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Finding out Serologically Active Gastritis Subjects by Conventional Endoscopy and Picking out Subjects Who might be Benefit from Helicobacter pylori Eradication as a Primary Prevention for Gastric Cancer

Byung Chul Kim, Sung Ho Kwon

Byung Chul Kim, Department of Internal Medicine, Hangsarang Hospital, Ulsan, Korea
Sung Ho Kwon, Department of Internal Medicine, Kangnam medical clinic, Ulsan, Korea

Correspondence to: Byung Chul Kim, Department of Internal Medicine, Hangsarang Hospital, Bunyeoungro 51 Nam-gu,Ulsan 680-804, Korea
Email: orion828@naver.com
Telephone: +82-55-269-0975
Fax: +82-52-256-7175
Received: May 2, 2015
Revised: May 30, 2015
Accepted: June 1, 2015
Published online: June 21, 2015

ABSTRACT

Aim: In Korea biennial endoscopy is performed on regular base, therefore endoscopic description regarding gastric cancer risk is very important. Based on recent studies classifying gastritis status by serum pepsinogen (PG) profiles we tried to find out relationships between serological gastritis status and specific endoscopic mucosal appearances.

Methods: We performed endoscopic examinations and serum PG sampling (PG I and II and I/II ratio) and rapid urea test for a total of 170 subjects who visited our health promotion center from June 2014 to September 2014, endoscopic images were collected and those images were compared with each PG test results.

Results: Among endoscopic parameters, PG based highly active inflammation groups were associated with body rugal hyperplastic gastritis (24.7), followed by body spotty erythema (16.6), body xanthoma (10.6), antrum swelling of areae gastrica (9.8) in order of high odds ratio (P-value <0.05). For serological mild atrophic gastritis, the cut-off value of endoscopic atrophic border (EAB) was closed type 3 by Kimura-Takemoto classification.

Conclusion: By conventional endoscopy we could discriminate highly active gastritis group with the aid of mucosal status, we also be able to select people who are benefit from H.pylori eradication as primary gastric cancer prevention with EAB.

Key words: Atrophic gastritis; Pepsinogen; Endoscopy

© 2015 The Authors. Published by ACT Publishing Group Ltd.

Kim BC, Kwon SH. Finding out Serologically Active Gastritis Subjects by Conventional Endoscopy and Picking out Subjects Who might be Benefit from Helicobacter pylori Eradication As a Primary Prevention for Gastric Cancer. Journal of Gastroenterology and Hepatology Research 2015; 4(6): 1643-1648 Available from: URL: http://www.ghrnet.org/index.php/joghr/article/view/1191

Introduction

With progression of technology it is possible to get high quality endoscopic images by conventional white light endoscopy and several studies have tried to achieve clues such as Helicobacter pylori (H.pylori) infection or mucosal activity and inflammation or gastric atrophy with gastric mucosal status. In addition to traditional useful value of endoscopic atrophic border (EAB) supported by Operative Link on Gastritis Assessment (OLGA) for gastritis staging, useful and reliable method to assess gastric mucosal status is pepsinogen (PG) based serological approach. Recent published study[1] showed that gastric mucosal status could be classified into four groups based on H.pylori status, PG I, II, I/II ratio, and serological chronic atrophic gastritis (CAG)-synonym for extensive atrophic gastritis- [Group A, H.pylori (-) and (CAG) (-); Group B, H.pylori (+) and CAG (-); B-α, PG I ≤ 70 ng/mL and PG I/II ratio > 3.0; B-β, PG I > 70 ng/mL and PG I/II ratio > 3.0; B-γ, PG I > 70 ng/mL and PG I/II ratio ≤ 3.0; II-30, PG II > 30 ng/ml; Group C, H.pylori (+) and CAG (+); CI-0, PG I ≤ 30 ng/mL; CI-30, PG I > 30 ng/ml and ≤ 50 ng/mL; CI-50, PG I > 50 ng/mL; Group D, H.pylori (-) and CAG (+)], and they found out some subgroups (group B-γ, II-30, H.pylori antibody titer >500 U/mL) have high risk of gastric cancer (GC) (especially diffuse type GC) comparable to that of group C. Yanaoka et al[2] showed H.pylori eradication was effective for preventing GC only in serological mild atrophic gastritis. Our main concern was how to correlate these meaningful serological gastritis status with endoscopic findings, which might help us decide which person should be followed strictly or could benefit from primary GC prevention such as H.pylori eradication.

MATERIALS and methods

1. Subjects and endoscopic examinations

We consecutively enrolled a total of 170 subjects from June 2014 to September 2014 who visited our health-promotion center for screening endoscopy showing H.pylori associated gastric mucosal appearances with positive H.pylori test (rapid urea test using CLO Helicobacter-detection kits-Asan Pharm Co., Ltd., Seoul, Korea), we used 11 endoscopic parameters mainly based on Nomura et al[3] and Cho et al[4] (Figure 1). Subjects were excluded from the study if they had history of H.pylori eradication or if they had been taking any medicine influencing gastric mucosal appearance (any acid suppressive medication or non-steroidal anti-inflammatory agent) within eight weeks prior to examination, also we excluded subjects when they had any of past medical illness like liver or heart problem or malignant diseases. All subjects had already requested H.pylori test and PG study for gastric cancer screening in pre-questionnaire. They were under conventional white light endoscopy using a GIF-Q260 (Olympus Co., Tokyo, Japan) and endoscopic mucosal images were collected for each individual such as body diffuse erythema (B_DE) (graded as 1 when it could be identified by close-up observation of mucosa due to light red color and 2 when easily identified at some distance due to dark red color), body type (B_type) A and B and C (A, mosaic-like appearance; B, diffuse homogenous redness; C, untypical pattern), body spotty erythema (B_SE) (graded as 1 when it could be seen only in body greater curvature and 3 when clearly seen in fundus and body, and 2 when observed but neither 1 or 3), body xanthoma (B_xan), body rugal hyperplastic gastritis (B_RHG): when gastric fold width was equal or over 5mm with the aid of opening width (7 mm) of jaw of biopsy forcep despite sufficient aeration, antrum swelling of areae gastrica (A_SAG), antrum diffuse erythema (A_DE) (graded as 1 or 2 as described above), antrum visible vessel (A_VV), antrum lymphofollicular gastritis (A_LFG), antrum intestinal metaplasia (A_IM) (when whitish plaques were scattered on the mucosal surface). Each type of EAB (as C-1~3, closed type 1~3; O1~3, open type 1~3) was also described as suggested by Kimura-Takemoto[5]. All endoscopic procedures were performed by main author to avoid inter-observer variability.

This study was approved by Korea National Institute for Bioethics Policy (KoNIBP).

2. Serum pepsinogen(PG) levels

Fasting blood samplings for serum PG test were done before each endoscopy session, and were centrifuged immediately at 4℃. Serum concentrations of PG I and II were measured by a latex enhanced turbidimetric immunoassay (HBI Co., Anyang, Korea), and PGI to PG II (PG I/II) ratio were calculated.

Statistical analysis

We used SPSS ver. 18.0 for Windows Software (SPSS Inc., Chicago, IL, USA) for logistic regression analysis to obtain odds ratio of each endoscopic finding associated with Group B-γ or II-30, and with MedCalc ver. 15 (MedCalc Software bvba Acacialaan 22 8400 Ostend Belgium) for receiver operator characteristic (ROC) curve and area under curve (AUC) to get optimal cut-off value of EAB compatible with extensive atrophic gastritis (Group C). P-value <0.05 was regarded as statistically significant.

Results

1. Characteristics of subjects

A total of 170 subjects were included in the study. The mean age was 47.4 years with a range from 14 to 73 years (102 men and 68 women). The mean serum PG I level was 74.5 ng/ml and mean serum PG II level was 20.1 ng/ml and mean PG I/II ratio was 4.1 (Table 1). We subdivided EAB into 12 categories and only 4 subjects showed no discernible EAB, and 56(33%) subjects were above EAB C-3 (Open type) by Kimura-Takemoto classification (Table 2). Among the specific mucosal findings, body diffuse erythema was the most common (92.3%) and followed by antrum diffuse erythema (64.7%), and antrum visible vessel (61.2%), when it comes to body type, type B was the most common (52.4%), and followed by type A (37.1%) and type C (7.1%), the remaining 6 cases showed normal mucosal appearance [regular arrangement of collecting venules (RAC)] (3.5%), numbers of respective gastric mucosal status were shown in Table 3. As for serological grouping, Group B was more frequent than Group C (82.9% vs 17.1%) and group B-γ cases were 14 (8.2%), and II-30 cases were 21 (12.4%), thus active gastritis cases were 26 cases (15.3%). In Group C, group CI-50 was the most frequent (7.1%) and group CI-0 was the least frequent (4.1%) (Table 4 ).







2. Association between endoscopic mucosal appearances andPG-based serologically active gastritis (Group B-γ or II-30).

All endoscopic mucosal appearances were categorical variables and all variables were used for logistic regression analyses, we used reference category as 0 for negative finding of respective mucosal pattern. Without regard to statistical significance (P-value <0.05) positive correlations (odds ratio > 1) for active gastritis were noted in the Body type C, body spotty erythema grade 2 and grade 3, body xanthoma, body rugal hyperplastic gastritis, antrum swelling of areae gastrica, antrum lymphofollicular gastritis, antrum visible vessel, and negative correlations (odds ratio < 1) were noted in the body diffuse erythema, body type A and type B, body exudate, body spotty erythema grade 1, antrum diffuse erythema, antrum intestinal metaplasia. We observed four statistically significant (P-value <0.05) endoscopic mucosal patterns all of which showed positive correlations for active gastritis, those were B_RHG, B_SE(3), B_xan, A_SAG and each odds ratio showed highest in B_RHG (24.7), followed by B_SE(3) (16.6), B_xan (10.6), A_SAG (9.8), this means if body RHG exist, the possibility of active gastritis will be 24.7 times higher than without body RHG. (Table 5).



3. Correlation between EAB and serological chronic atrophic gastritis (Group C)

Receiver operator characteristic (ROC) curve and area under curve were obtained to find out optimal EAB type to predict serological chronic atrophic gastritis (Group C), the AUC was 0.758 and the optimal cut-off value of EAB type was type C-3, with 64.2% sensitivity and 73.2% specificity (Figure 2).

Discussion

Non-cardia GC could be occurred via two pathways, one is slowly progression type as suggested by Correa[6], the other suggestion[7] is fast progression type bypassing the Correa pathway. As Uemura et al[8] showed that Intestinal type gastric cancer was related with corpus dominant gastritis, intestinal metaplasia, severe atrophic gastritis and diffuse type gastric cancer was more related to pan-gastritis, moderate atrophic gastritis. Handy EAB has been proved to be useful tool assessing intestinal type GC (mainly slow progressing type) risk[9-10], however EAB classification supported by OLGA has a weak point, that is OLGA itself has no significance of body gastritis that can contribute to GC with poorer histologic type without high stage of OLGA system[11].

Several studies have revealed that highly active inflammation in H.pylori infected subjects could directly cause diffuse type gastric cancer by bypassing the atrophy and intestinal metaplasia[12-14]. Yanaoka et al[15] showed elevated PG II level was correlated with diffuse type gastric cancer and several other studies revealed PG II elevation was related to severity of gastritis activity in non-atrophic gastritis[16-17]. There have been efforts to identify these subgroups, actually Kiyohira et al[18] showed gastritis severity and gastric mucosal status could be well documented by serum PG. Recent Japanese studies[1,19] uncovered some groups of atrophy free subject showed GC risk equivalent to extensive atrophic gastritis especially diffuse type GC, the main characteristics of these subgroups were elevated PG II.

Considering Hunter et al[20] that H.pylori infection contribute more to PG II elevation than to PG I, and Iranian study[21] suggesting that PG II could be good surrogate marker for body morphological change after H.pylori infection, and major portion of PG II was originated from the active gastritis by neutrophil cell infiltration, we could come to conclusion that H.pylori infected active gastritis creating more neutrophil infiltration would cause more PG II elevation.

Referring to Kiyohira et al[18], PG II continue to elevate till histologic atrophy reach to moderate grade, in contrast, PG I remained relatively stable level. We can easily infer from them that maximal PG II level could be achieved at the moderate atrophy, which means maximal neutrophil induced active gastritis would be in that time and naturally the highest chance of diffuse type GC would be supposed to occur, these could be supported by carcinogenesis by unique H.pylori induced neutrophilic proliferative zone foveolitis (PNF) and Malgun cell change suggested by Lee[22], also that is just the moment when H.pylori eradication would be the most effective thing for preventing GC.

As Korean physician practicing daily routine screening endoscopy it is natural to pursue practical method to assess the risk of GC by conventional white light endoscopy. Luckily as progression of optical and electronic technology, various mucosal findings have been identified. As for H.pylori infection status, Yan et al[23] and Cho et al[4] revealed valuable results. Watanabe et al[24] showed more various and realistic mucosal findings related to current H.pylori infection and after H.pylori eradication. Nomura et al[3] assessed gastritis activity and inflammation using the similar mucosal findings suggested by Watanabe et al[24], they showed that combination of swelling of areae gastrica with diffuse redness in the corpus and swelling of areae gastrica with visible vessel in the antrum were useful findings for neutrophil infiltration in gastric mucosa.

The main concern was endoscopic findings that could be useful to assess the risk of the two GC type (slowly growing intestinal type and rapid progressing diffuse type). Therefore bearing in mind EAB as a yardstick for intestinal type GC and various mucosal patterns for diffuse type GC, we could make reasonable strategy.

Recently Lee et al[25] revealed PGI and PG I/II ratio decreased significantly as EAB progressed, and we also searched relationships between serology and EAB. Yanaoka et al[2] showed H.pylori eradication was effective for preventing GC only in serologically mild atrophic gastritis, we uncovered which EAB could be matched with upper limit of serologically mild atrophic gastritis, the cut-off value of EAB for group C being above type C-3, this identification was similar to that of several previous studies, however there were differences, first most of previous studies identified serologic values to discriminate open type atrophic gastritis from closed type, we took different approach from opposite side: defining optimal EAB for serologically significant value, second we subdivided EAB in more detail (12 categories) because in Korea endoscopy is more dominant GC screening tool than any other method including serologic study, consequently we need to get much more delicate description for endoscopic findings than just simple delineation of open or closed type. When it comes to therapeutic consideration our result could be partially supported by recent study by Take et al[26], they reported one of significant factors for prophylactic effect of H.pylori eradication against GC was initial endoscopic mild atrophic gastritis (EAB type C-1 and C-2). If we consider H.pylori eradication, EAB type C-3 could be a valid limitation [in this study 114 subjects (67%)], and above EAB type C-3 we might consider strict endoscopic follow up [in this study 56 subjects (33%)].

Evaluating mucosal status to make up for weak point of EAB, our finding showed four significant mucosal appearances suggesting serologically active gastritis (Group B-γ or II-30). If endoscopists bump into these mucosal findings, they could recommend H.pylori eradication to patient with better confidence.

We could not performed H.pylori antibody titer test being originally included in Yoshida et al[1], this study was based on “Health check-up protocol” not focusing individual active gastritis study and actually when we made the protocol we referred to watanabe et al[27] reporting that all cancers in high H.pylori titer group belonged to Group B-γ, inevitably some portion of active gastritis subjects in Group B might be omitted and performing genuine Korean active gastritis study would be the way to go. Because we depend on CLO test for H.pylori identification, some H.pylori positive subjects might be exempted from the study, however we used EAB and various endoscopic findings: we must have tried to find out H.pylori by other methods if we had confronted abnormal mucosal findings with negative CLO test (actually all of four subjects who showed no visible EAB had abnormal mucosal patterns), consequently most of the exempted cases might be Group D not Group B and thinking of our main purpose they would not be considered as candidate for primary GC prevention. Unlike Cho et al[4] our study showed body type B (52.4%) was more frequent than body type A (37.1%), this could be attributed to subjects showing very small sized mosaic pattern, we regarded them as type B. Lymphofollicular gastritis as a rising risk factor for GC did not show statistically significant feature (P-value 0.188, odd ratio 4.0) but we expect larger scale study may improve its significance. We hope better endoscopic GC risk stratification strategy will emerge in the near future.

CONFLICT OF INTERESTS

There are no conflicts of interest with regard to the present study.

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Peer reviewers: Natalia Elguezabal, Animal Health Department, NEIKER-Tecnalia, Basque Institute for Agricultural Research and Development, Parque Tecnologico Bizkaia, Edif. 812-L 48160, Derio, Bizkaia, Spain; Michael Kew Lim, Department of Colorectal Surgery, Christchurch Hospital, Riccarton Avenue, Christchurch 8011, New Zealand.

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