Nodular gastritis and pathologic findings in children and young adults with Helicobacter pylori infection

PURPOSE: The aim of this study was to investigate the pathologic characteristics of nodular gastritis in children and young adults infected with Helicobacter pylori (H. pylori). MATERIALS AND METHODS: A total of 328 patients were enrolled in this study, and the diagnosis of H. pylori infection was done with gastroduodenal endoscopy concomitant with a CLO(TM) test and pathologic analysis of the biopsy specimens. Diagnoses of normal, superficial gastritis, nodular gastritis, and peptic ulcer disease were made from the gastroduodenal endoscopic findings. The density of H. pylori organisms in the gastric mucosa was rated as normal, mild, moderate, or marked. The pathologic findings of nodular gastritis were based on the histopathologic findings of inflammation, immune activity, glandular atrophy and intestinal metaplasia. Each of these findings was scored as either normal (0), mild (1), moderate (2), or marked (3) according to the updated Sydney system and using visual analog scales. The gastritis score was the sum of the four histopathologic scores. RESULTS: In this study, nodular gastritis (50.6%) was most common, and mild density (51.5%) H. pylori infection was also common upon microscopic examination. Intestinal metaplasia occurred in 9 patients (2.7%). CONCLUSION: Logistic regression revealed a significant increase in the incidence of nodular gastritis with gastritis score (p=0.008), but not an association with sex, age, or H. pylori density. Gastritis score was the only significant factor influencing the occurrence of nodular gastritis. Intestinal metaplasia, which was originally thought to be a pre-malignant lesion, occurred in 2.7% of the patients with H. pylori infection.     

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.     

Virulence factors of Spanish Helicobacter pylori isolates and correlation with gastritis or ulcer production

Objective: To study the cagA , vacA and iceA status of Helicobacter pylori clinical isolates obtained from adult patients suffering from peptic ulcer or gastritis in order to find if these virulence factors are useful in determining a strain to be a gastritis or ulcer producer.
Methods: One hundred and five H. pylori strains from patients with gastritis and ulcer were studied. Culture and identification was done by standard methodology. cagA, vacA and iceA detection was performed by PCRs previously described. Results were visualized by agarose gel electrophoresis.
Results: Amplified fragments of 297 bp ( cagA ), 259 bp ( vacA s1), 286 bp ( vacA s2) and 975 bp ( iceA ) were detected. cagA was detected in 83.3% and 91.3% of gastritis and ulcer strains respectively (p>0.05). s1 was detected in 57.1% of gastritis strains and 62.3% of ulcer strains (p>0.05). cagA was strongly related with the s1 allele. iceA was more prevalent in strains from gastritis (82.4% versus 66.7%). The combination of cagA, vacA and iceA was not correlated with the production of peptic ulcer disease.
Conclusions: These data suggest that the combination of cagA, vacA and iceA cannot be used to predict severe gastric disease in Spanish H. pylori clinical isolates.     

Production of IL-12 in gastritis relates to infection with Helicobacter pylori.

Increased production of proinflammatory cytokines, including tumour necrosis factor-alpha (TNF-alpha), IL-1beta, IL-6 and IL-8, has been demonstrated in Helicobacter pylori-associated gastric mucosal inflammation. IL-12, a newly characterized cytokine, is thought to be a key mediator in host responses to bacterial infections. The aim of this study was to investigate differences in cytokine patterns between H. pylori-positive and -negative gastritis and normal mucosa. Secretion of IL-12, TNF-alpha, IL-1beta, IL-6, IL-8 and IL-10 was measured in 176 patients with chronic gastritis in whole biopsy cultures. Gastritis was graded for chronic inflammation or acute inflammatory activity, respectively, according to the Sydney system. Biopsies with similar scores were matched for analysis from H. pylori-infected and non-infected patients. Secretion of IL-12 was significantly increased in H. pylori-associated gastritis in comparison with H. pylori-negative gastritis (P < 0.0001). In contrast, secretion of TNF-alpha, IL-1beta, IL-6, and IL-8 correlated with the degree of inflammation but was not different between H. pylori-positive and -negative patients. Moreover, IL-10 secretion was found to be higher in H. pylori-positive than in H. pylori-negative patients. IL-12 may play a specific role in H. pylori-associated gastric disease, whereas production of the proinflammatory cytokines TNF-alpha, IL-1beta, IL-6 and IL-8 does not seem to be restricted to H. pylori-induced inflammation. The contra-inflammatory cytokine IL-10 may be a contributor to the chronicity of H. pylori-associated gastritis by impairing clearance of the pathogen.     

Up-regulation of cathepsin X in Helicobacter pylori gastritis and gastric cancer

Recently, we identified increased cathepsin X expression in H. pylori-infected gastric mucosa. Here, we describe further up-regulation in gastric cancer and report on the role of inflammatory cytokines required for cathepsin X up-regulation in H. pylori-infected gastric mucosa, as well as on consequences for cellular invasion. Biopsy specimens were taken from the antrum, corpus and cardia of H. pylori-infected and non-infected patients. Gastric cancer samples were obtained from patients undergoing gastric surgery. Cathepsin X was detected in gastric mucosa by quantitative real-time RT-PCR, western blotting and immunohistochemistry. Induction of cathepsin X expression in epithelial and inflammatory cells caused by H. pylori infection was tested in in vitro contact and non-contact co-cultures of AGS cells and monocytic cells. Patients with H. pylori gastritis showed significantly higher cathepsin X mRNA (2.5-fold) and protein (1.6-fold) expression than H. pylori-negative patients. Cathepsin X was also up-regulated in gastric cancer (3-12-fold) compared to non-neoplastic mucosa. Cathepsin X was predominantly expressed by macrophages in the mucosal stroma and in glands of the antral mucosa. In addition, tumour cells stained for cathepsin X in 26 (68%) patients with gastric carcinoma. In general, staining was significantly more common (20 vs. 6 patients) and more intense (3.55 vs. 0.83) in intestinal type gastric cancer than in the diffuse type. In vitro cell culture experiments revealed that intercellular signalling between pathogenicity island (PAI)-positive H. pylori-infected epithelial cells and macrophages via soluble factors in the culture medium seems to be responsible for increased expression of cathepsin X in monocytes. Using antisense oligonucleotides, cathepsin X up-regulation was directly associated with higher invasiveness in vitro. Although no correlation of cathepsin X expression and TNM stage was found, our study demonstrates that cathepsin X plays a role not only in the chronic inflammation of gastric mucosa but also in the tumourigenesis of gastric cancer.     

Immune response to Helicobacter pylori and its association with the dynamics of chronic gastritis in the antrum and corpus

The aim of the study was to establish possible factors which play a role in progression of gastritis to atrophic gastritis in long-term follow-up among the Estonian population, to assess the association between the host immune response and different Helicobacter pylori antigens and autoantigens in relation to the histological parameters of gastritis in the antrum and corpus. ELISA and immunoblot were used for detection of IgG to H. pylori acid glycine-extracted cell surface proteins, CagA protein, and H. pylori HSP60. Anticanalicular autoantibodies (ACAB) in the serum were evaluated according to Faller et al. (1996). Apoptosis was evaluated using the TUNEL method. Study subjects were 1958 persons from an unselected Estonian population, and 70 persons from a sample from Saaremaa Island, who had been investigated over a period of 18 years. Seropositivity for CagA was a sign of gastritis activity [OR=14.8 (4.5-50.3)] and atrophy [OR=7.0 (2.1-23.1)] and might predict development of atrophy, particularly in the corpus [OR=7.1 (1.8-27.7)]. The prevalence of ACAB increased significantly with duration of H. pylori gastritis from 22% in 1985 to 46% in 1997 (p=0.004). Immune response to H. pylori HSP60 indicates chronic inflammation in the antrum (p=0.003). Apoptosis of gastric epithelial cells is largely dependent on grade of activity of gastritis, and, particularly in the antrum, on grade of H. pylori colonization (p=0.01; p=0.02), but is not associated with development of atrophy. Seropositivity for different H. pylori antigens (CagA, HSP 60) serves as a marker of different histological manifestations in the antrum and corpus mucosa.     

Histopathology of gastroduodenal inflammation: the impact of Helicobacter pylori

In this article the histological features of acute and chronic gastritis are reviewed. The histopathological gastric biopsy report can now encompass an aetiological, topographical (when antrum and corpus are sampled) and morphological comment on the gastric mucosa. The degree of detail included in the report (e.g. grading of the severity of inflammation, atrophy, density of Helicobacter pylori ) will vary according to local requirement. However, the distinct recognisable patterns of inflammation categorised in the Sydney system provide a common terminology for a succinct diagnosis. The overall condition of the patient's gastric mucosa assigns him/her to one of the H. pylori -positive or negative categories of chronic gastritis. This may not only have relevance to current clinical management, but may be a valuable record if the patient returns with dyspeptic symptoms in the future. For example, duodenal ulcers are unlikely to develop except in patients with antrum predominant H. pylori -associated gastritis. Knowledge of the natural history of different types of gastritis is rapidly evolving, and the biopsy provides a permanent 'snapshot' of the state of the gastric mucosa at the time of the endoscopy.     

Relationship of TT virus and Helicobacter pylori infections in gastric tissues of patients with gastritis

Blood and gastric tissue biopsies of 34 patients with gastritis were tested for the presence of TT virus (TTV), a ubiquitous virus found in the blood of most humans. Thirty-one of these patients were TTV positive, and 27 patients had virus in both tissues. In addition, 13 of the patients who had TTV in gastric tissue were Helicobacter pylori positive. There was an association of higher TTV titers in gastric tissues of patients who were H. pylori positive than in those in whom the bacterium could not be detected. Furthermore, this association was stronger in H. pylori-positive patients with the presence of the cagA protein. Of 10 specimens in which genogroup determination was carried out in the gastric corpus, 5/5 that were H. pylori positive showed the presence of TTV genogroup 3, while for those that were H. pylori negative, 5/5 showed the presence of genogroup 1t. By contrast, genogroup 1 was found in the corpus of only one H. pylori-positive patient, and genogroup 3 in only one H. pylori-negative patient. The histological severity of gastritis did correlate significantly with loads in the gastric tissues. There was no significant difference in TTV titer in blood of patients regardless of H. pylori infection status. These findings pique interest in clarifying the role of TTV, alone or in association with H. pylori infection, in the pathogenesis of gastritis.     

Immunostaining of antral gastrin cells is quantitatively increased in Helicobacter pylori gastritis

The amount of gastrin-like immunostaining in gastrin (G) cells of the antral mucosa was quantified using a computer-assisted method of measuring immunoreaction product. Biopsies from 25 patients without Heliobacter-like organisms and 60 patients with varying degrees of infection were immunostained for gastrin. Twenty-five G cells from each patient were measured both subjectively and by image analysis. Gastrin-like immunoreactivity was found to be significantly increased in the presence of Heliobacter-like organisms.     

The number of Helicobacter pylori CagA EPIYA C tyrosine phosphorylation motifs influences the pattern of gastritis and the development of gastric carcinoma

Ferreira R M, Machado J C, Leite M, Carneiro F & Figueiredo C
(2012) Histopathology  60, 992–998 The number of Helicobacter pylori CagA EPIYA C tyrosine phosphorylation motifs influences the pattern of gastritis and the development of gastric carcinoma Aims: To characterize the variation in virulence of Helicobacter pylori associated with CagA Glu‐Pro‐Ile‐Tyr‐Ala (EPIYA) motifs, and to explore its relationship with the histopathological features of chronic gastritis and with the development of gastric carcinoma. Methods and results: A total of 169 H. pylori‐infected patients with chronic gastritis and gastric carcinoma were studied. The presence of cagA and the number and type of EPIYA motifs were determined by polymerase chain reaction. Infection with strains harbouring two or more CagA EPIYA C motifs was associated with the presence of surface epithelial damage, and with atrophic gastritis and gastric carcinoma. The magnitude of risk for atrophic gastritis and gastric carcinoma increased with increasing number of EPIYA C motifs: strains with one EPIYA C motif conferred a risk (odds ratio [OR]) of 7.3 [95% confidence interval (CI) 2.1–25] for atrophic gastritis, whereas strains with two or more EPIYA C motifs conferred a risk (OR) of 12 (95% CI 2.5–58); strains with one EPIYA C motif conferred a risk (OR) of 17 (95% CI 5.4–55) for gastric carcinoma, whereas strains with two or more EPIYA C motifs conferred a risk (OR) of 51 (95% CI 13–198). Conclusions: Characterization of the number of H. pylori EPIYA C motifs is important in better defining gastric carcinoma risk.     

根除儿童口腔幽门螺杆菌预防胃内幽门螺杆菌感染的多中心研究

目的:探讨根除儿童口腔幽门螺杆菌（Hp）预防胃内Hp感染的可能性。方法:采用多中心前瞻随机研究,选取口腔Hp阳性但胃内Hp阴性的幼儿园儿童共计427例,随机分为使用“无幽梅”牙膏组与普通牙膏组,分别接受“无幽梅”牙膏和普通牙膏。疗程结束后,再次检测口腔Hp,将口腔Hp阳性及阴性患者各分为一组,1年后行C13呼气试验检查,分析两组患者胃内Hp感染情况。口腔Hp检测方法采用特异度及敏感度双高的套式PCR方法。结果:随访1年,口腔Hp阴性组胃内Hp感染率为0.51%,口腔Hp阳性组胃内Hp感染率为6.51%,两组统计差异具有显著性（P<0.01）。结论:儿童根除口腔Hp可以降低胃内Hp感染的发生。     

The chemokine receptor CCR7 is expressed on epithelium of non-inflamed gastric mucosa, Helicobacter pylori gastritis, gastric carcinoma and its precursor lesions and up-regulated by H. pylori

CCR7 chemokine-receptor expression on tumour cells of gastric carcinoma has been associated with lymph-node metastasis and is thought to play an important role in metastasis. However, so far it is unknown whether CCR7 is newly up-regulated on gastric carcinoma or already expressed in non-neoplastic gastric epithelium. Therefore, epithelial CCR7 expression was investigated in the process of gastric carcinogenesis: non-inflamed mucosa --Helicobacter pylori gastritis -- intestinal metaplasia/dysplasia -- gastric carcinoma. CCR7 was expressed by gastric epithelium in non-inflamed gastric mucosa (n = 5), H. pylori gastritis (n = 17), intestinal metaplasia (n = 10), dysplasia (n = 3) and on tumour cells in 20 of 24 patients with gastric carcinoma (13/14 intestinal-type; 7/10 diffuse-type) as tested by immunohistochemistry. As CCR7 expression by gastric epithelium was significantly stronger in H. pylori gastritis than in non-infected mucosa, the influence of H. pylori on CCR7 receptor expression of gastric epithelial cells was investigated by fluorescence activated cell sorter analysis. H. pylori strains up-regulated the CCR7 chemokine-receptor in CCR7-positive cell lines. No difference in CCR7 up-regulation between cag(+) and cag(-)H. pylori strains was found. Epithelial CCR7 up-regulation by H. pylori may alter the metastatic fate of gastric carcinoma. Additionally, CCR7 expression not only on gastric carcinoma, but also on non-neoplastic gastric epithelium, suggests a novel biological function.     

Severe gastritis in the Peruvian Andes

OBJECTIVE: To compare the Helicobacter pylori-associated pathology in gastric biopsies taken from patients living at sea level with those taken from patients living at high altitude. METHODS AND RESULTS: We included 38 patients from a hospital in the Andean city of La Oroya, Peru, located at 3700 m in altitude, and 40 control patients taken from Comas Clinic located in the city of Lima at sea level. Fibrepanendoscopy and multiple biopsies were performed in all the patients followed by histopathological examination. In the antrum, patients from the Andean town had a higher prevalence of glandular lymphoid adherence lesions, active germinal centres, moderate to severe chronic atrophic gastritis, intestinal metaplasia and moderate to severe total deep gland loss, than did patients from the coastal town. Furthermore, the severity of the histological lesions seen in the gastric body and cardia was significantly greater in the high-altitude patients than in those from sea level. CONCLUSION: This study suggests that the severity of H. pylori-associated gastric lesions seen on histopathological examination is greater in patients living at high altitude, the cause of which is most probably multifactorial but nonetheless principally altitude related.     

Five month persistence of Helicobacter pylori infection in guinea pigs

Seven Dunkin-Hartley guinea pigs were infected with the Sydney strain of H. pylori (SS1). Gastric histopathology was evaluated and serum antibody response to H. pylori cell-surface proteins was analysed by enzyme immunoassay (EIA) and immunoblot. Tissue and faecal samples from five control animals were analysed for the presence of naturally occurring Helicobacter spp. infection by culture and Helicobacter genus-specific PCR. The H. pylori infection persisted for 5 months, in most animals accompanied by a histologically severe antral gastritis, exhibiting focal degeneration and necrosis of gastric crypt epithelium. Increased numbers of mitotic figures were observed in the gastric epithelium, indicating a regenerative process. Infected animals displayed specific antibodies towards H. pylori cell-surface proteins in immunoblot, whereas EIA was of dubious value creating false-positive results. Serum complement C3 and cholesterol levels appeared to be elevated in infected animals. Helicobacter spp. infection was not detected in the control animals. The persistent infection, accompanied by severe gastritis and a prominent serum antibody response, and the apparent absence of a natural Helicobacter spp. infection makes the guinea pig model useful in H. pylori research.     

Helicobacter pylori and gastric adenocarcinoma

Gastric cancer is the second most common cause of cancer death worldwide. A large body of evidence supports a causal role of Helicobacter pylori in the majority of gastric malignancies. Great strides have been made in understanding the pathogenesis of this relationship, but much remains to be learned. Moreover, because of the high prevalence of infection, the lack of definitive trials, and the challenges of H. pylori treatment, there remains no consensus on the role of routine screening and treatment of this infection to prevent cancer. This article reviews the current knowledge on H. pylori and gastric cancer and presents some of the clinical and public health challenges associated with this pathogen.     

Interobserver variation in the classification of thymic tumours--a multicentre study using the WHO classification system

Aims:  To test the reproducibility of the current World Health Organization (WHO) classification of thymic epithelial tumours and to determine the level of interobserver variation within a group of pathologists, all with experience and expertise in thoracic pathology.
Methods and results:  Ninety-five thymic tumours were circulated to a group of 17 pathologists in the UK and The Netherlands over a 1-year period. Participants were asked to classify them according to WHO criteria. The diagnoses were subjected to statistical analysis and κ values calculated. The overall level of agreement was moderate (κ 0.45). When the categories were reduced in number by creating two groups, (A + AB + B1 + B2 and B3 + C), the level of agreement increased to 0.62. An alternative grouping (A + AB + B1 and B2 + B3 + C) increased it slightly further. The best agreement was in tumour types A and AB. Difficulties arose in distinguishing B1 tumours from B2 tumours and B2 tumours from B3 tumours.
Conclusions:  Although the WHO system describes a number of well-defined tumour types with clear diagnostic criteria, the overall level of agreement was moderate and improved if some groups were amalgamated.     

Assessment of different methods for staining Helicobacter pylori in endoscopic gastric biopsies

The recent implication of Helicobacter pylori in the pathogenesis of gastritis-peptic ulcer syndrome and its relevance for the development of upper gastrointestinal malignancy warrant efficient methods for the detection and demonstration of the organism in biopsy specimens. We have compared 5 staining methods, namely, haematoxylin and eosin (H & E), immunohistochemistry (IHC), the silver staining HpSS, the alcian yellow-toluidine blue (Leung) method (A-Y) and Genta staining, for the demonstration of the organism in gastric biopsies taken from antrum, body and fundus of 118 patients who presented to our hospital with upper gastrointestinal symptoms. We found no significant differences in the efficacy of H & E, IHC, HpSS and A-Y in the demonstration of H. pylori in all 3 gastric sites. The least reproducible stain in our hands was the Genta stain. We conclude that H & E is adequate for the initial assessment of gastric biopsies in symptomatic upper gastrointestinal patients. This is because it is a well-tested, cheap and easy staining method, requiring a relatively short period of time to perform, with highly reproducible results. It has an added advantage of enabling simultaneous assessment of morphological changes accompanying H. pylori infection. When the density of the organism is expected to be low, we recommend addition of HpSS staining because of its high sensitivity and low cost. The disadvantages of the other staining methods (IHC, A-Y and Genta) are discussed.     

Quantitative assessment of histological changes in chronic gastritis after eradication of Helicobacter pylori.

AIMS: To evaluate the effect of 10 day triple treatment on H pylori eradication and associated gastritis. METHODS: Fifty patients with H pylori positive non-ulcer dyspepsia were treated for 10 days with amoxicillin, tinidazole, and bismuth salts. Histological examination of the antral mucosa was performed before (T0), six weeks (T1), and six months (T2) after treatment. The new Sydney classification of gastritis was used, using a score from 0 to 3 to grade degree of inflammation, atrophy, activity (intraepithelial or lamina propria damage) and H pylori. RESULTS: At T0 all patients had chronic active gastritis. Lymphoid follicules were present in 12 cases. At T1 33 patients were H pylori negative: the score showed a decrease of activity (from 2.5 to 0.54). The result was confirmed at T2 (mean score 0.22). Inflammation decreased from 1.8 to 1.4 at T2. Only one case of follicular gastritis was observed. In H pylori positive patients the scores did not show significant modifications. CONCLUSIONS: Ten day triple treatment is effective in eradicating H pylori in 69% of cases, causing a decrease of the total score for gastritis. Activity, defined by polymorph infiltration, was promptly reduced when H pylori was eradicated. There was a trend to a reduction in inflammation, but atrophy was irreversible.