Comment

The ICD-10 classification of gastritis was formulated in 1989 and is still in effect in most countries. At the time of formulation, the ICD-10 classification of gastritis and duodenitis (K29) was rudimentary as it was based on macroscopic and histomorphological criteria; the only aetiological factor assigned was alcohol6 (box 1). The histological classification of gastritis considered mainly aspects of atrophy and autoimmunity.1

The discovery of H. pylori had not been taken into account, possibly because even though release came after the discovery of Campylobacter pylori (H. pylori), the role of H. pylori in disease was still controversial. The recognition of H. pylori infection as the primary cause of chronic gastritis proved to be a breakthrough that reopened the chapter on gastritis and its role in disease.2 ,24 ,25 At present, no classification of gastritis would be complete without including H. pylori as the aetiological cause.

CQ2. Is the proposed ICD-11 classification for gastritis appropriate?

Statement 2

The newly proposed classification of gastritis in the ICD11 β version is an improvement because it is based on aetiological factors.

Grade of recommendation: strong

Evidence level: moderate

Consensus level: 100%

Comment

Although the ICD-10 has been updated regularly to accommodate new diseases and concepts, WHO recognised the necessity of overall systematic changes in the ICD and decided to revise the current ICD-10 to ICD-11 in 2007. As the intermediate process for this revision, the ICD11 β version was formulated with input from various scientific advisory groups. This version was open to the public so that opinions from various interest groups and a broader range of medical specialists could be reflected before compiling the ICD-11. ICD11 β foundation component consists of the core of the ICD-11 classification from which mortality and morbidity classifications will derive. However, it remains a draft and can be changed from time to time before finalisation of ICD-11 (for more details, please visit http://www.who.int/classifications/icd/revision/betaexpectations/en/).

In the ICD11 β foundation component of the gastritis section, classification of gastritis was principally based on aetiological factors with consideration of their specific pathophysiological principles (box 2). Accordingly, H. pylori gastritis is categorised as a specific nosological entity.

The assessment of gastritis based on histopathological criteria was completely changed after recognition of H. pylori as the most common cause of chronic gastritis. The Sydney System was developed as a consequence and has been integrated into clinical practice. The Sydney classification of gastritis combined histological parameters of activity, chronicity, atrophy, intestinal metaplasia, topographical distribution and aetiopathogenic information for reporting the pathology of gastritis in endoscopic biopsies.19 ,20

As described above, classification of gastritis in the foundation component of ICD11 β version is principally based on causative factors, in order to cover the three most important and best defined categories of gastritis—namely, (a) H. pylori-induced, (b) drug-induced and (c) autoimmune gastritis. A specific diagnosis among these different categories of gastritis is required to direct specific management and treatment strategies. The diagnosis of H. pylori-induced gastritis has major implications for life-long healthcare. H. pylori gastritis may cause dyspeptic symptoms26 ,27 and result in gastroduodenal pathologies, including peptic ulcer disease (PUD) and gastric cancer. The recognised role of H. pylori as a carcinogen makes eradication of H. pylori infection the preferred strategy for the prevention of gastric cancer.5 ,11 ,28 There is more to learn about aetiologies other than H. pylori in gastritis and this is dealt with as ‘H. pylori-negative or idiopathic gastritis’.29

The proposed aetiology-based classification for gastritis in the foundation component of ICD11 β version was further refined by this consensus meeting (box 3). Clinical validation is needed to further define and confirm the usefulness of the new classification.

Furthermore, duodenitis, which was in the gastritis section in ICD-10, is now categorised in an independent section in the foundation component. It should be noted that the Joint Linearisation of Mortality and Morbidity of ICD11 β version is now publicly available (see online supplementary table S3) and differs significantly from the foundation component (box 2) or aetiology-based classification proposed in this paper (box 3). This linearisation did not adopt the principle of aetiology-based classification, thus requiring further revision.

CQ3. Is it necessary to categorise gastritis according to gastric subsite?

Statement 3

It is useful to categorise H. pylori-induced gastritis according to gastric subsites, because the risks of gastric cancer and peptic ulcer are affected by the patterns of gastritis.

Grade of recommendation: strong

Evidence level: high

Consensus level: 97.4%

Comment

The categorisation of H. pylori gastritis according to gastritis subsites together with the assessment of gastritis severity allows prediction of an individual’s risk of developing severe gastroduodenal complications and, in particular, gastric cancer.30–32

Depending on the gastric subsites involved, gastric function and, in particular, gastric acid secretion may be profoundly affected, resulting in gastric acid hypersecretion, hyposecretion or even achlorhydria.33–35

Subsite characterisation of gastritis is also critically important for identifying those patients who remain at high risk after H. pylori eradication and thus are candidates for regular endoscopic and histological follow-up.36 Patients with severe atrophic gastritis (with or without intestinal metaplasia) in the corpus or with severe corpus predominant gastritis are those at highest risk for progression to gastric cancer of the intestinal type31 ,37 and for diffuse-type gastric cancer. In diffuse-type gastric cancer the prevalence of antral atrophic gastritis is almost identical to that seen in the intestinal type but is slightly less with corpus atrophic gastritis than with intestinal type gastric cancer.38

CQ4. Is it necessary to categorise gastritis according to histology (severity) and/or endoscopy?

Statement 4

It is advisable to categorise gastritis according to histology, because the risk of development of gastric cancer in H. pylori gastritis varies according to the extent and severity of inflammation and atrophy.

Grade of recommendation: strong

Evidence level: high

Consensus level: 100%

Comment

The updated Sydney System has been globally implemented into clinical practice and requires proper assessment of all the relevant characteristics of H. pylori gastritis including atrophy and intestinal metaplasia at different gastric subsites.19 ,20 Categorising gastritis is clinically relevant because the ‘phenotype’ of H. pylori gastritis determines the risk of progression to gastroduodenal complications.

Severity and extent of atrophic gastritis and intestinal metaplasia are well established as indicators of the increased risk for developing gastric cancer.31 ,39 ,40 Similarly, severe H. pylori-induced corpus gastritis is associated with an increased risk for gastric cancer.31 ,41 New staging systems for the characterisation of gastritis have been introduced to assess the gastric cancer risk. They are used in clinical practice and are either based on the severity of atrophy in various gastric subsites (OLGA)16 ,17 or on intestinal metaplasia (OLGIM).18 Both systems, discussed further in section 3, are reported to have a positive impact on patient management.

CQ5. How should we classify gastric erosions in the context of chronic gastritis?

Statement 5

Gastric erosions should be reported separately from gastritis. The natural history and clinical significance of gastroduodenal erosions depend on aetiology and need further clarification.

Grade of recommendation: strong

Evidence level: low

Consensus level: 100%

Comment

Gastric erosions are defined as superficial mucosal breaks with a diameter of <3 mm or <5 mm.42 This small size makes it less likely to confound erosions with peptic ulcers which, by definition, penetrate the muscularis mucosae.3

Gastric erosions can be detected in the context of H. pylori infection but are more frequently caused by intake of mucosal damaging drugs—in particular, aspirin and non-steroidal anti-inflammatory drugs (NSAIDs).43 ,44

Furthermore, several different morphological forms were noted after eradication of H. pylori as (a) flat, (b) raised, (c) haemorrhagic and (d) appearing as bleeding spots with localisation in the antrum in the absence of drugs,45 possibly owing to hyperacidity after eradication therapy.46 ,47

From a clinical perspective, the most relevant aspect of erosions is that patients taking NSAIDs and having numerous erosions in the stomach are at increased risk of developing ulcers subsequently.48

Few studies on the clinical significance or natural history of gastric or duodenal erosions have been reported. Thus, it is important to conduct a prospective research in which erosions in the stomach and duodenum are separately reported in conjunction with the category of gastritis, which is needed to better understand the natural history of gastric erosions and their potential to progress to ulceration and bleeding. Validated scores for reporting erosions for research purposes should be used.49

CQ6. Is H. pylori gastritis an infectious disease irrespective of symptom and complications?

Statement 6

H. pylori gastritis should be defined as an infectious disease, even when patients have no symptoms and irrespective of complications such as peptic ulcers and gastric cancer.

Grade of recommendation: strong

Evidence level: high

Consensus level: 100%

Comment

H. pylori gastritis is an infectious disease and leads to chronic active gastritis of varying severity in virtually all infected subjects.50

There is a significant variability in the interindividual expressions of gastric mucosal structural damage and accordingly the associated physiological perturbations also vary.30 ,35 H. pylori gastritis may remain clinically unapparent or evolve into severe complications. The rate of progression is unpredictable. The most severe clinical expression is gastric cancer, which is often incurable by the time of diagnosis.

Cure of H. pylori infection leads to healing of the inflamed gastric mucosa, which may return to normal. H. pylori eradication may improve or resolve dyspeptic symptoms and usually cures PUD. H. pylori gastritis is a disease which can be cured and thus prevent severe complications. If H. pylori gastritis has progressed to more severe forms of gastritis, including atrophic gastritis with or without intestinal metaplasia, or severe corpus predominant gastritis, the risk of gastric cancer is increased and eradication of the infection at this stage needs to be integrated with a follow-up strategy.5 ,11 ,28 ,31 ,36 ,40

Comment

A large number of observations support the conclusion that H. pylori infection may be a cause of symptoms in a proportion of patients presenting with dyspepsia.26 ,27 First, acute iatrogenic or self-administered infection with H. pylori can induce acute dyspeptic symptoms.24 ,25 However, while persistent colonisation virtually always leads to chronic gastritis,48 in the majority of individuals severe dyspeptic symptoms are transient.24 ,25 ,51 Second, most but not all, epidemiological studies show associations between H. pylori infection and (uninvestigated) dyspeptic symptoms.52–55 The most convincing evidence can be derived from H. pylori eradication studies in infected patients with uninvestigated or FD.12 ,56–61 In these studies, eradication is associated with a small but statistically significant benefit for symptom control over no eradication; the estimated number needed to treat is 1412 and in a more recent study the number was 8.61 At present there are no criteria to predict whether a patient with dyspeptic symptoms will respond to eradication therapy or not. Therefore, the only way in clinical practice is to eradicate the H. pylori infection and see whether symptoms resolve or whether additional treatments will be required. The symptomatic gain takes at least 6 months to become significant over no eradication and this has been attributed to the time it takes for gastritis to recover.12 ,59–61

CQ8. Should we categorise H. pylori-associated dyspepsia as a specific entity?

Statement 8A

In H. pylori-infected patients with dyspepsia, symptoms can be attributed to H. pylori gastritis if successful eradication therapy is followed by sustained symptom remission.

Grade of recommendation: strong

Evidence level: high

Consensus level: 97.4%

Statement 8B

H. pylori-associated dyspepsia (as in statement 8A) is a distinct entity.

Grade of recommendation: strong

Evidence level: moderate

Consensus level: 92.1%

Comment

Based on the Rome III consensus,9 ,62 FD is defined as “the presence of chronic dyspeptic symptoms (postprandial fullness, early satiation, epigastric pain or burning) without evidence of structural disease (including at upper endoscopy) that is likely to explain the symptoms” (figure 1). This group was contrasted with those in whom chronic dyspeptic symptoms have an identified organic or metabolic cause, where elimination of that cause or improvement of the disease leads to resolution or improvement of symptoms.9

• Download figure
• Open in new tab
• Download powerpoint

Figure 1

Diagnostic algorithm of Helicobacter pylori-associated dyspepsia. Patients with dyspeptic symptoms after negative routine laboratory and upper gastrointestinal endoscopy except for positive H. pylori tests, should undergo eradication therapy. If sustained symptomatic relief is obtained, their dyspeptic symptoms are considered as H. pylori-associated dyspepsia. On the other hand, if dyspeptic symptoms do not resolve or recur after eradication therapy, they are judged to have functional dyspepsia. EGD, oesophagastroduodenoscopy.

The Rome III consensus mentions a subset of patients with H. pylori gastritis as representative of organic dyspepsia if they respond to eradication. Patients with H. pylori gastritis in whom symptoms persist despite eradication therapy eliminating the infection were identified as having FD.9 As mentioned above, eradication therapy studies showed that a subset of H. pylori-infected patients with FD derive symptomatic benefit from eradication, with a delay of at least 6 months from cure of the infection.12 ,59–61

Based on these considerations, sustained symptom control after successful eradication identifies H. pylori as the organic cause of the symptoms in these patients and provides the rationale to consider H. pylori-associated dyspepsia as a separate clinical entity. H. pylori-infected patients with chronic dyspeptic symptoms and negative endoscopy are now treated and labelled depending on their treatment response as outlined in figure 1.

CQ9. Is eradication of H. pylori infection first-line treatment for improving dyspeptic symptoms?

Statement 9

Eradication of H. pylori is first-line treatment for H. pylori-infected dyspeptic patients.

Grade of recommendation: strong

Evidence level: high

Consensus level: 94.7%

Comment

As is apparent from statement 8, there is a group of patients with FD for whom H. pylori is considered the cause of their symptoms, and this can be established if eradication is associated with sustained symptom benefit.9 ,59–61 This scenario is the only one where patients with chronic dyspeptic symptoms and a negative endoscopy can be ‘cured’, albeit with some delay after successful eradication therapy.12 ,59–61 Moreover, very few effective alternative therapeutic approaches have been proved to have substantial and sustained benefit in FD.63 Finally, eradication therapy is a short treatment, with acceptable cost–benefit for controlling dyspeptic symptoms, and with other potential benefits for prevention of peptic ulcer and gastric cancer.5 Based on these considerations, eradication therapy can be proposed as first-line treatment for H. pylori-infected dyspeptic patients, which is in line with a recent management algorithm by the Rome foundation.64

CQ10. How effective is H. pylori eradication on dyspeptic symptoms—in the short and long term—and how does it compare with other treatments (such as proton pump inhibitors (PPIs))?

Statement 10

In H. pylori-infected dyspeptic patients, eradication therapy for dyspeptic symptoms is better than placebo and is the preferred option.

Grade of recommendation: strong

Evidence level: high

Consensus level: 97.4%

Comment

Eradication therapy studies have confirmed that a subset of H. pylori-infected patients with FD is relieved of dyspeptic symptoms by eradication therapy.12 ,56–61 To date, only a limited number of studies have directly compared eradication therapy with other treatments that are used for FD, such as PPIs or prokinetic therapy.57 ,60 ,61 Hence, although the symptomatic gain takes at least 6 months,57 ,60 ,61 eradication is the preferred treatment. Future trials should compare eradication with treatment modalities other than placebo in H pylori-infected patients with chronic dyspeptic symptoms and a negative endoscopy.

CQ11. Should patients who remain dyspeptic after successful H. pylori eradication be considered to have FD?

Statement 11

Patients who remain symptomatic after successful H. pylori eradication should be considered to have FD.

Grade of recommendation: weak

Evidence level: moderate

Consensus level: 97.4%

Comment

As indicated in statements 8A and 8B and in agreement with the Rome III criteria,9 ,62 H. pylori infected dyspeptic patients with negative endoscopy who experience sustained symptom control are labelled as having H. pylori-associated dyspepsia. Conversely, when symptoms do not benefit in the long term from successful eradication, this indicates that H. pylori gastritis did not cause the symptoms in these patients. Consequently, they can keep the label ‘functional dyspepsia’ (figure 1).

Comment

Conventional endoscopy is, in most hands, an inadequate tool for diagnosing atrophy and intestinal metaplasia and therefore it remains mandatory that a biopsy is carried out, allowing histomorphological assessment of the gastric mucosa according to the Sydney classification.19 ,20 However, image-enhanced endoscopy has improved the accuracy and reproducibility of endoscopic diagnosis of premalignant gastric lesions. This includes chromoendoscopy,65 high-resolution magnification endoscopy66 ,67 and image-enhanced endoscopy combined with magnification15 ,68–72 (figure 2). These methods are now routinely available in Japan and will be increasingly used worldwide. Adequate evaluation of the stomach mucosa with each of these methods requires appropriate training66 and offers the advantage of targeted biopsies.

• Download figure
• Open in new tab
• Download powerpoint

Figure 2

Image enhanced endoscopy. (A) Narrow band imaging (NBI) of the gastric mucosa. Round homogeneous sized pits with regularly arranged collecting venules are shown (left). This pattern (regular arrangement of collecting venules) named ‘RAC’ pattern in the corpus mucosa highly indicates a Helicobacter pylori negative state.13 In the H. pylori-infected mucosa with inflammation, pit patterns are elongated, varied in sizes and shapes with spaces between them. Collecting venules are obscured owing to inflammation (centre).14 When intestinal metaplasia develops, the pit pattern is further elongated with light blue lines (light blue crest sign) decorating the pits margins (right).66 The images were provided by Dr Kazuyoshi Yagi. (B) Blue laser imaging (BLI) of the gastric mucosa. BLI is a new modality of image enhancement.70 The BLI-bright mode can easily obtain lower magnification images, similar to the NBI images in (A) (left). With BLI-magnification mode, further mucosal details including periglandular capillary networks (red coloured circles surrounding the pits) are seen (centre). BLI endoscopy is useful for identifying the area of intestinal metaplasia where greenish coloured elongated pit patterns predominate (right). The images were provided by Dr Hiroyuki Osawa, Jichi Medical University.

CQ13. Is the updated Sydney System appropriate for histological diagnosis of gastritis?

Statement 13

Accurate histological assessment of gastritis requires biopsy sampling of both antrum and corpus.

Grade of recommendation: strong

Evidence level: high

Consensus level: 92.1%

Comment

Premalignant lesions of the stomach may be unevenly distributed. Therefore, accurate histological assessment of gastritis requires biopsy sampling of both antrum and corpus. This may facilitate the classification and grading of preneoplastic gastric lesions.73 Various studies have shown that more extensive biopsy sampling increases the diagnostic yield for identifying patients with premalignant lesions and provides a better overview of the severity and distribution of these lesions.74–76 This also has practical limitations, which led to the updated Sydney System. This provides guidance on the methods of sampling and the histopathological grading of individual abnormalities—in particular, inflammation, gland loss and metaplasia.20 The Sydney System recommends routine sampling of five gastric biopsy specimens: antrum greater and lesser curvature, incisura and corpus greater and lesser curvature. Specimens need to be put into separate vials and grouped for each site or lesion. The system is widely used; the most common modification being to leave out the separate incisura sample.36 It is of key importance that separate specimens are obtained from endoscopically visible lesions. The accuracy of image-enhanced endoscopy in trained hands further increases the yield of targeted biopsies.66 ,77 ,78

CQ14. Are grading systems such as OLGA and OLGIM useful for risk stratification?

Statement 14A

Gastric cancer risk correlates with the severity and extent of atrophic gastritis.  Grade of recommendation: strong

Evidence level: high

Consensus level: 94.7%

Statement 14B

Histological staging systems such as OLGA and OLGIM are useful for risk stratification.

Grade of recommendation: strong

Evidence level: low

Consensus level: 97.3%

Comment

Most gastric cancers are triggered by longstanding gastritis, primarily due to H. pylori infection. This can occur via a multistep pathway of precancerous lesions—in particular, atrophic gastritis, intestinal metaplasia and dysplasia/intraepithelial neoplasia. Various studies confirm an increased gastric cancer risk in patients with premalignant gastric lesions. For instance, a nationwide study from the Netherlands including approximately 98 000 patients with premalignant gastric lesions reported, on average, a 2–3% gastric cancer risk over 10 years.79 This risk varied with the baseline stage of premalignant lesions, being 0.8%, 1.8%, 3.9% and 32.7% for patients with atrophic gastritis, intestinal metaplasia, mild-to-moderate dysplasia and severe dysplasia, respectively.79

These data confirmed the association between presence of premalignant gastric lesions and development of gastric cancer, yet also showed that the risk for developing gastric cancer in an individual with premalignant lesions is nevertheless small (2–6 per 1000 people per year). This necessitates the use of risk stratification methods.

Gastric biopsy sampling can be used to provide the most important information for risk classification. This led to the OLGA staging system.16 ,17 This histological staging system grades patients with gastritis into stages with corresponding gastric cancer risk. Further studies showed that this staging system provides relevant clinical information.80–82 Based on the high prevalence of atrophic gastritis in at-risk populations and the limited reproducibility and high interobserver variability in histological diagnosis of atrophic gastritis, a further proposal was made for the OLGIM system based on diagnosis and distribution of intestinal metaplasia.18

The interobserver reproducibility was improved for intestinal metaplasia compared with atrophic gastritis, and the correlation between the severities of gastritis remained at least as strong.18 Subsequent studies with both the OLGA and OLGIM systems showed a higher gastric cancer risk in patients in stage III or IV of OLGA or OLGIM.82–84 As a result, upper gastrointestinal surveillance endoscopy should be offered to patients in these subcategories.

CQ15. Are serological tests (pepsinogen I, II, I/II, H. pylori antibody) useful for risk stratification?

Statement 15

Serological tests (pepsinogen I and II and H. pylori antibody) are useful for identifying individuals at increased risk for gastric cancer.  Grade of recommendation: strong

Evidence level: high

Consensus level: 91.9%

Comment

Serological tests for the diagnosis of chronic gastritis and gastric atrophy have been in use for more than 25 years. These include H. pylori serology (crude antigen with or without additional determination of anti-CagA antibodies) for the diagnosis of gastritis, and serum pepsinogen I and II and gastrin for the diagnosis of gland loss resulting in hypoacidity.85 These tests are usually applied in panels of multiple tests and have been shown to be a useful non-invasive diagnostic tool in an individual patient, and as a population screening and surveillance tool.86 ,87 A Japanese cohort of 9293 screenees underwent serological assessment by means of H. pylori serology and pepsinogen I and II measurement.86 The annual progression to gastric cancer was very low in subjects with normal pepsinogens, irrespective of H. pylori status. The annual progression to gastric cancer was substantially higher (3.5–6 per 1000 per year) in individuals with low serum pepsinogen levels, compatible with presence of atrophic gastritis.86 In the latter group, the incidence of gastric cancer was higher among those with negative H. pylori serology than among those with positive H. pylori serology, which is indicative of progressive and widespread atrophy and metaplasia impairing further H. pylori colonisation. Similar findings were obtained in other studies.88 ,89

CQ16. When is it appropriate to search and screen for H. pylori gastritis?

Statement 16

Depending on the epidemiological context, it is appropriate to search and screen for H. pylori gastritis at an age before development of atrophic gastritis and intestinal metaplasia.

Grade of recommendation: strong

Evidence level: moderate

Consensus level: 97.3%

Comment

H. pylori infection is mainly acquired in childhood, up to the age of 12 years, in developed countries mostly by intrafamilial transmission.90–92 The bacterium and associated gastritis persist lifelong, unless treated by eradication therapy, or unless end-stage widespread atrophic gastritis and intestinal metaplasia occur. The risk for gastric cancer depends on the grade of gastric atrophy and intestinal metaplasia.31 ,82–84 ,86 H. pylori eradication can reduce the risk for cancer, but this effect is largely confined to patients without atrophy and metaplasia.93–95 In patients with these lesions, H. pylori eradication reduces gastritis, but may not stop further progression to cancer. As a result, cancer can occur more than 10 years after H. pylori eradication treatment.96 Against this background, it is appropriate to search and screen for H. pylori gastritis at an age when new infections become less likely (>12 years) and before development of atrophic gastritis and intestinal metaplasia. This all depends on the geographical location and epidemiological context, taking into account the prevalence of infection and age-related cancer incidence.97

Section 4 Management of gastritis

CQ17. Should all H. pylori-positive individuals receive eradication therapy?

Statement 17

H. pylori infected individuals should be offered eradication therapy, unless there are competing considerations.

Grade of recommendation strong

Evidence level: high

Consensus level: 100%

Comment

H. pylori is a major human pathogen that causes chronic and progressive gastric mucosal damage and is aetiologically related to peptic ulcer, gastric cancer and gastric atrophy. It is also closely associated with gastric MALT lymphoma, dyspepsia, hyperplastic gastric polyps and idiopathic thrombocytopenic purpura.5 ,12 ,46 ,47 ,61 ,98–104 H. pylori-positive individuals are also the major reservoir for transmission of the infection.

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 genes121–123 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.