Cancer development based on chronic active gastritis and resulting gastric atrophy as assessed by serum levels of pepsinogen and Helicobacter pylori antibody titer

Abstract

Our study investigated the relationship between gastric cancer development and activity of Helicobacter pylori-associated chronic gastritis or the resulting chronic atrophic gastritis (CAG). A cohort of 4,655 healthy asymptomatic subjects, in whom serum pepsinogen (PG) and H. pylori antibody titer had been measured to assess the activity and stage of H. pylori-associated chronic gastritis, was followed for up to 16 years, and cancer development was investigated. In subjects with a serologically diagnosed healthy stomach (H. pylori-negative/CAG-negative), cancer incidence rate was low, at 16/100,000 person-years. With the establishment of H. pylori infection and progression of chronic gastritis, significant stepwise cancer risk elevations were seen from CAG-free subjects (H. pylori-positive/CAG-negative) [hazard ratio (HR) 5 8.9, 95% confidence interval (CI) 5 2.7-54.7] to subjects with CAG (H. pylori-positive/CAG-positive) (HR 5 17.7, 95% CI 5 5.4-108.6) and finally to subjects with metaplastic gastritis (H. pylori-negative/CAG-positive) (HR 5 69.7, 95% CI 5 13.6-502.9). In H. pylori-infected CAG-free subjects, significantly elevated cancer risk was observed in the subgroup with active inflammation-based high PG II level or potent immune responsebased high H. pylori antibody titer; the former was associated with a particularly high risk of diffuse-type cancer, and both subgroups showed high cancer incidence rates of around 250/100,000 person-years, comparable to that in subjects with CAG. No such risk elevation was observed in H. pylori-infected subjects with CAG. These results clearly indicate that gastric cancer develops mainly from the gastritis-atrophy-metaplasia-cancer sequence and partly from active inflammation-based direct carcinogenesis, and that serum levels of PG and H. pylori antibody titer provide indices of cancer development in H. pylori-infected subjects.Despite worldwide declines in the incidence of gastric cancer and associated mortality over the past 50 years, this pathology remains one of the leading causes of cancer-related death in Eastern Asia, including Japan, South America and Eastern Europe.1-4 In Japan, more than 100,000 new cases of gastric cancer are diagnosed every year, and the Japanese Ministry of Health, Labor and Welfare reported that 50,136 deaths attributed to the cancer in 2010.5 Gastric cancer thus remains a major health problem in Japan. Development of gastric cancer represents a classical example of host-genetic and environmental interactions and is characterized by a multistep process of molecular and morphological events known as the gastritisatrophy-metaplasia-dysplasia-cancer sequence.6,7 Based on a large number of epidemiological and clinicopathological studies and also on animal experiments using Mongolian gerbils, this sequence, which predominantly leads to intestinal-type cancer, is considered to represent a major route of stomach carcinogenesis, particularly in areas of high cancer risk, such as Japan. Although other environmental and lifestyle factors together wi...

Natural Course of <b><i>Helicobacter pylori</i></b> Infection in Japanese Hemodialysis Patients

“…When we deleted data of patients treated with PPI/H2RA, mean PG I level and PG I/II ratio in H. pylori -negatives were 318.6 ± 241.6 and 9.5 ± 4.3 ng/mL, which were significantly higher than those in H. pylori -positives (212.8 ± 197.9 [ p = 0.004] and 10.5 ± 3.8 ng/mL [ p < 0.001], respectively; Table 1). These values were higher than those generally reported in subjects with normal renal function (estimated glomerular filtration rate >60 mL/min/1.73 m 2 ) [23,24,25,26]. …”

Finding out Serologically Active Gastritis Subjects by Conventional Endoscopy and Picking out Subjects Who might be Benefit from Helicobacter pylori Eradication as a Primary Prevention for Gastric Cancer

“…There have been efforts to identify these subgroups, actually Kiyohira et al [18] showed gastritis severity and gastric mucosal status could be well documented by serum PG. Recent Japanese studies [1,19] uncovered some groups of atrophy free subject showed GC risk equivalent to extensive atrophic gastritis especially diffuse type GC, the main characteristics of these subgroups were elevated PG II. Considering Hunter et al [20] that H.pylori infection contribute more to PG II elevation than to PG I, and Iranian study [21] suggesting that PG II could be good surrogate marker for body morphological change after H.pylori infection, and major portion of PG II was originated from the active gastritis by neutrophil cell infiltration, we could come to conclusion that H.pylori infected active gastritis creating more neutrophil infiltration would cause more PG II elevation.…”

“…We could not performed H.pylori antibody titer test being originally included in Yoshida et al [1] , this study was based on "Health check-up protocol" not focusing individual active gastritis study…”

“…In addition to traditional useful value of endoscopic atrophic border (EAB) supported by Operative Link on Gastritis Assessment (OLGA) for gastritis staging, useful and reliable method to assess gastric mucosal status is pepsinogen (PG) based serological approach. Recent published study [1] showed PG I ≤ 70 ng/mL and PG I/II ratio > 3.0; B-β, PG I > 70 ng/mL and PG I/II ratio > 3.0; B-γ, PG I > 70 ng/mL and PG I/II ratio ≤ 3.0; II-30, PG II > 30 ng/ml; Group C, H.pylori (+) and CAG (+); CI-0, PG I ≤ 30 ng/mL; CI-30, PG I > 30 ng/ml and ≤ 50 ng/mL; CI-50, PG I > 50 ng/mL; Group D, H.pylori (-) and CAG (+)], and they found out some subgroups (group B-γ, II-30, H.pylori antibody titer >500 U/mL) have high risk of gastric cancer (GC) (especially diffuse type GC) comparable to that of group C. Yanaoka et al [2] showed H.pylori eradication was effective for preventing GC only in serological mild atrophic gastritis. Our main concern was how to correlate these meaningful serological gastritis status with endoscopic findings, which might help us decide which person should be followed strictly or could benefit from primary GC prevention such as H.pylori eradication.…”

Preneoplastic Conditions in the Stomach: Always a Point of No Return

“…Indeed, the pathogenesis of GC is multifactorial and severe GA, even in the presence of IM, is a necessary but insufficient condition for the development of distal intestinal-type GC. Factors increasing the risk for GC in patients with severe preneoplastic changes and hypo- or achlorhydria include the following: (1) diets that are high in salted food [14], (2) smoking [15], (3) alcohol [16], (4) a long-standing chronic inflammation ( H. pylori infection) [17], (5) loss of H. pylori infection and (6) pernicious anemia [18] (table 1). Bacterial overgrowth due to reduced acid secretion in patients with FGA has also been proposed as a possible causal mechanism for gastric carcinogenesis.…”