Population studies have shown that the prevalence

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1 Volume 6 Number HELICOBACTER Blackwell Science Ltd Atrophic Gastritis and Intestinal Metaplasia in Japan: Results of a Large Multicenter Study Masahiro Asaka, * Toshiro Sugiyama, * Aichiro Nobuta, * Mototsugu Kato, * Hiroshi Takeda * and David Y. Graham *Third Department of Internal Medicine, Hokkaido University School of Medicine, Sapporo, Japan; Department of Medicine, Baylor College of Medicine, Houston, Texas, USA ABSTRACT Background. This study evaluated the relationship between Helicobacter pylori infection, atrophic gastritis and intestinal metaplasia in Japan. Materials and Methods. This was a multicenter study performed in 21 centers in Japan. A total of 2455 individuals were enrolled. H. pylori status was determined by validated ELISAs. Atrophic gastritis was diagnosed by histology, endoscopy with Congo Red dye scattering or the Kimura-Takemoto endoscopic classification. Results. Atrophic gastritis increased from 9.4% in those less than 20 years of age to > 70% in those aged 60 or older and was strongly associated with H. pylori infection. The overall prevalence of atrophic gastritis in H. pylori infection was 82.9% (1272/1534) compared with 9.8% (90/921) among uninfected (OR = 44.8; 95% CI = ). Intestinal metaplasia was present in 43.1% (542/1258) of H. pylori positive persons compared with 6.2% (51/823) among the uninfected (OR = 11.5; 95% CI = ). Atrophic gastritis in H. pylori positive Japanese was very high in the younger generation (38.5% in those aged 20 or less and 58.5% in those 21 30). Conclusions. Atrophic gastritis and intestinal metaplasia were strongly associated with H. pylori and not with aging. The fall in prevalence of H. pylori in Japan has not been associated with a corresponding fall in the prevalence of atrophic gastritis among those with H. pylori infection. The high prevalence of the precursor lesion, atrophic gastritis with intestinal metaplasia, among those with H. pylori infection suggests that the risk of development of early gastric cancer will continue to remain high in Japan. Keywords. Helicobacter pylori, atrophic gastritis, intestinal metaplasia, gastric cancer, endoscopy. Population studies have shown that the prevalence of Helicobacter pylori infection in asymptomatic Japanese born after 1950 increased at approximately 1% per year. In contrast, for those born before 1950, the frequency was high and relatively constant [1]. These data suggest that Westernization of Japan with the coincident reduction in the rate of acquisition of H. pylori infection, may be in part responsible for the progressive decrease in the incidence of an H. pylorirelated disease, gastric carcinoma, in Japan. In a cross-sectional study, Kimura reported that proximal migration of the fundic-pyloric junction occurred with aging and was associated with Reprint requests to: Masahiro Asaka, md, Third Department of Internal Medicine, Hokkaido University School of Medicine, Kita 15, Nishi 7, Kita-ku, Sapporo 060, Japan. Supported in part by Grants-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports and Culture, Japan. the increased prevalence of chronic gastritis and gastric atrophy in the Japanese population [2]. Prior to the identification of H. pylori as the major cause of gastritis, the decline in the ability to secrete gastric acid due to atrophic change of gastric mucosa was considered a consequence of aging [3,4]. The discovery of H. pylori has led to a reassessment of the importance of aging and has focused on the long-term effects of H. pylori infection and its role in the development of atrophic gastritis [5,6]. Recently, it was suggested that H. pylori infection is apparently a much more important factor than age per se in the chronological changes of the gastric mucosa leading to the development of atrophic gastritis in many Japanese adults. Previous studies have shown that although the frequency of H. pylori infection in Japan is remarkably similar in different regions, the prevalence of atrophic gastritis differs [7]. The current study was designed to evaluate the 294

2 Atrophic Gastritis and Intestinal Metaplasia in Japan 295 relation between H. pylori infection, atrophic gastritis and intestinal metaplasia in a large scale multicenter trial in different parts of Japan. Materials and Methods Subjects This was a multicenter study performed in 21 centers in various areas in Japan. Individuals undergoing endoscopic examinations were invited to participate. Each completed a standard questionnaire regarding personal health, drug use and gastrointestinal symptoms. Exclusion criteria included: a history of peptic ulcer disease and gastric cancer; a history of gastric surgery; systemic disease requiring chronic medication. Written informed consent was obtained from each subject under a protocol approved by the Ethical Review Board of each hospital before the study. Endoscopy All subjects underwent endoscopy with gastric mucosal biopsy. Paired biopsy specimens were taken from the antrum and corpus of the stomach. Biopsy specimens were examined with hematoxylin and eosin stain. Assessment of Atrophic Gastritis and Intestinal Metaplasia Atrophic gastritis was diagnosed by histology by three methods: histologically using the Sydney system classification [8,9], endoscopically using the Congo red dye scattering method [10], or endoscopically using the Kimura-Takemoto classification [2,11,12]. Intestinal metaplasia was diagnosed by histology following the Sydney system classification [8,9]. Diagnosis of H. pylori Infection Helicobacter pylori infection was diagnosed by enzyme-linked immunosorbent assay (ELISA) for anti-h. pylori immunoglobulin G (IgG) using an HM-CAP kit (Enteric Products Incorporated, Stony Brook, NY, USA) or the GAP IgG kit (Bio-Rad, Hercules, USA). Statistical Analysis Statistical analyses were performed using the Mann Whitney U-test, Fisher s exact test and the χ 2 analysis with Yates correction. p-values less than.05 were considered significant. Results A total of 2455 patients were included in the study. Of these, the diagnostic test was histology in 1122 cases, 289 cases were diagnosed by endoscopy using the Congo red dye scattering method [10] and 1044 using the Kimura-Takemoto endoscopic classification [2,11,12]. The positive rate for the diagnosis of atrophic gastritis was similar with each method (53.7% by histology, 56.4% by endoscopy with the Congo red dye scattering method and 57.1% by endoscopy following the Kimura-Takemoto classification). There was no significant difference in the positive rate of atrophic gastritis between the three different methods. The prevalence of atrophic gastritis in the population studies increased with age (e.g. from 9.4% in those aged less than 20 and over 70% in those aged 60 or older). Atrophic gastritis was strongly associated with H. pylori infection. The prevalence of atrophic gastritis in H. pylori positive persons was 38.5% in those less than aged 20, 58.0% at ages 21 30, and 81.3% in those aged 31 or older. The overall prevalence of atrophic gastritis among those with H. pylori infection was 82.9% (1272/1534) compared with 9.8% (90/921) of those without (OR = 44.8; 95% CI = ) (Table 1). The pattern with intestinal metaplasia was similar, increasing from 2.5% in those less than 30 years of age to more than 45% in those 60 or older; it was found predominantly among those with H. pylori infection. The overall prevalence of intestinal metaplasia was 43.1% (542/1258) in H. pylori positive persons compared with 6.2% (51/823) among H. pylori negative individuals (OR = 11.5; 95% CI = ) (Table 2). The prevalence of intestinal metaplasia in H. pylori positive persons was 8.9% in those less than 30 and 57.1% in those age 60 or older. The prevalence of H. pylori in patients with atrophic gastritis was high and similar in each age group (e.g. 90.3% at approximately 30 years and 91.3% at 70 + years) ( p = not significant) (Figure 1). In contrast, the prevalence of H. pylori increased with age among those without atrophic gastritis (Figure 1). A similar trend was seen with the prevalence of H. pylori infection among patients with intestinal metaplasia with no significant difference between the

3 296 Asaka et al. H. pylori IgG antibody Age group Positive Negative OR 95% CI Overall % (5/13) 2.8% (2/72) % % (51/88) 1.8% (4/225) % % (120/142) 4.0% (7/173) % % (266/311) 11.8% (18/152) % % (347/427) 16.4% (20/122) % % (336/384) 21.6% (25/116) % > 71~ 87.0% (147/169) 23.0% (14/61) % Total 82.9% (1272/1534) 9.8% (90/921) % Table 1 Prevalence of atrophic gastritis in Helicobacter pylori positive or negative individuals H. pylori IgG antibody Age group Positive Negative OR 95% CI Overall % (8/90) 0.7% (2/296) % % (34/126) 0.6% (1/159) % % (95/278) 7.9% (10/126) % % (160/337) 9.2% (9/98) % % (156/271) 20.2% (17/84) % > % (89/156) 20.0% (12/60) % Total 39.2% (542/1258) 6.2% (51/823) % Table 2 Prevalence of intestinal metaplasia in Helicobacter pylori positive or negative individuals % 100 Controls Atrophic gastritis % 100 Controls Intestinal metaplasia OR %CI ( ) ( ) ( ) ( ) ( ) ( ) Figure 1 Age-related Helicobacter pylori positive rates between control and atrophic gastritis OR %CI ( ) ( ) ( ) ( ) ( ) ( ) Figure 2 Age-related Helicobacter pylori positive rates between controls and intestinal metaplasia. frequency of intestinal metaplasia between age groups (Figure 2). Discussion Previously we studied the serum pepsinogen I/II ratio among 426 asymptomatic volunteers. We found that the pepsinogen I/II ratio was significantly lower in H. pylori-infected volunteers compared with those without the infection. As the serum pepsinogen I/II ratio was known to be a good marker for gastric atrophy [13,14], we hypothesized that the development of atrophic gastritis and intestinal metaplasia in the gastric mucosa was strongly associated with H. pylori infection [1]. Recently, it was clarified

4 Atrophic Gastritis and Intestinal Metaplasia in Japan 297 that serum pepsinogen I/II ratio was also a good marker of inflammation of the gastric mucosa [15,16], thus weakening our hypothesis and requiring an additional study to compare the prevalence of atrophic gastritis with H. pylori infection directly. In a preliminary study we performed a case-control study of 85 asymptomatic healthy adults recruited from a health screening center in Sapporo [17]. All subjects underwent endoscopy and gastric biopsy. The prevalence of atrophic gastritis and intestinal metaplasia as assessed by pathological findings was significantly greater in those with H. pylori infection compared with those without H. pylori infection. The present study was an extension of that study and was a large scale multicenter study involving different regions in Japan. We used three different methods to assess the prevalence of atrophic gastritis as well as evaluation of the presence of intestinal metaplasia by endoscopic biopsy. In the present study we found that both atrophic gastritis and intestinal metaplasia were strongly associated with H. pylori infection and not with aging per se. In all age groups the prevalence of atrophic gastritis assessed endoscopically or pathologically was significantly higher among those with H. pylori infection compared with those without, with odds ratios between 22.4 and Intestinal metaplasia was found in more than half of H. pylori sero-positive individuals but was remarkably low in the H. pylori seronegative group. The prevalence of intestinal metaplasia in any age group of H. pylori positive persons was significantly higher than in negative persons with odds ratios between 5.3 and The prevalence of H. pylori in patients with atrophic gastritis and intestinal metaplasia was on average over 90% independent of the age group, whereas the prevalence of H. pylori in controls increased with age. These results confirm the tight link between H. pylori infection, atrophic gastritis and intestinal metaplasia in Japanese stomachs. In the stomach, the area affected by atrophic gastritis expands with age [2]. The age-specific prevalence of atrophic gastritis and intestinal metaplasia in normal Japanese adults [18] seems clearly different from that reported from recent studies in Western populations [19 21], suggesting that both the phenomena and the speed of its spread are greater in Japan. While it was believed that the high incidence of atrophic gastritis in Japanese, based on the chronological changes in the gastric mucosa, was a specific feature of the Japanese population [2], the current data are more consistent with H. pylori infection being a much more important factor than age in the chronological changes of the gastric mucosa leading to the development of atrophic gastritis and intestinal metaplasia in Japan. The process leading from chronic gastritis through the stages of chronic atrophic gastritis, intestinal metaplasia, dysplasia and gastric cancer is thought to take many decades [15,22]. The present data clearly showed that the prevalence of atrophic gastritis in H. pylori positive asymptomatic Japanese was very high in the younger generation (38.5% in those 20 or less and 58.5% in those aged years). In contrast, the prevalence of atrophic gastritis was very low in those without H. pylori infection. The fact that the prevalence of H. pylori infection is falling in every age group [23] suggests that many, if not most, of those with atrophic gastritis but without H. pylori infection are actually those who have lost the infection. These results differ from Western countries where both the rate of acquisition of H. pylori and the rate of transformation into atrophic gastritis has fallen. In Japan, it appears that the major change has been in the prevalence of H. pylori infection without a marked decrease in the rate of progression of the gastritis to atrophic gastritis. It is unclear why there is this apparent difference between Japan and Western countries. One possibility is diet which is different in Japan than in the West. Another is that H. pylori in Japan may be more virulent. For example, in the US, the prevalence of caga negative strains is higher than in Japan where both caga positivity and OipA positivity is the norm [24 27]. Subsequent studies will be required to unravel this problem. H. pylori infection has been etiologically associated with the development of early gastric cancer in Japan [28 30]. The high prevalence of the precursor lesion, atrophic gastritis with intestinal metaplasia among those with H. pylori infection suggests that the risk of development of early gastric cancer will continue to remain high in Japan until H. pylori is eliminated either naturally or by therapy. The participants in the Multicentre Study Group included: Masahiro Asaka, Third Department of Internal Medicine, Hokkaido University School of Medicine; Shuichi Ohara, Third Department of Internal Medicine, Tohoku University School of Medicine; Daizo Saito, Internal Medicine, National Cancer

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