Helicobacter pylori Infection and Gastric Autoimmune Diseases: Is There a Link?

Background. Helicobacter pylori is thought to be involved in atrophic body gastritis. We explored the prevalence of H. pylori infection in asymptomatic subjects with gastric parietal cell antibodies, as well as in patients with pernicious anemia, to evaluate a possible role of H. pylori gastric infection in gastric autoimmunity. Patients and Methods. We studied 79 consecutive asymptomatic subjects with parietal cell antibodies, 24 patients with pernicious anemia, and 66 parietal cell antibody‐negative controls. All patients underwent gastric biopsies for histology and detection of H. pylori. Red blood cell count and volume, serum levels of gastrin, pepsinogen I, iron, folic acid, vitamin B₁₂, and circulating antibodies to H. pylori and to intrinsic factor were also determined. Results. We found an atrophic body gastritis in 14 of the 79 asymptomatic subjects with parietal cell antibodies (18%) and in 2 of the 66 controls (3%) (p = .01). Mean levels of gastrin were increased (p < .0001), while those of pepsinogen were reduced (p < .001) compared with controls. H. pylori was identified at the gastric level and/or circulating anti‐H. pylori antibodies were detected in 46 parietal cell antibody‐positive subjects (58%) compared with 26 controls (39%) (p = .03). In patients with pernicious anemia we found an atrophic body gastritis in 18 of 24 cases (75%) (p < .001 vs. controls). Mean levels of gastrin were markedly increased (p < .0001) and those of pepsinogen I decreased (p < .0001) relative to controls. Only five of these patients (21%) had evidence of H. pylori infection compared with 46 of the parietal cell antibody‐positive subjects (58%) (p = .003) and 26 of the controls (39%). Considering all patients with gastric autoimmunity (i.e. with parietal cell antibodies and/or with pernicious anemia), H. pylori was found in 44 of 72 of those without atrophy (61%) but in 6 of 31 with gastric body atrophy (19%) (p < .001), indicating that H. pylori infection is greatly reduced when gastric acid secretion decreases. Conclusions. The frequent detection of H. pylori infection in subjects with early gastric autoimmunity, indicated by the presence of parietal cell antibodies, suggests that H. pylori could have a crucial role in the induction and/or the maintenance of autoimmunity at the gastric level.     

Is the Association Between Helicobacter pylori Infection and Anemia Age Dependent?

Background: The relationship between H. pylori infection and anemia in childhood is still unclear. The aim of the study was to examine the association between H. pylori infection and anemia or iron deficiency in school‐age children and in infants. Materials and Methods: Six‐ to 9‐ year‐old Israeli Arab children (N = 202) and infants (N = 197) were examined for hemoglobin and ferritin levels. ELISA was used to detect H. pylori antigens in stool specimens collected from the participants. Household characteristics were obtained through personal interviews with the mothers. Results: The prevalence of anemia was 15.5 versus 5.5% in H. pylori‐positive and ‐negative school‐age children, respectively and 34.5 versus 29.8% in H. pylori‐positive and ‐negative infants, respectively. The Mantel–Haenszel age‐adjusted prevalence ratio (PR) and 95% confidence intervals (CIs) were 1.6 (95%CI 1.0, 2.6). In multivariate analysis controlling for socioeconomic variables, H. pylori infection was associated with 2.8 higher prevalence of anemia only in school‐age children: adjusted PR 2.8 (95% CI 0.9, 9.3). The adjusted mean difference in hemoglobin levels between H. pylori infected school‐age children and uninfected ones was ?0.372 gr/dL (95% CI ?0.704, ?0.039) (p = .04). The respective mean ferritin difference was ?6.74 μg/L (95% CI ?13.38, ?.011) (p = .04). Such differences were not found in infants. Conclusions: H. pylori infection is associated with higher prevalence of anemia in school‐age children independently of socioeconomic variables. Such association was not observed in infants. These findings are of clinical and public health importance.     

Different Expression of Helicobacter pylori Gastritis in Children: Evidence for a Specific Pediatric Disease?

Background Infection with Helicobacter pylori causes active chronic gastritis. Once the infection is acquired, gastritis will persist for almost the rest of one's life. To date, very few data are available on H. pylori gastritis in relation to age. Therefore, we attempted to inestigate whether H. pylori gastritis in children exhibits features different from H. pylori gastritis in adults of two different age groups. Materials and Methods. Fifty consecutive children with a median age of 11 years (range, 3–18 years) were compared with two groups of 50 adult patients, one group with a median age of 43 (range, 19–56 years) and another group with a median age of 70 years (range, 59–86 years). All patients had H. pylori gastritis unrelated to active peptic ulcer disease. Two biopsy specimens were taken from the antrum and two from the corpus, and the following gastritis parameters were evaluated: degree and activity of gastritis, H. pylori colonization, replacement of foveolar epithelium by regenerative epithelium, mucous depletion, presence of atrophic gastritis with intestinal metaplasia, and presence of lymphoid follicles. Results. Degree and activity of gastritis, extent of H. pylori colonization, degree of replacement by regenerative epithelium, extent of mucous depletion, degree of atrophic gastritis with intestinal metaplasia, and the presence of lymphoid follicles in the antrum, as well as the presence of lymphoid follicles in the corpus differed significantly (chi-square test: p < .05). All these differences—except the once frequent occurrence of atrophic gastritis with intestinal metaplasia in adults—were attributable to a higher expression of these gastritis parameters in children. Conclusions. We conclude that H. pylori gastritis, particularly in the antrum, is more severely expressed in childhood. One reason for this might be a child-specific immune response to an infection with H. pylori. Alternatively, infection may represent a pediatric disease characterized by a nonatrophic, highly expressed form of gastritis, which changes its appearance once the host becomes adapted over time.     

Helicobacter pylori CagA Status,Mucosal Oxidative Damage and Gastritis Phenotype: A Potential Pathway to Cancer?

Background. Oxidative DNA damage is associated with Helicobacter pylori infection, atrophy and intestinal metaplasia. H. pylori‐cagA‐positive strains are associated with the highest risk of gastric cancer. Aims. To ascertain whether cagA‐positive H. pylori infection correlates with higher concentrations of 8OHdG and the presence of precancerous changes. Patients and Methods. 118 patients were studied (65M/53F, age 61 ± 14 years). Twelve were H. pylori‐negative. Among the H. pylori‐positive patients, 34 were cagA‐positive and 40 were cagA negative. In 32 patients H. pylori had been eradicated at least 6 months before endoscopic sampling. The phenotype of the gastritis (atrophic compared with nonatrophic, with and without intestinal metaplasia) was scored in biopsy samples obtained from the antrum, corpus, and angularis incisura. In antral biopsy samples, 8‐hydroxydeoxyguanosine was assessed by HPLC (electrochemical detector). CagA status was determined by PCR. Results. The highest scores for both mononuclear inflammation and activity of gastritis were significantly associated with cagA status (p = 0.036 antrum and p = 0.02 corpus). cagA‐positive infection significantly correlated with a higher prevalence of atrophic‐metaplastic lesions (p = 0.04). cagA‐positive patients had higher 8‐hydroxydeoxyguanosine levels than both cagA‐negative and H. pylori‐negative cases (p = 0.01). The 8‐hydroxydeoxyguanosine levels were significantly higher in multifocal atrophic gastritis (p = 0.04). The odds ratio for cagA‐positive patients having 8OHdG levels above a cut‐off calculated on the basis of the ROC curves were 7.12, overall, reaching 11.25 when only patients younger than 50 were considered. Conclusions. cagA‐positive patients were characterized: first, for higher scores for gastritis, activity and atrophic and metaplastic lesions; and second for greater oxidative DNA damage overall, at younger age and in the presence of multifocal atrophy. This setting may represent a cancer‐prone biological context.     

Oxidative Stress in Helicobacter pylori Infection: Does Supplementation with Vitamins C and E Increase the Eradication Rate?

Aim: This study aims to assess the antioxidant property of vitamins E and C in Helicobacter pylori infection, and to determine if adding them to standard triple therapy plus bismuth subcitrate increases the H. pylori eradication rate. Methods: This study included 160 patients infected with H. pylori, who were randomized into one of two groups. Patients in group A (n = 80) received lansoprazole (30 mg, b.i.d.), amoxicillin (1000 mg, b.i.d.), clarithromycin (500 mg, b.i.d.), and bismuth subcitrate (300 mg, q.i.d.) for 14 days, while patients in group B (n = 80) received vitamin C (500 mg, b.i.d.) and vitamin E (200 IU, b.i.d.) for 30 days, in addition to lansoprazole (30 mg, b.i.d.), amoxicillin (1000 mg, b.i.d.), clarithromycin (500 mg, b.i.d.), and bismuth subcitrate (300 mg, q.i.d.) for 14 days. Total antioxidant capacity (TAC) was evaluated with a Randox kit. Success rate was calculated using both intention‐to‐treat (ITT) and per‐protocol (PP) analyses. Results: One hundred and sixty patients were analyzed using ITT analysis. One hundred and fifty‐three patients completed the study. In group A, H. pylori eradication was achieved in 48 (60%) of the 80 patients included in the ITT analysis, and in 48 (64%) of the 75 patients included in the PP analysis. In group B, H. pylori eradication was achieved in 73 (91.25%) of the 80 included in the ITT analysis and in 73 (93.5%) of the 78 patients included in the PP analysis. The eradication rate was significantly higher in group B than in group A (p < .005). TAC was at the lower limit of normal in both groups and the difference between them was not statistically significant (p > .05). Conclusion: In group B, H. pylori eradication rate was 91.25%, which is higher than the ideal 80% eradication rate. The results of the present study show that adding the prescribed doses of vitamins E and C to antimicrobial therapy is effective in eradicating H. pylori infection.     

Helicobacter pylori and autoimmune pancreatitis: role of carbonic anhydrase via molecular mimicry?

Autoimmune pancreatitis is a recently defined nosological entity, which accounts for 4.6-6% of all forms of chronic pancreatitis and is often associated with other autoimmune diseases, particularly Sjogren's syndrome. Possession of the HLA DRB1*0405-DQB1*0401 genotype confers a risk for the development of autoimmune pancreatitis. Autoantibodies against carbonic anhydrase II and lactoferrin are frequently present in affected subjects and are suspected to have a pathogenic role. A link between gastric infection by Helicobacter pylori and autoimmune pancreatitis has been hypothesized. We used in silico protein analysis and search for HLA binding motifs to verify this hypothesis. We found a significant homology between human carbonic anhydrase II and alpha-carbonic anhydrase of Helicobacter pylori, an enzyme which is fundamental for the survival and proliferation of the bacterium in the gastric environment. Moreover, the homologous segments contain the binding motif of the HLA molecule DRB1*0405. Our data strengthen the hypothesis that gastric Helicobacter pylori infection can trigger autoimmune pancreatitis in genetically predisposed subjects.     

Helicobacter pylori vaccines and mechanisms of effective immunity: is mucus the key?

In this theoretical article, the hypothesis is proposed that immunization against gastric helicobacter infection is mediated by CD4+ T-cell induced changes in mucus production. Vaccine development for the gastric pathogen Helicobacter pylori has encountered several problems. Resolving these problems is impeded by our lack of understanding of the mechanisms by which the immune response influences bacterial colonization. Protective immunity requires CD4+ T cells, but the majority of helicobacters are located in the mucus of the gastric lumen, away from the epithelial surface. Evidence suggests that this mechanism functions independently of antibodies, so how this is achieved is unknown. Clues to this mechanism may be provided by immune clearance of nematode infection. Similar to H. pylori, expulsion of the intestinal nematode, Nippostrongylus brasiliensis, in rodents is mediated by CD4+ T-cell changes in the numbers of goblet cells and the type of mucins secreted into the gut. Immune-mediated changes in secretion of gastric mucins could similarly be responsible for the reductions in helicobacter colonization seen in immunized animals. Helicobacter pylori are highly motile bacteria that have evolved to inhabit their specialized niche. Alterations in their mucus environment could influence their motility, such that the bacteria cannot remain efficiently within the mucus and are flushed away.     

Lipid peroxidation in chronic gastritis; any influence of Helicobacter pylori?

In an attempt to investigate the significance of lipid peroxidation in the pathogenesis of gastritis associated with or without Helicobacter pylori infection, malonodialdehyde (MDA) levels were measured by the thiobarbiturate assay in the gastric juice of 101 patients undergoing upper GI endoscopy and correlated with histopathological findings. Elevated MDA levels were found in all patients with gastritis compared with controls. MDA levels were significantly correlated with the extent of the mucosal inflammation and with disease activity in patients with reactive gastritis. In patients with H. pylori associated gastritis MDA levels were not correlated with disease activity but rather with the degree of atrophy. In this case, MDA levels were equal or even less than in patients with reactive gastritis. MDA levels were not affected by the history of consumption of PPIs, of H(2)-blockers or of NSAIDs over the last month before the endoscopy. It is concluded that lipid peroxidation is a mechanism involved in the pathogenesis of gastritis associated or not to H. pylori infection.     

Helicobacter pylori‐Associated Chronic Gastritis and Unexplained Iron Deficiency Anemia: a Reliable Association?

Background and aim. About 35% of iron deficiency anemia cases remain unexplained after a gastrointestinal evaluation. An association between Helicobacter pylori and iron malabsorption has been suggested. The aim of this study was to determine whether H. pylori‐associated chronic gastritis is linked to unexplained iron deficiency anemia in adults. Methods. From 1996 to 2001, we identified 105 patients with unexplained iron deficiency anemia after upper endoscopy, colonoscopy, small bowel radiographic examination and duodenal biopsies. Two biopsies were obtained from the gastric antrum and two from the corpus of each patient. Gastritis status was described according to the Sydney System and H. pylori infection was assessed by an immunohistochemical test on biopsy specimens. This group was compared to a control group matched for sex and age. Results. There were 76 women and 29 men (mean age 57.4 ± 21.4 years) examined in the study. A H. pylori‐associated chronic gastritis was identified in 63 cases (60%) vs. 45 cases (43%) cases in the control group (p < .01). Atrophic gastritis was significantly associated with iron deficiency anemia compared with the control group [16 (15%) vs. 6 (6%); p < .03]. In the unexplained iron deficiency anemia group, (1) patients with chronic gastritis were significantly younger (52 ± 22 vs. 64 ± 20 years; p < .005), and (2) chronic gastritis was not linked to sex [sex ratio (male/female): 0.5 vs. 0.34, p = .34]. The prevalence of H. pylori infection was similar between premenopausal and postmenopausal women [28 (27%) vs. 26 (25%); p = .7] with iron deficiency anemia. Conclusion. H. pylori infection and chronic gastritis, especially atrophic gastritis, are significantly associated with unexplained iron deficiency anemia. Relationships between H. pylori‐associated chronic gastritis and unexplained iron deficiency anemia should be considered.     

Is Helicobacter pylori the cause of dyspepsia?

OBJECTIVE--To determine the association between infection with Helicobacter pylori and dyspepsia. DESIGN--Cross sectional study of dyspeptic subjects and age and sex matched controls identified by a questionnaire survey of all inhabitants aged 20-69. (Endoscopy, histological examination, and microbiological examinations of biopsies from the gastric mucosa were performed blind.) SETTING--Population based survey in Sørreisa, Norway. SUBJECTS--All 782 dyspeptic subjects (excluding those with a previous history of peptic ulcer, gall stones or kidney stones, and coronary heart disease) and controls were offered an endoscopy, of whom 309 dyspeptic subjects and 310 controls attended. MAIN OUTCOME MEASURES--Prevalences of endoscopic and histological diagnoses and of cultures positive for H pylori. RESULTS--A high prevalence of positive cultures, increasing with age, was found in both dyspeptic subjects (48%) and non-dyspeptic controls (36%) (p = 0.004). Positive cultures in both dyspeptic subjects and controls were strongly associated with histological gastritis (70%, 95% confidence interval 65.5 to 85.3; 60%, 52.7 to 67.7, respectively) and peptic ulcer (92%, 61.5 to 99.8; 64.1, 9.4 to 99.2, respectively). Only 3% of subjects with a histologically non-inflamed gastric mucosa had this infection (dyspeptic subjects 2%, 0.2 to 7.0; controls 4%; 1.2 to 8.8). CONCLUSIONS--The relation between dyspeptic symptoms and H pylori is dubious; H pylori seems to have a pathogenetic role in gastritis and may be a contributing factor but not a cause of peptic ulcer.     

A Curcumin‐Based 1‐Week Triple Therapy for Eradication of Helicobacter pylori Infection: Something to Learn From Failure?

BACKGROUND: Curcumin is the principal element of turmeric powder extracted from the root of Curcuma longa. Studies on curcumin have demonstrated some anti-Helicobacter pylori activity as well as immunomodulating properties. N-acetylcysteine and lactoferrin with their respective mucolytic and antibacterial activities might also be effective in H. pylori eradication therapy. AIM: To determine if a 7-day non-antibiotic therapy comprised of curcumin, lactoferrin, N-acetylcysteine, and pantoprazole was effective for eradication of H. pylori infection and reduction of gastric inflammation, assessed by serum pepsinogens and relief of symptoms. SUBJECTS AND METHODS: Twenty-five consecutive H. pylori-positive patients (12 males, mean age 50 +/- 12 years, range 31-76) with functional dyspepsia were enrolled. Patients were administered for 7 days curcumin 30 mg b.i.d., bovine lactoferrin 100 mg b.i.d., N-acetylcysteine 600 mg b.i.d., and pantoprazole 20 mg b.i.d. H. pylori status and upper gastrointestinal symptoms were assessed by (13)C-urea breath test and a scale of upper gastrointestinal symptoms intensity (absent, mild, moderate, and severe), as well as a blood test for serum pepsinogens (sPGI, sPGII), gastrin-17 (G-17), and anti-H. pylori IgG (IgG-Hp) at baseline (T0) and after 2 months (T1). RESULTS: Three of 25 patients (12%) were cured of H. pylori infection. A significant decrease in the overall severity of symptoms (T0: 6, interquartile range [IQR]: 4.5-8; T1: 2, IQR: 2-3; p < or = .001), and sPGII (T0: 16 microg/L, IQR: 13-22; T1: 10 microg/L, IQR: 8-16; p < or = .001) and sPGI (T0: 82 microg/L, IQR: 67-97; T1: 74 microg/L, IQR: 62-94; p = .02) levels were observed after 2 months of the treatment. IgG and G-17 values did not significantly decrease after 2 months. CONCLUSIONS: This novel therapy was not effective for H. pylori eradication. However, despite the bacterium persistence, significant improvement of dyspeptic symptoms and reduction of serologic signs of gastric inflammation were observed after 2 months at the end of the 7-day treatment schedule.     

Infection by Helicobacter pylori and acute myocardial infarction. Do cytotoxic strains make a difference?

The classical risk factors for acute myocardial infarction (AMI) fail to explain all the epidemiological variations of the disease. Among the risk factors recently reported, several infectious agents appear to increase the risk of AMI. Helicobacter pylori (H. pylori) infection, a bacterium involved in duodenal and gastric ulcer, gastric cancer and MALT-lymphoma, seems to be strongly associated with AMI. More virulent (anti-CagA positive) strains of the bacterium are almost exclusively the causative agents of such diseases. To determine the prevalence of H. pylori infection and of virulent strains, a case-control study was conducted in a group of male patients with AMI. A group of patients consecutively admitted to the Emergency Care Unit served as controls. We studied 223 consecutive male patients, mean age 60.2 (range 40-79) years, admitted for AMI to the Coronary Care Units at Hospitals in two towns of Northern Italy, 223 age matched male patients (mean age 61.8, range 40-79 years) admitted to the Emergency Care Unit, served as control. H. pylori seroprevalence was assessed by presence of antibodies (IgG) against H. pylori and anti-CagA in circulation. Among the patients we investigated the presence of hypertension, levels of cholesterol and glucose in serum, fibrinogen in plasma and smoking habits. H. pylori infection was present in 189/223 (84.7%) of the patients and in 138/223 (61.8%) of the control population (p < 0.0001 OR 3.42 [IC 95% 2.12-5.54]). The anti-CagA antibodies were detected in 33.8% of infected patients with AMI (64/189) versus 26.8% in the control subjects (37/138) (p:0.17, OR 1.40 [IC 95% 0.84-2.33]). Classical risk factors for AMI did not differ among patients with and without H. pylori infection. Patients admitted to the Coronary Care Unit for acute myocardial infarction had a notably higher prevalence of anti-H. pylori not restricted to virulent strains, when compared to a population of patients referred to the Emergency Care Unit. The classical risk factors for coronary disease were present in the patients with AMI irrespective of H. pylori status.     

Defining the Roles of IFN-γ and IL-17A in Inflammation and Protection against Helicobacter pylori Infection

CD4⁺ T cells have been shown to be essential for vaccine-induced protection against Helicobacter pylori infection. However, the effector mechanisms leading to reductions in the gastric bacterial loads of vaccinated mice remain unclear. We have investigated the function of IFN-γ and IL-17A for vaccine-induced protection and inflammation (gastritis) using IFN-γ-gene-knockout (IFN-γ^-/-) mice, after sublingual or intragastric immunization with H. pylori lysate antigens and cholera toxin. Bacteria were enumerated in the stomachs of mice and related to the gastritis score and cellular immune responses. We report that sublingually and intragastrically immunized IFN-γ^-/- mice had significantly reduced bacterial loads similar to immunized wild-type mice compared to respective unimmunized infection controls. The reduction in bacterial loads in sublingually and intragastrically immunized IFN-γ^-/- mice was associated with significantly higher levels of IL-17A in stomach extracts and lower gastritis scores compared with immunized wild-type mice. To study the role of IL-17A for vaccine-induced protection in sublingually immunized IFN-γ^-/- mice, IL-17A was neutralized in vivo at the time of infection. Remarkably, the neutralization of IL-17A in sublingually immunized IFN-γ^-/- mice completely abolished protection against H. pylori infection and the mild gastritis. In summary, our results suggest that IFN-γ responses in the stomach of sublingually immunized mice promote vaccine-induced gastritis, after infection with H. pylori but that IL-17A primarily functions to reduce the bacterial load.