Gastric cancer is one of the most common types of cancer worldwide¹⁾. Despite some improvement in its treatment, the 5-year survival rate of gastric cancer is still low. The prevalence of intestinal metaplasia (IM) is closely related to H. pylori infection²⁾. Furthermore, chronic gastritis due to H. pylori infection may progress to IM and even gastric cancer^3–5). H. pylori-induced inflammation facilitates gastric carcinogenesis by increasing the rate of cell replication, decreasing the concentration of ascorbic acid and inducing DNA damage via reactive oxygen species^{6, 7)}. Both environmental and genetic factors are crucial in the multistage model of gastric tumorigenesis³⁾. A preliminary observation has suggested that both IM and H. pylori infection are important targets in the prevention of gastric cancer⁸⁾.

Telomerase, located at the distal end of human chromosomes, comprises simple, repetitive and G-rich hexameric sequences (TTAGGG), and is vital for chromosomal stability and replication. Telomerase is a ribonucleoprotein polymerase that adds telomeric sequences onto the ends of the chromosome to compensate for the DNA end-replication problem. Thus, this activity is strongly associated with cell immortalization and carcinogenesis, and its presence is elevated in 85% of human cancers, including those associated with the stomach, colon, breast, bladder, prostate, liver, lung and ovary. The measurement of telomerase activity may become a diagnostic tool for cancer⁹⁾. However, telomerase activity can also be found in precancerous lesions, such as IM¹⁰⁾.

In this study, we evaluated the relationships of both H. pylori infection and telomerase activity with endoscopic and histologic features in IM. The effects of H. pylori eradication on endoscopic, histologic and biochemical changes were evaluated.

This study involved 43 patients who, between January 1999 and June 2000, were diagnosed with IM without any gastroenterologic diseases by an upper gastrointestinal endoscopic examination at a gastrointestinal endoscopy unit of Soonchunhyang University Chonan hospital. Thirty-four of these patients were diagnosed as having H. pylori infection. Eight patients exhibited elevated telomerase activity. Twenty-three of the patients with H. pylori infection were treated with an H. pylori eradication regimen and fifteen of them were able to be followed up for changes in endoscopic, pathologic and telomerase results after 4 months of complete therapy.

Telomerase activity in humans has been detected in germ lines and tumor tissues as well as in established cultured-cell lines¹⁴⁾. In normal somatic cells, the absence or low expression of telomerase is thought to result in progressive telomeric shortening with each cell division. Therefore, it has been proposed that reactivation of telomerase is a critical step in tumorigenesis. The expression of telomerase may occur at different stages of cancer progression, depending on the type of malignancy^15–19).

Telomerase activity has been detected in approximately 35% of noncancerous lesions, such as gastric IM,¹⁰⁾ although the level is generally lower than in cancerous tissue. In addition, genetic alterations, such as p53²⁰⁾ and APC gene mutations²¹⁾, are found in IM and gastric cancer. These genetic changes and the activation of telomerase in IM and so-called precancerous lesions may contribute to the carcinogenic process in intestinal gastric cancers²⁰⁾. Furthermore, detection of telomerase activity in both cancer and IM suggests that telomerase activation is an early event in stomach carcinogenesis. In our study, telomerase activity was detected in 18.6% of patients.

IM is the common endoscopic feature that occurs at an average age of 14 years after superficial and/or atrophic gastritis. The occurrence of chronic atrophic gastritis has a complex relationship to H. pylori infection, genetics, diet, drugs, smoking, alcohol, high salt intake, vitamin-C deficiency and environmental factors. IM is the replacement of gastric mucosal cells with intestinal cells (including goblet cells). Regression of IM after H. pylori eradication is debatable in many histologic studies^22–31), and studies on endoscopic changes are also limited.

We randomly classified the endoscopic grade and extent of IM according to the nature of gross severity. Through the classification, we assessed the relationship between endoscopic features and H. pylori infection or telomerase activities and we evaluated the significance of these endoscopic findings on the basis of histology and molecular biology. We also observed the changes of these endoscopic classifications and histologic and molecular biologic changes as detailed markers of precancerous lesions after H. pylori eradication. In our study, changes in the grade of the pattern of IM were not statistically significant and the extent of IM tended to decrease. These changes represent the possibility of regression of endoscopic findings. The H. pylori infection rate was high in the endoscopic granular type which was suspected as being a relatively low-grade lesion. The H. pylori infection rate had a tendency to be higher in the grade-I extent of IM than grade-II or III extent. These results suggest indirectly that the H. pylori infection rate is high in the early stages of IM, and suggest that H. pylori cannot survive for long enough to allow migration from the antrum to the upper body by the progression of IM. Among the eight patients with telomerase activity, there was no significant relationship between the endoscopic pattern of IM and telomerase activity, but telomerase activity tended to be detected in grade-III extent. These findings suggest that the endoscopic extent of IM represents the duration of H. pylori infection and premalignant tendency of IM.

The relationships between the histologic characteristics of IM and H. pylori infection have been studied extensively. In the present study, the H. pylori infection rate did not differ significantly with histologic subtype and severity. Telomerase activity tends to be high in subtype III of IM; this subtype is known to be more precancerous in nature than other histologic types in pathologic studies.³²⁾ The number of subjects in our study is too small to allow us to say definitively that subtype III of IM has a precancerous nature at the molecular level. There was no relation between the histologic severity of IM and telomerase activity. The nature of the precancerous lesion did not depend on histologic severity, but subtype is more important in the prediction of cancerous changes in IM. The histologic subtype was changed in 73.3% of cases with IM and the severity of IM tended to decrease. Metaplastic changes disappeared in 20% of cases. Taken together, these observations suggest the possibility of reversibility of IM after H. pylori eradication.

Our study suffered from some limitations associated with the use of endoscopic biopsies, but these are unavoidable in a clinical study. However, we used special staining techniques to maximize our ability to assess the pattern and extent of IM, and we recorded the lesion site to allow re-examining of the same site by endoscopic biopsy. Another problem is that a relatively small number of subjects was included in this study to induce a statistically significant result for comparing the relationship among various factors, which needs subsequent more studies to confirm the clinical significance of relating factors in patients with IM.

The changes in quantitation of telomerase activities (relative telomerase activity) was significantly decreased in patients regardless of the positivity of the telomerase activity. These results suggest that H. pylori eradication is needed in H. pylori-infected patients with IM, especially those that have endoscopic findings of widespread and histologic subtype III IM.

To conclude, in IM a widespread endoscopic lesion and histologic subtype III produces a tendency for high telomerase activity, which is a predictable marker of malignant changes. H. pylori eradication improved the endoscopic and histologic features and decreased telomerase activity. We carefully suggest that H. pylori eradication can be considered one of the methods to prevent gastric cancer in patients with H. pylori infected IM. Further long-term and large scaled study will be needed.