Review article: 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.     

Review article: 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.     

Review article: the control of gastric acid and Helicobacter pylori eradication

This review focuses on the gastric acid pump as a therapeutic target for the control of acid secretion in peptic ulcer and gastro-oesophageal reflux disease. The mechanism of the proton pump inhibitors is discussed as well as their clinical use. The biology of Helicobacter pylori as a gastric denizen is then discussed, with special regard to its mechanisms of acid resistance. Here the properties of the products of the urease gene clusters, ureA, B and ureI, E, F, G and H are explored in order to explain the unique location of this pathogen. The dominant requirement for acid resistance is the presence of a proton gated urea transporter, UreI, which increases access of gastric juice urea to the intrabacterial urease 300-fold. This enables rapid and continuous buffering of the bacterial periplasm to approximately pH 6.0, allowing acid resistance and growth at acidic pH in the presence of 1 mM urea. A hypothesis for the basis of combination therapy for eradication is also presented.     

Review article: Helicobacter pylori and gastric cancer--the clinicians'point of view

Although the incidence of gastric cancer has declined dramatically in Western countries, the most recent data from the International Agency for Research on Cancer show that it remains the second most common cancer worldwide and caused 628 000 deaths in 1990. The incidence and prevalence of gastric cancer are projected to increase over the next few decades in less developed countries as a result of the increased longevity of H. pylori-infected populations and improved therapies. Gastric carcinogenesis is a multistep and multifactorial process beginning with H. pylori-associated gastritis in most cases. H. pylori infection, together with other environmental factors and individual susceptibility, determine the final risk for the development of gastric cancer. The magnitude of H. pylori infection as a risk factor for gastric cancer in the published H. pylori and gastric cancer epidemiology studies may have been underestimated due to the inclusion of improperly selected controls. Eradication of the infection has been shown to prevent the occurrence of metachronous gastric cancer following endoscopic resection of early gastric cancer in a Japanese study. However, the generalization of this study to other populations is difficult because of the vast differences in the definition of gastric atrophy and early gastric cancer between Japanese and Western pathologists. Until an international consensus on the pathological diagnosis of gastric atrophy and early gastric cancer is reached, interpretation of studies performed in different countries remains difficult. Clinicians rely on the correct pathological diagnosis to guide the management of H. pylori infection-associated gastrointestinal diseases.     

Review article: recent advances in the management of bleeding gastric varices

Gastric variceal bleeding can be challenging to the clinician. Tissue adhesives can control acute bleeding in over 80%, with rebleeding rates of 20-30%, and should be first-line therapy where available. Endoscopic ultrasound can assist in better eradication of varices. The potential risks of damage to equipment and embolic phenomena can be minimized with careful attention to technique. Variceal band ligation is an alternative to tissue adhesives for the management of acute bleeding, but not for secondary prevention due to a higher rate of rebleeding. Endoscopic therapy with human thrombin appears promising, with initial haemostasis rates typically over 90%. The lack of controlled studies for thrombin prevents universal recommendation outside of clinical trials. Balloon occluded retrograde transvenous obliteration is a recent technique for patients with gastrorenal shunts, although its use is limited to clinical trials. Transjugular intrahepatic portosystemic stent shunt is an option for refractory bleeding and secondary prophylaxis, with uncontrolled studies demonstrating initial haemostasis obtained in over 90%, and rebleeding rates of 15-30%. Non-cardioselective beta-blockers are an alternative to transjugular intrahepatic portosystemic stent shunt for secondary prophylaxis, although the evidence is limited. Shunt surgery should be considered in well-compensated patients. Splenectomy or embolization is an option in patients with segmental portal hypertension.     

Review article: Pathogenesis and management of gastric carcinoid tumours

BACKGROUND: Gastric carcinoid tumours are rare, but are increasing in incidence. AIM: To discuss tumour pathogenesis and outline current approaches to patient management. METHODS: Review of published articles following a Pubmed search. RESULTS: Although interest in gastric carcinoids has increased since it was recognized that they are associated with achlorhydria, to date there is no definite evidence that humans taking long-term acid suppressing medication are at increased risk. Type I tumours are associated with autoimmune atrophic gastritis and hypergastrinaemia, type II are associated with Zollinger-Ellison syndrome, multiple endocrine neoplasia-1 and hypergastrinaemia and sporadic type III carcinoids are gastrin-independent and carry the worst prognosis. Careful investigation of these patients is required, particularly to identify the tumour type, the source of hypergastrinaemia and the presence of metastases. Treatment can be directed at the source of hypergastrinaemia if type I or II tumours are still gastrin responsive and not growing autonomously. Type III tumours should be treated surgically. CONCLUSIONS: Advances in our understanding of the pathogenesis of gastric carcinoids have led to recent improvements in investigation and management. Challenges remain in identifying the genetic and environmental factors, in addition to hypergastrinaemia, that are responsible for tumour development in susceptible patients.     

Apoptosis and proliferation in Helicobacter pylori-associated gastric intestinal metaplasia

BACKGROUND: Imbalance between apoptosis and proliferation may be one of the mechanisms underlying H. pylori associated gastric carcinogenesis. AIM: To examine the cell kinetics of gastric intestinal metaplasia and the effect of H. pylori eradication. METHODS: Endoscopic gastric biopsies were obtained from 100 H. pylori-infected patients. Apoptosis was determined by triphosphate nick-end labelling (TUNEL) and apoptotic nuclei counting, whereas proliferation was assessed by Ki67 immunostaining. Gastric biopsies were repeated in a sub-group of intestinal metaplasia patients after H. pylori eradication. RESULTS: Antral apoptotic index was significantly lower in intestinal metaplasia than in non-intestinal metaplasia (0.19% vs. 0.51%; P < 0.0001) whereas the level of proliferation was comparable (28% vs. 22%, P=0.15). Serial antral biopsies taken from 14 intestinal metaplasia patients before and 1 year after H. pylori eradication showed a significant drop in proliferation in both intestinal metaplasia (50% vs. 12%, P < 0.001) and non-intestinal metaplasia area (47% vs. 9%, P < 0.001). A similar fall in apoptosis was detected in non-metaplastic region (0.58% vs. 0.38%, P < 0.001) but not in intestinal metaplasia (0.24% vs. 0.27%, P=0.56), resulting in a significant increase in the apoptosis/proliferation ratio (0.005-0.021; P=0.03). CONCLUSIONS: Dysregulation in apoptosis control of gastric intestinal metaplasia may contribute to gastric carcinogenesis, which may be retarded by clearance of H. pylori.     

Review article: Helicobacter pylori and gastro-oesophageal reflux disease-clinical implications and management

A significant proportion of patients with gastro-oesophageal reflux disease (GERD) have Helicobacter pylori infection, but it is unclear whether or not H. pylori should be treated in this clinical setting. The aim of this review was to critically assess the relationship between H. pylori and GERD and its potential implications for the management of GERD. Data for this review were gathered from the following sources up to April 1998-the biomedical database MEDLINE, a detailed review of medical journals, and a review of abstracts submitted to relevant international meetings. On average, 40% of GERD patients carry H. pylori infection, with a reported infection prevalence ranging from 16% to 88%. To date, there has been no reported controlled trial of effective H. pylori therapy in GERD. GERD has been reported to develop de novo following the cure of H. pylori in peptic ulcer disease. In the presence of H. pylori, proton pump inhibitor therapy appears to accelerate the development of atrophic corpus gastritis, a potentially precancerous condition. Conversely, proton pump inhibitor therapy seems to become less effective after cure of H. pylori. The mechanisms underlying these important contrasting phenomena are poorly understood. The relationship between H. pylori and GERD is complex, and it is difficult to give definitive guidelines on the management of H. pylori infection in GERD. Controlled trials of H. pylori therapy in GERD are urgently needed, as well as further long-term data on both the natural history of gastric histopathological changes in the H. pylori-positive GERD patient treated with proton pump inhibitors, and the impact of H. pylori status on the clinical efficacy of antisecretory therapy. Pending these data, it is perhaps advisable to advocate cure of H. pylori in young patients with proton pump inhibitor-dependent GERD who, in the absence of anti-reflux surgery, are faced with the likelihood of long-term medical therapy.     

Review article: nitroimidazole resistance in Helicobacter pylori

The efficacy of a nitroimidazole-containing regimen for the treatment of Helicobacter pylori infection is decreased by nitroimidazole resistance. Nitroimidazoles are meta- bolized by H. pylori by several nitro-reductases of which an oxygen-insensitive NADPH nitroreductase encoded by the rdxA gene is the most important. Null mutations in this gene are associated with resistance.
Susceptibility testing to nitroimidazoles may give variable results. This is not only related to the slow growth under specific conditions, but also to variability in the activity of the other nitroreductases and the ability to deactivate toxic metabolites of an NI and to repair DNA damage. Moreover, co-infections with resistant and susceptible bacteria are frequently found. The presence of nitroimidazole resistance is related to the previous use of this drug. The prevalence of resistance is rising and nowadays 10–50% of the isolates are resistant.
Resistance reduces the efficacy of a treatment regimen to a variable degree. This is related to efficacy of the other components of the regimen and the treatment duration. Whether a nitroimidazole is still effective in resistant strains remains unresolved.
When nitroimidazole resistance is present, a nitro-imidazole-containing regimen should be avoided or a regimen with other highly effective components should be used.     

Correlation of kinin generating activity with Helicobacter pylori-associated gastric infection

The kallikrein-kinin system involves a biologically complex set of interactive proteases that signal the first-line onset of inflammation and associated cellular processes. The basic enzymatic cleavage of kininogen substrate by the serine protease tissue kallikrein to liberate kinins is regulated by a number of factors. These may include the recently discovered bacterial involvement in the causation of gastritis. The gram-negative Helicobacter pylori organism, colonises the human gastric epithelium and initiates ulcerogenesis and may induce, in the longer term, tumour formation. The aim of this study was to investigate the role of kinins in H. pylori-induced gastric dyspepsia. During endoscopic examination, lavage aspirates of 23 patients were collected, and the tissue kallikrein content measured by a kinin-generating assay and an enzyme-linked immunosorbent assay. Gastric antral and pyloric biopsy tissue was histologically examined for degrees of inflammation and H. pylori infection, and then immunolabelled for tissue kallikrein and kinin receptors. Results show that labelled tissue kallikrein in the fundic glands and parietal cells of the diseased antrum was elevated with increasing severity of gastritis. Further, kinin-generating potential of the lavage fluid appeared to be greater with increasing evidence of infection. Tissue kallikrein immunosorbent assay levels were significantly raised in patients showing mild to moderate H. pylori infection. One outcome of this study may be the inclusion of kinin antagonists in management of gastric dyspepsia.     

Review article: esomeprazole in the treatment of Helicobacter pylori

Proton pump inhibitor-based triple therapy is the most commonly used treatment for eradication of Helicobacter pylori, with pooled eradication rates of approximately 90%. In the USA, per protocol eradication rates with 10-day proton pump inhibitor-based triple therapy are approximately 85%. Esomeprazole, a new proton pump inhibitor that is the S-isomer of omeprazole and produces a greater inhibition of acid secretion than omeprazole, has recently been evaluated in the treatment of H. pylori. Seven-day twice daily triple therapy with esomeprazole 20 mg, amoxicillin 1 g and clarithromycin 500 mg provided intention-to-treat eradication rates of 86-90% and per protocol eradication rates of 90-91% in duodenal ulcer patients in Europe and Canada. Ten-day triple therapy with esomeprazole 40 mg q.d.s., amoxicillin 1 g b.d. and clarithromycin 500 mg b.d. achieved intention-to-treat eradication rates of 77-78% and per protocol eradication rates of 84-85% in USA duodenal ulcer patients. Thus, esomeprazole triple therapy with amoxicillin and clarithromycin is effective in the treatment of H. pylori, with eradication rates comparable to previously studied proton pump inhibitor-based triple therapies.     

Review article: the treatment of Helicobacter pylori infection

The discovery of Helicobacter pylori has stimulated great interest in its role in gastritis, non-ulcer dyspepsia and peptic ulceration. Treatment regimens to eradicate this organism from gastric mucosa have also received considerable attention. Current recommendations limit the use of triple drug combinations only to specific patient groups.     

Review article: diagnosis of Helicobacter pylori infection

Helicobacter pylori (H. pylori) infection can be diagnosed by invasive techniques requiring endoscopy and biopsy (histological examination, culture, polymerase chain reaction) and by noninvasive techniques (serology, urea breath test, urine or blood, detection of H. pylori antigen in stool specimen). At present, no single test can be absolutely relied upon to detect colonization by H. pylori, and a combination of two tests is recommended if feasible. The tests used should depend on the clinical circumstances, the likelihood ratio of positive and negative tests, the cost-effectiveness of the testing strategy, and the availability of the tests. Some clinical circumstances warrant invasive studies, principally patients with alarm symptoms (bleeding, weight loss, etc.) as well as older patients with new-onset dyspepsia. Endoscopy may also be advisable in patients who have failed eradication therapy and need culture and antimicrobial sensitivity testing to determine an appropriate regimen. Recent studies have also demonstrated that a strategy to 'test and treat' for H. pylori in uninvestigated, young (< 50 years), dyspeptic patients in primary care is safe and reduces the need for endoscopy. Indeed, a number of clinical guidelines recommend noninvasive testing followed by treatment of H. pylori for dyspeptic patients in primary care based on clinical and economic analyses.     

Review article: the management of Giardiasis

Giardiasis is the intestinal infection resulting from infestation with the human parasite Giardia intestinalis, also called Giardia lamblia. The infection may be asymptomatic or present with a variety of symptoms such as diarrhoea, weight loss, abdominal cramps, and failure to thrive. Giardiasis is most often diagnosed after recent travel or in day care centres. The organism has two stages in its life cycle. It is usually ingested as a cyst with as few as 10-25 cysts being sufficient to cause infection. After excystation, the organism is a replicative trophozoite which may attach to the small bowel wall. Giardia intestinalis does not invade the bowel wall. Trophozoites may encyst and be shed in faeces for future ingestion by another host. Diagnosis of infection is by stool examination which may also eliminate other possible infectious agents. Small bowel biopsy may be necessary in difficult individual cases or to rule out non-infectious illnesses, and stool ELISA may serve for large population screening examinations. The mainstay of treatment is metronidazole 250-400 mg three times per day by mouth for 5 days.     

Helicobacter pylori-associated peptic ulcer disease in older patients: current management strategies

The incidence of peptic ulcer and its severe complications, i.e. bleeding or perforation, is increasing in elderly patients worldwide. The prevalence of Helicobacter pylori infection in patients with peptic ulcer aged over 65 years has been reported to range from 58 to 78%. However, in elderly patients hospitalised for ulcer disease, the rate of diagnostic screening or treatment for H. pylori infection was less than 60%, and only 50 to 73% of patients who had a positive H. pylori test were treated with antibacterials. The eradication of H. pylori infection is known to be of proven benefit for elderly patients with H. pylori-associated ulcer disease. Significant improvement of the clinical outcome, and reduction of ulcer recurrences, symptoms and histological signs of ulcer-associated chronic gastritis activity, as well as decreased costs in elderly healthcare, all result from successful therapy. Proton pump inhibitor (PPI)-based triple therapy regimens including clarithromycin, amoxicillin and/or nitroimidazoles are highly effective and well tolerated in elderly patients, particularly if therapy is of a short duration and low doses of both the PPI and clarithromycin are used. Resistance of H. pylori to antibacterials and low compliance are the major reasons for treatment failure. Surveillance of H. pylori susceptibility to antibacterials at the regional level and enhanced compliance programmes give promising results that suggest new approaches to anti-H. pylori treatment, especially in elderly patients. The role of H. pylori infection in nonsteroidal anti-inflammatory drug (NSAID)-related peptic ulcer still remains controversial. At present, no clear evidence supports the testing and treatment of H. pylori infection for the prevention of drug-related peptic ulcer in elderly patients receiving an NSAID or aspirin (acetylsalicylic acid). After therapy, elderly patients with peptic ulcer may be re-evaluated by invasive methods, i.e. endoscopy and gastric biopsies. or by noninvasive methods. In elderly patients, the 13C-urea breath test demonstrated significantly higher sensitivity, specificity and diagnostic accuracy for detecting H. pylori infection than anti-H. pylori antibodies.     

Review article: rabeprazole-based therapy in Helicobacter pylori eradication

Rabeprazole's favourable pharmacodynamic profile is a result of its rapid onset and its 24-h control of gastric parietal secretion. These qualities, and its antimicrobial properties, make it particularly effective in the treatment of Helicobacter pylori (H. pylori), which is a short course of treatment compared to other conditions treated with proton pump inhibitors. Recently completed trials in combination with amoxicillin, clarithromycin and metronidazole for 7 days achieved high eradication of H. pylori. An additional study assessing the efficacy of combined rabeprazole and antibiotic treatments of 3, 7, and 10 days' duration vs. FDA-approved 10-day omeprazole triple therapy is under way to address the possibility of shorter duration therapies in the USA.