Review Article Consensus on Chronic Gastritis in China (9-10 November 2012 Shanghai)

Am J Digest Dis 2014;1(1):3-21 www.ajdd.us /ISSN:2329-6992/AJDD0000111

Review Article Consensus on chronic gastritis in china (9-10 November 2012 Shanghai)

Jing-Yuan Fang1, Wen-Zhong Liu1, Zhao-Shen Li2, Xiao-Long Ji3, Zhi-Zheng Ge1, Yan-Qing Li4, Jian-Min Si5, Nong-Hua Lv6, Kai-Chun Wu7, Ying-Xuan Chen1, Shu-Dong Xiao1

1Department of Gastroenterology and Hepatology, Renji Hospital, Shanghai Jiaotong University School of Medi- cine, Shanghai, China; 2Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China; 3Department of Pathology, Wujing Hospital, Beijing, China; 4Department of Gastroenterology, Shandong University Qilu Hospital, Jinan, China; 5Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; 6Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Jiangxi Institute of Gastroenterology & Hepatology, Nanchang, Jiangxi, China; 7Xijing Hospital of Digestive Diseases, Xijing Hospital, The Fourth Military Medical University, Xi’an, China Received February 27, 2014; Accepted April 16, 2014; Epub July 25, 2014; Published July 30, 2014

Abstract: Since the Consensus on chronic gastritis in China was developed in September 2006 in Shanghai, much progress has been made in the diagnosis and treatment of chronic gastritis, including the Operative Link for Gas- tritis Assessment (OLGA), European Consensus On management of precancerous conditions of gastric cancer, and Maastricht-IV consensus. Therefore, the “2012 Chinese National Consensus Meeting on the Diagnosis and Treat- ment of Chronic Gastritis” was held in Shanghai in November 2012, sponsored by the Chinese Society of Gastro- enterology, to revise the Consensus. Eighty-two gastroenterology experts from all over China discussed and passed the new consensus by an anonymous vote. The voting options were: 1. Totally agree; 2. Agree, but have some reservations; 3. Agree, but have greater reservations; 4. Disagree, but have reservations; 5. Totally disagree. If the item received “1”> 66.7% or “1+2” > 85% of the votes, the term was then considered as passed and included in the consensus. The terms with otherwise votes were considered failed to pass and not reported here. This consensus is aimed to serve as the position statement of Chinese Society Gastroenterology on the prevention, diagnosis, treatment and follow-up of chronic gastritis.

Keywords: Chronic gastritis, epidemiology, H. pylori, diagnosis, treatment, follow-up

Since the Consensus on chronic gastritis in by the Chinese Society of Gastroenterology, China [1] was formed during the Chinese undertaken by Renji Hospital of Shanghai National Chronic Gastritis Meeting held in Jiaotong University School of Medicine and September 2006 in Shanghai, progress has Shanghai Institute of Digestive Disease. Eighty- been made in the diagnosis and treatment of two gastroenterology experts from all over chronic gastritis. This includes the Operative China discussed and revised the previous draft Link for Gastritis Assessment (OLGA) [2, 3] and and passed the consensus by an anonymous the European Consensus On management of vote. The voting options were: 1. Totally agree; precancerous conditions of gastric cancer [4]. 2. Agree, but have some reservations; 3. Agree, The Maastricht-IV consensus [5] proposed the but have greater reservations; 4. Disagree, but relationship between Helicobacter pylori (H. have reservations; 5. Totally disagree. If “1” > pylori) with chronic gastritis and gastric cancer, 2/3 or “1+2” > 85%, the term was considered as well as the effects of H. pylori eradication as passed. The full text of the consensus is as [1]. Progress in endoscopic and pathological follows: diagnosis techniques for chronic gastritis requires the previous consensus to be updat- Epidemiology ed. Therefore, the “2012 Chinese National Consensus Meeting on the Diagnosis and 1. Exact morbidity is difficult to obtain because Treatment of Chronic Gastritis” was held in most chronic gastritis patients lack symptoms. Shanghai on 9-10 November 2012, sponsored The estimated morbidity of chronic gastritis Consensus on chronic gastritis patients is roughly comparable with the H. pylo- Digestive Endoscopy, covering 10 cities, 30 ri infection in local population, and may be centers and 8907 chronic gastritis patients slightly higher than that of H. pylori infection with upper gastrointestinal symptoms con- [6]. firmed by gastroscopy. The results showed that chronic non-atrophic gastritis was the most Almost all patients recently infected with H. common (59.3%) among various chronic gastri- pylori have chronic gastritis (see the next sec- tis types, followed by chronic non-atrophic or tion). When tested with serological methods, atrophic gastritis with erosions (49.4%), chronic most positive cases (recent or previous infec- atrophic gastritis was up to 23.2% (but mostly tion) have chronic gastritis. In addition to H. were mild). The H. pylori positive rate was pylori infection, factors such as bile reflux, 33.5% in the gastric antrum and 23.0% in the drugs and autoimmunity can also cause chron- corpus gastricum. The proportion of atrophy ic gastritis. Therefore, the morbidity of chronic suggested by pathological changes of the gas- gastritis is probably higher, or slightly higher, tric antrum was 35.1%, which was higher than than that of H. pylori infection. that of endoscopy (23.2%). The atrophy rate associated with IM was 32.0% and was 10.6% 2. The morbidity of chronic gastritis generally for intraepithelial neoplasia (synonymous with increases with age, especially for chronic atro- dysplasia, for details see the Appendix). The phic gastritis. research showed that currently, the morbidity The morbidity of chronic gastritis generally of chronic atrophic gastritis is comparatively increases with age, including chronic atrophic high in China. The correspondence rate gastritis, which is mainly related to increasing between macroscopic observation and patho- infection with H. pylori with age, atrophy and logical diagnosis under endoscopy remains to intestinal metaplasia (IM), which are also relat- be further improved. ed to aging. This also reflects the evolution of gastric mucosal damage caused by the immune Endoscopy response to H. pylori infection [7]. The morbidi- 1. Endoscopic diagnosis of chronic gastritis ty has little to do with gender. indicates mucosal inflammatory changes 3. The proportion of chronic atrophic gastritis in observed by the naked eye or by special imag- chronic gastritis patients varies greatly in differ- ing methods; however, the results of pathologi- ent countries and regions. Generally, it is posi- cal examination are required to make a final tively correlated with the incidence of gastric judgment. cancer [8]. The diagnosis of chronic atrophic gastritis is Chronic atrophic gastritis is a result of H. pylori performed by endoscopic and pathological infection, together with environmental factors methods; however, the rate of atrophy con- and genetic factors. The morbidity of chronic firmed by both endoscopy and pathological atrophic gastritis varies greatly in different diagnosis is comparatively low [9, 10]: the countries and regions; which is associated with definitive judgment depends mainly on patho- regional infection rates of H. pylori, differences logical examination. in virulence genes of H. pylori, environmental factors and genetic background. The morbidity 2. Under endoscopy, chronic gastritis can be of chronic atrophic gastritis in high-risk areas categorized into non-atrophic gastritis (previ- for gastric cancer is higher than that in low-risk ously known as superficial gastritis) and atro- areas. phic gastritis. If there are also flattened or uplifted erosions, hemorrhage, coarse rugae or 4. The morbidity of chronic atrophic gastritis is bile reflux, then the diagnosis is non-atrophic comparatively high in China: the correspon- gastritis or atrophic gastritis accompanied with dence rate between macroscopic observation erosion, bile reflux, etc. and pathological diagnosis under endoscopy remains to be further improved. The fundamental lesions of most chronic gastritis are inflammations (hyperemia and exuda- In 2011, a cross-sectional survey was conduct- tions) or atrophy; therefore, it is reasonable to ed under the organization of Chinese Society of categorize chronic gastritis into non-atrophic

4 Am J Digest Dis 2014;1(1):3-21 Consensus on chronic gastritis gastritis and atrophic gastritis, which also the gastric mucosa, which is valuable for the favors the unification of pathological diagno- diagnosis and differential diagnosis of gastritis, sis. as well as the early discovery of intraepithelial neoplasia and IM. Nowadays, magnifying 3. Under endoscopy, the fundamental manifes- endoscopy plus methylene blue staining is tations of chronic non-atrophic gastritis show highly accurate for IM and intraepithelial neo- as mucosal erythema, mucosal hemorrhagic plasia detection [11]. Hematoxylin and indigo spots or plaques, coarse mucosa with or with- carmine staining also have a role in the diagno- out edema, and hyperemia and exudations. sis of intraepithelial neoplasia [12, 13]. There are two types of erosive gastritis: flattened or uplifted. The former is characterized 8. Endoscopic electronic dyeing technology by single or multiple erosive lesions, whose plus magnifying endoscopy has a certain value sizes vary from pinpoint to a few centimeters. for the diagnosis and differential diagnosis of The latter is characterized by single or multiple chronic gastritis. With confocal laser endomi- verrucous uplifts, bulking folds or papular croscopy, it is feasible to observe the micro- uplifts. Their largest diameter is 5~10 mm, and structure of the gastric mucosa in real time. mucosal defects or umbilical sag are visible on The diagnosis of chronic gastritis, IM and the apex, with erosion in the center. intraepithelial neoplasia is highly consistent with that of biopsy [14]. 4. Under endoscopy, the fundamental manifestations of chronic atrophic gastritis are alternat- Electron staining plus magnifying endoscopy is ing red and white mucosa, with white predomi- comparatively highly sensitive and specific for nant. The rugae become flattened or even chronic gastritis and precancerous lesions of disappear; some mucosal blood vessels are gastric cancer [15, 17-19]; however, there is no exposed, sometimes with granular or nodular unified standard for its specific performance appearance on the mucosa. and classification. 5. Diagnosis of special types of gastritis must consider both the etiology and pathology. With optical biopsy technology (hereinafter referred to as a biopsy) such as confocal laser The classification of special types of gastritis is endomicroscopy, it is feasible to observe the related to their etiology and pathology, includ- gastric mucosa at the cellular level. It also per- ing chemical, radioactive, lymphocytic, granulo- mits identification of microstructural changes matous, eosinophilic and other infectious disea- of the gastric pit, epithelial cells and goblet ses. cells in real time, having a certain reference value for the diagnosis of chronic gastritis and 6. At endoscopy, chronic gastritis can be sub- the grading of histological changes (chronic classified into antral gastritis, corpus gastritis, inflammation, activity, atrophy and IM) [20-23]. pangastritis with antrum predominant or pan- At the same time, optical biopsy can be used to gastritis with corpus predominant, according to selectively target suspected sites, which helps the distribution of lesions. to improve the sampling accuracy [24].

Under endoscopy, it is difficult to grade the 9. It is suggested that two or more biopsy speci- lesions of chronic gastritis into mild, moderate mens should be taken, according to the nature and severe, mainly because of subjective fac- of the lesions and need. tors and the cumbersome nature of endoscopic classification [10]. Reasonable and practical Endoscopists should provide necessary infor- grading needs to be further studied and mation to the pathologist, concerning the sam- improved. pling sites, endoscopic findings and a brief his- 7. Magnifying endoscopy plus staining has tory. Conditionally, a biopsy can be performed helped the pathological classification of gastri- under the guide of pigment staining or electron tis under endoscopy. staining plus magnifying endoscopy. Key biopsy sites should be located in the gastric antrum, Magnifying endoscopy plus staining may facili- stomach angle, in the lesser curvature of the tate more subtle and detailed observation of corpus gastricum and in suspicious lesions.

5 Am J Digest Dis 2014;1(1):3-21 Consensus on chronic gastritis

Histopathology The relationship between H. pylori infection and active chronic gastritis coincides with the 1. Gastric mucosal inflammation caused by four fundamental requirements of Koch’s pos- various etiologies is termed gastritis [25]. Acute tulation concerning the definition of a pathogen gastritis is characterized by acute inflammatory as the etiology of a disease: H. pylori infection cells infiltration (neutrophils), while chronic gas- is present in the gastric mucosa in 80-95% of tritis is characterized by chronic inflammatory patients with active chronic gastritis, and the cells infiltration (mononuclear cells, mainly lym- 5-20% H. pylori negative chronic gastritis cases phocytes and plasma cells). Active chronic gas- merely reflects the diverse causes of chronic tritis or chronic gastritis with activity is associ- gastritis; in patients with H. pylori-related gas- ated with chronic inflammatory cell infiltration tritis, the distribution of H. pylori coincides with in the gastric mucosa. inflammation; eradication of H. pylori can lead to regression of gastric mucosal inflammation. The gastrointestinal mucosa is the main part of Generally, the regression of neutrophils comes the human immune system, having physiologi- sooner, whereas the regression of lymphocytes cal immune cells (mainly lymphocytes, tissue and plasma cells needs more time [28]. H. pylo- cells, dendritic cells and plasma cells). Under ri infection-induced gastritis has been con- routine microscopy, it is difficult to distinguish frmed in volunteers [29] and in animal immune cells from chronic inflammatory cells models. histopathologically. Pathologists advise that for specimens with only one mononuclear cell infil- In nodular gastritis, the H. pylori infection rate tration per gland on average, they should not is the highest, close to 100% [30, 31]. This type be considered as “pathological” gastric muco- of gastritis mostly occurs among young women sa. [32] and the characteristic histopathological feature of the gastric mucosa is a large number 2. For accurate judgment and a high degree of of lymphoid follicles [30, 32]. reproducibility, the basic requirement of gastric mucosa biopsy specimens is: the number and 2. Almost all H. pylori infection can cause an positions of sampling sites of biopsy specimens active inflammation of the gastric mucosa. should be determined by the endoscopist, Gastric mucosal atrophy and IM occurs in some according to the need. They should be fixed as patients after long-term infection. The synergis- soon as possible after sampling and attention tic effect of H. pylori, the host and environmen- should be paid to the embedding direction. tal factors determines the type and progress of H. pylori-related gastritis. 3. The observation of chronic gastritis includes five histological changes and four grades [26]. Almost all H. pylori infection can cause an The five histological changes include H. pylori active inflammation of the gastric mucosa, the infection, chronic inflammation (mononuclear presence of which is highly suggestive of H. cells infiltration), activity (neutrophils infiltra- pylori infection [28]. An inflammatory and tion), atrophy (reduction of the proper gastric immune response induced by long-term H. pylo- glands) and IM (intestinal metaplasia). The four ri infection can cause the development of gas- grades are: 0, none; +, mild; + +, moderate; + + tric mucosal atrophy and IM in some patients +, severe. See Appendix of “visual analog [33, 34]. There are two prominent types of H. scale”. pylori-related chronic gastritis: pangastritis with antrum predominant and pangastritis with Relationship between helicobacter infection corpus predominant. An increase in gastric acid and chronic gastritis secretion occurs in the former, which increases the risk of developing a duodenal ulcer, where- At present, nearly 40 species in the genus heli- as gastric acid decreases in the latter and the cobacter have been confirmed [27] with new risk of developing gastric cancer increases. The species being discovered all the time. H. pylori synergistic effect of the host (gene polymor- or Helicobacter helimannii infection can cause phism of cytokines [35, 36], such as interleu- chronic gastritis. kin-1B), environmental factors (such as smok- 1. H. pylori infection is the major etiology of ing or a high-salt diet) and H. pylori factors active chronic gastritis. (virulence genes) determines the type of H.

6 Am J Digest Dis 2014;1(1):3-21 Consensus on chronic gastritis pylori-related gastritis and the development 5. Helicobacter helimannii infection can also and progress of atrophy and IM [37]. cause chronic gastritis [48-50].

3. Eradication of H. pylori can improve the dys- In chronic gastritis patients, the Helicobacter peptic symptoms in some chronic gastritis helimannii infection rate is about 0.15%~0.20%. patients. Compared with H. pylori infection, Helicobacter helimannii infection causes much less gastric Most patients with H. pylori-related gastritis mucosal inflammation, and eradication of have no symptoms. Patients with dyspeptic Helicobacter helimannii can also result in the symptoms might belong to the category of func- recession of gastric mucosal inflammation [51]. tional dyspepsia [38]. Therefore, determining Helicobacter helimannii infection can also whether eradication of H. pylori can eliminate cause mucosa-associated lymphoid tissue the dyspeptic symptoms of chronic gastritis (MALT) lymphoma [50]. should be based on the results of studies on functional dyspepsia. Meta-analysis has shown Clinical manifestations, diagnosis and treat- that eradication of H. pylori can result in the ment long-term improvement of dyspeptic symptoms in some patients with functional dyspepsia, 1. Most chronic gastritis patients [52] have no which also is a cost-effective strategy for elimi- symptoms. In patients who do have symptoms, nating or ameliorating dyspeptic symptoms they are mainly non-specific dyspepsia: the [39]. Several studies have shown that for presence or absence of dyspeptic symptoms patients with a high gastric mucosal inflamma- and severity of dyspeptic symptoms have no tion and activity [40], or mainly with epigastric significant relation to histopathological grades pain [41], significant improvement in their and endoscopic findings of chronic gastritis symptoms can be achieved by eradicating H. [55]. pylori. Some chronic gastritis patients have dyspepsia 4. Eradication of H. pylori can eliminate the symptoms, such as epigastric pain, abdominal activity of H. pylori-related chronic gastritis, fullness, etc. There is no significant difference alleviate the chronic inflammatory reaction, in clinical manifestations and psychological prevent further development of gastric mucosa status between chronic gastritis with dyspep- atrophy and IM and even reverse the atrophy in sia symptoms and patients with functional dys- some patients. pepsia [54]. Some scholars have found that 85% of patients with functional dyspepsia have Many studies have confirmed that eradication gastritis, and 51% are accompanied by H. pylori of H. pylori could cause histological changes in infection [55], which varies by regions. the gastric mucosa in chronic gastritis patients, Gastroesophageal reflux and alimentary canal including elimination of the activity and reduc- motility disorders are present in some chronic ing the degree of chronic inflammation [40, 42]. gastritis patients at the same time, especially Meta-analysis has shown that eradication of H. in elderly patients with severe esophageal pylori can result in the reversion of gastric sphincter relaxation and gastrointestinal motil- mucosal atrophy in some patients, but causes ity disorder [56]. Epidemiological studies have only slight reversion of IM [43, 44]. Many fac- shown that about 50%~70% of the elderly pres- tors can influence the judgment the reversion ent with chronic atrophic gastritis [57]. The of atrophy and IM, such as the variation of biop- symptoms in patients are non-specific, even sy sites; the follow-up period, the mimicked with different endoscopic performances and “atrophy” caused by mass inflammatory cell histopathological results, and the severity of infiltration in the gastric mucosa with H. pylori symptoms has no significant relation to histo- infection, and so on. There may be a point of no pathological grades and endoscopic findings return during the progress of atrophy, beyond [53]. which reversion is difficult. Many studies have shown that eradication of H. pylori could pre- 2. The diagnosis of chronic gastritis depends vent the further progress of gastric mucosal mainly on endoscopic examination and biopsy atrophy and IM to some extent [40, 42, 45-47]. of gastric mucosa, especially the latter.

7 Am J Digest Dis 2014;1(1):3-21 Consensus on chronic gastritis

Given that most chronic gastritis patients have cial attention should be paid to the prevention no symptoms, and the symptoms and signs are of canceration. not specific even if they are present. Therefore, diagnosis of chronic gastritis cannot be made 5. Eradication of H. pylori is recommended in through symptoms and signs. The diagnosis of patients with H. pylori-positive chronic gastritis chronic gastritis depends mainly on endoscopic associated with gastric mucosa atrophy, ero- examination and histopathological examination sions or dyspeptic symptoms. of biopsy specimens, especially the latter (for Whether eradication of H. pylori is needed for details, see the sections entitled “Endoscopy” H. pylori-related gastritis is still a matter of con- and “Histopathology”). troversy. The Chinese consensus on the treat- 3. Diagnosis of chronic gastritis should include ment of H. pylori infection [63] recommends H. the etiology, and H. pylori should be routinely pylori eradication therapy for those with gastric tested for. mucosa atrophy, erosions or dyspeptic symptoms. As mentioned above, the main symptoms H. pylori infection is the major cause of chronic of chronic gastritis are dyspepsia, mainly func- gastritis, and H. pylori detection should be rou- tional dyspepsia. Eradication therapy can result tine in the etiological diagnosis of chronic gas- in the long-term improvement of functional dys- tritis. In patients with atrophic corpus gastritis, peptic symptoms in H. pylori-positive patient serum gastrin G17 is markedly elevated, and [64, 65]. Such eradication can improve the his- the serum level of pepsinogen I or the pepsino- topathology of the gastric mucosa [66], help gen I/II ratio is significantly reduced. In patients prevent peptic ulcers and gastric cancer, and is with atrophic antral gastritis, serum G-17 is cost-effective. reduced, and the serum level of pepsinogen I or pepsinogen I/II ratio is normal. Both serum 6. For patients with gastric mucosal erosion G-17 and serum level of pepsinogen I or pep- and (or) with sour regurgitation and epigastric sinogen I/II ratio are reduced in patients with pain, antacids, H2 receptor antagonists or pro- atrophic pangastritis. The determination of ton pump inhibitors (PPIs) can be administered serum gastrin G17, and pepsinogen I and II may according to the conditions or severity of be helpful for judging the presence of gastric symptoms. mucosal atrophy and the site of atrophy [58- Gastric acid and pepsin play an important role 60]. Atrophic corpus gastritis can be caused by in the occurrence of gastric mucosa erosion H. pylori infection or by autoimmunity [61, 62]. (especially flattened erosion), sour regurgita- For gastritis suspected of being caused by tion, epigastric pain and other symptoms. autoimmunity, serum gastrin, vitamin B12, Antiacids or acid suppression therapy could parietal cell antibodies and intrinsic factor anti- heal the erosion and eliminate the above symp- bodies should be measured. toms. The effect of antacids is transient, while 4. The therapeutic aim for chronic gastritis is to PPIs have strong and persistent acid suppres- ameliorate the symptoms and reduce the sion effects, and include omeprazole, esome- inflammation of gastric mucosa. Therapy prazole, lansoprazole, rabeprazole and panto- should target the etiology as much as possible, prazole, which can be selected according to the and follow the principle of individualization. conditions or severity of symptoms [67]. For some patients, it may be a more economical The therapeutic aim for chronic gastritis is to option to choose moderate acid suppression ameliorate the symptoms and improve the his- therapy, with fewer adverse reactions. topathology of gastric mucosa. The management of the dyspeptic symptoms of chronic 7. According to the symptoms of patients, proki- gastritis is similar to that of functional dyspep- netics or digestive enzyme preparations can be sia. For those chronic non-atrophic gastritis considered. Prokinetics may be used in the patients with negative H. pylori and absence of patients who mainly have upper abdominal full- symptoms, specific treatment is not required. ness, nausea and vomiting. Those associated However, for those with atrophic gastritis, espe- with bile reflux may consider prokinetics and/or cially severe atrophic gastritis or gastritis gastric protective agents that have the effect of accompanied by intraepithelial neoplasia, spe- binding bile acids. Those with dyspepsia symp-

8 Am J Digest Dis 2014;1(1):3-21 Consensus on chronic gastritis toms, such as abdominal fullness obviously 9. Chinese traditional medicine can be used for related with feeding and lack of appetite, may the treatment of chronic gastritis. consider digestive enzyme preparations. More data are needed. Outcome of chronic gastritis, follow-up of chronic atrophic gastritis and prevention of Bile reflux is also a potential etiology of chronic canceration gastritis. Insufficiency of the pyloric sphincter leads to the reflux of bile into the stomach, less- 1. Outcomes of chronic gastritis include rever- ening or destroying the barrier function of the sion, persistent stabilization and aggravation. gastric mucosa, which would expose the gas- Most chronic atrophic gastritis is stable, but tric mucosa to digestive fluid, resulting in further progress may occur in moderate or inflammation, erosions, hemorrhage and epi- severe patients without any intervention. The thelial metaplasia. Upper abdominal fullness, risk of developing into gastric cancer increases or nausea and vomiting may be related to the for those patients accompanied with intraepi- delay in gastric emptying. Gastric dynamic thelial neoplasia [82-84]. anomaly is a factor that should not be ignored Most chronic atrophic gastritis is relatively sta- for chronic gastritis [68]. Prokinetics such as ble, especially for those without H. pylori infec- Mosapride, Itopride and domperidone, may tion. The presence of histopathological chang- improve the above-mentioned symptoms [69, es, such as atrophy, may increase with age

70] and may also prevent or reduce bile reflux. [85]. Current opinion states that persistent H. Gastric mucosa-protective agents, such as pylori infection can lead to chronic atrophic sucralfate, teprenone, gefarnate, rebamipide, gastritis, regardless of age. and ecabet [71-77], may strengthen the gastric mucosal barrier, and promoting healing of gas- Repeated or persistent H. pylori infection and tric mucosal erosions. However, the ameliorat- poor dietary habits can potentially aggravate ing effect on these symptoms is still controver- atrophy and IM of the gastric mucosa [86]. The sial. A hydrotalcite preparation [78, 79] may following factors can all increase or aggravate strengthen the gastric mucosal barrier and the risk of chronic atrophic gastritis, even the bind bile acid, thereby eliminating or reducing possibility of canceration [87, 88]: excessive the gastric mucosal damage caused by bile nitrate and nitrite in the water and soil; dispro- reflux. portionate trace elements; smoking; chronic alcohol intake; lack of fresh vegetables, fruits, Under the circumstance that gastric mucosal and essential nutrients; regular consumption of lesions (such as those accompanied by peptic fast-food, such as mildew, pickled, smoked and ulcers and severe erosion) are not caused by fried foods; excessive intake of salt; and a fam- abdominal fullness because of the delay in gas- ily history of gastric cancer. tric emptying, by gastric outlet obstruction, by reduced gastric mucosa barrier or by hyper- Chronic atrophic gastritis is often accompanied acidity, digestive enzyme preparations (such as with IM, and a minority have intraepithelial neo- Compound Azimtamide, Oryz-Aspergillus Enzy- plasia. After long-term evolution, some cases me, Pancreatin tablets, and all kinds of pancre- develop into gastric cancer [82-84]. Most atin) can be selected to alleviate dyspepsia patients with low-grade intraepithelial neopla- symptoms, like abdominal fullness, obviously sia can revert, having little possibility of can- related to feeding and lack of appetite [80, 81]. ceration [86, 89, 90].

8. Anti-depression and anti-anxiety drugs may 2. H. pylori-related antral gastritis frequently be used in, but not limited to, the chronic gastri- develops into a duodenal ulcer; gastric ulcers tis patients with obvious psychiatric factors. commonly occur in multifocal atrophic gastritis. Psychological factors are associated with dyspepsia symptoms. For those with somnipathy, Some patients with H. pylori-related gastritis (< obvious mental factors, or no or poor response 20%) might develop a peptic ulcer: patients to conventional treatment, psychological thera- with antral gastritis frequently develop a duo- py may be considered. denal ulcer, and patients with multifocal atro-

9 Am J Digest Dis 2014;1(1):3-21 Consensus on chronic gastritis phic gastritis commonly develop a gastric ulcer tant indicator for judging the severity, which [91]. Some cases of chronic non-atrophic gas- cannot be reflected by target biopsy. tritis may progress to chronic atrophic gastritis. 4. Eradication of H. pylori may slow canceration process and reduce the incidence of gastric 3. Patients with chronic atrophic gastritis, espe- cancer, but the best intervention time is before cially those with moderate or severe IM or the onset of precancerous lesions (including intraepithelial neoplasia, should be followed up atrophy, IM and intraepithelial neoplasia). regularly with endoscopic and histopathological examinations. More studies have found that H. pylori infection promotes the development of chronic atrophic It is generally believed that a certain cancera- gastritis into gastric cancer [96]. Eradication of tion rate is present for moderate and severe H. pylori can significantly slow the progress of chronic atrophic gastritis. To decrease the inci- precancerous lesions, and may reduce the risk dence of gastric cancer, and to benefit the of gastric cancer [97-99]. patients and keep costs down patients with moderate to severe chronic atrophic gastritis According to newly published research on erad- accompanied with IM should be followed up ication of H. pylori with a follow-up period of once a year with a biopsy. Those without IM or 14.7 years, the incidences of gastric cancer intraepithelial neoplasia should be followed up were 3.0% and 4.6% for H. pylori eradication with endoscopy and histopathology [93]. group (1130 cases) and placebo group (1128 Patients with low-grade intraepithelial neopla- cases), respectively [100]. Eradication of H. sia confirmed not to be from the adjacent can- pylori shows better prevention of canceration cerous tissues, should be followed up once for mild chronic atrophic gastritis [46]. every 6 months in accordance with the endo- Eradication of H. pylori is beneficial to the histo- scopic and clinical findings. Those with high- pathological improvement of precancerous grade intraepithelial neoplasia should be con- lesions [45]. firmed immediately, with surgical treatment or Some bioactive vitamins [100-104], such as local treatment under endoscopy when neces- vitamin C [105-108] and the trace element sary [1]. selenium [109-111] may reduce the risk of gastric cancer. For some patients with low folate To facilitate the monitoring and follow-up of levels, a moderate supplementation of folic lesions, conditionally mucosa target biopsy acid can improve the histopathological condi- (MTB) should be considered [94, 95]. This tech- tions of chronic atrophic gastritis, preventing nology adopts mucosa target biopsy forceps the occurrence of gastric cancer [112-120]. and calibration solution for positioning the biopsy sites and sampling at the same time, Issues requiring further study enabling the accurate positioning of suspicious lesions and long-term follow-up review. For ero- 1. The influence of H. pylori virulence genes on sive gastritis, the lesion is the recommended different clinical outcomes after H. pylori infec- positioning site, while for chronic atrophic gas- tion requires further research and comprehen- tritis, the gastric antrum at the lesser and sive analysis. greater curvature, stomach angle, corpus gastricum at the lesser and greater curvature, and H. pylori infection has different clinical out- lesions are the recommended sites. comes, such as chronic non-atrophic gastritis, atrophic gastritis, peptic ulcers and gastric can- In addition, atrophied lesion manifest as “focal cer. It is generally believed that the variability of distribution”; the change of target sites is not outcomes of H. pylori infection is a combined equal to that of non-targeted sites. Endoscopists result of H. pylori, the host and environmental cannot simply resample the last biopsy site and factors. H. pylori’s influence mainly resides in neglect the biopsy of new lesions. Currently its virulence or the virulence-related genes, opinion states that the scope of atrophy or IM such as cagA, vacA and cagA, and pathogenic- (see the OLGA staging system in “issues need ity island genes, iceA and babA2. However, the further study” of this consensus) is an impor- relationship between the infection of H. pylori

10 Am J Digest Dis 2014;1(1):3-21 Consensus on chronic gastritis

Table 1. The OLGA staging frame

with these genes and clinical outcome is still (3) Autoimmune gastritis: a type of gastritis controversial [121, 122], and remains to be developed on the basis of autoimmunity, char- determined by further studies. acterized by inflammation and atrophy of the corpus mucosa. In genetically susceptible indi- 2. H. pylori infection may play a role in the viduals, H. pylori infection can activate gastric pathogenesis of lymphocytic gastritis, Méné- CD4+ Th1 lymphocytes, which may cross-iden- trier disease and autoimmune gastritis or tify the epitopes shared by protein and parietal Russell body gastritis. H+K+-ATPase; i.e., it participates in the process of gastric autoimmunity through a molecular (1) Lymphocytic gastritis is a rare, specific type mimicry mechanism. H. pylori plays a role in the of chronic gastritis whose etiology is not yet early stage of autoimmune gastritis, before the fully clear. Its histopathological characteristic is development of atrophy, and eradication of H. marked lymphocytic infiltration in the gastric pylori may form a partial cure for autoimmune mucosal epithelium. A large sample (51 cases) gastritis. multi-center study showed that for the majority of patients with H. pylori-positive lymphocytic (4) Russell body gastritis: a rare kind of gastritis gastritis (95.8%), their gastritis was significant- characterized with marked plasma cell infiltra- ly ameliorated after eradication of H. pylori. In tion in the gastric mucosa, with many Russell contrast, there was only a 53.8% improvement bodies (PAS staining positive) in the cytoplasm. in patients treated with omeprazole or placebo, This type of gastritis can be complicated by and for those who had not improved, all showed gastric ulcers, and should be histologically dif- improvement after eradication of H. pylori ferentiated from signet-ring cell carcinoma and [123]. These results suggest that eradication of MALT lymphoma. Eradication of H. pylori can H. pylori is effective in some cases of H. pylori- improve most Russell body gastritis [128-131]. positive lymphocytic gastritis. 3. The prevention of gastric cancer by cyclooxy- (2) Ménétrier disease: giant mucosal rugae and genase (COX) 2 inhibitors requires further stu- hypoproteinemia are the main characteristics. dy. Its etiology is not yet known. There are several reports showing that H. pylori-positive Ménétrier Some reports have suggested that COX2 inhibi- disease remitted or healed after eradication of tors could reduce the incidence of gastric can- H. pylori [127, 128]. Therefore, H. pylori eradi- cer [47, 132]; however, given the possibility of cation therapy should be considered as a treat- induced cardiovascular events, it is not recom- ment for H. pylori-positive Ménétrier disease mended for application in the general popula- [126]. tion.

11 Am J Digest Dis 2014;1(1):3-21 Consensus on chronic gastritis

4. Whether the OLGA staging system proposed [7] Veldhuyzen van Zanten SJ, Pollak PT, Best LM, by some international experts is suitable for Bezanson GS, Marrie T. Increasing prevalence application in China has yet to be determined. of Helicobacter pylori infection with age: con- tinuous risk of infection in adults rather than In 2005, the international group of pathologists cohort effect. J Infect Dis 1994; 169: 434-437. (Atrophy club) put forward staging criteria for [8] Weck MN, Brenner H. Prevalence of chronic gastric mucosa inflammation and atrophy, sum- atrophic gastritis in different parts of the world. marized as the OLGA staging system [2, 3] Cancer Epidemiol Biomarkers Prev 2006; 15: which were different from the updated Sydney 1083-1094. classification system of gastritis [91] (Table 1). [9] Kim S, Harum K, Ito M, Tanaka S, Yoshihara M, The OLGA system aims to comprehensively Chayama K. Magnifying gastroendoscopy for diagnosis of histologic gastritis in the gastric analyze the histopathology, clinical manifesta- antrum. Dig Liver Dis 2004; 36: 286-291. tions and canceration risk of chronic gastritis. [10] Kaminishi M, Oohara T, Sakai S, et al. Endo- However, whether it is suitable for the clinical scopic classification of chronic gastritis based work in China is yet to be determined. on a pilot study by the Research Society for Gastritis. Dig Endosc 2002; 14: 138-151. Address correspondence to: Dr. Jing-Yuan Fang, [11] Areia M, Amaro P, Dinis-Ribeiro M, Cipriano Department of Gastroenterology and Hepatology, MA, Marinho C, Costa-Pereira A, Lopes C, Renji Hospital, Shanghai Jiaotong University School Moreira-Dias L, Romãozinho JM, Gouveia H, of Medicine, Shanghai, China. E-mail: fangjingyuan_ Freitas D, Leitão MC. External validation of a [email protected] classification for methylene blue magnification chromoendoscopy in premalignant gastric le- References sions. Gastrointest Endosc 2008; 67: 1011- [1] Chinese Society of Gastroenterology. Chinese 1018. Consensus on Chronic Gastritis. Chinese Jour- [12] Tanaka K, Toyoda H, Kadowaki S, Hamada Y, nal of Gastroenterology 2006; 11: 674-684. Kosaka R, Matsuzaki S, Shiraishi T, Imoto I, (in Chinese). Takei Y. Surface pattern classification by en- [2] Rugge M, Meggio A, Pennelli G, Piscioli F, Gia- hanced-magnification endoscopy for identify- comelli L, De Pretis G, Graham DY. Gastritis ing early gastric cancers. Gastrointest Endosc staging in clinical practice: the OLGA staging 2008; 67: 430-437. system. Gut 2007; 56: 631-636. [13] Mouzyka S, Fedoseeva A. Chromoendoscopy [3] Rugge M, Correa P, Di Mario F, El-Omar E, Fioc- with hematoxylin in the classification of gastric ca R, Geboes K, Genta RM, Graham DY, Hattori lesions. Gastric Cance 2008; 11: 15-22. T, Malfertheiner P, Nakajima S, Sipponen P, [14] Nguyen NQ, Leong RW. Current application of Sung J, Weinstein W, Vieth M. OLGA staging for confocal endomicroscopy in gastrointestinal gastritis: a tutorial. Dig Liver Dis 2008; 40: disorders. J Gastroenterol Hepatol 2008; 23: 650-658. 1483-1491. [4] Dinis-Ribeiro M, Areia M, de Vries AC, et al. [15] Tahara T, Shibata T, Nakamura M, Yoshioka D, Management of precancerous conditions and Okubo M, Arisawa T, Hirata I. Gastric mucosal lesions in the stomach (MAPS): guideline from pattern by using magnifying narrow-band im- the European Society of Gastrointestinal En- aging endoscopy clearly distinguishes histo- doscopy (ESGE),European Helicobacter Study logical and serological severity of chronic gas- Group (EHSG), European Society of Pathology tritis. Gastrointest Endosc 2009; 70: 246-253. (ESP),and the Sociedade Portuguesa de En- [16] Kato M, Kaise M, Yonezawa J, Toyoizumi H, Yo- doscopia Digestiva (SPED). Endoscopy 2012; shimura N, Yoshida Y, Kawamura M, Tajiri H. 44: 74-94. Magnifying endoscopy with narrow-band imag- [5] Malfertheiner P, Megraud F, O’Morain CA, ing achieves superior accuracy in the differen- Atherton J, Axon AT, Bazzoli F, Gensini GF, Gis- tial diagnosis of superficial gastric lesions bert JP, Graham DY, Rokkas T, El-Omar EM, Kui- identified with white-light endoscopy: a- pro pers EJ; European Helicobacter Study Group. spective study. Gastrointest Endosc 2010; 72: Management of Helicobacter pylori infection- 523-529. the Maastricht IV/ Florence Consensus Re- [17] Ezoe Y, Muto M, Horimatsu T, Minashi K, Yano port. Gut 2012; 61: 646-664. T, Sano Y, Chiba T, Ohtsu A. Magnifying narrow- [6] Sonnenberg A, Lash RH, Genta RM. A national band imaging versus magnifying white-light study of Helicobacter pylori infection in gastric imaging for the differential diagnosis of gastric biopsy specimens. Gastroenterology 2010; small depressive lesions: a prospective study. 139: 1894-1901. Gastrointest Endosc 2010; 71: 477-484.

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Appendix: pathological diagnosis criteria of chronic gastritis and related matters needing attention

Visual analogue scale

Notes [133]: tric glands proper. Histopathologically there are two types: (1) metaplastic atrophy, when the 1. Common lesions of chronic gastritis are gastric mucosa lamina propria are partly or all mainly grouped into atrophic and non-atrophic. replaced by intestinal epithelial glands; and (2) “Superficial” is no longer used because “super- non-metaplastic atrophy, when the amount of ficial” is the opposite of “deep”, which is used to gastric glands proper in the gastric mucosa is distinguish depth, and cannot reflect the diminished, and replaced by fibrous or fibro- amount of gastric mucosal glands. muscular tissue, or inflammatory cells (mainly 2. Chronic gastritis can be subclassified into chronic inflammatory cells). antral gastritis, corpus gastritis and pangastritis according to the distribution of lesions. 5. A diagnosis of chronic atrophic gastritis can be made if the histopathology has shown atro- 3. A small proportion of chronic gastritis cases phic changes of the gastric glands proper, no are special types of gastritis, such as chemical, matter what number of biopsy specimens show lymphocytic, granulomatous, eosinophilic, col- atrophy and degrees of atrophy. Clinicians can lagenous, radioactive, infectious (bacterial, finally judge the extent and degree of atrophy viral, fungal and parasitic) gastritis and Méné- according to the results of histopathological trier disease. examination and endoscopic findings.

4. Definition of atrophy [3, 134]: atrophy of the 6. Mucosal atrophy at an early stage, or multifo- gastric mucosa indicates the reduction of gas- cal chronic atrophic gastritis, has a patchy dis-

19 Am J Digest Dis 2014;1(1):3-21 Consensus on chronic gastritis tribution. As the destruction of gastric glands in clumps, distributed on the full length of the frequently occurs in specimens taken from the specimen. Usually, there is no H. pylori coloni- edges of erosive or ulcerated mucosa, the zation on the surface of the intestinal metapla- resulting decrease in the amount of gastric sia, and the non-intestinal metaplasia sites glands cannot be regarded as chronic atrophic should be explored. For patients with an obvi- gastritis. Furthermore, the biopsy tissue may ous inflammation, yet in whom no H. pylori is be too thin, and inappropriate dissection of found in the HE stained section, a specific stain embedded tissue might also influence the judg- and careful observation should be done. The ment of atrophy. If full lamina propria are not Giemsa stain is recommended, but other stains visible, one cannot judge the presence of to which the endoscopist is accustomed can atrophy. also be used.

7. The histopathological changes of each biop- (2) Chronic inflammation (mononuclear cell infil- sy specimen from different sites should be tration): Chronic gastritis can be graded accord- reported [135, 136]. The biopsy specimens ing to the density of chronic inflammatory cells from different sites should be separately fixed and the depth of infiltration in the mucosal and clearly labeled. Serial numbers and embed- layer, depending mainly on the former. 0: no ding should be given to each specimen during more than five mononuclear cells in each high the pathological examination. After observa- power field (including the indistinguishable lym- tion, reports should be separately issued on phocytes and plasma cells under optical micro- specimens from different sites. This kind of scope), if the number slightly exceeds this fig- report could provide more direct information to ure but no obvious endoscopic abnormality is the clinician, helping endoscopists to inspect present, pathologically it can be diagnosed as their observation ability under the gastroscope fundamentally normal; +: a few chronic inflam- and improve their judgment accuracy. matory cells localized in the superficial layer of the mucosa, but not over more than 1/3 of the 8. “Dysplasia” has long been used to represent mucosa layer; + +: a more intensive accumula- a precancerous lesion. Recently, it has been tion of chronic inflammatory cells, but not replaced by “intraepithelial neoplasia” [137, exceeding 2/3 of the mucosa layer; + + +: a 138]. Dysplasia can be categorized as mild, intensive accumulation of chronic inflammatory moderate and severe, while intraepithelial neo- cells occupying the whole mucous layer. When plasia can be categorized into low grade and calculating the density, one should avoid the high grade. Dysplasia and intraepithelial neo- areas of lymphoid follicles and surrounding plasia are synonyms, but intraepithelial neopla- small lymphocytes. sia is the term recommended by the Inter- national Agency for Research on Cancer, World (3) Activity (neutrophils infiltration). 0: no neu- Health Organization. The use of this term, trophils infiltration in a chronic inflammatory together with its translation into Chinese, has background; +: some neutrophil infiltration in not yet been agreed both internationally and in the mucosal lamina propria; + +: more neutro- this country. phils visible in the mucosa layer, also between superficial epithelial cells, pit epithelial cells or 9. Detailed information of five histological ductal epithelial cells; + + +: a more intensive changes and four grades. neutrophils infiltration, or an abscess on pits can be seen in addition to what is seen in mod- (1) H. pylori infection: Observe H. pylori on the erate activity. surface of mucus layer of gastric mucosa, superficial epithelium, pit epithelium and glan- (4) Atrophy: the degree of atrophy is calculated dular epithelium. 0: no H. pylori seen in specific in ranks of a 1/3 reduction of the gastric gland stain section; +: a few H. pylori are present proper. 0: the number of gastric gland proper is occasionally or on less than 1/3 of the full not reduced; +: the number of gastric gland length of the specimen; + +: the distribution of proper is reduced by no more than 1/3 of the H. pylori exceeds 1/3 but is less than 2/3 of original glands; + +: the number of gastric gland the full length of the specimen, or it is continu- proper is reduces by 1/3 to 2/3 of the original ously but sparsely distributed through the glands. + + +: the number of gastric gland prop- superficial epithelium; + + +: H. pylori appears er is reduced by more than 2/3 of the original

20 Am J Digest Dis 2014;1(1):3-21 Consensus on chronic gastritis glands, with only a few glands remaining or all (7) Grades should be noted when accompanied have completely disappeared. IM limited to with intraepithelial neoplasia. areas of gastric pits should not be considered as atrophy. Lymphoid follicles appearing in the 10. Sampling of gastroscope biopsy speci- mucosal layer also cannot be considered as mens: due to the uneven distribution of histo- atrophy, and should depend on the condition of pathological changes of chronic gastritis, such the glands in their peripheral areas. The histo- as inflammatory reaction degree, gland IM, pathological process of mucosal damage gland atrophy and interstitial proliferation, cer- induced by all causes may lead to the reduction tain basic conditions must be met for the gas- of gastric glands, it does not necessarily indi- troscope biopsy. cate chronic atrophic gastritis. If the specimen (1) The diameter of the gastroscope biopsy for- is too shallow to reach the muscularis mucosa, ceps must more than 2 mm (both the width and a diagnosis of atrophy cannot be made. depth of a gastric area are 1.5 mm); biopsy for- (5) Intestinal metaplasia (IM). 0: without IM; +: ceps can be opened fully (or half). the IM area accounts for less than 1/3 of the (2) The biopsy samples must be placed immedi- total area of the glands and superficial epithe- ately into fixative (within 10 seconds would be lium; + +: IM accounts for 1/3 to 2/3; + + +: IM better, lest drying affects production; fixative is accounts for more than 2/3. 4% formaldehyde solution in neutral buffer). (6) Other histological characteristics: Histolo- (3) The surface and deeper layers of the muco- gical changes do not need to be graded, but sa should be confirmed by a pathologist when should be mentioned when they appear. They embedding, ensuring that the full mucous layer may be divided into two types: non-specific and can be observed after sectioning; otherwise, specific. The former includes lymphofollicular, the fundamental conditions for determining the pit epithelial hyperplasia, pancreatic metapla- presence or absence of atrophy will not be met. sia and pseudo-pyloric metaplasia. The latter includes granulomatous, clustering eosinophils infiltration, obvious intraepithelial lymphocyte infiltration and specific pathogens. Pseudo- pyloric metaplasia is a marker of acid secretory gland atrophy. The sampling site should be checked when judgment is made. Mucus secretory glands seen in the gastric angularis should not be diagnosed as pseudo-pyloric metaplasia.

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