Kyoto global consensus report on Helicobacter pylori gastritis

The decision to eradicate a chronic infection in a society should be based on quantitative data regarding the outcome of untreated infections. H. pylori causes a chronic infection, similar, for example, to asymptomatic syphilis or tuberculosis, and the final outcome for any individual cannot be predicted. [105] H. pylori infection differs from many other chronic infectious diseases because it is always transmissible, thus putting others at risk. Because the gastric damage is progressive, the lack of an obvious clinical manifestation at diagnosis has no predictive value for life-time risk to an individual patient, their family or to the community. Benefits of H. pylori eradication for an individual depend in part on the degree and extent of damage that has already occurred and the reversibility of that damage. Potential benefits of eradication include stopping the progression of mucosal damage, stabilisation or reduction in risk of developing gastric cancer, resolution of mucosal inflammation, stabilisation or improvement of gastric mucosal function, return of the normal mechanisms governing acid secretion, cure of H. pylori-related PUD, reduction in risk of gastrointestinal complications of NSAID therapy and prevention of future development of H. pylori-related peptic ulcer. [2, 5, 11, 28, 46, 47, 106-115]

For society, the benefits include reduction of the reservoir of infected individuals capable of transmitting the infection to others, and avoidance of the costs associated with diagnosis, management and outcomes of H. pylori-related diseases that are prevented. Thus, H. pylori-infected patients should be offered eradication therapy unless there are competing considerations such as comorbidities, re-infection rates in their communities, competing health priorities of society and financial cost. It has to be remembered, however, that there are concerns about the negative impact of eradication therapies on human health, such as increase in allergy or obesity and perturbation of microbiota. [116, 117]

CQ18. What is the optimal timing for H. pylori eradication in asymptomatic subjects?

Statement 18

The maximum benefit of H. pylori eradication is obtained if it is done while the mucosal damage is still non-atrophic.

Grade of recommendation: strong

Evidence level: high

Consensus level: 100%

Comment

H. pylori eradication always confers a benefit by halting progression of gastric mucosal damage, reducing the reservoir of infected individuals and reducing or preventing H. pylori-associated diseases. The maximum benefit of eradication for an individual is obtained if eradication is done while the H. pylori-induced mucosal damage has not progressed beyond the non-atrophic stage. This population is found in countries where gastric cancer is still prevalent and is concentrated in the younger generation. H. pylori eradication of adolescents and young adults has an additional advantage of reducing or preventing transmission of the infection to their children.

As noted above (Section 3), the risk for development of gastric cancer correlates with the extent and severity of atrophic gastritis. It is impossible to define the risk for an individual based on age. Cancer risk in any population relates to the rate of progression of gastric mucosal damage, which is high in populations at high risk of cancer and low in H. pylori-infected populations with a low cancer risk. Thus, while it is possible to identify an average age at which the transition from non-atrophic to atrophic phenotype occurs for any population, one should expect that any age group will contain individuals with a wide range of damage, ranging from uninfected (normal) to advanced atrophy. This emphasises the need for risk stratification based on objective parameters including a validated histological staging system rather than on age, to identify whether one eradication treatment is needed or whether the patient might require surveillance.

The incidence of gastric cancer increases with age, which is a surrogate marker for the time required for progression of atrophic gastritis. When atrophic gastritis becomes extensive and severe, the risk increases exponentially. Cancer is the culmination of a multistep process of genetic instability, with cancer cells possessing mutations in coding regions, somatic gene rearrangements and epigenetic changes such as methylation. Current data are consistent with the notion that H. pylori eradication halts the progression of damage and reduces or eliminates the H. pylori-associated events that increase genetic instability in the gastric mucosa. These include infection-associated DNA double-strand breaks, [118] impaired DNA mismatch repair, [119] aberrant activation-induced cytidine deaminase expression, which induces nucleotide alterations involved in DNA mutations, [120] aberrant methylation in a number of gene promoters in the gastric mucosa, including cell growth-related genes, DNA-repair genes, tumour-suppressor genes, the cell adherence gene E-cadherin and CpG islands of microRNA genes [121-123] and aberrant microRNA expression. [124] H. pylori infection also causes an inflammatory response with mucosal infiltration of acute and chronic inflammatory cells. Cancer risk is increased in relation to the ability of the infecting strain to cause inflammation (eg, those possessing the Cag pathogenicity island). However, all strains cause inflammation, and gastric cancer is associated with infections lacking putative virulence factors. Thus all H. pylori infections should be considered pathogenic and should be eradicated.

Because of the damage and premalignant changes, H. pylori eradication cannot `reset the clock' to zero (ie, no risk) but can stop the progression of risk and stabilise or decrease the subsequent risk.

CQ19. Do we need to adopt eradication regimens according to the geographical area?

Statement 19

Eradication regimens should be based on the best locally effective regimen, ideally using individual susceptibility testing or community antibiotic susceptibility, or antibiotic consumption data and clinical outcome data. The agents available differ in different regions and this, in part, dictates what regimens are possible.

Grade of recommendation: strong

Evidence level: high

Consensus level: 100%

Comment

The success of a proven successful H. pylori eradication regimen depends on the pattern of resistance in the population and on the common host genotypes of drug metabolising enzymes in the population. The prevalence of H. pylori resistance to commonly used antimicrobial agents greatly varies geographically and is linked to consumption of antibiotics in the region, [125] so the preferred eradication regimen often differs between regions. Ideally, treatment regimens should be chosen based on susceptibility testing. Within any region, only regimens that reliably produce eradication rates of ?90% in that population should be used for empirical treatment. [5, 126-129]

CQ20. Does eradication of H. pylori prevent gastric cancer?

Statement 20

Eradication of H. pylori reduces the risk of gastric cancer. The degree of risk reduction depends on the presence, severity and extent of atrophic damage at the time of eradication.

Grade of recommendation: strong

Evidence level: high

Consensus level: 100%

Comment

H. pylori infection is the most important cause of gastric cancer as it is estimated that 89% of non-cardia gastric cancer, representing 78% of all cases of gastric cancer, can be attributed to chronic H. pylori infection. [130] Prevention of H. pylori infections removes the primary cause of gastric cancer and will thus reduce the incidence of gastric cancer in that population. The effectiveness of H. pylori eradication for prevention of gastric cancer depends on the severity and extent of atrophic damage at the time of eradication and ranges from essentially complete prevention for those with non-atrophic gastritis to stabilisation or reduction of risk in those with established atrophic changes. [94, 95] As noted in Section 3, risk can be stratified using a variety of approaches, such as one of the validated histological stratification systems (eg, OLGA or OLGIM), [16-18] and H. pylori eradication can stabilise risk and halt the progression of risk. [28, 94] Prevention of acquisition of H. pylori infections and eradication of the infection before the development of atrophic changes are forms of primary prevention. Secondary prevention involves identification and surveillance of those at risk in order to remove intraepithelial lesions and early gastric cancer(s) before they become invasive. [5, 71, 72, 77, 131] There may be also a role for cancer immunotherapy to treat premalignant lesions and halt their progression to more advanced lesions. [132]

CQ21. Should the outcome of eradication therapy always be assessed (ie, test for cure)?

Statement 21

The outcome of eradication therapy should always be assessed, preferably non-invasively.

Grade of recommendation: strong

Evidence level: high

Consensus level: 100%

Comment

Failure of eradication is common and allows the mucosal damage to progress, and so eradication should always be confirmed, preferably using a non-invasive test such as a urea breath test or a validated monoclonal-based stool antigen test. [5] For patients requiring endoscopic follow-up, such as after endoscopic removal of a gastric adenoma, histological assessment can be used. Confirmation of cure also provides an early warning system for the increasing antibiotic resistance in a population that will manifest as increasing rates of treatment failure. [125, 128, 129]

CQ22. Which patients need long-term follow-up after eradication?

Statement 22

H. pylori eradication may not completely eliminate the risk of gastric cancer. Patients who remain at risk, as defined by the extent and severity of atrophy, should be offered endoscopic and histological surveillance.

Grade of recommendation: strong

Evidence level: high

Consensus level: 97.3%

Comment

Long-term follow-up such as regular endoscopic surveillance should be based on estimating the risk of developing gastric cancer after H. pylori eradication (ie, risk stratification). [95, 133] Cancer risk correlates with the extent and severity of atrophic gastritis and risk stratification should be confirmed using a validated histological risk scoring systems such as OLGA or OLGIM. [16-18] In areas with proven expertise in endoscopic scoring, a system such as that of Kimura and Takemoto can be used initially, although histological confirmation is still recommended. [134, 135] Patients whose H. pylori infection was diagnosed non-invasively (eg, urea breath test or stool antigen) should be considered for histological assessment. These patients should include those within the age range in which atrophic changes are common in that population and those with a history of gastric ulcer as well as those with a pretreatment serum pepsinogen I of ?70 ng/mL and a pepsinogen I:II ratio ?3. [136-138] All those at especially high risk, including those at risk for intraepithelial neoplasia (dysplasia) or early gastric cancer, are candidates for regular endoscopic surveillance.

Discussion

The global consensus meeting on H. pylori gastritis has set a new landmark for gastritis, which has continued to be an ill-conceived clinical entity placed between a histological picture and upper abdominal symptoms.

In spite of the fact that gastritis had been long recognised as an important clinical entity, generations of gastroenterologists have neglected the importance of treatment of this nosological entity. Rudolf Schindler described chronic gastritis as a serious disease and a precursor of gastric cancer and considered their relationship as being of outstanding importance in the fight against gastric cancer. [139]

The discovery of H. pylori has revolutionised the pre-existing concepts of gastritis by assigning a specific aetiology to this entity underlying PUD and gastric cancer. The majority of these serious conditions are manifestations developed on the background of chronic gastritis caused by a unique infectious agent, H. pylori. For PUD, guidelines unanimously recommend eradication as the primary treatment for those with positive H. pylori tests. However, there has been no consensus on how and when to manage individuals with H. pylori gastritis itself, which is crucial to the efficiency of gastric cancer prevention because most patients with chronic gastritis may remain asymptomatic until the appearance of severe complications. Furthermore, both gastritis and duodenitis were recognised as important causes of upper gastrointestinal bleeding, [140] encouraging our attention to these conditions now that anti-thrombotic therapies are increasingly being used.

To further compromise the concept of gastritis as a significant clinical entity, the term `gastritis' has historically, but wrongly, been used as a substitute for a clinical diagnosis of FD. Historical studies, however, failed to demonstrate a significant association between histological findings of gastritis and the dyspeptic symptom complex. [141, 142] Hence, a potential pathogenetic role for H. pylori in causing dyspeptic symptoms was initially considered doubtful and its eradication in FD controversial. [143, 144] Meta-analysis of a large number of controlled trials with longer follow-up confirmed that eradication of H. pylori in patients with FD conveys a small but statistically significant benefit. [12] Consequently, dyspepsia attributable to H. pylori gastritis involves an underlying organic cause and should be excluded from the FD category. Additionally, `dyspeptic' patients should not automatically be labelled as having `gastritis' without any histological confirmation.

Diagnostic assessment of gastritis has been advanced by the recent introduction of high-resolution endoscopy with image-enhanced modalities, and magnification is now used routinely in major hospitals in Japan. This endoscopic technology allows the identification of mucosal changes (for targeted biopsies) more precisely, leading to more accurate evaluation of cancer risks such as preneoplastic changes. Wider use of this new endoscopic system outside Japan may be limited at present.

The Kyoto consensus meeting focused attention on gastritis in all its clinical expression and dealt with four main topics: classification of gastritis in relation to ongoing ICD revision, FD and H. pylori infection, diagnosis of gastritis and the management of gastritis. The methodology of the meeting adopted all modern means for reaching consensus and included an internet-based Delphi method with full access to published data in a completely `neutral' environment.

In summary, The Kyoto meeting proposed an aetiology-based classification for gastritis and concluded that H. pylori gastritis is an infectious disease. As such, H. pylori gastritis requires treatment whether or not it is associated with symptoms because it represents a condition that may evolve towards serious complications, including peptic ulcer and gastric neoplasia.

Consensus was reached on the existence of a separate category of patients with dyspeptic symptoms that are due to H. pylori gastritis. In these patients, eradication therapy is the recommended first-line treatment. Because of the diagnostic problems related to `gastritis', these patients should be labelled as having H. pylori-associated dyspepsia and are identified by sustained dyspeptic symptom relief after eradication.

For the diagnosis of gastritis, it was agreed that risk stratification systems such as OLGA and OLGIM are useful as are the serological markers. In view of recent technological advancements, image-enhanced endoscopy should be encouraged for identifying mucosal changes which carry a high risk of developing into gastric neoplasia. Finally, it was recommended that early eradication therapy, ideally before preneoplastic changes occur, should be undertaken. However, the feasibility of implementing this strategy should be regionally tailored. As eradication therapy does not guarantee elimination of the risk of gastric cancer, follow-up should be considered for patients who have preneoplastic conditions.

Although there are still many remaining areas to be discussed, we believe the outcome of the Kyoto consensus meeting presented in this report will improve patient care and will provide a cornerstone for further refinement and research in the area of gastritis.

Correction notice This article has been corrected since it published Online First. Hidekazu Suzuki has been added to the collaborators list.

Acknowledgments We thank the Japanese Society of Gastroenterology (JSGE) for providing financial support, enabling this global consensus meeting. Technical support by Omura Publishing Co Ltd and Mr Osamu Iimura of the JSGE is greatly appreciated. We also thank Japan Convention Service Co Ltd for their excellent management of the conference.

Collaborators List of faculty members and affiliations (alphabetical order of family names): Takeshi Azuma, Department of Gastroenterology, Kobe University; Franco Bazzoli, Department of Gastroenterology, University of Bologna; Francis Ka-Leung Chan, Department of Medicine and Therapeutics, The Chinese University of Hong Kong; Minhu Chen, Department of Gastroenterology, The first affiliated hospital, SunYat-sen University; Naoki Chiba, McMaster University; Tsutomu Chiba, Department of Gastroenterology, Kyoto University; Luiz Gonzaga Vas Coelho, Department of Internal Medicine, Faculty of Medicine, Federal University of Minas Gerais; Francesco Di Mario, Department of Clinical Experimental Medicine, University of Parma; Kwong Ming Fock, Department of Gastroenterology, Changi General Hospital; Yasuhiro Fukuda, Sasayama Medical Center, Hyogo College of Medicine; Takahisa Furuta, Center for Clinical Research, Hamamatsu University School of Medicine; Robert Maximilian Genta, Department of Pathology, Miraca Life Sciences Research Institute and University of Texas Southwestern; Khean-Lee Goh, Division of Gastroenterology and Hepatology, Department of Medicine, University of Malaya; Masanori Ito, Department of Gastroenterology and Metabolism, Hiroshima University; Tomonori Kamada, Department of Internal Medicine, Kawasaki Medical School; Peter Harry Katelaris, Department of Gastroenterology, Concord Hospital, University of Sidney; Mototsugu Kato, Division of Endoscopy, Hokkaido University Hospital; Takashi Kawai, Endoscopy Center, Tokyo Medical University Hospital; Nayoung Kim, Department of Internal Medicine, Seoul National University Bundang Hospital; Ryuji Kushima, Department of Pathology, Shiga University of Medical Science; Varocha Mahachai, Division of Gastroenterology, Chulalongkorn University Hospital; Takeshi Matsuhisa, Nippon Medical School Tama Nagayama Hospital; Francis Mйgraud, INSERM U853 and Department of Bacteriology; Hiroto Miwa, Department of Gastroenterology, Hyogo College of Medicine; Kazunari Murakami, Department of Gastroenterology, Oita University; Colm Antoine O'Morain, Faculty of Health Sciences, Trinity College; Massimo Rugge, Department of Pathology, Padova University; Kiichi Sato, International University of Health and Welfare; Tadashi Shimoyama, Department of Gastroenterology and Hepatology, Hirosaki University; Akiko Shiotani, Department of Internal Medicine, Kawasaki Medical College; Toshiro Sugiyama, Department of Internal Medicine, Toyama University; Hidekazu Suzuki, Department of Gastroenterology, Keio University; Kazuyoshi Yagi, Department of Medicine, Niigata Prefectural Yoshida Hospital; Ming-Shiang Wu, Department of Internal Medicine, National Taiwan University.

Contributors KS, NU, EME-O and PM planned the meeting and prepared the clinical questions. KS, JT, EJK, EME-O, DYG and PM wrote the manuscipt. SM, KH and MA helped to summarise the voting results of sections 1, 3 and 4, respectively. All other faculty members contributed to formulating one or two statements for each clinical question, participated in the meeting and voted. They also read and approved the manuscript.

Competing interests KS has received research grants from Eisai, Daiichi Sankyo and Takeda. He has also received lecture fees from Astellas, Fuji Film and Takeda. JT has provided scientific advice to AlfaWassermann, Almirall, AstraZeneca, Danone, GI Dynamics, GlaxoSmithKline, Ironwood, Janssen, Menarini, Novartis, Rhythm, Shire, Sucampo, Takeda, Theravance, Tsumura, Will-Pharma, Yuhan and Zeria. He has also served on speaker bureaus for Abbott, Almirall, AstraZeneca, Danone, Janssen, Menarini, MMS, Novartis, Shire, Takeda and Zeria. He has received research grants from Novartis, Shire and Zeria. DYG is a consultant for RedHill Biopharma and has received research support. He is also a consultant for Otsuka Pharmaceuticals and for BioGaia. KH has received lecture fees from Astellas, AstraZeneca, Daiich Sankyo, Dainippon Sumitomo, Eisai, Otsuka, Takeda and Zeria. He has also received research funds from Astellas, Daiichi Sankyo, Eisai and Takeda. MA belongs to the department funded by Eizai Co Ltd at Hokkaido University Graduate School of Medicine. NU has received lecture fees from Astellas, AstraZeneca, Eisai and Takeda. PM has received speaker's fee from Abbvie, Aptalis, AstraZeneca and Takeda.

Provenance and peer review Not commissioned; externally peer reviewed.

Open Access This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http:// creativecommons.org/licenses/by-nc/4.0/



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