Topographic expression of MUC5AC and MUC6 in the gastric mucosa infected by Helicobacter pylori and in associated diseases

We investigated the topographic expression of MUC5AC and MUC6 in relationship with gastric diseases. The immunoexpression of MUC5AC and MUC6 was evaluated in 75 adults presenting Helicobacter pylori gastritis (n = 22; 11 cagA positive), duodenal ulcer (DU, n = 11), gastric ulcer (GU, n = 9), gastric carcinoma (GC, n = 20), and normal mucosa (H. pylori negative, n = 13). Five gastric areas (antral and corporeal lesser and greater curvatures and incisura) were studied. H. pylori was detected by carbolfuchsin, urease, and culture; cagA was determined by PCR. All patients with DU (eight with GU and 13 with GC) were H. pylori-positive. In H. pylori gastritis, MUC5AC expression was higher in the antrum than in the corpus; no difference was observed with respect to cagA status. MUC5AC expression was higher in the antrum of gastritis than in DU, and it was lower in the incisura among GU patients compared to DU. MUC6 expression was higher in the antrum of H. pylori gastritis compared to DU and to uninfected patients. No difference was observed in the topographic pattern of expression of MUC5AC and MUC6 among GC cases. The topographic over- and under-expression of mucins in H. pylori-associated gastritis and peptic disease suggest a role for these mucins in the pathogenesis of H. pylori infection and associated diseases.     

Features of gastritis predisposing to gastric adenoma and early gastric cancer

BACKGROUND/AIMS: Helicobacter pylori gastritis is a risk factor for the development of gastric cancer. The results of several studies indicate that gastric adenomas, which are considered premalignant lesions, may also be associated with H pylori gastritis. However, it is not clear whether there are different patterns of gastritis in these patients compared with patients with gastric cancer or patients with H pylori gastritis alone. Therefore, this study was designed to investigate the patterns of gastritis in these three groups of patients. METHODS: The histological features of gastric mucosa at a distance from the tumour were analysed prospectively in 118 patients with gastric adenoma (mean age, 71.8; female to male ratio, 6 : 4). In addition, for every patient with H pylori associated gastric adenoma an age and sex matched control patient with either H pylori associated early gastric cancer of the intestinal type or H pylori gastritis only was investigated. RESULTS: Only 60 patients (50.9%) with gastric adenoma were infected with H pylori. In the remaining patients, complete atrophic gastritis predominated. In those patients with adenoma and H pylori infection, the gastritis was similar to that seen in patients with early gastric cancer (median score, 2 for activity and degree of gastritis in the antrum and corpus); intestinal metaplasia was common to both groups. These two groups differed significantly from patients with H pylori gastritis only (median grade and activity of gastritis, 1 in antrum and corpus), in whom intestinal metaplasia was rare. CONCLUSIONS: It appears that gastric adenomas and gastric intestinal cancer arise by analogous mechanisms. However, owing to severe atrophic gastritis and a lower incidence of H pylori, adenomas do not appear to be definite precursor lesions for gastric cancer.     

Lymphoid aggregates in gastric biopsies: relationship to other mucosal lesions

The purpose of this study is to estimate the prevalence of lymphocyte aggregates (precursor of MALT lymphomas) in gastric mucosal biopsies and to associate gastric lymphoid tissue with the age of patients, Helicobacter-associated gastritis and other gastric mucosal pathology. A consecutive series of gastric mucosal samples from 150 children and 256 adults were assessed for the presence of lymphoid aggregates as well as morphological characteristics, Helicobacter pylori status, signs of gastritis, mucosal atrophy and lymphoepithelial lesions. Fifteen selected samples with prominent lymphoid aggregates and 10 controls were examined immunohistochemically for the immunoglobulins A, G, M, lymphocytes B and T, clonality of B cell population, atypical lymphocytes and Epstein-Barr virus (EBV) antigen. There was an increase of H. pylori infection and mucosal lymphoid aggregates (MALT) rates in parallel with the increasing age of patients noted in the histological assessment of the mucosal samples. A close association of lymphoid aggregates with H. pylori infection and prominent active gastritis was found, but in adults with chronic non-active, particularly atrophic gastritis this association became weaker. No morphological and immunohistochemical signs of MALT lymphoma were present. Lymphoid aggregates in children were larger, with follicles, but less numerous and tended to be located in the intermediate and deeper parts of the gastric mucosa. Immunohistochemical studies showed an increase of IgA, IgM and lymphocytes T in the deeper part of the lamina propria in H. pylori-associated gastritis and lymphocyte T accumulation in the periphery of the lymphoid follicles. No evidence of monoclonality, CD31 positive lymphocytes or EBV antigen was detected. Lymphoid aggregates are related, but not exclusively, to H. pylori infection. Their detection rates achieve a peak in young adults with H. pylori infection. Lymphocytic aggregates are also present in chronic atrophic gastritis without H. pylori infection and may relate to autoimmune inflammatory response to other factors.     

The prevalence of lymphoid follicles in Helicobacter pylori associated gastritis in patients with ulcers and non-ulcer dyspepsia.

AIMS--To determine the prevalence of lymphoid follicles in Helicobacter pylori positive and negative gastritis in antral and body type gastric mucosa in patients with non-ulcer dyspepsia (NUD), duodenal ulcer, or gastric ulcer; to correlate follicle presence with patient age; to evaluate the correlation between the prevalence of lymphoid follicles and active and inactive gastritis and its severity; and to assess the positive predictive value of lymphoid follicle prevalence with respect to H pylori infection. METHODS--Gastric biopsy specimens, graded according to the Sydney system, from 337 patients were studied. RESULTS--Lymphoid follicles occurred more often in antral mucosa (78%) than in body type mucosa (41%) and were observed in 85% of patients with H pylori positive gastritis. There was no significant difference between NUD and gastric and duodenal ulcer disease with regard to the presence of lymphoid follicles. The positive predictive value of the presence of lymphoid follicles in H pylori infection was 96%. Lymphoid follicles were more commonly observed in patients aged between 10 and 29 years. Lymphoid follicles were more frequently found in pangastritis of all subtypes than in antral gastritis and also in active gastritis than in inactive gastritis. The presence of lymphoid follicles correlated strongly with the degree and severity of gastritis. CONCLUSION--Lymphoid follicles are a constant morphological feature of H pylori associated gastritis.     

Role of corpus gastritis and cagA-positive Helicobacter pylori infection in reflux esophagitis

Considering that the role of Helicobacter pylori infection in gastroesophageal reflux and reflux esophagitis (GERD) is still controversial and that the role of virulence markers of the bacterium has not been evaluated in most studies of GERD, we investigated the association among H. pylori infection with cagA-positive and -negative strains, corpus gastritis, and GERD in a large group of patients by controlling for confounding factors. We studied prospectively 281 consecutive adult patients: 93 with GERD and 188 controls. H. pylori infection status was diagnosed by culture, by the preformed urease test, with a carbolfuchsin-stained smear, and by histology. The cagA status was determined by PCR of H. pylori isolates and gastric biopsy specimens. H. pylori infection was diagnosed in 191 (68.0%) of 281 patients. Among the 93 patients with GERD, 84 presented with mild or moderate esophagitis and 9 presented with severe esophagitis. In the multivariate analysis, the age of the patients and the degree of oxyntic gastritis were associated with GERD. Among the strains isolated from patients with GERD and from the control group, 24.4 and 66.9%, respectively, were positive for cagA (P < 0.001). Compared to infection with cagA-negative strains, infection with cagA-positive H. pylori strains was associated with a more intense gastritis in the corpus (P = 0.001). cagA status (odds ratio [OR] = 0.16, 95% confidence interval [CI] = 0.07 to 0.40), gastritis of the corpus (OR = 0.69, 95% CI = 0.48 to 0.99), and age (OR = 1.04, 95% CI = 1.01 to 1.07) were associated with GERD. In conclusion, the study provides evidence supporting the independent protective roles of cagA-positive H. pylori strains and the degree of corpus gastritis against GERD.     

Serum pepsinogen and Helicobacter pylori infection—a Japanese population study

The decreased ratio of serum pepsinogen (PG) I and II has good correlation with the presence of atrophic gastritis. A total of 1,540 residents aged 30-89?years were enrolled into this study to investigate which serum PG level of residents with Helicobacter pylori infection would represent an adjunct to the diagnosis and progression of atrophic gastritis. All participants received esophagogastroduodenoscopy. Serum antibody to H. pylori (anti-H. pylori) was measured by an enzyme-linked immunosorbent assay (ELISA). Serological atrophic gastritis was defined as serum PG I isozyme level ≤70?ng/ml and a PG I/II ratio of ≤3.0. Of the 1,540 participants, 923 (59.9%) were positive for anti-H. pylori. Serological atrophic gastritis was found significantly more often in anti-H. pylori-positive participants (40.8%) than in anti-H. pylori-negative participants (7.9%) (p?≤?0.0001). The endoscopic findings of anti-H. pylori-positive participants with serological atrophic gastritis were significantly more frequent by 4.06 times for atrophic gastritis (p?≤?0.0001) than anti-H. pylori-negative participants without serological atrophic gastritis. Eight anti-H. pylori-positive participants were diagnosed with gastric cancer, but no cancer was found in anti-H. pylori-negative participants without serological atrophic gastritis. Serum PG testing is clinically useful for the prediction of gastric lesions in H. pylori-infected persons.     

Involvement of mast cells in gastritis caused by Helicobacter pylori: a potential role in epithelial cell apoptosis

BACKGROUND: The role(s) of mast cells (MC) in gastric mucosal inflammation caused by Helicobacterpylori is (are) still debated. AIM: To determine whether there is an association between MC density and epithelial cell apoptosis in antral gastric mucosa infected by H pylori. Patients and methods: Biopsy specimens from 122 H pylori-positive subjects with chronic active gastritis, 84 patients with non-steroidal anti-inflammatory drug-induced gastritis and 48 volunteers were included. H pylori genotypes were determined by PCR amplification of bacterial cultures. Immunohistochemical analysis was performed on tissue microarrays with anti-CD117, anti-chymase, anti-tryptase, anti-myeloperoxidase, anti-Bcl-2, anti-Bcl-x, anti-Bax and anti-caspase 3 antibodies. RESULTS: Of the 122 patients infected with H pylori, 76 (62.3%) harboured cagA positive strains. H pylori isolates belonged to the vacAs1/m1 genotype in 82 (67%) cases, to the vacAs2/m2 genotype in 23 (18.8%) cases and to the vacAs1/m2 genotype in 17 (13.9%) cases. 61 (50%) H pylori isolates were babA2+. In patients infected with H pylori, the density of MC, and in particular the number of MC-associated epithelial cells, was correlated with a high number of apoptotic epithelial cells. Moreover, the density of MC was correlated with the number of neutrophils infiltrating the antral gastric mucosa, and was strongly increased in patients infected with cagA, vacAs1/m1 and babA2 positive strains. CONCLUSIONS: Taken together, these data show that the density of MC can be considered as a histopathological criterion of gastritis activity in patients infected with H pylori.     

Histological heterogeneity and somatic mtDNA mutations in gastric intraepithelial neoplasia.

Somatic mutations of mitochondrial DNA (mtDNA) are associated with various types of human cancer. To elucidate their role in gastric carcinogenesis, we analyzed mutations in the displacement loop region of mtDNA in 24 paraffin-embedded gastric intraepithelial neoplasias (formerly dysplasia) from a high gastric cancer risk area in northern Italy. Helicobacter pylori infection was assessed by histological examination (Giemsa staining). Gastritis was classified according to the guidelines of the Updated Sydney System. The mtDNA displacement loop region was amplified and sequenced from gastric intraepithelial neoplasia samples and adjacent non-neoplastic gastric mucosa. The gastric intraepithelial neoplasias were divided into two groups by their association with H. pylori gastritis. Group A with lesions arising on a background of H. pylori-positive gastritis contained 7 patients, and group B with lesions associated with H. pylori-negative gastritis contained 17 patients. Group A had a larger proportion of high-grade lesions than group B and showed a foveolar phenotype (type II dysplasia). Group B had a larger proportion of cases with mtDNA displacement loop region mutations than group A (P=0.004, Fisher's exact test) and exhibited an intestinal phenotype. No evidence of heteroplasmic variants in the mtDNA displacement loop, suggestive of mutations, was detected in gastric biopsies from 25 H. pylori-negative subjects and 60 cancer-unaffected H. pylori-positive patients. These results provide further evidence for the morphologic and mtDNA biomolecular differences of gastric intraepithelial neoplasias, and suggest the existence of two distinct pathways to gastric cancer--corpus-dominant H. pylori gastritis and the atrophy-metaplasia pathway.     

Gastrin (G) cells and somatostatin (D) cells in patients with dyspeptic symptoms: Helicobacter pylori associated and non-associated gastritis

BACKGROUND: Gastrin G cells and somatostatin D cells are important regulators of gastric acid secretion and alterations in their relative numbers may play a key role in gastroduodenal disease. AIM: To investigate the effect of Helicobacter pylori infection on the density of immunoreactive G and D cells in gastric antral and corpus biopsies from patients with dyspeptic complaints. METHODS: One hundred and twenty two patients with dyspeptic complaints had two antrum and two corpus biopsies taken during upper endoscopy. The severity of inflammation and the density of H pylori were evaluated semiquantitatively. In addition, the density and distribution of neuroendocrine cells, especially G and D cells, were examined using immunohistochemistry. Patients were divided into three groups, those with H pylori positive gastritis, H pylori negative gastritis, and histologically normal gastric mucosa. RESULTS: The number of immunoreactive G cells was significantly higher and the number of immunoreactive D cells lower in patients with H pylori positive gastritis compared with H pylori negative gastritis or histological normal gastric mucosa. The percentage of G cells as a percentage of mucosal endocrine cells was also raised and that of D cells was decreased. CONCLUSIONS: Helicobacter pylori infection produces alterations in the number of endocrine cells responsible for regulating acid secretion in relation to intragastric pH and feeding. The alterations correlate best with the severity of inflammation and not with H pylori density.     

Spontaneous disappearance of Helicobacter pylori antibodies in patients with advanced atrophic corpus gastritis

Background. Only a few reported studies focus on the natural history and course of advanced and severe chronic atrophic gastritis. Methods. In this study we followed 47 men (mean age 62 years) with advanced (moderate or severe) Helicobacter pylori-positive atrophic corpus gastritis. Duration of endoscopic follow-up was 6 years and follow-up based on serum levels of pepsinogen I and antibodies to H. pylori covered a period of 10 years. None of the patients was treated for H. pylori infection prior to end of follow-up. Results. The median H. pylori antibody titre declined (IgG from 4000 to 1300; IgA from 200 to 50) in the study population, and 11 men (23%) converted to seronegative (p=0.0005, Fisher's exact test). There was a small but significant (p=0.0004, Page's test) declining trend in mean atrophy score of the corpus during follow-up (from 2.5 to 2.2). However, no significant changes were observed in grade of atrophy or intestinal metaplasia of the antral mucosa or in grade of intestinal metaplasia in the corpus. The mean SPGI level remained at the initial low level during the entire follow-up. Conclusions. H. pylori antibodies disappear spontaneously within 10 years in almost one fourth of patients with advanced atrophic corpus gastritis. The disappearance of H. pylori antibodies is accompanied by no or more than a mild improvement of the gastric mucosa.     

Ten year follow up study of lymphocytic gastritis: further evidence on Helicobacter pylori as a cause of lymphocytic gastritis and corpus gastritis.

AIMS--To examine the course of lymphocytic gastritis and its relation to Helicobacter pylori (H pylori) infection in a 10 year follow up. METHODS--Ninety six patients were originally examined for dyspepsia in 1981. Gastroscopies with stepwise biopsies were performed on all the patients initially and after an interval of 10 years. RESULTS--Nine per cent of the patients (9/96) had features of lymphocytic gastritis in gastric biopsy at the first examination, and 12.5% (12/96) at the second examination; 7/9 patients (78%) had persistent lymphocytic gastritis during the follow up; in two the diagnostic features of lymphocytic gastritis had disappeared, and five had a new diagnosis of lymphocytic gastritis at the second examination. At the second examination 9/12 lymphocytic gastritis patients (75%) were H pylori positive histologically, while all had specific antibodies to H pylori. The lymphocytic gastritis patients had higher grades of gastritis (p = 0.009), neutrophilic and eosinophilic granulocytes, mononuclear inflammatory cells, and foveolar hyperplasia in the corpus mucosa, but smaller numbers of H pylori, than the H pylori positive patients without lymphocytic gastritis. The appearance of lymphocytic gastritis during the 10 year interval was associated with increases in the grades of corpus gastritis and neutrophilic granulocytes (p = 0.043 for both). During the follow up, the patients with lymphocytic gastritis, but not the H pylori positive patients without lymphocytic gastritis, appeared to have a significant increase in the grade of intestinal metaplasia in the corpus mucosa (p = 0.043). CONCLUSIONS--In some patients H pylori may cause a gastritis that predominates in the corpus and is associated with an increase in the intraepithelial lymphocyte count. This form of gastritis may cause progression of intestinal metaplasia.     

Serum pepsinogen I and II concentrations and IgG antibody to Helicobacter pylori in dyspeptic patients.

AIMS--To investigate the association between histologically confirmed gastritis, carriage of Helicobacter pylori and pepsinogen (PG) I and PG II concentrations. METHODS--Prospective study of 81 dyspeptic patients undergoing upper gastrointestinal endoscopy was made. The extent of gastric mucosal inflammation and the presence of H pylori was determined, and serology to evaluate PG I and II concentrations and IgG titres to H pylori was carried out. RESULTS--The presence of H pylori was strongly correlated with high IgG antibody titres to H pylori and gastritis. Patients who were H pylori positive had significantly higher PG I and PG II concentrations and a significantly lower PG I:PG II ratio than patients who were negative for H pylori. In 13 patients with duodenal ulcer and H pylori positive gastritis serum PG I concentrations were significantly higher than in H pylori positive patients without duodenal ulcer. Significant correlations were found between the age of patients and serum PG II, the PG I:PG II ratio, IgG antibodies to H pylori, the severity of body gastritis and H pylori infection, and between the degree of gastritis in the body of the stomach and the PG II concentration. CONCLUSIONS--Serum PG I and II concentrations, together with a fall in the PG I:PG II ratio, could be used as predictors of H pylori infection as well as serum IgG antibody response to H pylori.     

Helicobacter pylori infection and chronic gastritis in gastric cancer.

AIMS: To investigate the prevalence of Helicobacter pylori associated chronic gastritis in patients with gastric cancer. METHODS: Serum IgG antibodies for H pylori were determined in 54 consecutive patients with gastric carcinoma. The prevalence of H pylori in gastric mucosa was also examined histologically (modified Giemsa) in 32 patients from whom adequate biopsy specimens of the antrum and corpus were available. Thirty five patients with gastrointestinal tumours outside the stomach and 48 with non-gastrointestinal malignancies served as controls. RESULTS: Of the 54 patients, 38 (70%) had H pylori antibodies (IgG) in their serum (three additional patients had H pylori antibodies IgA, class specific but not IgG specific). This prevalence was significantly higher (p less than 0.05) than that (49%) in the 35 controls. No differences in prevalence of H pylori antibodies were found between gastric cancer cases of intestinal (IGCA) or diffuse (DGCA) type, both these types showing H pylori antibodies (IgG) in 71% of the patients. In the subgroup of 32 subjects, five patients had normal gastric mucosa and four showed corpus limited atrophy ("pernicious anaemia type" atrophy of type A). All of these nine patients had no evidence of current or previous H pylori infection in serum (no IgG antibodies) or in tissue sections (negative Giemsa staining). The remaining 23 patients had antral or pangastritis, and all had evidence of current or previous H pylori infection. CONCLUSIONS: H pylori associated chronic gastritis was the associated disease in 75% of the patients with gastric cancer occurring equally often in both IGCA and DGCA groups. About 25% of cases seem to have a normal stomach or severe corpus limited atrophy, neither of which showed evidence of concomitant H pylori infection.     

CagA antibodies in Japanese children with nodular gastritis or peptic ulcer disease

cagA(+) Helicobacter pylori strains have been linked to more severe gastric inflammation, peptic ulcer disease, and gastric cancer in adults, but there have been few studies of cagA in children. We examined the relationship between H. pylori cagA status and clinical status in Japanese children. Forty H. pylori-positive children were studied: 15 with nodular gastritis, 5 with gastric ulcers, and 20 with duodenal ulcers. H. pylori status was confirmed by biopsy-based tests and serum anti-H. pylori immunoglobulin G (IgG) antibody. As controls, 77 asymptomatic children with sera positive for anti-H. pylori IgG were enrolled. Levels of IgG antibodies to CagA in serum were measured by an antigen-specific enzyme-linked immunosorbent assay. In 16 patients with successful H. pylori eradication, posttreatment levels of CagA and H. pylori IgG antibodies also were studied. The CagA antibody seropositivities of asymptomatic controls (81.8%) and patients with nodular gastritis, gastric ulcers, and duodenal ulcers (80.0 to 95.0%) were not significantly different. Compared with pretreatment levels of CagA antibodies, posttreatment levels decreased progressively and significantly. We conclude that, as in Japanese adults, a high prevalence of cagA(+) H. pylori strains was found in Japanese children, and that there was no association with nodular gastritis or peptic ulcer disease. In the assessment of eradicative therapies, monitoring of serum anti-CagA antibodies does not appear to offer any direct benefit over monitoring of anti-H. pylori antibodies.     

Characteristics of Helicobacter pylori infection in Jamaican adults with gastrointestinal symptoms

Helicobacter pylori infection is common in Jamaica. Describing its epidemiology in a population-based study depends largely on serology, but serologic assays have not been validated in this population. To address this issue, we examined the presence of H. pylori infection in 30 sequential adult patients with gastroduodenal symptoms by three biopsy-based methods (rapid urease test, histology, and culture) as well as by one research and two commercial enzyme-linked immunosorbent assays (ELISAs). A patient was considered H. pylori positive if the organism was detected by at least one biopsy-based method. Eighteen (60%) of the 30 patients were H. pylori positive by these criteria, whereas 21 (70%) were seropositive for H. pylori immunoglobulin G by our research ELISA. The presence of H. pylori infection in patients with gastric cancer and those with chronic gastritis was missed by biopsy-based methods but was detected by serologic assays. This observation indicates that serologic assays may be better suited for the detection of this infection in a population in which H. pylori-associated pathology is prevalent. The performance of our research ELISA in detecting biopsy-based H. pylori-positive cases was excellent, with a sensitivity and specificity of 100% and 75%, respectively. Molecular genotyping of the isolates revealed that the predominant H. pylori genotypes in this cohort of Jamaicans were cagA(+) vacA slb-m1, and iceA2. The validated serologic assay enables us to interpret epidemiologic data from population-based studies in Jamaica by comparison to those from other populations.     

Gastritis and its relation to gastric carcinogenesis

There have been rapid changes in understanding of chronic gastritis recently, fueled largely by the recognition of gastric infection by Helicobacter pylori. This report reviews the newer classifications of chronic gastritis, and describes the characteristics of H pylori-positive and -negative patterns of gastritis. The relevance of H pylori infection to gastric carcinogenesis is also discussed.