, performing endoscopy on all patients complaining of upper gastrointestinal symptoms is difficult, and some supplementary parameters would be useful to gather more information to make the diagnosis of GERD. The aim of this study was to examine the relationship of H.pylori and PG status with GERD.

MATERIALS AND METHODS
Study subjects

In Japan, health checkup programs are performed to identify selected diseases (e.g., gastric cancer) in their early stages of development. Both symptom-free subjects and subjects showing specific symptoms took part in upper gastrointestinal endoscopic examinations at our institution. Between January 2006 and March 2008, a total of 1165 factory workers (1147 males, 18 females) ranging in age from 40 to 70 years who underwent upper gastrointestinal endoscopy and completed the FSSG questionnaire were enrolled. In addition, all enrolled subjects underwent serological testing and their H.pylori-Ab titers and serum PG levels were measured. Subjects who had a previous history of surgical resection of the stomach, H.pylori eradication, or those who had been prescribed a proton pump inhibitor (PPI), which might affect gastrointestinal function, were excluded from the study. Furthermore, subjects with and without H.pylori infection were selected for the study using serum-specific antibody titers as described in the following section. Thus, 825 subjects (812 males, 13 females) were eligible for this study. The ethics committee of Wakayama Medical University approved the study protocols.

Diagnosis of H.pylori infection and extensive CAG by serological tests

H.pylori-Ab titers were measured using an enzyme-linked immunosorbent assay (ELISA) (MBL, Nagoya, Japan)[18]. In the present study, H.pylori-Ab titers ≥ 50 U/mL were taken to be H.pylori-positive, and < 30 U/mL indicated H.pylori-negative. H.pylori-Ab titers ≥ 30 but < 50 U/mL were considered unclassifiable, and subjects showing titers within this range were excluded from H.pylori infection assessment. The sensitivity and specificity of the ELISA test used in this study were 93.5% and 92.5%, respectively[18]. Serum PG levels were measured by radioimmunoassay (Dainabot, Tokyo, Japan)[19]. PG, a measure of gastric atrophy, was considered positive for values of PG I ≤ 70 μg/L with a PG I/II ratio of ≤ 3[20,21]. These criteria offer a sensitivity of 70.5% and a specificity of 97% for the diagnosis of extensive CAG, using pathological diagnosis as the gold standard[20]. Subjects for whom both H.pylori infection and PG level could be determined were divided into the following four groups in terms of H.pylori-related chronic gastritis stage: Group A, H.pylori-negative/PG-negative; Group B, H.pylori-positive/PG-negative; Group C, H.pylori-positive/PG-positive; and Group D, H.pylori-negative/PG-positive[8].

Endoscopic findings of RE

RE was diagnosed by upper gastrointestinal endoscopy. According to the Los Angeles classification system[22], Grades A through D indicate erosive esophagitis. In the present study, only patients with erosive esophagitis were diagnosed with RE, and subjects with Grade M (minimal change)[23]or Grade N were not diagnosed with RE. Hiatal hernia was diagnosed endoscopically when the distance between the crural impression and the gastroesophageal junction was 2 cm or more.

Assessment of FSSG questionnaire and determination of GERD

Using the FSSG questionnaire, subjective symptoms of GERD were quantified, and total, acid reflux, and gastrointestinal dysmotility scores were calculated. GERD was defined as a total score ≥ 8, which is the recommended cut-off FSSG value for GERD[4]. Furthermore, NERD was defined as total score ≥ 8 without endoscopic erosive esophagitis.

Statistical analysis

All data analyses were performed using SPSS version 11.0 software (SPSS, Chicago, IL, USA). Pair-wise differences in the FSSG score were analyzed using the unpaired Student’s t-test, and overall differences in age and FSSG score were analyzed using the Kruskal-Wallis test. Pair-wise and overall differences in categorical variables were analyzed by Fisher’s exact test. All tests were 2-sided, and values of P < 0.05 were considered significant. Data are expressed as means ± standard deviation.

RESULTS
Clinical characteristics of study subjects

As mentioned above, of the 1165 subjects in whom H.pylori-Ab titers and serum PG levels were measured, those meeting the exclusion criteria were removed. Most of the remaining 825 subjects were men (98.4%) and drinkers (74.9%). Reflecting the high incidence of H.pylori infection among middle-aged and elderly individuals in Japan, the incidence of H.pylori infection was high (71.4%). With regard to RE, Grade D (the most severe LA grade) was not seen in any subjects, and Grades A and B (mild grades) accounted for 94.6% of cases.

Comparison of upper gastrointestinal symptoms and RE between H.pylori-positive and H.pylori-negative subjects and between PG-positive and PG-negative subjects

The analysis was conducted between H.pylori-positive (n = 589) and H.pylori-negative (n = 236) subjects and between PG-positive (n = 296) and PG-negative (n = 529) subjects (Table 1). The prevalence of RE was significantly higher for PG- and H.pylori-negative subjects than for their positive counterparts (P < 0.001). The acid reflux score was significantly higher for PG-negative subjects than for PG-positive subjects (P < 0.05), but no significant difference existed between H.pylori-positive and -negative subjects. No significant differences in gastrointestinal dysmotility scores between H.pylori-positive and -negative subjects or between PG-positive and -negative subjects were present. The prevalence of GERD patients with total FSSG scores ≥ 8 tended to be high for PG-negative subjects (P = 0.076), but no significant difference existed between H.pylori-positive and -negative subjects. While no significant difference in the prevalence of NERD patients was evident between H.pylori-positive and -negative subjects or between PG-positive and -negative subjects, the prevalence of NERD among GERD patients was significantly higher for H.pylori-positive subjects (P = 0.027).

Table 1 Relationship between H.pylori infection or serum PG test and upper abdominal symb to ms erosive reflux esophagitis.
H.pylori infection
P valueSerum PG test
P value
-+-+
n236589529296
FSSG
-total score (mean ± SD)3.58 ± 4.003.17 ± 3.900.1753.45 ± 3.962.99 ± 3.870.104
-acid reflux score (mean ± SD)1.78 ± 2.211.62 ± 2.320.3501.79 ± 2.331.45 ± 2.200.038
-dysmotility score (mean ± SD)1.80 ± 2.321.55 ± 1.990.1271.66 ± 2.141.54 ± 2.020.432
Erosive esophagitis (LA grade A-D)28.4%(67/236)10.7%(63/589)0.00021.2%(112/529)6.1%(18/296)0.000
FSSG total score ≥ 8 (= GERD)13.6%(32/236)11.7%(69/589)0.46513.8%(73/529)9.5%(28/296)0.076
FSSG total score ≥ 8 and non-erosive esophagitis (= NERD)8.1%(19/236)9.5%(56/589)0.5109.8%(52/529)7.8%(23/296)0.377
NERD/GERD59.4%(19/32)81.2%(56/69)0.02771.2%(52/73)82.1%(23/28)0.317
Relationship of the stage of H.pylori-related chronic gastritis to upper gastrointestinal symptoms and RE

The stage of H.pylori-related chronic gastritis was assessed in the 825 subjects (Table 2). With regard to background factors, significant differences were seen in age. The prevalence of RE showed significant decreases with the stage of the chronic gastritis (from Group A to D) (P < 0.001). Acid reflux scores showed a significant decrease with the chronic gastritis stage (P < 0.05). The gastrointestinal dysmotility score showed no significant differences between stages (P = 0.800). The ratios of GERD patients with total FSSG scores ≥ 8 showed no significant differences related to the chronic gastritis stage. No significant differences existed in the prevalence of NERD patients among Groups A, B, and C. However, the prevalence of NERD among GERD patients for Groups A, B, and C tended to increase with the chronic gastritis stage (P = 0.081).

Table 2 Relationship between the stage of H.pylori-related chronic gasrtritis ang upper abdominal symptoms or erosive reflux esophagitis.
Stages of H.pylori-related chronic gastritisGroup AGroup BGroup CGroup DOverall P value
H.pylori infection-++-
Serum PG test (extensive CAG)--++
n21931027917
Age (years: mean ± SD)55.23 ± 4.2355.84 ± 4.056.79 ± 3.9153.94 ± 5.010.001
Sex (male/female)214/5308/2273/617/00.306
Smokers44.29%35.16%41.58%41.18%0.164
Drinkers75.34%75.48%74.19%70.59%0.939
Serum PG I(ng/mL mean ± SD)59.82 ± 26.5281.76 ± 48.1636.59 ± 18.4221.98 ± 15.99-
Serum PG II(ng/mL mean ± SD)10.80 ± 5.8125.89 ± 18.4220.70 ± 8.6012.89 ± 4.84-
PG I/II5.70 ± 1.133.74 ± 1.311.76 ± 0.691.53 ± 0.95-
H.pylori Ig G Ab titer (U/mL mean ± SD)13.54 ± 5.26475.31 ± 632.73441.07 ± 50.9416.71 ± 6.44-
FSSG
-total score (mean ± SD)3.69 ± 4.013.33 ± 3.873.00 ± 3.942.88 ± 2.550.183
-acid reflux score (mean ± SD)1.83 ± 2.261.77 ± 2.391.46 ± 2.251.29 ± 1.260.038
-dysmotility score (mean ± SD)1.81 ± 2.371.56 ± 1.961.54 ± 2.031.59 ± 1.770.800
Erosive esophagitis (LA grade A-D)30.6%(67/21914.5%(45/310)6.5%(18/279)0%(0/17)0.000
LA grade A/B/C/D45/18/4/030/13/2/011/6/1/00/0/0/0-
Hiatal hernia3.2%(7/219)5.8%(18/310)7.2%(20/279)5.9%(1/17)0.231
FSSG total score ≥ 8 (=GERD)14.6%(32/219)13.2%(41/310)9.7%(28/279)0%(0/17)0.177
FSSG total score ≥ 8 and non-erosive esophagitis (=NERD)8.7%(19/219)10.6%(33/310)8.2%(23/279)0%(0/17)0.496
NERD/GERD59.4%(19/32)80.5%(33/41)82.1%(23/28)-0.081
DISCUSSION

Previously, we have investigated the risk of gastric cancer based on H.pylori-related chronic gastritis stage as assessed by a combination of H.pylori-Ab titer and serum PG level[8]. The present results suggest that the disease states of GERD and NERD can also be assessed by evaluating the risk for RE and upper gastrointestinal symptoms accompanying gastric acid reflux and gastrointestinal dysmotility. As reported previously[11], the prevalence of RE was low for subjects with CAG. The FSSG was used to closely examine upper gastrointestinal symptoms, and acid reflux scores were low for the group in the advanced stages of H.pylori-related chronic gastritis, but no marked difference in gastrointestinal dysmotility scores was seen in relation to the chronic gastritis stage. The prevalence of NERD patients among GERD patients was lowest for Group A and highest for Group C, clarifying the relationship between NERD and the stage of H.pylori-related chronic astritis.

Compared to Western countries, the number of GERD patients is lower in Japan, and the prevalence of NERD among GERD patients is higher[24]. Differences exist in the extent of CAG and in its associated reduction in gastric acid secretion that strongly correlate to H.pylori infection differences between Japan and Western countries[25], and the present study also showed that they most closely reflected the disease state of GERD in Japan. The prevalence of CagA+ H.pylori[26], which correlates pathologically to atrophic gastritis, is particularly high in Japan[27]. This is believed to contribute to differences in the relationship between GERD and H.pylori infection[28] in Japan and Western countries[29].

The present study also assessed the difference between H.pylori-positive and H.pylori-negative subjects and between PG-positive and PG-negative subjects. No significant differences existed in acid reflux and dysmotility scores between H.pylori-positive and H.pylori-negative subjects. Upper gastrointestinal symptom scores, particularly acid reflux scores, were significantly higher for PG-positive subjects than for PG-negative subjects. No significant differences existed in the prevalence of GERD patients with total FSSG scores ≥ 8 between H.pylori-positive and H.pylori-negative subjects, but the prevalence was greater for PG-negative subjects than for PG-positive subjects. GERD-related upper gastrointestinal symptoms are thus more closely influenced by extensive CAG than H.pylori infection. However, the finding that the incidence of endoscopy-diagnosed RE for H.pylori-negative subjects and PG-negative subjects was higher compared to their positive counterparts was very interesting. In other words, reduced acid secretion due to CAG has a great effect on the suppression of esophageal mucosal erosion, and, of the various subjective symptoms, acid reflux symptoms are suppressed because gastric acid secretion is markedly low. This might be the reason why the prevalence of NERD among GERD patients changes according to the H.pylori-related chronic gastritis groups.

The prevalence of NERD among subjects with total FSSG scores ≥ 8 was higher for H.pylori-positive subjects than for their negative counterparts. Groups A-D showed no marked differences in gastrointestinal dysmotility scores, and no marked differences were apparent between H.pylori-positive and H.pylori-negative subjects or between PG-positive and PG-negative subjects. These findings are extremely important when studying the disease state of GERD. In other words, in Groups C and D, where gastric mucosal atrophy is severely advanced, the symptoms and onset of NERD are influenced by gastrointestinal dysmotility rather than acid reflux, thus affecting therapy planning[6].

At present, the incidence of H.pylori infection is decreasing in Japan, and the number of patients with chronic atrophic gastritis or gastric cancer is expected to decrease in the future. However, the number of Group A subjects (H.pylori-negative and PG-negative) is likely to increase. Therefore, RE in Group A subjects who may experience both acid reflux and dysmotility symptoms must be managed. In Groups C and D, with a higher risk of gastric cancer[8,30], treatments are provided less frequently for RE, but because acid reflux symptoms are lacking, these subjects are less likely to visit a medical center on their own and undergo thorough testing, such as upper gastrointestinal endoscopy.

Instead of prospectively observing the onset rate of GERD over a long period of time, the present study analyzed GERD-related symptoms and the prevalence of endoscopic RE, based on the stage of H.pylori-related chronic gastritis at a single time point when endoscopy and history-taking were performed. A prospective study based on long-term follow-up observation is needed to more accurately assess GERD risks. However, acid reducers, including PPIs, are often prescribed to patients with upper abdominal symptoms, and various therapeutic modifications make such studies difficult to implement. The present study involved a group of workers, consisting of almost all males, who underwent endoscopy as part of regular checkup programs of gastric cancer screening. Thus, since most study subjects were men, this must be taken into account when interpreting the results. The present study clarified that H.pylori infection and CAG stage correlate closely with acid reflux and dysmotility symptoms. However, because GERD is a disease that is closely related to diet and lifestyle diseases such as obesity and diabetes[31-33], thorough investigation of the correlations of these factors to upper gastrointestinal symptoms is necessary using a GERD-specific questionnaire. Furthermore, ambulatory esophageal pH (with/without impedance) monitoring was not done in this study, and the term "NERD" might not be appropriate. NERD cases include functional heartburn cases in this study, and this should be taken into consideration when interpreting the data.

In conclusion, the present results suggest that the disease state of GERD was related to the stage of H.pylori-related chronic gastritis based on measurements of H.pylori-Ab titers and serum PG levels (Figure 1). These two serum markers can be measured conveniently, noninvasively, and relatively inexpensively. The reproducibility of test results is high, and many specimens can be measured at the same time. Like Japan, the prevalence of H.pylori infection is high and the development of CAG is closely involved with gastric cancer in East Asian countries, such as China and Korea and in Eastern Europe, and Middle and South America. Conducting serum tests along with routine endoscopic examination is useful not only for gastric cancer screening, but also to obtain more information about patients with reflux disease.

Figure 1
Figure 1 Schematic of the results of this study. H.pylori: Helicobacter pylori infection; PG: serum pepsinogen test; CAG: chronic atrophic gastritis.
COMMENTS
Background

We have classified the progression of Helicobacter pylori (H.pylori)-related chronic gastritis into 4 groups (A-D) on the basis of two serum parameters, H.pylori antibody (H.pylori-Ab) titer and serum pepsinogen (PG) level, as a screening test for extensive chronic atrophic gastritis (CAG), and reported a stepwise increase in the incidence of gastric cancer. In this study, the association of H.pylori-related chronic gastritis progression with upper gastrointestinal symptoms and gastroesophageal reflux disease (GERD) was evaluated, because there are only a few previous studies in which this association has been examined.

Research frontiers

This study can help us to understand the natural history of GERD, as well as other illnesses including gastric cancer.

Innovations and breakthroughs

Conducting serum tests along with routine endoscopic examination is useful for not only gastric cancer screening, but also to obtain more information about patients with GERD.

Applications

A prospective study based on long-term follow-up observation is needed to more accurately assess GERD risks.

Terminology

H.pylori-related chronic gastritis stage: The groups were determined by the results of the 2 serologic tests (H.pylori-Ab and PG). This classification reflects each stage of the serial changes in stomach mucosa induced by chronic H.pylori infection. The H.pylori-free healthy condition corresponds to 2 negative tests (Group A). With the establishment of H.pylori infection, the antibody test becomes positive (Group B). As the infection spreads, the PG test also turns positive (Group C). Group C has extensive CAG. Intestinal metaplasia develops and spreads in the presence of CAG, leading to reduction of the bacterial load in the stomach. This results in a negative specific antibody test (Group D). Thus, Group D comprises those subjects with metaplastic gastritis.

Peer review

This article provides interesting data about H.pylori-Ab and serum PG levels in subjects with GERD. These data are of epidemiological interest and provide some insight into theoretical aspects.

Footnotes

Peer reviewers: Young-Tae Bak, MD, PhD, Professor, Division of Gastroenterology, Department of Internal Medicine, Korea University, Guro Hospital, 97 Gurodong-gil, Guro-gu, Seoul 152-703, South Korea; Oscar Tatsuya Teramoto-Matsubara, MedCenter, Av. Paseo de las Palmas 745-102, Lomas de Chapultepec, Mexico D.F. 11000, Mexico; Peter Born, MD, Professor, D-80634 second Department of Medicine, Red Cross Hospital, Munich, Germany

S- Editor Zhang HN L- Editor Hughes D E- Editor Zhang L

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