Abstract
The purpose is to elucidate factors related to negative results of anti-H. pylori antibody test in cases with gastric mucosal atrophy. A total of 859 individuals without past history of eradication therapy for H. pylori (545 males, 314 females; mean age 52.4 years) who underwent an upper GI endoscopy examination and serological test were enrolled as subjects. Serological testing was performed using SphereLight H. pylori antibody J®, and endoscopic findings of gastric mucosal atrophy by the classification of Kimura and Takemoto and post-eradication findings were analyzed. The positive rates for the anti-H. pylori antibody test in subjects with and without gastric mucosal atrophy were 85.6% and 0.9%, respectively. In analysis of subjects with gastric mucosal atrophy, a low positive rate and serum titer was observed in subjects with C1, C2 and O3 atrophy. When the analysis was performed separately in male and female subjects, low positive rate was observed in males with O3 atrophy and females with C2 atrophy. Suspected post-eradication endoscopic findings were more frequently observed in cases with C2 atrophy. In conclusion, negative result of anti-H. pylori antibody test was frequently observed in middle-aged subjects with C1, C2 and O3 gastric mucosal atrophy.
Keywords: Helicobacter pylori, diagnosis, serologic tests, endoscopy, atrophy
Introduction
Helicobacter pylori (H. pylori) infection is known to cause several types of gastrointestinal diseases, such as gastritis, peptic ulcers and gastric cancer,(1–7) thus eradication therapy is widely recommended to prevent their occurrence.(7–12) As a result, it is very important to accurately diagnose H. pylori infection in clinical situations, with several different invasive and non-invasive methods available.(13,14) Among the available methods, a serologic test for H. pylori infection is easily performed using obtained serum samples for both epidemiologic studies involving large numbers of subjects as well as in clinical practice for individual patients. It has been reported that the sensitivity and specificity of serological methods for detection of H. pylori infection range from 80% to 90%.(14) On the other hand, the diagnostic accuracy of serological methods for diagnosis of H. pylori infection has been shown to vary based on the duration of exposure to H. pylori, cross-antigenicity with other prevalent antigenically related bacteria such as Campylobacter, the diversity of H. pylori strains in different regions, host immune response, the grade of histological gastritis, and the density of H. pylori.(14–20) The diagnostic accuracy of serological tests for H. pylori in Japanese subjects has been repeatedly demonstrated to increase when using kits derived from antigens of H. pylori strains obtained from Japanese patients.(17–20) SphereLight H. pylori antibody J® (Wako Pure Chem. Ind., Ltd., Osaka), a recently introduced anti-H. pylori IgG antibody detection kit, was developed using antigens from H. pylori strains derived from Japanese patients. This kit has been shown to have a high efficacy for diagnosis of infection,(21,22) and the serum titer of this test is nearly equal to that of another anti-H. pylori IgG antibody test (Eiken Chemical Co., Ltd., Tokyo) (unpublished data). In order to increase the sensitivity of diagnosis for H. pylori infection, an antibody titer of ≥4.0 U/ml is defined as positive in the SphereLight H. pylori antibody J test, while the cut-off value in the Eiken anti-H. pylori IgG antibody test is set at 10 U/ml. We have found that some patients without past-history of eradication therapy for H. pylori also show a negative result in the SphereLight H. pylori antibody J test, even though they have endoscopic evidence of gastric mucosal atrophy, which is mainly caused by long-term H. pylori infection.(23,24) Therefore, we performed the present retrospective study to elucidate factors related to a negative result in the SphereLight H. pylori antibody J test in cases with gastric mucosal atrophy by analyzing the presence of post-eradication endoscopic findings, based on several recent studies.(25–30)
Materials and Methods
The subjects were individuals who visited the Health Center of Shimane Environment and Health Public Corporation for a detailed medical checkup examination between April 2014 and March 2015. The majority were socially active and productive, and considered to be socioeconomically middle class. Those with a history of gastric surgery and eradication therapy for H. pylori infection, carefully confirmed by a public health nurse, were excluded. Those who had taken such medications as proton pump inhibitors and H2 receptor antagonists were also excluded. Finally, 859 subjects (545 males, 314 females; mean age 52.4 years) who underwent upper GI endoscopic examinations and serum anti-H. pylori IgG antibody testing on the same day were enrolled as subjects. None had severely abnormal findings in renal and liver function tests.
Serum anti-H. pylori IgG antibody detection was performed using SphereLight H. pylori antibody J®. The antibody titer was automatically measured using a chemiluminescent enzyme immunoassay method. An antibody titer ≥4.0 U/ml was defined as positive, according to the manufacturer’s instruction sheet.
All upper endoscopic examinations were performed by licensed experienced endoscopists (K.A., T.M., S.T.) using an EG-530NW or EG-530NP endoscope (Fujifilm, Tokyo, Japan). When gastric mucosal atrophy was endoscopically observed, its degree was evaluated using the classification of Kimura and Takemoto, in which gastric mucosal atrophy is classified into 6 groups (C1, C2, C3, O1, O2, O3).(31) The cases without gastric mucosal atrophy was diagnosed as C0 in this study. The presence of gastric mucosal atrophy was carefully determined by the presence or absence of regular arrangement of collecting venules at angular portion and atrophic border in the cases with thin gastric mucosa. When cases with endoscopic evidence of gastric mucosal atrophy showed a negative result in the anti-H. pylori IgG antibody test, we investigated the existence of endoscopic evidence of post-eradication by examining for the presence of characteristic endoscopic findings in the stomach. For this study, we defined suspected post-eradication cases based on the presence of map-like redness or depressed patchy redness, as well as absence of diffuse redness, mucosal swelling, sticky mucous, and enlarged folds in endoscopic images.(25–30) The degree of endoscopically evident gastric mucosal atrophy and presence of suspected post-eradication findings in each study subject were simultaneously reviewed and determined by the same 3 licensed endoscopists.
Statistical analyses were performed using chi-squared, Kruskal-Wallis, and Mann-Whitney U tests. All calculations were done using the Stat View 5.0 software program (Abacus Concepts Inc., Berkeley, CA) for Macintosh and differences of p<0.05 were considered to be statistically significant.
This study was performed in accordance with the Declaration of Helsinki, and the protocol was approved by the ethics committee of the Shimane Environment and Health Public Corporation. Written informed consent indicating that clinical data would be used for a clinical study without release of individual information was obtained from all subjects before performing the medical checkup examinations.
Results
We found that 468 subjects were positive and 391 were negative for the anti-H. pylori IgG antibody. Furthermore, the positive rates for the anti-H. pylori IgG antibody in subjects with and without gastric mucosal atrophy were 85.6% and 0.9%, respectively (Table 1). The characteristics of our subjects without as well as with several degrees of gastric mucosal atrophy are shown in Table 2. Cases with higher grades of gastric mucosal atrophy were older as compared to those with lower grades or no atrophy. When the positive rate and serum titer of the anti-H. pylori IgG antibody were analyzed as variables, the subjects with C2 and O3 of gastric mucosal atrophy had a low positive rate. In addition, the serum titer was low in subjects with C1, C2 and O3 gastric mucosal atrophy, and the number of cases with serum titer of ≥40.0 U/ml was relatively small in these subjects. The serum titers of all cases without gastric mucosal atrophy (C0) were less than 10 U/ml (Table 2).
Table 1.
Results of serum anti-H. pylori IgG test and presence of gastric mucosal atrophy
| Serum anti-H. pylori IgG test |
||
|---|---|---|
| Positive | Negative | |
| Cases with gastric mucosal atrophy | 465 | 78 |
| Cases without gastric mucosal atrophy | 3 | 313 |
Data are expressed as number of cases.
Table 2.
Results of serum anti-H. pylori IgG test and degree of gastric mucosal atrophy
| Gastric mucosal atrophy | C0 | C1 | C2 | C3 | O1 | O2 | O3 |
|---|---|---|---|---|---|---|---|
| Number of subjects | 316 | 27 | 162 | 139 | 93 | 75 | 47 |
| Gender (male/female) | 196/120 | 19/8 | 101/61 | 80/59 | 58/35 | 59/16 | 32/15 |
| Age in years (mean ± SE) | 49.2 ± 0.5 | 49.3 ± 1.9 | 51.8 ± 0.7 | 52.8 ± 0.7 | 55.4 ± 0.9 | 57.4 ± 1.0 | 62.4 ± 1.3 |
| Positive of serum anti-H. pylori IgG test (%) | 3 (1.0) | 25 (92.6) | 127 (78.4) | 127 (91.4) | 81 (87.1) | 68 (90.7) | 37 (78.7) |
| Titer of serum anti-H. pylori IgG test (U/ml) (mean ± SE) | 0.8 ± 0.0 | 16.0 ± 3.3 | 23.4 ± 2.1 | 35.5 ± 4.7 | 32.4 ± 4.2 | 31.8 ± 3.5 | 26.3 ± 5.8 |
| Distribution of titer of serum anti-H. pylori IgG test | |||||||
| Number of subjects with titer of 0.0~0.9 U/ml (%) | 226 (71.5) | 1 (3.7) | 9 (5.6) | 6 (4.3) | 4 (4.3) | 0 | 2 (4.3) |
| Number of subjects with titer of 1.0~1.9 U/ml (%) | 53 (16.8) | 0 | 9 (5.6) | 2 (1.4) | 1 (1.1) | 2 (2.7) | 5 (10.6) |
| Number of subjects with titer of 2.0~2.9 U/ml (%) | 26 (8.2) | 0 | 7 (4.3) | 4 (2.9) | 4 (4.3) | 3 (4.0) | 2 (4.3) |
| Number of subjects with titer of 3.0~3.9 U/ml (%) | 8 (2.5) | 1 (3.7) | 10 (6.1) | 0 | 3(3.2) | 2 (2.7) | 1 (2.1) |
| Number of subjects with titer of 4.0~9.9 U/ml (%) | 3 (0.9) | 10 (37.0) | 35 (21.6) | 21 (15.1) | 20 (21.5) | 15 (20.0) | 12 (25.5) |
| Number of subjects with titer of 10.0~39.9 U/ml (%) | 0 | 13 (48.1) | 64 (39.5) | 72 (51.8) | 34 (36.6) | 32 (42.7) | 16 (34.0) |
| Number of subjects with titer of ≥40.0 U/ml (%) | 0 | 2 (7.4) | 28 (17.3) | 34 (24.5) | 27 (29.0) | 21 (28.0) | 9 (19.1) |
The degree of gastric mucosal atrophy was endoscopically evaluated using the classification of Kimura and Takemoto. There is significant difference in the distribution of titer of serum anti-H. pylori IgG test among the subjects with different degrees of gastric mucosal atrophy (C1~O3).
When the positive rate and serum titer of the anti-H. pylori IgG antibody were analyzed separately in male and female subjects, male subjects with O3 gastric mucosal atrophy and female subjects with C2 gastric mucosal atrophy had a low positive rate. In addition, low serum titer was observed in both males and females with mild gastric mucosal atrophy. When endoscopic post-eradication findings were investigated in 78 cases with gastric mucosal atrophy and negative result in the anti-H. pylori IgG antibody test, 52 cases had suspected post-eradication findings endoscopically. In 24 among these 52 cases, previous other diagnostic methods in our institute or other medical centers also showed negative results for H. pylori infection by their medical records. Interestingly, suspected post-eradication findings were more frequently observed in both females and males with C2 gastric mucosal atrophy (Table 3).
Table 3.
Gender and the results of serum anti-H. pylori IgG test
| Gastric mucosal atrophy | C1 | C2 | C3 | O1 | O2 | O3 |
|---|---|---|---|---|---|---|
| Male subjects (number of subjects) | 19 | 101 | 80 | 58 | 59 | 32 |
| Age in years (mean ± SE) | 50.3 ± 2.1 | 51.4 ± 0.9 | 53.4 ± 1.0 | 55.2 ± 1.2 | 57.7 ± 1.0#2,3 | 61.8 ± 1.4#1–5 |
| Positive of serum anti-H. pylori IgG test (%) | 18 (94.7) | 86 (85.1)* | 72 (90.0) | 51 (87.3) | 52 (88.1) | 23 (71.9)#1,3 |
| Titer of serum anti-H. pylori IgG test (U/ml) (mean ± SE) | 14.8 ± 3.0 | 25.9 ± 2.7* | 39.7 ± 7.7#2 | 37.8 ± 6.1#2 | 32.5 ± 4.1 | 24.8 ± 5.5 |
| Cases with suspected post-eradication findings† (%) | 0 | 12 (11.9)* | 5 (6.3) | 6 (10.3) | 3 (5.1) | 4 (12.5) |
| Female subjects (number of subjects) | 8 | 61 | 59 | 35 | 16 | 15 |
| Age in years (mean ± SE) | 46.8 ± 4.7 | 52.5 ± 1.2 | 52.1 ± 1.0 | 55.6 ± 1.5#1,2 | 56.4 ± 2.5#1 | 63.9 ± 2.7#1–5 |
| Positive of serum anti-H. pylori IgG test (%) | 7 (87.5) | 41 (67.2)* | 55 (93.2)#2 | 30 (85.7)#2 | 16 (100)#2 | 14 (93.3)#2 |
| Titer of serum anti-H. pylori IgG test (U/ml) (mean ± SE) | 18.8 ± 8.8 | 19.1 ± 3.3* | 29.7 ± 3.7#2 | 23.4 ± 4.5 | 29.4 ± 6.2#2 | 29.3 ± 14.0 |
| Cases with suspected post-eradication findings† (%) | 0 | 17 (27.9)* | 2 (3.4)#2 | 3 (8.6)#2 | 0#2 | 0#2 |
The degree of gastric mucosal atrophy was endoscopically evaluated using the classification of Kimura and Takemoto.
†Suspected post-eradication findings: presence of map-like redness or patchy redness, and absence of diffuse redness, mucosal swelling, sticky mucous, and enlarged folds. *Significant difference between males and females. #1,2,3,4,5Significant difference vs C1, C2, C3, O1, O2 gastric mucosal atrophy, respectively.
Discussion
In this study, we investigated the factors causing a negative result in the SphereLight H. pylori antibody J test in cases with gastric mucosal atrophy. Continuous H. pylori infection is a main cause of gastric mucosal atrophy, and nearly all Japanese individuals with gastric mucosal atrophy and without a past history of H. pylori eradication therapy are considered to be infected.(23,24) However, 78 of the present 543 study subjects with evidence of gastric mucosal atrophy were not positive in results of anti-H. pylori IgG antibody testing of their serum. Male subjects with O3 grade of gastric mucosal atrophy showed a lower positive rate in antibody test, and subjects with with C2 gastric mucosal atrophy showed a low positive rate and titer of the antibody in this study. There are several possibilities to explain why our subjects with gastric mucosal atrophy had negative results in the anti-H. pylori IgG antibody test, including the antigens used to produce the anti-H. pylori IgG antibody test kit did not match those possessed by the subjects. However, the kit employed for this study was produced using antigens from H. pylori strains derived from Japanese patients and its good accuracy has been demonstrated.(21,22) Low serum titer of the anti-H. pylori IgG antibody easily induces to a negative result in an anti-H. pylori IgG antibody test, although the cut off value for the SphereLight H. pylori antibody J test is set at 4.0 U/ml to increase sensitivity for diagnosis of H. pylori infection. The disappearance of H. pylori in the stomach is well known to occur due to intestinal metaplasia after long-term infection, while several investigators have also reported that a lower serum titer of the antibody is correlated with the progression of gastric mucosal atrophy.(32–35) Indeed, a relatively low positive rate in antibody test was observed in subjects with O3 gastric mucosal atrophy in the present study, especially in male. On the other hand, we could not clearly explain the lower positive rate and titer of the antibody in subjects with mild gastric mucosal atrophy. The titer of the antibody has been shown to vary based on the duration of exposure to H. pylori, the grade of histological gastritis and the density of H. pylori.(9,15–20) A majority of our study subjects were middle-aged, and the subjects with H. pylori infection are considered to have long exposure duration to H. pylori, since H. pylori infection generally occurs during childhood.(23,36) Therefore, the lower titer of the antibody in subjects with mild gastric mucosal atrophy may be caused by the low grade immune response to H. pylori, low grade of histological gastritis and low density of H. pylori. In addition, unplanned natural eradication is considered to correlate with low positive rate and titer of the antibody in subjects with C2 gastric mucosal atrophy, since suspected post-eradication was more frequently observed in cases with C2 atrophy. When serum antibody test is negative in middle-aged cases with mild gastric mucosal atrophy in clinical practice, we should carefully examine the presence of H. pylori infection by other diagnostic methods, since low titer of antibody test could cause the negative results. In addition, the possibility of unplanned eradication should be considered in these cases.
Our study has several limitations. We only utilized one type of serum anti-H. pylori IgG antibody test to evaluate the status of H. pylori infection and did not employ other diagnostic methods, as the study was a retrospective examination of individuals who visited a medical center for a detailed medical checkup. In addition, a majority of our subjects were socially active, productive, and socioeconomically middle class, thus young and elderly individuals were relatively few. Additional large-scale investigations employing other anti-H. pylori IgG antibody tests are needed to clarify the present observations, including our findings that subjects, especially females, with a mild degree of gastric mucosal atrophy had a low positive rate and serum titer in the anti-H. pylori IgG antibody test.
In summary, we investigated the factors causing a negative result in anti-H. pylori IgG antibody testing in subjects with evidence of gastric mucosal atrophy. We found that the middle-aged subjects with a mild degree of gastric mucosal atrophy had a low positive rate and titer in serum, and endoscopic suspected post-eradication findings was more frequently observed in these cases.
Acknowledgments
Declaration of funding interest: none.
Conflict of Interest
No potential conflicts of interest were disclosed.
References
- 1.Correa P, Houghton J. Carcinogenesis of Helicobacter pylori. Gastroenterology. 2007;133:659–672. doi: 10.1053/j.gastro.2007.06.026. [DOI] [PubMed] [Google Scholar]
- 2.Kuehn BM. Nobels honor research on ulcer microbe, “green” drug production method. JAMA. 2005;294:2289–2290. doi: 10.1001/jama.294.18.2289. [DOI] [PubMed] [Google Scholar]
- 3.Bayerdörffer E, Neubauer A, Rudolph B, et al. Regression of primary gastric lymphoma of mucosa-associated lymphoid tissue type after cure of Helicobacter pylori infection. Lancet. 1995;345:1591–1594. doi: 10.1016/s0140-6736(95)90113-2. [DOI] [PubMed] [Google Scholar]
- 4.Nomura A, Stemmermann GN, Chyou PH, Kato I, Perez-Perez GI, Blaser MJ. Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N Engl J Med. 1991;325:1132–1136. doi: 10.1056/NEJM199110173251604. [DOI] [PubMed] [Google Scholar]
- 5.Parsonnet J, Friedman GD, Vandersteen DP, et al. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med. 1991;325:1127–1131. doi: 10.1056/NEJM199110173251603. [DOI] [PubMed] [Google Scholar]
- 6.Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 2001;345:784–789. doi: 10.1056/NEJMoa001999. [DOI] [PubMed] [Google Scholar]
- 7.Hirata K, Suzuki H, Matsuzaki J, et al. Improvement of reflux symptom related quality of life after Helicobacter pylori eradication therapy. J Clin Biochem Nutr. 2013;52:172–178. doi: 10.3164/jcbn.12-107. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Asaka M, Kato M, Sugiyama T, et al. Follow-up survey of a large-scale multicenter, double-blind study of triple therapy with lansoprazole, amoxicillin, and clarithromycin for eradication of Helicobacter pylori in Japanese peptic ulcer patients. J Gastroenterol. 2003;38:339–347. doi: 10.1007/s005350300061. [DOI] [PubMed] [Google Scholar]
- 9.Miwa H, Sakaki N, Sugano K, et al. Recurrent peptic ulcers in patients following successful Helicobacter pylori eradication: a multicenter study of 4940 patients. Helicobacter. 2004;9:9–16. doi: 10.1111/j.1083-4389.2004.00194.x. [DOI] [PubMed] [Google Scholar]
- 10.Uemura N, Mukai T, Okamoto S, et al. Effect of Helicobacter pylori eradication on subsequent development of cancer after endoscopic resection of early gastric cancer. Cancer Epidemiol Biomarkers Prev. 1997;6:639–642. [PubMed] [Google Scholar]
- 11.Fukase K, Kato M, Kikuchi S, et al. Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomised controlled trial. Lancet. 2008;372:392–397. doi: 10.1016/S0140-6736(08)61159-9. [DOI] [PubMed] [Google Scholar]
- 12.Take S, Mizuno M, Ishiki K, et al. Seventeen-year effects of eradicating Helicobacter pylori on the prevention of gastric cancer in patients with peptic ulcer; a prospective cohort study. J Gastroenterol. 2015;50:638–644. doi: 10.1007/s00535-014-1004-5. [DOI] [PubMed] [Google Scholar]
- 13.Vaira D, Holton J, Menegatti M, et al. Review article: invasive and non-invasive tests for Helicobacter pylori infection. Aliment Pharmacol Ther. 2000;14 Suppl 3:13–22. doi: 10.1046/j.1365-2036.2000.00096.x. [DOI] [PubMed] [Google Scholar]
- 14.Patel SK, Pratap CB, Jain AK, Gulati AK, Nath G. Diagnosis of Helicobacter pylori: what should be the gold standard? World J Gastroenterol. 2014;20:12847–12859. doi: 10.3748/wjg.v20.i36.12847. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Sheu BS, Shiesh SC, Yang HB, Su IJ, Chen CY, Lin XZ. Implications of Helicobacter pylori serological titer for the histological severity of antral gastritis. Endoscopy. 1997;29:27–30. doi: 10.1055/s-2007-1004057. [DOI] [PubMed] [Google Scholar]
- 16.Tu H, Sun L, Dong X, et al. Serum anti-Helicobacter pylori immunoglobulin G titer correlates with grade of histological gastritis, mucosal bacterial density, and levels of serum biomarkers. Scand J Gastroenterol. 2014;49:259–266. doi: 10.3109/00365521.2013.869352. [DOI] [PubMed] [Google Scholar]
- 17.Marchildon PA, Sugiyama T, Fukuda Y, et al. Evaluation of the effects of strain-specific antigen variation on the accuracy of serologic diagnosis of Helicobacter pylori infection. J Clin Microbiol. 2003;41:1480–1485. doi: 10.1128/JCM.41.4.1480-1485.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Matsuo K, Hamajima N, Tominaga S, et al. Helicobacter pylori IgG antibody test established in the United States showed a substantially lower sensitivity for Japanese population. Am J Gastroenterol. 2000;95:1597–1598. doi: 10.1111/j.1572-0241.2000.02111.x. [DOI] [PubMed] [Google Scholar]
- 19.Okuda M, Sugiyama T, Fukunaga K, Kondou M, Miyashiro E, Nakazawa T. A strain-specific antigen in Japanese Helicobacter pylori recognized in sera of Japanese children. Clin Diagn Lab Immunol. 2005;12:1280–1284. doi: 10.1128/CDLI.12.11.1280-1284.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Ueda J, Okuda M, Nishiyama T, Lin Y, Fukuda Y, Kikuchi S. Diagnostic accuracy of the E-plate serum antibody test kit in detecting Helicobacter pylori infection among Japanese children. J Epidemiol. 2014;24:47–51. doi: 10.2188/jea.JE20130078. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Kita M, Take S, Okada H, Matsushita O, Yokota K. A study to determine the optimum antigens for the serodiagnosis of Helicobacter pylori infection in Japanese patients and the association with IgG subclass and gastric cancer. Rinsho Byori. 2015;63:180–186. (in Japanese with English abstract) [PubMed] [Google Scholar]
- 22.Karasawa H, Sugiyama A, Takeda M, et al. ABC classification of gastric cancer risk based on a new kit to detect serum Helicobacter pylori antibodies: comparison with another antibody detection kit. J Gastrointestinal Cancer Screen. 2016;54:18–29. (in Japanese with English abstract) [Google Scholar]
- 23.Satoh K, Kimura K, Yoshida Y, et al. Relationship between Helicobacter pylori and atrophic gastritis. Eur J Gastroenterol Hepatol. 1994;6 Suppl 1:S85–S88. [PubMed] [Google Scholar]
- 24.Koike T, Ohara S, Sekine H, et al. Helicobacter pylori infection inhibits reflux esophagitis by inducing atrophic gastritis. Am J Gastroenterol. 1999;94:3468–3472. doi: 10.1111/j.1572-0241.1999.01593.x. [DOI] [PubMed] [Google Scholar]
- 25.Watanabe K, Nagata N, Nakashima R, et al. Predictive findings for Helicobacter pylori-uninfected, -infected and -eradicated gastric mucosa: validation study. World J Gastroenterol. 2013;19:4374–4379. doi: 10.3748/wjg.v19.i27.4374. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Kato T, Yagi N, Kamada T, et al. Diagnosis of Helicobacter pylori infection in gastric mucosa by endoscopic features: a multicenter prospective study. Dig Endosc. 2013;25:508–518. doi: 10.1111/den.12031. [DOI] [PubMed] [Google Scholar]
- 27.Nomura S, Terao S, Adachi K, et al. Endoscopic diagnosis of gastric mucosal activity and inflammation. Dig Endosc. 2013;25:136–146. doi: 10.1111/j.1443-1661.2012.01357.x. [DOI] [PubMed] [Google Scholar]
- 28.Kato M, Terao S, Adachi K, et al. Changes in endoscopic findings of gastritis after cure of H. pylori infection: multicenter prospective trial. Dig Endosc. 2013;25:264–273. doi: 10.1111/j.1443-1661.2012.01385.x. [DOI] [PubMed] [Google Scholar]
- 29.Nomura S, Ida K, Terao S, et al. Endoscopic diagnosis of gastric mucosal atrophy: multicenter prospective study. Dig Endosc. 2014;26:709–719. doi: 10.1111/den.12286. [DOI] [PubMed] [Google Scholar]
- 30.Kamada T, Haruma K, Inoue K, Shiotani A. Helicobacter pylori infection and endoscopic gastritis -Kyoto classification of gastritis- Nihon Shokakibyo Gakkai Zasshi. 2015;112:982–993. doi: 10.11405/nisshoshi.112.982. (in Japanese with English abstract) [DOI] [PubMed] [Google Scholar]
- 31.Kimura K, Takemoto T. An endoscopic recognition of the atrophic border and its significance in chronic gastritis. Endoscopy. 1969;1:87–97. [Google Scholar]
- 32.Tatemichi M, Sasazuki S, Inoue M, Tsugane S, ; Japan Public Health Center Study Group Different etiological role of Helicobacter pylori (Hp) infection in carcinogenesis between differentiated and undifferentiated gastric cancers: a nested case-control study using IgG titer against Hp surface antigen. Acta Oncol. 2008;47:360–365. doi: 10.1080/02841860701843035. [DOI] [PubMed] [Google Scholar]
- 33.Tatemichi M, Sasazuki S, Inoue M, Tsugane S, ; JPHC Study Group Clinical significance of IgG antibody titer against Helicobacter pylori. Helicobacter. 2009;14:231–236. doi: 10.1111/j.1523-5378.2009.00681.x. [DOI] [PubMed] [Google Scholar]
- 34.Yoshida T, Kato J, Inoue I, et al. Cancer development based on chronic active gastritis and resulting gastric atrophy as assessed by serum levels of pepsinogen and Helicobacter pylori antibody titer. Int J Cancer. 2014;134:1445–1457. doi: 10.1002/ijc.28470. [DOI] [PubMed] [Google Scholar]
- 35.Boda T, Ito M, Yoshihara M, et al. Advanced method for evaluation of gastric cancer risk by serum markers: determination of true low-risk subjects for gastric neoplasm. Helicobacter. 2014;19:1–8. doi: 10.1111/hel.12101. [DOI] [PubMed] [Google Scholar]
- 36.Asaka M, Kimura T, Kudo M, et al. Relationship of Helicobacter pylori to serum pepsinogens in an asymptomatic Japanese population. Gastroenterology. 1992;102:760–766. doi: 10.1016/0016-5085(92)90156-s. [DOI] [PubMed] [Google Scholar]