Previous Helicobacter pylori infection–induced atrophic gastritis: A distinct disease entity in an understudied population without a history of eradication

Abstract Individuals with chronic atrophic gastritis who are negative for active H. pylori infection with no history of eradication therapy have been identified in clinical practice. By excluding false‐negative and autoimmune gastritis cases, it can be surmised that most of these patients have experienced unintentional eradication of H. pylori after antibiotic treatment for other infectious disease, unreported successful eradication, or H. pylori that spontaneously disappeared. These patients are considered to have previous H. pylori infection–induced atrophic gastritis. In this work, we define these cases based on the following criteria: absence of previous H. pylori eradication; atrophic changes on endoscopy or histologic confirmation of glandular atrophy; negative for a current H. pylori infection diagnosed in the absence of proton‐pump inhibitors or antibiotics; and absence of localized corpus atrophy, positivity for autoantibodies, or characteristic histologic findings suggestive of autoimmune gastritis. The risk of developing gastric cancer depends on the atrophic grade. The reported rate of developing gastric cancer is 0.31%‐0.62% per year for successfully eradicated severely atrophic cases (pathophysiologically equal to unintentionally eradicated cases and unreported eradicated cases), and 0.53%‐0.87% per year for spontaneously resolved cases due to severe atrophy. Therefore, for previous H. pylori infection–induced atrophic gastritis cases, we recommend endoscopic surveillance every 3 years for high‐risk patients, including those with endoscopically severe atrophy or intestinal metaplasia. Because of the difficulty involved in the endoscopic diagnosis of gastric cancer in cases of previous infection, appropriate monitoring of the high‐risk subgroup of this understudied population is especially important.


| INTRODUC TI ON
Since the International Agency for Research and Cancer (IARC) of the World Health Organization designated H. pylori a type 1 carcinogen in 1993, 1 H. pylori infection has been widely accepted as the strongest risk factor for the development of gastric cancer, and numerous studies have supported this association. [2][3][4][5] The high prevalence of gastric cancer in H. pylori-positive subjects likely occurs because H. pylori infection leads to the progression of chronic atrophic gastritis with intestinal dysplasia, which significantly increases the risk of gastric cancer. 6 Eradication of H. pylori can be an effective method of treatment for peptic ulcer disease 7 and mucosa-associated lymphoid tissue lymphoma. 8 Furthermore, eradication is especially important for reducing the development of new-onset gastric cancer 3,9,10 as well as secondary gastric cancer after endoscopic treatment. 4,11,12 Therefore, eradication of H. pylori has been used globally for approximately 30 years. In 2014, the IARC recommended population-based screening and eradication of H. pylori, if feasible, because H. pylori causes 90% of non-cardia cancers, and a 30%-40% reduction in the incidence of gastric cancer is expected with the use of eradication therapy. 13 Several investigators have reported that a certain percentage of subjects, excluding false-negative cases and post-eradication cases, showed endoscopic or histologic atrophy without a current H. pylori infection. A similar subpopulation has also been recognized in Japan, with patients showing atrophic gastritis endoscopically despite serologically normal gastric cancer screening using a pepsinogen (PG) and H. pylori antibody titer (ie, the ABC method). [14][15][16][17][18] Plausible explanation for this phenomenon includes the spontaneous elimination of H. pylori because of the following: unintentional H. pylori eradication treatment, which could occur after exposure to antibiotics for the treatment of another infection; spontaneous disappearance of H. pylori as a result of severe atrophy; or previous administration of eradication treatment that patients had forgotten. Another explanation for this phenomenon could be autoimmune gastritis. However, it is important to note that compared with autoimmune gastritis, the spontaneous elimination of H. pylori is a distinct disease entity in the sense that the development of gastritis originates from H. pylori despite patients being negative for the presence of H. pylori infection. Clinicians should be aware of this distinction.
Herein, we highlight these previous H. pylori infection-induced atrophic gastritis cases, especially because this subpopulation is at high risk of gastric carcinogenesis despite their H. pylori-negative infection status. To date, only a few investigators have focused on these subjects. [14][15][16][17] In this review, we describe the disease entity, definition, epidemiology, and serologic characteristics of these subjects. Furthermore, we propose an optimal endoscopic surveillance interval for such patients.

| DEFINITI ON OF PRE VI OUS H . PYLORI INFEC TION-INDUCED ATROPHIC G A S TRITIS
To date, only Hiyama et al defined unintended eradication, which is similar to our definition of disease entity as negative results of three H. pylori tests; the presence of glandular atrophy according to histologic examination; and no medical history of H. pylori treatment. However, autoimmune gastritis was found during their analysis, even though they did not specifically discuss these conditions. 14 When defining previous H. pylori infection-induced atrophic gastritis, we aim for a simple diagnosis based on the results of H. pylori tests, a medical examination, and endoscopic findings during daily clinical practice; diagnostic assistance using histology and specific serologic examination were necessary in some circumstances. We defined the criteria for unintended elimination of H. pylori as follows: absence of a medical history of specific H. pylori eradication therapy; atrophic changes according to endoscopy or histologic diagnosis of glandular atrophy; absence of endoscopically localized corpus atrophy or positive autoantibody or characteristic histology suggestive of autoimmune gastritis; and negative for a current H. pylori infection. These criteria are detailed in Table 1.
A flowchart for the diagnosis is shown in Figure 1.

| Evaluation of chronic atrophic gastritis
The definition of chronic atrophic gastritis is not usually based on macroscopic findings; instead, it is based on histologic findings. 19,20 The most well-known histologic criterion is the Sydney classifica- Nordenstedt et al defined gastritis as "at least grade 1 neutrophils or mononuclear cells in the Sydney system in at least two gastric sites or at least grade 2 in at least one gastric site." 22 Therefore, we suggest that glandular atrophy of at least grade 1 in at least two gastric sites or at least grade 2 in at least one gastric site is the criterion for histologic atrophy, similar to the recommendations of Hiyama et al 14 The recent increase in the use of antiplatelet or anticoagulant therapy 23 makes it difficult to perform a biopsy merely for the evaluation of atrophy in all cases of endoscopy; therefore, it is not common. Several recent studies have suggested diagnostic concordance between endoscopic atrophy and histology. [24][25][26] An atrophic border more severe than C2 in the Kimura-Takemoto classification (atrophy limited to the gastric angle of the lower body) should be the minimum criterion for atrophic change when diagnosing unintended eradication based on the Kyoto classification. 20,27,28 Recently, several investigators have reported that endoscopic staging using high-resolution white light endoscopy plus virtual chromoendoscopy (Narrow Band Imaging, etc) is more accurate than white light endoscopy. [29][30][31] Although the endoscopic diagnosis of atrophy may be feasible at experienced centers, it is difficult at centers that are less experienced with diagnosing atrophic gastritis endoscopically. Therefore, if an endoscopic diagnosis including chromoendoscopy is not possible, then histologically detected chronic atrophic gastritis is an option ( Table 1).
The exclusion of autoimmune gastritis (0.49%-1.1% in the general population) is another important step in the diagnosis of previous H. pylori infection-induced atrophic gastritis, because most subjects with autoimmune gastritis fulfill three out of four of our criteria. [32][33][34] The endoscopic findings of corpus-dominant atrophy with preservation of the antrum are characteristic of autoimmune gastritis and are diagnostic in clinical practice. 32 The strict diagnosis of autoimmune gastritis should meet at least two criteria: positive specific autoantibodies to parietal cells or intrinsic factor and/or characteristic pathological features such as profound loss of oxyntic mucosa, infiltrates of lymphocytes and plasma cells in lamina propria, and enterochromaffin-like (ECL) cell hyperplasia. [35][36][37] However, it is not practical to evaluate autoantibodies and histology in daily clinical practice. We propose that exclusion of patients with suspected autoimmune gastritis with endoscopic findings is a minimum requirement, although this is practically difficult in some cases. Therefore, serology or histology to determine autoimmune gastritis is also desirable, especially for patients with severe atrophy who are negative for H. pylori infection (Table 1).

Strict exclusion of individuals with a present H. pylori infection is
necessary, and we consider this the third step in the diagnosis.
The widely recommended method to evaluate H. pylori status in patients post-treatment is the 13C-urea breath test (UBT), but the monoclonal stool antigen test (SAT) can be used alternatively. 38 Previous investigators have reported high false-negative UBT and SAT rates for patients using PPIs. 39

Three different populations have been defined as having previous
H. pylori infection-induced atrophic gastritis. They are described here. Therefore, eradication occurs in many subjects administered antibiotic treatment under acid inhibition by vonoprazan alone.

| Unreported successful eradication
Subjects who fail to report H. pylori eradication despite a history of successful eradication treatment comprise the second population.
This may occur due to an insufficient explanation of the eradication treatment from their physician, or the patient may have simply forgotten receiving eradication treatment. Unintentionally eradicated subjects (Section 3.1) and unreported successful eradication cases (Section 3.2) have the same pathophysiologic states because they were both eradicated by previous antibiotic use.

| Spontaneous disappearance of H. pylori
The third population of subjects includes those who have experienced spontaneous disappearance of H. pylori due to the progression of atrophic gastritis. 45 This subgroup shows severely progressed atrophy and is similar to group D characterized by the ABC method (serologically atrophic PG and seronegative for H. pylori). 48 Because the disappearance of H. pylori occurs independently of antibiotic use, the clinical background of this subgroup is quite different from both true unintended eradication cases and unreported successfully eradicated cases. However, it is possible that antibiotics were administered incidentally to patients with severely progressed atrophy under conditions of achlorhydria, resulting in eradication. The frequency of these subjects is low even in regions with a high H. pylori prevalence like East Asia. [49][50][51][52] It is important to note that these three types of populations cannot be distinguished from one another, even using endoscopy, serology, or a medical examination. There is a great difference in the prevalence of severe atrophy cases, but this is not a differential point in the diagnosis. We must not misunderstand that these cases are which may also become the serologic differential point.

| D IFFEREN CE B E T WEEN PRE VI OUS H . PYLORI INFEC TION-INDUCED ATROPHIC G A S TRITIS AND H . PYLORI-NEG ATIVE G A S TRITIS DEFINED IN WE S TERN COUNTRIE S
Helicobacter pylori-negative gastritis is a recently defined disease entity diagnosed primarily based on histology in Western countries, which is similar but not identical to our criteria. 22

| Serologic characteristics of unintended or unreported eradication
The ABC method is used to screen for serum gastric cancer with Several studies have reported a cutoff value to distinguish unintended eradication cases among group A subjects, which is defined as normal PG and seronegative for H. pylori. First, we reported that PGI levels ≤ 37 ng/mL and PGI/II ratios ≤ 5.1 effectively identified unintentionally eradicated cases in group A. 54 We also suggested that a PGI/II ratio ≤ 4.3 and H. pylori antibody titer ≥ 3.0 were independent predictor of gastric neoplasia in patients serologically classified as group A, 68 and all of these cases showed atrophy on endoscopy, suggesting that they indeed were unintentionally eradicated cases. Chinda et al also reported similar cutoff values of PGI and the PGI/II ratio for determining unintentionally eradicated cases. 17 The cutoff values of PGI and the PGI/II ratio in this study were ≤ 31.2 ng/mL and ≤ 4.6, respectively.
Kikuchi et al showed that a PGII value ≤ 10 ng/mL or PGI/II ratio ≤ 5.0 is the optimal criterion for differentiating never-infected versus infected and formerly infected subjects. 69

| Serologic characteristics of spontaneously disappeared cases
With the ABC classification, PGI ≤ 70 ng/mL and PGI/II ratio ≤ 3 with negative H. pylori serology are the classical criteria of group D, defined as unintentional disappearance due to severe atrophy (

| CHAR AC TERIS TI C S OF G A S TRI C C AN CER IN PRE VI OUS H . PYLORI INFEC TION-INDUCED ATROPHIC G A S TRITIS
Endoscopic characteristics of gastric cancer after eradication, which are similar to those of unintentionally eradicated cases of H. pylori, have been discussed by several investigators. Difficulty diagnosing cancer itself has been reported due to non-neoplastic epithelium histologically appearing on the lesion surface after eradication. 71 The most reported histologic feature of gastric cancer in cases after successful eradication is differentiated type (75%; 15/20). 72 The rates of differentiated type cancer in gastric cancer cases classified as group A range from 86.9% (93/104) 18 to 88.9% (8/9), 68 and that of group D subjects has been reported as 83.3% (10/12). 73 The characteristics of gastric cancer in cases of previous H. pylori infection-induced atrophic gastritis include difficult visual recognition by endoscopy and histologically differential type.

| RIS K OF G A S TRI C C AN CER DE VELOPMENT IN PRE VI OUS H . PYLORI INFEC TION-INDUCED ATROPHIC G A S TRITIS AND INTERVAL S OF ENDOSCOPI C SURVEILL AN CE
The risk of gastric cancer in unintentionally eradicated subjects is theoretically equal to that of successfully eradicated cases. However, there is no established interval or risk stratification method for endoscopy. 74 The effectiveness of H. pylori eradication for the prevention of gastric cancer depends on the severity of atrophy at the time of eradication. 75

ACK N OWLED G EM ENTS
This study was not funded by any specific grants or organizations.

CO N FLI C T O F I NTE R E S T
The authors have no competing interests.