Review article: Helicobacter pylori and NSAID gastropathy

Non-steroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori are known to share a number of pathogenic mechanisms, but there is no evidence to show a significant synergic action between the two risk factors. Studies assessing this subject have differed in almost every aspect of their methodology, including the definition of a NSAID user as well as the types, doses, duration and their indications for NSAID use. They also differed in their end-points, the definition of dyspepsia and the regimes used for eradication of H. pylori. However, some conclusions may be drawn from the results of clinical trials. In H. pylori-positive patients without mucosal lesions, NSAIDs may aggravate dyspeptic symptoms but, with the exception of elderly patients, they do not present a definite major risk of gastric and duodenal lesions and, above all, of ulcer-correlated complications. So what recommendations can be made with regard to H. pylori eradication in patients requiring treatment with NSAIDs? The microorganism and the anti-inflammatory drugs are undoubtely independent causes of gastric and duodenal damage. Patients taking NSAIDs who are found to have gastric or duodenal ulcers should therefore be tested for the bacterium and specifically treated, since H. pylori and NSAID-induced ulcers may be macroscopically indistinguishable. Whether asymptomatic patients taking NSAIDs should be tested and treated for H. pylori infection is still a matter of debate.     

Helicobacter pylori, parietal cell antibodies and autoimmune gastropathy in type 1 diabetes mellitus

BACKGROUND: Fifteen to 20% of type 1 diabetic patients exhibit parietal cell antibodies (PCA), which are associated with autoimmune gastritis, hypochlorhydria, iron deficiency and pernicious anaemia. AIM: To examine whether Helicobacter pylori infection could explain the high prevalence of PCA and autoimmune gastropathy in diabetes. If so, H. pylori eradication could prevent autoimmune gastritis. METHODS: In 229 type 1 diabetics (M/F: 135/94; age: 41 +/- 12 years) PCA were measured. H. pylori infection was assessed by serology, urea breath test in all and by histology (updated Sydney system) in 88 subjects. Pentagastrin tests were performed in 42 patients. RESULTS: Sixty-nine patients were PCA-positive. H. pylori infection was present in 72 patients and was negatively associated with HLA-DQA1*0103-B1*0603 (OR=0.12, P=0.015) and positively with DQA1*0501-B1*0201 (OR=1.9, P=0.032). PCA-positivity was linked to HLA-DQA1*0501-B1*0301 (OR=3.9, P=0.017). A link between H. pylori and PCA was observed when PCA-positivity was defined as a titre > or = 1/20 (OR=2.0, P=0.03), but not if > or =1/40 was the cut-off point. PCA-positivity, but not H. pylori infection, was associated with iron deficiency anaemia (OR=2.7, P=0.008), pernicious anaemia (OR= 33.5, P < 0.0001), hypochlorhydria (OR=12.1, P=0.0008) and autoimmune gastritis (OR=12.5, P < 0.0001). CONCLUSIONS: The HLA-bound susceptibility of H. pylori and PCA differed. PCA-positivity but not ongoing H. pylori infection is associated with autoimmune gastritis. Low titres of PCA might reflect H. pylori infection rather than autoimmune gastropathy.     

Helicobacter pylori screening for individuals requiring chronic NSAID therapy: a decision analysis

INTRODUCTION: Although it is incontrovertible that Helicobacter pylori causes peptic ulcer disease, controversy persists regarding the impact of H. pylori infection on the incidence of NSAID-related complications and whether H. pylori eradication reduces the rate of adverse events. METHODS: A symptom-driven decision analytic model was developed to compare the clinical and economic impact of H. pylori screening compared to a strategy of no H. pylori testing for individuals requiring chronic NSAID therapy. In the principal analysis, it was assumed that untreated H. pylori infection increased the ulcer risk by 50% and that successful eradication reduced the risk of adverse events to that of uninfected patients. Patients' ulcer risk and the protective effect of H. pylori eradication were evaluated using sensitivity analysis. RESULTS: When compared to no H. pylori testing, H. pylori screening led to fewer symptomatic ulcers (no test, 5.4; H. pylori test, 4.6 per 100 patient years) and ulcer complications (no test, 2.6; H. pylori test, 2.3 per 100 patient years) and a higher cost per patient (no test, $435; H. pylori test, $556). The incremental cost attributable to the H. pylori screening strategy to prevent a symptomatic and complicated ulcer was $16,805 and $31,842, respectively. The clinical and cost-effectiveness advantage of H. pylori screening improved as patients' ulcer risk increased or the protective effect of H. pylori eradication was enhanced. CONCLUSIONS: Based upon the available evidence, H. pylori screening has the potential to reduce NSAID-related adverse events for average-risk patients at an incremental cost. Until controlled investigations definitively quantify the effect of H. pylori eradication on clinically significant NSAID-related adverse events, a compelling argument can be made for H. pylori testing for chronic NSAID users at increased risk of ulcer disease.     

NSAID gastropathy and enteropathy: distinct pathogenesis likely necessitates distinct prevention strategies

The mechanisms underlying the ability of nonsteroidal anti-inflammatory drugs (NSAIDs) to cause ulceration in the stomach and proximal duodenum are well understood, and this injury can largely be prevented through suppression of gastric acid secretion (mainly with proton pump inhibitors). In contrast, the pathogenesis of small intestinal injury induced by NSAIDs is less well understood, involving more complex mechanisms than those in the stomach and proximal duodenum. There is clear evidence for important contributions to NSAID enteropathy of enteric bacteria, bile and enterohepatic recirculation of the NSAID. There is no evidence that suppression of gastric acid secretion will reduce the incidence or severity of NSAID enteropathy. Indeed, clinical data suggest little, if any, benefit. Animal studies suggest a significant exacerbation of NSAID enteropathy when proton pump inhibitors are co-administered with the NSAID. This worsening of damage appears to be linked to changes in the number and types of bacteria in the small intestine during proton pump inhibitor therapy. The distinct mechanisms of NSAID-induced injury in the stomach/proximal duodenum versus the more distal small intestine likely dictate distinct strategies for prevention.     

NSAID gastropathy: prevention by celery seed extracts in disease-stressed rats

Previous studies showed that some anti-inflammatory celery seed extracts (CSEs) were not gastrotoxic, in contrast to many OTC NSAIDs, when dosed to arthritic rats. The present investigation was designed to quantify the potential activity of CSEs against NSAID injury in rats with severe acute or chronic inflammation and to define the possible relationship of this to effects on mucosal prostaglandin production. Oral doses of alcoholic (A-CSE) (150-300 mg/kg) and supercritical fluid (S-CSE)(20-50 mg/kg) extracts of seeds of wild celery Apium graveolens from north India (Beagle Int. Nerang, Qld.) profoundly suppressed gastric injury elicited in disease-stressed female rats (Wistar, DA) with (a) chronic arthritic inflammation or (b) severe acute inflammation (from oleyl alcohol, 0.1 ml in tail base), fasted overnight and then dosed either (i) orally with ibuprofen (50 mg/kg), sodium naproxen (27.5 mg/kg), ketoprofen (5 mg/kg) or acidic ethanol (150 mg/kg); or (ii) parenterally with piroxicam (5 mg/kg) or nabumetone (100 mg/kg). By contrast several conventional gastroprotectants, e.g. sucralfate, cimetidine, bismuth salts, all given orally were ineffective in preventing gastric injury from parenteral piroxicam. Gastroprotection by CSEs was not over-ridden by co-dosing with isotonic HCl. Most other celery seed 'oils' were ineffective in these assays. A-CSE was found to have marked inhibitory effects on PGE₂ production by porcine gastric (fundic) mucosal explants in organ culture. Quercetin and mycrecetin which are reported components of some CSEs also inhibited PGE₂ production in concentrations of 10 _M, whereas limonene, another reported component of CSEs had little effect at the same concentration. These results suggest that gastroprotective effects of CSEs are probably mediated through non-prostaglandin mechanisms.     

Meta-analysis: role of Helicobacter pylori eradication in the prevention of peptic ulcer in NSAID users

Aim : To evaluate whether eradication of Helicobacter pylori prevents peptic ulcer in non‐steroidal anti‐inflammatory drug users by means of a meta‐analysis. Material and methods : A systematic search was performed in MEDLINE, EMBASE, the Cochrane Controlled Trials Register and the AGA congress. Randomized trials comparing H. pylori eradication vs. non‐eradication or eradication vs. a proton pump inhibitor in patients receiving a non‐steroidal anti‐inflammatory drug were selected. Results : Five studies and 939 patients were included in the analysis; 34 of 459 (7.4%) patients developed a peptic ulcer in the eradicated group vs. 64 of 480 (13.3%) in the control group. The odds ratio was 0.43 (95% confidence interval: 0.20–0.93). Sub‐analyses showed a significant reduction of risk for non‐steroidal anti‐inflammatory drug‐naive (odds ratio = 0.26; 95% confidence interval: 0.14–0.49) but not for previously treated patients (odds ratio = 0.95, 95% confidence interval: 0.53–1.72). Two studies with a total of 385 patients compared eradication vs. a proton pump inhibitor; five of 196 (2.6%) developed a peptic ulcer in the eradicated group vs. zero of 189 (0%) in the proton pump inhibitor group (odds ratio = 7.43; 95% confidence interval: 1.27–43.6). Conclusion : Helicobacter pylori eradication reduces the incidence of peptic ulcer in the overall population receiving non‐steroidal anti‐inflammatory drugs. It appears to be especially effective when performed in non‐steroidal anti‐inflammatory drug‐naïve patients. Nonetheless, eradication seems less effective than treatment with a maintenance proton pump inhibitor for preventing non‐steroidal anti‐inflammatory drug‐associated ulcers.     

两种三联疗法治疗幽门螺旋杆菌相关性胃病的疗效分析

目的评价两种三联疗法治疗幽门螺杆菌相关性胃病的疗效。方法136例幽门螺旋杆菌相关性胃病患者,其中消化性溃疡85例、慢性胃炎51例。消化性溃疡患者随机分为奥美拉唑组（42例）和枸橼酸铋钾组（43例）,慢性胃炎患者随机分为奥美拉唑组（26例）和枸橼酸铋钾组（25例）。消化性溃疡患者给予三联治疗1周后分别予奥美拉唑和枸橼酸铋钾治疗6周、慢性胃炎给予三联治疗1周,疗程结束4周后复查胃镜,观察幽门螺杆菌（HP）根除率、溃疡愈合率。结果消化性溃疡患者奥美拉唑组与枸橼酸铋钾组HP根除率分别为95.2%和93.0%,差异无显著性（P〉0.05）;溃疡愈合率分别为95.2%和48.8%,差异有显著性（P〈0.01）;胃炎患者奥美拉唑组与枸橼酸铋钾组幽门螺旋杆菌根除率分别为92.3%和88.0%（P〉0.05）。结论奥美拉唑方案治疗HP阳性的消化性溃疡疗效显著,枸橼酸铋钾方案治疗HP阳性胃炎疗效肯定而价廉。     

Helicobacter pylori and inflammation

Helicobacter pylori is a spiral-shaped, flagellated, microaerophilic Gram-negative bacillus which colonizes the gastric mucosa of more than 50% of human population. The chronic infection generates a state of inflammation, which however is asymptomatic in the majority of the subjects. Nevertheless, in a subset of the H. pylori-infected population, the gastric inflammation may evolve toward chronic gastritis, peptic ulcer, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer. In brief, the stages of the H. pylori colonization are the following: crossing of the gastric mucus layer, adhesion to the gastric epithelium, and then obtaining nutrients while avoiding to be defeated by the host immune response. For some H. pylori colonization/virulence factors a specific role has been suggested in the development of the inflammation and in the impact on the host immune system. On the other hand, some host's factors have been found relevant in originating chronic gastric inflammation and the subsequent pathological outcome in the presence of H. pylori infection. In other words, both bacterial action and host response contribute to the pathogenesis. The host-pathogen co-adaptation resulted in a H. pylori colonization that in most of the cases might remain harmless; however, the concomitance of particular genotypes of both pathogen and host may concur to the development of severe pathology. Although a large body of clinical and experimental observations have been provided since the discovery of H. pylori, a further knowledge of the mechanisms of host-pathogen interaction and of those that lead to achieve protective immunity against this pathogen is still necessary to guide and make efficacious the fight against H. pylori.     

Helicobacter pylori and gastric adenocarcinoma

Gastric adenocarcinoma is still the second most common cause of death from cancer, even though it is on the decline in developed countries. Although H. pylori gastritis appears to be a necessary antecedent to the development of gastric adenocarcinoma, it is not a sufficient factor in and of itself. Other required factors for the progression of this disease are poorly understood. Patients with antral predominant gastritis seem protected from the disease, while patients with pangastritis are predisposed to both diffuse- and intestinal-type adenocarcinoma. Development of a vaccine against H. pylori might yield promising results in decreasing the incidence of gastric adenocarcinoma.     

Helicobacter pylori and nonulcer dyspepsia

Although up to 50% of patients diagnosed with nonulcer dyspepsia (NUD) have Helicobacter pylori infection and underlying chronic gastritis, it remains controversial whether any causal relationship exists. The results of worldwide epidemiological studies have been unconvincing. No clear-cut link has been documented between H. pylori and any specific symptom profile or pathophysiological mechanism in NUD. In the randomized controlled trials, methodological weaknesses may explain in part the conflicting results, but even in the well-conducted trials controversy persists. Although meta-analyses have attempted to resolve the issue, inherent methodological difficulties with meta-analysis remain a problem. Moreover, even the methodologically sound meta-analyses have reported conflicting results. In addition, predictors of treatment response remain obscure, and there continue to be theoretical concerns about the treatment of H. pylori infection in all patients with NUD. Hence, the management of these patients is challenging, but eradication of H. pylori infection may be beneficial in a small subgroup of cases with NUD that cannot be identified before treatment.     

Helicobacter pylori and uninvestigated dyspepsia

Although dyspepsia is a very common disorder, the incidence of Helicobacter pylori infection in Western medical clinics is very low (20–35%). In cases where H. pylori is detected, elimination of it may be cost-effective in the long term, but even eradication is not a guarantee for long-term relief. Further studies to determine the connection between H. pylori and dyspepsia need to be completed before H. pylori eradication becomes the treatment of choice for that minority of patients. The majority of dyspeptic patients are not as simple to diagnose, and may need several empirical trials of therapy, or more specific diagnostic assessment.     

Gastric cancer and Helicobacter pylori

Gastric cancer is the second commonest cause of death from malignancy in the world. Its pathogenesis is comparatively well understood and its aetiology multifactorial. Non-cardia gastric cancer usually arises in a stomach that has been inflamed over a long period and where atrophy and intestinal metaplasia have supervened. The commonest cause of gastric inflammation is infection with Helicobacter pylori. Colonization with this organism increases the relative risk of developing this cancer by about six [ Helicobacter and Cancer Collaborative Group. Gut 2001; 49: 347–53]. Its likelihood increases with the severity and extent of the gastritis. Severity is influenced by the virulence of the infecting organism, the genetics of the host, bile reflux, dietary factors and the presence of hypochlorhydria which influences the extent, as well as the severity, of the inflammation. The only predisposing factor which can easily be manipulated is H. pylori infection, which can be successfully treated in 80–90% of cases using a 1-week therapeutic regimen.     

Helicobacter pylori infection is a protective factor for bleeding gastric ulcers but not for bleeding duodenal ulcers in NSAID users

BACKGROUND: The effect of Helicobacter pylori infection on NSAID-induced gastroduodenal damage is unclear. AIM: To determine the role of H. pylori and NSAID use in complicated peptic ulcers. METHODS: A total of 185 consecutive patients with bleeding peptic ulcers and 185 hospitalized matched controls were studied prospectively. Additionally, 75 consecutive uncomplicated peptic ulcers and 75 community controls were also studied. Active H. pylori infection was determined by urea breath test and/or both urease test and histology. Serum CagA and VacA status were determined at random in 135 infected patients and 82 controls. NSAID use was determined by structured data collection. RESULTS: H. pylori (odds ratio [OR]=5. 98; 2.9-12.3) and NSAID use (OR=5.74; 3.4-9.7) were independent risk factors for duodenal ulcer bleeding, whereas NSAID use was the main risk factor for bleeding gastric ulcers (OR=12.4; 5.5-27.9). Interaction of both factors was associated with reduced risk for bleeding gastric ulcers (OR=0.19; 0.04-0.88) but not for bleeding duodenal ulcers, which showed a similar risk to any one factor alone. This was observed for all types of NSAID use, including low-dose aspirin, and infection by CagA positive strains. H. pylori was the only factor involved in common uncomplicated duodenal ulcers. CONCLUSION: Interaction of both H. pylori infection and NSAID use decreases the risk of bleeding due to gastric ulcers, but not that due to duodenal ulcers.     

Treatment of Helicobacter pylori

Recognition in the last 12 years that H. pylori is a common infection which causes the majority of peptic ulcers and many gastric cancers has revolutionised understanding of these diseases. However, genuinely novel treatments have in the main not yet emerged. Eradication of H. pylori is difficult because of the problems of delivering bactericidal levels of antibiotics to the gastric mucus where the organism resides, because of the emergence of resistance to nitroimidazoles and clarithromycin, and possibly because H. pylori can assume a resting coccoid form which is not susceptible to antibiotic treatment. To date, eradication treatment has been based upon the use of existing antibiotics employed in intensive multi-drug regimes of three basic types. Bismuth-based triple therapy employed ampicillin or a nitroimidazole, tetracycline and bismuth and achieved eradication rates of approximately 80%. Dual therapy in which amoxycillin was added to omeprazole was briefly popular because of its greater simplicity but fell from favour when it was realised that eradication rates were considerably lower. However, the recognition that proton pump inhibitors enhance eradication by either direct or indirect mechanisms led to the development of what is currently the most effective treatment - proton pump-based triple therapy in which a nitroimidazole or amoxycillin is combined with a proton pump inhibitor and clarithromycin. Such regimes achieve approximately 90% eradication. So far, the only therapy specifically developed for the treatment of H. pylori is ranitidine bismuth citrate (Pylorid). This new chemical entity based on ranitidine and bismuth citrate uses the antibacterial effects of bismuth to kill H. pylori but requires co-administration of another antibiotic to achieve reasonable eradication rates. In the future, further novel, specific anti-Helicobacter treatment can be expected, as a result of strategies targeted at key virulence factors or metabolic pathways such as the organism's urease, adhesin, cytotoxin, oxidase or nitro reductase activities. Some of these strategies will involve vaccination. Other possible approaches include targeting the coccoid form, achieving single treatment eradication and more effective gastric mucus delivery systems.     

幽门螺杆菌粪便抗原用于幽门螺杆菌感染检验观察

目的分析幽门螺杆菌粪便抗原（HpSA）对幽门螺杆菌感染的诊断价值。方法收集304例患者粪便标本,运用ELISA法定性检测HpSA,同时对照用快速尿素酶试验、Gram染色镜检联合检测的胃黏膜标本。结果HpSA的敏感度为96．7％（240／249）,特异度为90．1％（44／49）,阳性预测值为96．4％（240／249）,阴性预测值为80．0％（44／55）,准确率为93．4％（284／304）。结论粪便HpSA检测具有操作简便、省时等特点,是较理想的非侵人性的Hp诊断方法。