Challenging epidemiological strategy for paradoxical evidence on the risk of gastric cancer from Helicobacter pylori infection.

Abstract

; The incidence of gastric cancer in the northeast Asian countries Japan, Korea and China is the highest in the world. The age-adjusted incidence rates (AAIRs) are 10 times higher than those in non-Hispanic Whites and four times higher than those in Japanese immigrants in Los Angeles, USA (1). The overall incidence rates of gastric cancer in Japan have been decreasing according to the changing pattern of Japanese dietary habit after World War II (2). A large number of epidemiological studies during the last several decades investigated dietary factors in relation to gastric cancer risk in the world and revealed dominant dietary and beverage factors: high intake of salted foods; low consumption of fresh vegetables and fruit and habitual cigarette smoking. The worldwide epidemic pattern of gastric cancer is closely associated with the characteristic lifestyle pattern in each country and ethnic group. Japanese immigrants to the USA were influenced by the American social and natural environment and changed their way of life, especially their dietary habits, generation by generation. In 1994, the International Agency for Research on Cancer (IARC) defined Helicobacter pylori as a carcinogenic agent of human gastric cancer based on sufficient evidence for positive relationships between H. pylori infection rate and risk impact of gastric cancer (3). As H. pylori emerged as a decisive carcinogenic agent for gastric cancer, many pathologists countered the arguments as follows: (1) lack of evidence from animal experiments regarding the carcinogenic agent of H. pylori products; (2) insufficient evidence for the spreading pattern of parasitic H. pylori in the gastric epithelium and further progression to gastric cancer; and (3) insufficient evidence for a population-based correlation between the infection rate of H. pylori and risk of gastric cancer throughout the world. It is well known that H. pylori was a major cause of refractory ulcers of the stomach and duodenum before the eradication of H. pylori infection. Theoretically, H. pylori would play a complementary role in carcinogenicity as a predisposing factor of gastric cancer, e.g., chronic and atrophic gastritis. A long-term repeated inflammatory condition with H. pylori might enhance carcinogenic progression by independent exposure to non-specific carcinogenic agents; however, H. pylori itself gradually disappears with the progression of cancerous tissue. Current animal experiments using Mongolian gerbils clarified the first point above, that is, H. pylori promotes glandular gastric carcinogenesis after treatment with a chemical carcinogen, N-methyl-N-nitrosourea (MNU) (4), and furthermore, eradication of H. pylori infection diminished its enhancing effects on glandular gastric carcinogenicity with MNU administration (5). With regard to the second of the above points, H. pylori gradually disappears in gastric membranes with progression of gastric atrophy, with concordant occurrence of gastric cancer as an outcome condition of H. pylori-related gastritis. A 10year follow-up study of patients with chronic atrophic gastritis (CAG) mainly caused by H. pylori infection demonstrated a moderate increase in gastric cancer risk with the presence of CAG, and the risk was greatest among subjects with a moderate level of CAG at baseline (6). The attenuation of risk with the length of follow-up period after a peak at 4–6 years supported hypothetical evidence that incomplete and unstable CAG in the process of atrophy is potently associated with the development of gastric cancer. Concerning the third point above, several pieces of evidence in Japan indicated concordance of H. pylori epidemics and risk of gastric cancer. The incidence rate of gastric cancer has been decreasing recently in concert with the decreasing trend of H. pylori infection in younger persons (7). The mode of infection is considered to be oral–oral and/or fecal–oral routes and the infection risk has diminished recently with improvements in sanitary conditions. In the northeast Asian countries, e.g. Japan, Korea and China, the incidence rate of gastric cancer is constantly high whereas it is extremely low in southeast Asia, especially in Indonesia, even though the infection rate of H. pylori among the general population is not very different from that among Japanese. Different exposure levels to other related risk factors, e.g. intake of salt and consumption of vegetables and fruit, could explain these discrepant epidemics of gastric cancer in Asian countries; however, further comprehensive epidemiological studies should be extended to clarify such a paradoxical feature. The incidence rate of gastric cancer in Japanese immigrants in Brazil is relatively high in the world, but slightly lower than that of the original Japanese in Japan. Probably variations of ecological background and additionally H. pylori epidemic patterns in Brazil influence the risk reduction of gastric cancer. When we discuss variations of risk factors for gastric cancer between Japanese and non-Japanese, comparative studies of the variations in genetic background in targeted groups is