Contribution Of Epidemiological Studies To Gastritis Immunology

Chronic gastritis, or chronic inflammation in gastric antral and/or corpus mucosa, is a common pathological condition affecting over half the general population. Progression of chronic gastritis from Helicobacter pylori infection to severe gastric mucosal atrophy usually takes decades and varies considerably from person to person. Therefore, studies of clinically selected material cannot provide a complete picture of natural evolution of the disease or its wide variability. An overview of immunological and morphological aspects of chronic gastritis in an epidemiological context, based on data from the literature and the author's studies, reveal dynamic interaction between H. pylori infection and host response to the organism's antigens, and to gastric autoantigens including gastric H⁺K⁺ ATPase. Further population and followup studies of antral and corpus gastritis at different stages of evolution are needed, in combination with new methods, to elucidate further the roles of infection, and gastric-antrum- and corpus-mucosa-related autoimmune responses, in the pathogenesis of chronic gastritis.     

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.     

Relation between IgG and IgA antibody titres against Helicobacter pylori in serum and severity of gastritis in asymptomatic subjects.

AIMS--To investigate whether the absorbance index of IgG and IgA antibodies against Helicobacter pylori is related to a semiquantitative assessment of the density of H pylori colonisation in gastric biopsy specimens and to the severity of gastritis. METHODS--The grade of gastritis was scored separately for antral and fundic mucosa using three different classifications. Serum IgA and IgG antibodies against H pylori were measured by ELISA. The density of gastric H pylori colonisation was graded semiquantitatively from 0 to 3. RESULTS--Among 48 healthy volunteers studied, 17 were found to have gastritis according to Whitehead''s criteria. H pylori was present in the biopsy specimens of 14 of 17 subjects with gastritis. The IgG H pylori antibody absorbance index was significantly (p < 0.05) correlated not only with the density of antral H pylori colonisation, but also with the degree of gastritis of the antrum, as assessed by the Whitehead score, activity, and the Sydney system (p < 0.05). The IgA H pylori antibody absorbance index was significantly correlated with the Whitehead score and Sydney system, but not with the activity score of the antrum or with the density of antral gastric H pylori infection. There were no significant correlations between the IgG H pylori antibody absorbance index and the gastritis scores of the fundus mucosa and the density of H pylori infection of the gastric body. The IgA H pylori antibody absorbance index was only significantly (p < 0.05) correlated with the density of H pylori colonisation and the Sydney system gastritis score of the corpus. CONCLUSIONS--The serological absorbance index of IgG antibodies against H pylori is related to the severity of antral gastritis and the density of antral H pylori colonisation. Thus a high absorbance index of IgG antibodies against H pylori points to severe antral gastritis and dense H pylori colonisation of the antrum.     

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.     

Improvement of gastric inflammation and resolution of epithelial damage one year after eradication of Helicobacter pylori.

AIMS--To investigate the effect of eradication of Helicobacter pylori infection on gastric epithelial damage and gastritis, scored according to the Sydney system. METHODS--Gastritis scores and epithelial damage were assessed in gastric biopsy specimens before, and five weeks and one year after anti-H pylori therapy in 66 patients with H pylori related gastritis. RESULTS--The mean initial levels of activity, inflammation, atrophy, intestinal metaplasia, and H pylori scores were higher in the antrum than in the corpus or fundus. Eradication of H pylori resulted in an improvement in the mean inflammatory score in antral biopsy specimens from 2.23 before treatment to 1.32 and 1.06, respectively, five weeks and one year after treatment. Corresponding values for fundic biopsy specimens were 1.30, 0.36 and 0.35. Activity scores improved from 1.41 before treatment to 0.13 and zero, respectively, five weeks and one year after treatment in antral biopsy specimens and from 0.60 before treatment to zero in fundic biopsy specimens. Before treatment, epithelial damage was present in 51% of biopsy specimens taken from the antrum and 23% of those from the corpus. Five weeks after eradication of H pylori none of the biopsy specimens revealed evidence of epithelial damage. CONCLUSION--Eradication of H pylori is followed by a rapid, significant improvement in the gastritis score and resolution of epithelial damage in antral and fundic mucosa.     

Helicobacter pylori associated gastric diseases and lymphoid tissue hyperplasia in gastric antral mucosa

AIM: To investigate the relation between Helicobacter pylori associated gastroduodenal diseases and lymphoid tissue hyperplasia in the antral mucosa and to pursue its evolution after eradication of H pylori. METHODS: Gastric antral biopsy specimens were obtained from 438 patients with H pylori positive gastroduodenal diseases (185 chronic gastritis, 69 gastric ulcer, and 184 duodenal ulcer) and 50 H pylori negative healthy controls. Lymphoid follicles and aggregates were counted and other pathological features were scored according to the updated Sydney system for classification of chronic gastritis. After a course of anti-H pylori treatment, biopsy specimens were obtained at four to six weeks, 12 months, and 24 months in the chronic gastritis patient group. RESULTS: The total prevalence of lymphoid follicles and aggregates in the biopsies was 79.9% (350 of 438; 95% confidence intervals (CI), 0.76 to 0.84). The prevalence and density of lymphoid follicles and aggregates were significantly different in the various gastroduodenal diseases. The highest prevalence (89.9%; 95% CI, 0.83 to 0.97) and density (0.82) of lymphoid follicles and aggregates occurred in patients with gastric ulcers. The lowest prevalence of lymphoid follicles and aggregates was found in patients with chronic gastritis (74.6%; 95% CI, 0.68 to 0.81), and the lowest density of lymphoid follicles and aggregates (0.56) was seen in patients with duodenal ulcers. The prevalence and density of lymphoid follicles and aggregates correlated strongly with the activity and severity of gastric antral mucosal inflammation. The eradication of H pylori resulted in a decrease in the prevalence and density of lymphoid follicles and aggregates. CONCLUSION: The prevalence and density of lymphoid follicles and aggregates in gastric antral mucosal biopsies correlated closely with H pylori infection.     

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.     

Detection of Helicobacter pylori DNA in the oral cavity and gastroduodenal system of a Venezuelan population

Dental plaque has been suggested as a reservoir for Helicobacter pylori but the hypothesis that the oral microflora may be a permanent reservoir of H. pylori is still controversial. The aims of this study were to determine the presence of H. pylori DNA in the gastric antrum and dental plaque of a Venezuelan population by PCR and to investigate the relationship between this infection and the oral hygiene index. Thirty-two patients from the Hospital Universitario de Caracas, attending for routine gastroscopy, and 20 asymptomatic subjects (control group) were evaluated. The patients' gingiva and plaque were assessed by the gingival and plaque indices of Sillness and L?e. Supragingival plaque was analysed by a PCR for a specific internal urease gene. Gastric antrum biopsies were taken for histological examination and PCR. H. pylori was detected in antral samples from 24 (75%) of 32 patients, all of whom had chronic gastritis. H. pylori was also detected in dental plaque samples of 12 (37.5%) of the 32 patients. In 7 (58%) of these 12 patients, H. pylori was identified in the gastric biopsy. Seven patients with chronic gastritis carried H. pylori in dental plaque and antral samples. Of these patients, four also had dysplasia and one had metaplasia. Three subjects in the control group were positive by PCR. In the present study there was no correlation between H. pylori infection and dental hygiene, dental caries, periodontal disease or use of dentures. The oral cavity may be a reservoir for H. pylori infection and oral secretions may be an important means of transmission of this micro-organism. H. pylori in dental plaque may represent a risk factor for gastrointestinal re-infection and ulcer relapse after antibiotic therapy.     

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.     

Histological study of chronic gastritis from the United Arab Emirates using the Sydney system of classification.

AIMS--To determine the prevalence of Helicobacter pylori in five main nationality groups with gastric ulcer, duodenal ulcer, and non-ulcer dyspepsia; and to determine the histopathological types of gastritis and assess the graded variables of Helicobacter associated gastritis. METHODS--Gastric antral and corpus biopsy specimens from 437 patients were examined for the prevalence of H pylori, 337 of which were classified and graded histologically according to the Sydney system. RESULTS--The overall colonisation rate of H pylori was 90%, and there was no significant difference between groups of different ethnic origins. The colonisation rates were 99%, 89%, and 78% in patients with duodenal ulcer, non-ulcer dyspepsia, and gastric ulcer, respectively. Helicobacter associated gastritis was the most common form of chronic gastritis (87%). H pylori density was greater in the antrum than the body. Gastric atrophy in helicobacter associated gastritis was seen in 54% of the cases (43% grade I, 10% grade II, 1% grade III) and increased the older the patients. Atrophy of the corpus alone was very rare (1%). Atrophy and intestinal metaplasia were more prevalent in patients with gastric ulcer than duodenal ulcer. CONCLUSION--The colonisation rate of H pylori was similar in the five groups studied and was almost invariably present in gastric biopsy specimens in patients with duodenal ulcer. H pylori associated gastritis was the most common form of gastritis. Atrophy was mainly of low grade and increased the older the patient.     

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.     

The story so far: Helicobacter pylori and gastric autoimmunity

The gastric mucosal pathogen Helicobacter pylori induces autoantibodies directed against the gastric proton pump H+,K+-ATPase in 20-30% of infected patients. The presence of these autoantibodies is associated with severity of gastritis, increased atrophy, and apoptosis in the corpus mucosa, and patients with these autoantibodies infected with H. pylori display histopathological and clinical features that are similar to those of autoimmune gastritis (AIG). This review will focus on the T helper cell responses, cytokines, and adhesion molecules involved in corpus mucosal atrophy in chronic H. pylori gastritis and in AIG, and the role of H. pylori in the onset of AIG.     

Observer variation in the assessment of chronic gastritis according to the Sydney system

The main aims of the Sydney system for the classification of gastritis are to improve uniformity in histopathological reporting and to provide a flexible matrix of rules for grading the histological features. We sought to determine the level of interobserver agreement between pathologists in the application of the Sydney system. Three histopathologists independently examined H & E, alcian blue/PAS and modified Giemsa stained sections of two antral and two corpus gastric biopsies from 69 consecutive dyspeptic patients. After elimination of five unsuitable cases, each observer graded chronic inflammation, polymorph activity, atrophy, intestinal metaplasia and Helicobacter pylori density in the antrum and corpus on a 0–3 scale according to the Sydney system criteria. The pairwise agreement on final diagnosis and the overall and conditional agreement on histological grades were examined by kappa statistics. Agreement on the final diagnosis ranged from 83–94% with kappa values of 0.699 ('good') to 0.887 ('excellent'). Conditional probability of agreement on a diagnosis of H. pylori positive gastritis was 99%, but wider disagreements were apparent in the recognition of H. pylori negative gastritis, reactive gastritis and even normal biopsies. Overall agreement for grade ranged from 70% for antral atrophy to 94% for intestinal metaplasia in the corpus with 'moderate' or 'good' kappa values. We conclude that the diagnostic and grading criteria described in the Sydney system can be applied consistently by histopathologists. The findings underline its potential usefulness in routine practice.     

Macrophages are mediators of gastritis in acute Helicobacter pylori infection in C57BL/6 mice

Helicobacter pylori is the etiological agent of human chronic gastritis, a condition seen as a precursor to the development of gastrointestinal ulcers or gastric cancer. This study utilized the murine model of chronic H. pylori infection to characterize the role of macrophages in the induction of specific immune responses and gastritis and in the control of the bacterial burden following H. pylori infection and vaccination. Drug-loaded liposomes were injected intravenously to deplete macrophages from C57BL/6 mice, and effective removal of CD11b+ cells from the spleens and stomachs of mice was confirmed by immunofluorescence microscopy. Transient elimination of macrophages from C57BL/6 mice during the early period of infection reduced the gastric pathology induced by H. pylori SS1 but did not affect the bacterial load in the stomach. These data suggest that macrophages are important to the severity of gastric inflammation during H. pylori infection.     

Die lymphozytäre Gastritis – eine seltene Erkrankung der Magenschleimhaut

Lymphocytic gastritis, first described by Haot et al. in 1986, is a very rare form of gastritis (0.8-1.6% of cases) with unclear pathogenesis. On endoscopy, lymphocytic gastritis may present either a normal appearance, such as gastritis varioliformis with multiple elevated chronic erosions in the corpus and fundus, or as a giant fold gastritis in the corpus and fundus. This type of gastritis is diagnosed histologically based on an accumulation of intraepithelial lymphocytes (more than 25/100 epithelial cells) in the surface cells of the gastric mucosa. Its etiopathogenesis is currently thought to be a sprue-associated reaction or an atypical reaction to Helicobacter pylori infection. Some studies report the lymphocytic gastritis in almost 45% of cases of sprue, with the gastritis regressing in response to a gluten-free diet, while others report a correlation of lymphocytic gastritis with serologically and/or histologically confirmed H. pylori infection, with the lymphocytic gastritis being cured by H. pylori eradication treatment in a high percentage of the cases. It is possible that a similar abnormal immune reaction to an inflammatory agent underlies both pathological entities, sprue and lymphocytic gastritis--in the one case gluten and in the other H. pylori--which would mean that sprue-induced and H. pylori-induced forms of lymphocytic gastritis exist side by side.     

Response of IgG1 and IgG2 subclasses to Helicobacter pylori in subjects with chronic inflammation of the gastric mucosa, atrophy and gastric cancer in a country with high Helicobacter pylori infection prevalence

Polarized immune response to Helicobacter pylori and induction of chronic inflammation may increase the risk of gastric atrophy and adenocarcinoma. We studied the association of the response of IgG1 and IgG2 antibodies to H. pylori with grade of gastric chronic inflammation and atrophy in a population with a high prevalence of H. pylori, and compared these data with the data obtained from the study of gastric cancer patients, as well as with the data for CagA positivity. Altogether, 114 persons from two adult population samples from Estonia and 45 consecutive gastric cancer patients were studied. All patients were positive for the H. pylori antibody determined by ELISA. Adenocarcinoma was classified histologically according to the Laurén's system. The response of the IgG subclasses to H. pylori (acid glycine-extracted whole cell proteins) was determined by ELISA and the results were compared with the ELISA results for the recombinant fragment of the CagA protein. Helicobacter pylori IgG level was lower in atrophic gastritis compared with nonatrophic gastritis (chronic inflammation) (p=0.001). In the group of cancer patients, the response of IgG and IgG1 was lower compared with both gastritis groups (p=0.01 and p=0.0002 for IgG, and p=0.001 and p=0.0005 for IgG1). IgG2 was lower for gastric cancer localized in the corpus (p=0.03). In conclusion, atrophic gastritis and gastric cancer were associated with a significant decline in IgG and IgG1 response to H. pylori compared with nonatrophic gastritis. Higher value of CagA antibodies was seen in gastric cancer and in gastric atrophy compared with nonatrophic gastritis; in gastric cancer patients, IgG1 response to H. pylori was correlated with CagA status.     

Bile reflux and intestinal metaplasia in gastric mucosa.

AIM: To determine associations between enterogastric bile reflux and gastric mucosal pathology. METHOD: A retrospective study using fasting gastric juice bile acid measurements and antral or prestomal biopsy specimens from 350 patients, 66 of whom had previously undergone surgery that either bypassed or disrupted the pyloric sphincter. RESULTS: Bile reflux was positively associated with reactive gastritis and negatively with Helicobacter pylori density. After stratification for previous surgery, age, and H pylori status, the histological feature most strongly associated with bile reflux was intestinal metaplasia, including all its subtypes. The prevalence of intestinal metaplasia was greatest in patients with both H pylori infection and high bile acid concentrations. Bile reflux was also positively associated with the severity of glandular atrophy, chronic inflammation, lamina propria oedema and foveolar hyperplasia. CONCLUSIONS: Bile reflux is a cause of reactive gastritis. It modifies the features of H pylori associated chronic gastritis. The changes are not confined to patients who have had surgery to their stomachs. The positive associations with atrophy and intestinal metaplasia have implications for models of gastric carcinogenesis.