Effect of Helicobacter pylori infection on gastric cell proliferation and genomic instability in a paediatric population of southern Italy.

BACKGROUND: The incidence of gastric cancer is high in areas with a high prevalence of Helicobacter pylori infection. Cell transformation and tumour progression occur over a long period of time and markers of genomic instability usually precede morphological changes. AIM: To evaluate the effect of Helicobacter pylori infection on cell proliferation, DNA status and oncogene expression in children. PATIENTS AND METHODS: Morphometric and immunohistochemical techniques were used to analyse DNA content, p53 and c-myc oncogene expression and cell proliferation on gastric biopsies of 53 children (27 Helicobacter pylori-negative and 26 Helicobacter pylori-positive). RESULTS: Gastric mucosa was normal in 11% of Helicobacter pylori-positive and in 33% of Helicobacter pylori-negative subjects. Most children had chronic non-atrophic gastritis regardless of Helicobacter pylori infection, and only a minority of children affected by Helicobacter pylori had mild atrophic gastritis. Cell proliferation was significantly higher in children with Helicobacter pylori-positive gastritis than in those with Helicobacter pylori-negative gastritis. No metaplasia, dysplasia, p53 overexpression or altered DNA content was found in any child. Interestingly, 46% of children with and 29% without Helicobacter pylori infection had c-myc overexpression closely related to the cell proliferation rate. CONCLUSION: Helicobacter pylori infection in children may coexist with a normal gastric mucosa, and it is not associated with genomic instability markers in cases of chronic gastritis.

The efficacy of octreotide therapy in chronic bleeding due to vascular abnormalities of the gastrointestinal tract.

BACKGROUND: The treatment of angiodysplasia and watermelon stomach, vascular abnormalities implicated in gastrointestinal bleeding of obscure origin, is a major clinical problem. AIM: To determine the efficacy of octreotide in patients with long-standing gastrointestinal bleeding due to acquired angiodysplasia and watermelon stomach, resistant to previous treatments and not suitable for surgery because of old age and/or concomitant disorders. PATIENTS AND METHODS: We treated 17 patients (seven had isolated angiodysplasia, seven had multiple upper and lower gastrointestinal angiodysplasia, and three had watermelon stomach) with octreotide (0. 1 mg subcutaneous t.d.s. for 6 months). Six of the patients had liver cirrhosis, one had Glanzmann-type platelet derangement, two had cardiovascular diseases and one had chronic uraemia. RESULTS: Octreotide treatment stopped bleeding in 10 patients. A transient improvement was observed in four, who needed subsequent cyclical retreatment to correct low haemoglobin levels. No effect was observed in three, probably due to the severity of the concomitant disorders. CONCLUSIONS: Octreotide is a safe drug that may be useful to control the recurrent gastrointestinal bleeding due to acquired angiodysplasia and watermelon stomach, especially in patients who are not candidates for surgery due to old age and/or concomitant disorders.

Immunohistochemical detection of Helicobacter pylori vacuolating cytotoxin in the hepatocytes of patients with isolated hypertransaminasaemia.

BACKGROUND AND AIM: Even if different Helicobacter species can colonise animal livers and induce hepatitis, there is no evidence that Helicobacter pylori can damage this organ and only a potential capacity of cytotoxic strains to increase transaminases in humans has been suggested. We have, therefore, carried out an immunohistochemical study on vacuolating cytotoxin in the hepatocytes of subjects with isolated hypertransaminasaemia. PATIENTS, METHODS AND RESULTS: Five male patients with isolated hypertransaminasaemia without signs of known causes of liver diseases were studied. Endoscopy demonstrated diffuse mucosal hyperaemia in 3 patients and duodenal ulcer in one. Histology revealed active chronic pangastritis in all. Helicobacter pylori was assessed by histology and culture and its cytotoxity, demonstrated by positive immunoblotting for both anti-CagA and VacA. Percutaneous liver biopsy showed minimal changes. Hepatic and gastric sections were tested either with autologous serum and rabbit antibody to VacA toxin. Immune reaction was revealed by immunoperoxidase. Both autologous sera and anti-VacA toxin antibody showed a reaction with a similar pattern which involved 60% of hepatocytes. Anti-VacA toxin showed a reaction to gastric epithelial cells and autologous sera to parietal cells in 4/5 patients. All patients received triple therapy and eradication of Helicobacter pylori was assessed by urea breath test. Serum transaminase levels 3 months after eradication, are still abnormal. CONCLUSIONS: Our immunohistochemical findings suggest that vacuolating cytotoxin could reach the hepatocytes of patients suffering from both isolated hypertransaminasaemia and infection by cytotoxic strains of Helicobacter pylori. Nevertheless, a clear relationship between these two condition remains uncertain.

Autoantibodies reacting with gastric antigens in Helicobacter pylori associated body gastritis of dyspeptic children.

BACKGROUND: Helicobacter pylori induced antibodies reacting with fundal mucosa have been shown to be involved in the pathogenesis of chronic atrophic gastritis in adults. Furthermore, previous reports have indicated that Helicobacter pylori increases the risk of gastric carcinoma, suggesting that the bacterium plays a role in mucosal changes representing especially in adulthood important steps in the progression from gastritis to cancer. PATIENTS AND METHODS: We investigated 16 Helicobacter pylori+ children from a series of 53 dyspeptic patients. Diagnosis of Helicobacter pylori infection was based on the positivity of at least 3 of the following tests: serology, 13C-urea breath test, rapid urease test and histology. Autoreaction was detected by incubation of gastric body sections with autologous sera and revealed by immunohistochemistry. Positive sera were tested with samples of unaffected gastric body to exclude a link with residual bacterial antigens. Proliferating cell nuclear antigen immunohistostain was also performed to evaluate the epithelial proliferative state. RESULTS: Histologically 6 out of 16 Helicobacter pylori+ patients showed chronic pangastritis. In the remaining 10 Helicobacter pylori-related mucosal inflammation was confined to the antrum. All 6 subjects with pangastritis and 3 out of 10 with antral gastritis were anti-CagA+. The autoreaction was found in a 10-year old male child with Helicobacter pylori+ pangastritis and a clinical history of ulcer-like dyspepsia. Parietal cells, in particular, were involved and showed diffuse cytoplasm staining. Proliferating cell nuclear antigen expression demonstrated, only in this case, a zone of regeneration extending from the normal site in the neck towards the base of the glands. CONCLUSIONS: Our finding demonstrates that an autoreaction of gastric mucosa may be found in Helicobacter pylori gastritis of childhood. Its association with some known risk factors (i.e., cytotoxic strains and increased proliferation of gastric epithelium with a changed pattern) may play a role in the progression from gastritis to atrophy and account for the increased risk of late gastric cancer when Helicobacter pylori infection occurs in paediatric age.

Effect of Helicobacter pylori eradication on gastric epithelial proliferation. Relationship with ras oncogene p21 expression.

BACKGROUND: Impaired changes in gastric epithelium proliferation have been described in Helicobacter pylori infection, and a progressive increase of proliferating cells has been shown with the progression of mucosal lesions. AIMS: Purpose of this investigation was to study the effect of eradication on bacterium-induced proliferative changes, evaluated by the proliferating cell nuclear antigen labelling index (PCNA LI) and its relationship to the ras oncoprotein p21, involved in early events of gastric carcinogenesis. PATIENTS AND METHODS: This retrospective study was performed, before and after therapy, in five different groups of patients with progressive stages of Helicobacter pylori damage (N: normality; HG: histological gastritis with normal endoscopy; EHG: histological gastritis with endoscopic chronic erosions; CIM: complete intestinal metaplasia; IIM: incomplete intestinal metaplasia). RESULTS: Six months after eradication, a normalization of PCNA LI was observed in the areas of gastritis, but not in those of intestinal metaplasia, which showed on unchanged type. Moreover, immunohistochemical membrane expression of ras oncoprotein p21 was only associated to intestinal metaplasia. The protein was also expressed in the cytoplasm in 3 patients with incomplete type. CONCLUSIONS: These results suggest that the development of intestinal metaplasia may be associated with an alteration in the control of gastric epithelium proliferation and could represent an initial stage in gastric carcinogenesis. Nevertheless, further genetic changes are necessary for a complete progression to neoplastic disease. A long-term follow-up on extension, type, proliferative situation and oncoprotein expression in areas of intestinal metaplasia may be helpful to explain whether the present data provide new information on the mechanism of Helicobacter pylori induced gastric carcinogenesis.

Proliferative activity of gastric epithelium in progressive stages of Helicobacter pylori infection.

Helicobacter pylori (HP) infection is the main etiopathogenetic agent responsible for inflammatory and ulcerative changes in gastroduodenal mucosa and the basis for both intestinal and diffuse types of gastric carcinoma. In this latter case, intestinal metaplasia is the intermediary between gastritis and cancer. In this study we describe the proliferative activity of gastric epithelium in the progressive stages of HP infection. The expression of proliferating cell nuclear antigen (PCNA), which has proven to be a reliable method for this evaluation, was used as a marker. The study was performed on endoscopic biopsies of the gastric antrum of 40 patients, who were divided into five groups, eight in each group: normal histology and endoscopy, HP-; histological HP+ gastritis with normal endoscopy; histological HP+ gastritis with endoscopic evidence of chronic erosions; complete and incomplete intestinal metaplasia in a HP+ stomach. PCNA was detected by immunohistochemistry and expressed as labeling index, ie, percentage of positive nuclei either in the whole or upper third of foveolae. Our data show a progressive increase of epithelial proliferation in the successive stages of HP infection ranging from gastritis alone to the development of incomplete intestinal metaplasia, a well-known precancerous condition. The proliferative pattern tended to expand towards the upper foveolar third, which in normal conditions does not represent a site of epithelial renewal. These alterations may be related to the development of neoplastic transformations of gastric epithelium. It is well known that genetic mutations are facilitated in proliferating cells. Therefore, our results indicate that the high epithelial turnover, expressed by PCNA LI, may be an indicator of increased risk of neoplastic changes in long-standing untreated HP+ chronic gastritis.