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

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) = 8.9, 95% confidence interval (CI) = 2.7–54.7] to subjects with CAG (H. pylori‐positive/CAG‐positive) (HR = 17.7, 95% CI = 5.4–108.6) and finally to subjects with metaplastic gastritis (H. pylori‐negative/CAG‐positive) (HR = 69.7, 95% CI = 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 response‐based 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.     

Helicobacter pylori, atrophic fundal gastritis and risk for gastric adenocarcinoma

Fundal atrophic gastritis and Helicobacter pylori have been implicated as possible etiologic factors in gastric cancer. This case-control study was performed to determine which risk factor is more closely related to gastric cancer. The endoscopic Congo red test was performed to evaluate the extent of fundal atrophic gastritis in 43 patients with gastric cancer and 86 cancer-free control subjects, who were individually matched by age, sex, and date of endoscopy (within 3 months). The prevalance of H. pylori infection and severe fundal gastritis were significantly higher in patients with differentiated adenocarcinoma, but not with undifferentiated adenocarcinoma, than in control subjects. The odds ratios for differentiated and undifferentiated adenocarcinomas were 6.85 (95% confidence interval, 1.94-11.82) and 1.50 (95% CI, 0.84-3.11), respectively. However, the odds ratio of H. pylori infection was greater than that of severe fundal gastritis. Moreover, multivariate analysis provided similar results. H. pylori infection is an independent indicator of a higher risk of the differentiated adenocarcinomas of the stomach than is severe fundal gastritis.     

Histological diagnosis of Helicobacter pylori gastritis is predictive of a high risk of gastric carcinoma

Chronic Helicobacter pylori infection has been identified as a major risk factor for the subsequent development of gastric carcinoma. On the basis of seroepidemiological studies the relative risk for infected persons was estimated to range between 3 and 6. Our study attempted to determine the relative risk of gastric carcinoma in H. pylori-infected individuals based on the histological evaluation of gastritis in gastric carcinoma patients in the light of a declining prevalence of H. pylori infection in Western countries. We histologically determined the H. pylori infection rate in 215 patients with early gastric carcinoma (tumor stage pT1), and compared it with that of 215 asymptomatic persons matched by age and sex who were tested by the 13C urea breath test. On the basis of these data an odds ratio of 16.7 (CI 9.6–29.1) was calculated for the relative risk of developing gastric carcinoma in H. pylori-infected people. The histological diagnosis of gastritis permits a separate risk assessment for patients with autoimmune gastritis, and by excluding these patients from the analysis we calculated an odds ratio for H. pylori-infected persons of 150 (CI 36.4–622.9). The endoscopic-histological diagnosis of H. pylori infection is associated with an increased risk of the subsequent development of gastric carcinoma of approximately 150-fold compared with H. pylori-negative patients who do not have chronic atrophic corpus gastritis of the autoimmune type (type A gastritis). Int. J. Cancer 73:837–839, 1997. © 1997 Wiley-Liss, Inc.     

FACTORS INFLUENCING SERUM PEPSINOGEN LEVELS IN A CHINESE POPULATION AT HIGH RISK OF STOMACH CANCER

The relationships between serum pepsinogen (PG) levels and age, sex, ABO blood type, cigarette smoking and diet were studied among over 3, 000 residents selected at random in an area with high risk of stomach cancer in Shandong Province, China. Males had significantly higher median PG Ⅰ and Ⅱ levels than feamles. PG Ⅰ tended to decrease and PG Ⅱ to rise with age. Subjects with blood type A had a higher PG Ⅱ level than subjects with other blood types. Both PG Ⅰ and Ⅱ levels rose with dally consumption of cigarettes. Alcohol consumption was not related to PG levels. The PG Ⅰ/Ⅱ ratio declined with increasing consumption of sour pancakes, a fermented staple food found to contain N-nitroso compounds and to be a risk factor for stomach cancer in this population.     

Serum pepsinogen levels in gastric cancer patients and their relationship with Helicobacter pylori infection: a prospective study.

BACKGROUND: Our aim was to study the serum pepsinogen levels in gastric cancer patients in our population in relation to histology and the presence of Helicobacter pylori. METHODS: Forty-six patients with gastric cancer and 70 controls were studied prospectively in a 1-year period. Serum levels of pepsinogen I (PG I), pepsinogen II (PG II), and gastrin were measured by radioimmunoassay. RESULTS: The mean PG I levels for cancer patients and controls were 83.5 microg/l and 60.9 microg/l, respectively (P = 0.03), the mean PG II levels were 27.2 microg/l and 12.1 microg/l respectively (P < 0.0001). The PG I/II ratio was significantly lower in cancer patients (P = 0.04) and in those with Helicobacter infection. Serum pepsinogen levels were not affected by any pathological characteristics. Histology showed that the prevalence of chronic gastritis, intestinal metaplasia, and gastric atrophy was 97%, 56%, and 15%, respectively. CONCLUSION: The prevalence of gastric atrophy is low in our population, and serum pepsinogen measurement is not useful as a screening tool for gastric cancer in this population.     

Risk of gastric cancer in asymptomatic, middle-aged Japanese subjects based on serum pepsinogen and Helicobacter pylori antibody levels

A total of 5,209 asymptomatic, middle-aged subjects, whose serum pepsinogen (PG) and Helicobacter pylori antibody levels had been assessed, were followed for 10 years. Subjects with positive serum H. pylori antibodies (>50 U/mL) had an increased cancer risk (HR = 3.48, 95% CI = 1.26-9.64). Risk of gastric cancer increased as the antibody level increased; the H. pylori-positive group with antibody levels >500 U/mL had the highest incidence rate (325/100,000 person-years). Cancer development also increased with a reduced serum PG I level or a reduced PG I/II ratio; the risk was significantly elevated with serum PG I level or=30 ng/mL (HR = 3.81, 95% CI = 1.10-13.21). Using H. pylori antibody and PG levels, subgroups with an especially high or low cancer incidence rate could be identified. H. pylori-negative or indeterminate subjects with low PG level (PG I 500 U/mL and a low PG level were among the subgroups with a high cancer incidence rate (over 400/100,000 person-years). In contrast, H. pylori-negative subjects with a PG I level >70 ng/mL or a PG I/II ratio >3.0 had the lowest risk; none of these subjects developed cancer. Thus, serum PG levels and/or H. pylori antibody levels can be used to predict the risk of cancer in individuals with H. pylori-related gastritis from the general population.     

Serum pepsinogen levels in gastric cancer patients and their relationship with Helicobacter pylori infection: a prospective study

Background: Our aim was to study the serum pepsinogen levels in gastric cancer patients in our population in relation to histology and the presence of Helicobacter pylori . Methods: Forty-six patients with gastric cancer and 70 controls were studied prospectively in a 1-year period. Serum levels of pepsinogen I (PG I), pepsinogen II (PG II), and gastrin were measured by radioimmunoassay. Results: The mean PG I levels for cancer patients and controls were 83.5 μg/l and 60.9 μg/l, respectively ( P = 0.03), the mean PG II levels were 27.2 μg/l and 12.1 μg/l respectively ( P < 0.0001). The PG I/II ratio was significantly lower in cancer patients ( P = 0.04) and in those with Helicobacter infection. Serum pepsinogen levels were not affected by any pathological characteristics. Histology showed that the prevalence of chronic gastritis, intestinal metaplasia, and gastric atrophy was 97%, 56%, and 15%, respectively. Conclusion: The prevalence of gastric atrophy is low in our population, and serum pepsinogen measurement is not useful as a screening tool for gastric cancer in this population. Received: July 8, 2002 / Accepted: September 2, 2002 Offprint requests to: J.B.-Y. So     

Development of gastric cancer in nonatrophic stomach with highly active inflammation identified by serum levels of pepsinogen and Helicobacter pylori antibody together with endoscopic rugal hyperplastic gastritis

This study aimed to elucidate groups at high risk of developing cancer among patients with serologically identified Helicobacter pylori infection and nonatrophic stomach. Annual endoscopy was performed for a mean of 5.4 years in 496 asymptomatic middle-aged men who were H. pylori antibody-positive and pepsinogen (PG) test-negative. Subjects were stratified according to the activity of H. pylori-associated gastritis measured by serum levels of PG and H. pylori antibody, and/or by endoscopic findings of rugal hyperplastic gastritis (RHG), and cancer development was investigated. During the study period, seven cases of cancer developed in the cohort (incidence rate, 261/100,000 person-years), with 85.7% developing in the group showing a PGI/II ratio ≤3.0, reflecting active inflammation-based high PGII levels. Cancer incidence was significantly higher in this group (750/100,000 person-years) than in groups with less active gastritis. Furthermore, cancer incidence for this group was significantly higher in the subgroup with high H. pylori antibody titers than in the low-titer subgroup. Meanwhile, endoscopic findings revealed that 11.7% of subjects showed RHG reflecting localized highly active inflammation, and cancer risk was significantly higher in patients with RHG than in patients without. Combining the two serum tests and endoscopic examination for RHG allowed identification of subjects with more active gastritis and higher cancer risk. No cancer development was observed in these high-risk subjects after H. pylori eradication. Subjects with highly active gastritis identified by the two serological tests and endoscopic RHG constitute a group at high risk of cancer development with H. pylori-infected nonatrophic stomach.     

Helicobacter pylori IgA and IgG antibodies, serum pepsinogen I and the risk of gastric cancer: changes in the risk with extended follow-up period

The prediction of Helicobacter pylori antibodies immunoglobulin A (IgA) and immunoglobulin G (IgG) and serum pepsinogen I (PG I) on gastric cancer occurrence was studied in a nested case-control study, based on 225 incident cancer cases and 435 matched controls from a Finnish cohort followed from 1966-1991. The odds ratio of noncardia gastric cancer between infected and noninfected persons was 3.12 (95% confidence interval (CI)=1.97-4.95) for elevated IgA and 2.88 (CI: 1.63-5.07) for elevated IgG antibodies. The odds ratio between low and high PG I was 2.24 (CI: 1.43-3.49). The strength of association was significant for IgA antibodies during the total follow-up, but for IgG antibodies this was only true for follow-up periods of 15 years or more. IgA antibodies were significantly associated with all registered histological subtypes apart from intestinal type adenocarcinoma. The highest gastric cancer risk was found among individuals with simultaneously elevated IgA and IgG antibodies and low PG I with an odds ratio of 10.9 (CI: 4.31-27.7) in comparison with those who were negative for both antibodies and had normal PG I. Elevated IgA and IgG antibodies and low PG I were not associated with cancers of the gastric cardia. The findings support the hypothesis that H. pylori infection is a cause of noncardia gastric cancer. Although elevated H. pylori IgA and IgG antibodies and low PG I independently could predict the occurrence of noncardia gastric cancer, their power to do so varied with the stage and length of the follow-up period and it increased when they were applied in combination.     

Correlation of Helicobacter pylori and interleukin-8 mRNA expression in high risk gastric cancer population prediction

AIM: To evaluate (1) the association of the Helicobacter pylori (H. pylori) test and interleukin-8 (IL-8) mRNA expression alone and the severity of gastric cancer (GC); (2) the association of both tests were added to patients'' characteristics to identifli Thai suspected patients of gastric cancer who would receive the most benefit; and (3) diagnostic value of levels of IL-8 mRNA expression for gastric cancer.METHODS: A cross-sectional analytical study was completed with 220 patients with 86 GC patients who underwent endoscopy with gastric surgery divided into non-metastasis and metastasis groups, and 134 patients with benign lesions who underwent endoscopic examination, at the Gastrointestinal Surgery and Endoscopy Unit, Chiang Mai University Hospital between 2006 and 2010. Of 220 patients, 86 cases of diagnosed gastric adenocarcinoma were in an advanced stage and 134 cases were non-cancer patients.RESULTS: The IL-8 mRNA expression showed predominant association with advanced GC when compared to H. pylori infection alone [OR (95%CI); 0.86 (0.49-1.53) vs 5.44 (3.08-9.62)] when including the patients’ characteristics the highest of the area under the receiver operating characteristic curves (AuROC) of the model were males older than 40 years of age [AuROC (95%CI); 0.81 (0.75-0.86)]. However, preliminary testing for diagnostic indices of four cut-off points of IL-8 mRNA expression to predict the severity of GC cases found an increasing suboptimal trend from the likelihood ratio of positive to differentiate the severity in the GC group. The IL-8 mRNA expression showed a predominant association with GC when compared to H. pylori infection, especially in males older than 40 years of age who may benefit most from this test.CONCLUSION: The future research of IL-8 mRNA expression to predict severity in the gastric cancer group should be warranted.     

Determinants of plasma pepsinogen levels in a population at high risk for stomach cancer in venezuela

Determinants of plasma pepsinogens (PG) levels were studied in 1365 participants in a chemoprevention trial for gastric pre-cancerous lesions being conducted in Venezuela. Gastric biopsies, plasma samples and information on smoking and dietary habits were obtained at baseline examination. Both PG-I and PG-II levels increased progressively with the level of Helicobacter pylori infection in gastric biopsies, resulting in no clear trend in the I/II ratio. Instead, there was a progressive decrease in the I/II ratio with increasing degrees of infiltration of polynuclear cells and monocytes, atrophy, intestinal metaplasia and the stage of pre-cancerous lesions. The mean I/II ratios for atrophic gastritis or more advanced lesions were less than 4.0. When subjects with the I/II ratio 4 or higher were used as controls, severe reduction in the I/II ratio (<2.0) was inversely associated with tobacco consumption. This may be due to a pharmacological effect of nicotine. The severe reduction of I/II ratio was also inversely associated with fresh fruit consumption. In addition, a decreased I/II ratio was positively associated with rice/pasta and arepas (tortilla made from corn) consumption and inversely associated with plantain consumption. Possible effects of vitamins and starchy food on the development of atrophic gastritis need to be studied further. © 1995 Wiley-Liss, Inc.     

Helicobacter pylori and gastric epithelial cells: from gastritis to cancer

Helicobacter pylori is a spiral, gram-negative rod-shaped pathogen that attaches to gastric epithelial cells in the human stomach and is a causative agent of chronic active gastritis, peptic ulcer and neoplasia. H. pylori is one of the most common pathogens afflicting humans and is the major environmental factor in the development of gastric cancer increasing from 4 to 6 folds the risk of its development. Several specific virulence factors are implicated in the mechanism of H. pylori infection like the bacterial motility; the secretion of large amounts of urease; specific adhesins for the interaction between H. pylori and the gastric surface epithelium; the traslocation into gastric ephitelial cells of the cytotoxin-associated gene A (CagA), the vacuolating cytotoxin A (VacA) and the heat shock protein HspB. Adherence of H. pylori to the gastric epithelium and secretion of interleukins are believed to be an important step in the induction of active inflammation of the mucosal layer. Several studies have demonstrated that H. pylori infection induces gastric epithelial cell proliferation activating ERK and MAPK pathways and increase of mitosis and mutations. Therefore, H. pylori infection seems to increase apoptosis, implying increased gastric epithelial cell turnover. Recently, it has been shown that H. pylori-induced apoptosis in gastric epithelial cells is mediated via the CD95-receptor/ ligand system but that TRAIL also plays an important role in this regulation.     

A case of a gastric cancer patient with high serum pepsinogen levels at relapse

A rare case of a 68-year-old female cancer patient with an extremely high serum level of pepsinogens (PG) at relapse is presented. She had stage 3 Borrmann 3 type gastric cancer which was a poorly differentiated adenocarcinoma. Her postoperative serum PG levels had been within normal limits (23.0 ng/ml for PG-I and 3.2 ng/ml for PG-II), but at the time of the peritoneal relapse they were 5,630 ng/ml and 3,380 ng/ml, respectively. After was chemotherapy initiated, her serum PG levels decreased in parallel with an improvement of her clinical status. Immunohistochemical examination with monoclonal antibodies revealed PG-I and PG-II production in the primary and the metastatic lesions.     

Chronic atrophic gastritis, gastric pH, nitrites and micronutrient levels in a population at risk for gastric carcinoma

One hundred and seventy-eight patients at risk for gastric carcinoma had upper gastrointestinal endoscopy. Twenty-seven selected patients with the type B of chronic atrophic gastritis, 32 patients with normal mucosa and 47 non-scoped healthy controls were tested for plasma vitamin C, retinol and tocopherol. The total vitamin C level was also assessed in gastric juice of scoped patients. Micronutrient levels were related to gastric pH, nitrites and gastric mucosal pathology. The study showed a higher level of pH (greater than 4) and high nitrites in gastric juice in patients with chronic atrophic gastritis, gastric malignant and dysplastic lesions. Neither the hypochlorhydria nor gastric nitrites affected the prevalence of C. pylori in gastric mucosa. Low gastric and plasma concentrations of vitamin C observed in patients with chronic atrophic gastritis showed an inverted relationship with pH level, and an inter-relationship of other vitamins with antioxidant properties (vitamins A and E).     

Low serum pepsinogen I and pepsinogen I/II ratio and Helicobacter pylori infection are associated with increased risk of gastric cancer: 14-year follow up result in a rural Chinese community

The correlation between low serum PG level and H. pylori infection with the development of gastric cancer has caused considerable concerns all over the world. Some authors exclaimed that gastric cancer developed only in patients infected with H. pylori, whereas the other had different findings. In this study, 1,501 adult local residents with determined serum PG levels and anti H. pylori IgG status were followed for 14 years for the development of gastric cancer in a rural community with high risk of gastric cancer in Hebei Province, China. The results showed the accumulated gastric cancer incidence in the subjects with abnormal PG level and those with H. pylori infection were all significantly higher than that in the corresponding normal controls (53.9‰ vs. 12.7‰, p < 0.05 and 23.1‰ vs. 5.93‰, p < 0.05). The highest gastric cancer incidence was seen in the subjects with both abnormal serum PG and positive H. pylori (56.0‰), and followed by the subjects with abnormal PG and negative H. pylori (47.6‰) and those with normal serum PG and positive H. pylori (18.4‰). The abnormal serum PG level (OR 3.029) and H. pylori infection (OR 4.345) were all risk factors for the development of gastric cancer. The results suggested that the subjects with abnormal serum PG level and/or positive H. pylori infection in the rural area of China were all high risk population for gastric carcinoma and the subjects with both abnormal serum PG and positive H. pylori infection were at especially high risk for the development of gastric carcinoma.     

Synergistic interaction between Helicobacter pylori gastritis and diet in gastric cancer

Infection with Helicobacter pylori increases the risk of gastric cancer. One possible mechanism is the higher likelihood of malignant transformation due to inflammatory responses in the epithelium. An alternative explanation is that these inflammatory responses induce chronic gastritis associated with decreased acidity in the stomach, which in turn increases the endogenous formation of carcinogenic N-nitroso compounds. Inflammatory responses seem to trigger two different causal pathways: one for the diffuse type of gastric cancer and the other for the intestinal type. The striking geographic variability in intestinal gastric cancer can be explained by the synergistic interaction between H. pylori infection and dietary factors, such as intake of salt and ascorbic acid. Screening and eradication of this organism, together with appropriate dietary modifications, offer promise in countries with a high prevalence of H. pylori infection and high risk of gastric cancer, but the safety of such interventions needs to be ensured.     

Helicobacter pylori strain types and risk of gastric cancer: a case-control study.

The aim of this novel endoscopy clinic-based case-control study was to explore the influence of different Helicobacter pylori strain types on the risk of gastric adenocarcinoma using isolated bacterial strains, tissue samples, and sera. We included 72 cases with gastric adenocarcinoma and 324 age- and sex-matched controls. Histological characterization, culture, molecular typing of H. pylori genes by PCR (cagA/vacA), conventional IgG ELISA, and immunoblotting (Western blot) for the CagA and VacA proteins were performed. With four tests combined, H. pylori infection was detected in 57 (79%) cases and 213 (66%) controls. A positive association between H. pylori infection and gastric cancer risk was found [odds ratio (OR), 2.1; 95% confidence interval, 1.1-3.9]. Type I (OR, 1.8), intermediate (OR, 2.0), and type H (OR, 0.2) strains of H. pylori presented different serum antibody levels and different levels of association with gastric cancer. Our case-control study, based on molecular characterization and serology, provides further evidence that infection by more virulent strains of H. pylori and the presence of antibodies toward the CagA protein can be used as markers for an increased risk of gastric adenocarcinoma and that the strain types of H. pylori could be used in the future to determine disease outcome.     

Chronic atrophic gastritis in a population at risk for gastric carcinoma

Gastric mucosa of 585 patients at risk for gastric carcinoma and undergoing oesophago-gastroscopy for dyspeptic symptoms was examined histologically and histochemically. Sixteen (2.7%) of the patients studied showed gastric carcinoma. The intestinal type of gastric carcinoma was the most common, present in males over 40 yrs old, and was found in 1:16. Early cancers were present in 3 patients. Chronic atrophic gastritis of the A, B and AB types was present in 32.8%. Types A and AB were noted sporadically. Males over 40 and tobacco smokers showed the prevalence of the type B (idiopathic chronic pangastritis) and incomplete intestinal metaplasia. No relationship of the mucosal precursor lesions to sulpho- and sialomucins were detected. Helicobacter pylori infestation of gastric mucosa was present in 81% of patients and relatively common in the young patients with normal gastric mucosa; therefore this finding confirms a predilection of Helicobacter pylori to the Third World.     

Progression of chronic atrophic gastritis associated with Helicobacter pylori infection increases risk of gastric cancer

We conducted a longitudinal cohort study to determine the association of Helicobacter pylori infection and the progression of chronic atrophic gastritis (CAG) with gastric cancer. A cohort of 4655 healthy asymptomatic subjects was followed for a mean period of 7.7 years. H. pylori infection was established by serum specific antibodies and the presence of CAG was confirmed by serum pepsinogen. During the follow-up period, 45 gastric cancer cases were detected (incidence rate, 126/100000 person-years). A univariate analysis after adjustment for age showed that both H. pylori and CAG were significantly associated with gastric cancer. To clarify the interaction between H. pylori and CAG, an analysis stratified by H. pylori- and CAG-status was performed. No cancer developed in the H. pylori(-)/CAG(-) group during the study period. This supports the theory that it is quite rare for any type of gastric cancer to develop in an H. pylori-free healthy stomach. With the progression of H. pylori-induced gastritis, the risk of gastric cancer increased in a stepwise fashion from CAG-free gastritis [H. pylori(+)/CAG(-) group] (HR=7.13, 95%CI=0.95-53.33) to CAG [H. pylori(+)/CAG(+) group] (HR=14.85, 95%CI=1.96-107.7) and finally to severe CAG with extensive intestinal metaplasia [H. pylori(-)/CAG(+) group] (HR=61.85, 95%CI=5.6-682.64) in which loss of H. pylori from the stomach is observed. Therefore, it is probable that H. pylori alone is not directly associated with stomach carcinogenesis. Instead, H. pylori appears to influence stomach carcinogenesis through the development of CAG. The observed positive correlation between the extent of H. pylori-induced gastritis and the development of cancer was strong, especially for the intestinal type. These results are compelling evidence that severe gastritis with extensive intestinal metaplasia is a major risk factor for gastric cancer, and they confirm the previously described model of stomach carcinogenesis: the gastritis-metaplasia-carcinoma sequence.