H. pylori infection occurs in approximately 40% of the population over 40 years 0f age and most patients with peptic ulcer disease are infected with H. pylori. Because ulcers recur in patients who have undergone "successful" H. pylori, eradication therapy, infection may not always be causative for the disease. Less than 5% of ulcer patients are H. pylori negative and in H. pylori positive patients only 10% of ulcers recur after eradicating the infection. Likely causes of ulcer recurrence are considered to be reinfection, the use of ulcerogenic drugs, and persistent gastric hypersecretion. However, true reinfection is rare and it is mcre likely that the most common cause of H. pylori recurrence is attributed to inadequate eradication. The significant reduction in H pylori density produced by a combination of antibiotic and antisecretory therapy may reduce the levels of infection to below detectable levels (22). Rapid urease tests for H. pylori have a sensitivity of only 80-90%. Therefore histological examination is also used to con-fhm an initial noninvasive test result. Whole blood or serum antibody testing are rapid, accurate, and cost-effective tests for establishing H. pylori status in rapid urease test-negative patients. These less invasive techniques could be used in place of endoscopy when the patient has not previously been treated for H. pylori (23).
In duodenal ulcer (DU) patients, H. pylori infection causes inflammation of the antral gastric mucosa, which is associated with an elevation in gastric acid secretion. Gastritis increases the release of the acid-stimulating antral hormone gastrin and reduces the expression of the inhibitory peptide somatostatin. Bacterial products and inflammatory cytokines may produce these changes in endocrine function. Gastritis involving the corpus tends to decrease acid secretion, given that bacterial products and cytokines inhibit parietal cells. After eradication, gastrin levels are restored to normal levels.
Gastric metaplasia is found in 90% of H. pylori-infected DU patients and about 60% of non-DU patients with increased acid secretory levels. The induction of gastric acid causes severe inflammation and increases the areas of metaplasia within the gastric mucosa. Combined eradication and acid-suppression therapy produces greater reduction in gastric indicating that both acid secretion and H. pylori infection contribute to ulcer formation. A number of putative virulence factors for H, pylori have been identified, including cagA, vacA. and iceA. Although disease-specific associations have been claimed, there are now sufficient data to state that none of these factors is specific for any disease. The presence of a functional cagA pathogenicity island, whose genes produce proinflammatory cytokines, increases mucosal IL-8 and inflammation, but is not predictive of the future development of a disease. The hypothesis that iceA has disease specificity has not been confirmed and vacA genotyping has also failed to predict the disease identification. Virulence appears to be a host-dependent factor. The pattern of gastritis is frequently used to indicate the different H. pylori-related diseases. The primary factors responsible for the different patterns of gastritis are suggested to be associated with environmental factors, with the H. pylori strain playing a minor role (24).
H. pylori infection is now proven to be a risk factor for gastric cancer and the organism was classified as a Group 1 carcinogen by the International Agency for Research on Cancer sponsored by the World Health Organization in 1994 (25). This has strengthened the case for H. pylori eradication to prevent gastric cancer. However, there are growing concerns that eradication may cause harm. In developed countries. an increase in the rate of cancers arising near the gastroesophageal junction may be linked to the disappearance of H. pylori. The conundrum is to either eradicate to avoid cancer of the distal stomach or leave it and hence avoid cancer of the proximal stomach or distal esophagus. More research is required to determine which patients should receive eradication therapy (26).
An increased incidence of GERD has been linked to the decrease in H. pylori infection produced by the current trend of eradication therapy. H. pylori may have a protective role by either reducing achlorhydria induced by PPIs or by increasing the activity of PPIs by increasing the formation of the active metab olite. The antisecretory effect of PPIs seems to depend on the presence of the infection because eradication of H. pylori has negative consequences on the efficacy of antisecretory drugs (27).Several hypotheses have been suggested to account for the reduction in efficacy of PPIs in H. pylori-negative patients. Hypersecretory disorders may be associated with increased expression of proton pumps on the membrane of the parietal cell; therefore PPIs would appear to be more effective in DU patients than in healthy controls. Other authors have suggested that H. pylori infection may inhibit proton-pump synthesis in the parietal cell because the amount of H+/K+-ATPase mRNA in the fundic gland mucosa was significantly increased in patients where H. pylori had been eradicated (28). If a decrease in the number of active proton pumps was the explanation for the higher effectiveness of PPIs in H. pylori-positive subjects, there should also be a lower acid output and consequently higher gastric pH in H. pylori-positive subjects during baseline recordings. However, under basal conditions, similar basal pH values are recorded both before and after the cure of infection. The most likely cause for the decreased effectiveness of PPIs is the production of ammonia by H. pylori in infected patients. H2-receptor antagonists do not inhibit acid secretion to the same degree as do PPIs; thus the small amount of ammonia produced by H. pylori would be unlikely to significantly affect the pH. However, the high gastric pH produced by PPI therapy would be influenced by the reduction in ammonia produced by eradication of H. pylori. The reduction in H. pylori-related gastritis produced during omeprazole therapy has also been suggested to contribute to the reduced activity of omeprazole after eradication. However, histological improvement of gastritis after a cure of H. pylori is a slow process and the effect of reducing the effectiveness of omeprazole is rapid.
Although the usefulness of H. pylori eradication is still controversial, a randomized controlled study has shown that patients, in whom the organism has been eradicated, benefit with regard to quality of life and there is also a reduction in financial costs to the health system (22).
6.4 Reflux Esophagitis esophagitis is a disorder of the defense mechanisms at the esophagealjunction, which is caused by regurgitation of the gastric contents, especially of gastric acid. GERD is associated with decreased gastric emptying and/or increased incidence of transient lower esoph-ageal relaxation (T-LESR). Smoking and obesity are factors that increase the incidence cf GERD-like symptoms such as heartburn, belching, and bloating. Reflux has been observed in humans and dogs but not in rodents.
can be subdivided into T-LESR. free reflux, and stress reflux. H. pylori infection does not necessarily correlate with GERD, although a reduction in acid secretion reduces the chances of reflux. The effectiveness cf PPIs is reduced in the absence of H. pylori infection; therefore the majority of patients with GERD require >20 mg/day to provide symptom relief and to heal the esophagitis produced by gastric acid reflux. This dose is much higher than that required to inhibit acid secretion associated with DU disease. If PPI therapy is stopped, then GERD patients appear to produce greater amounts of gastric acid and their reflux is potentiated. 11 has been reported that if the prevalence of H. pylori continues to decline, then PPI consumption will continue to increase for GERD (29). Ideally, future therapy for GERD should be independent of H. pylori status and additionally be devoid of the acid-rebound effect produced with PPI therapy.
GERD causes significant discomfort but is not in itself life threatening. The incidence of adenocarcinoma of the esophagus is increasing in the United States (30), with almost 100% of cases occurring in patients with Barrett's esophagus, a condition in which mucin-secreting, metaplastic, columnar epithelium replaces the normal squamous epithelium of the esophagus (31). There is substantial evidence that GERD may increase the incidence of Barrett's esophagus. Fass reported that the length of Barrett's esophagus tissue correlated with the duration of esophageal acid exposure (32). The use of antireflux medication in patients with GERD leads to an improvement or alleviation of symptoms and healing of mucosal inflammation. Antisecre-
tory agents have been used to reduce the exposure of the esophagus to acid in Barrett's esophagus. However, even high doses of PPIs have not resulted in regression of Barrett's mucosa. Not all GERD patients develop Barrett's esophagus and the causative agents for this progression to a precancerous state have not been fully determined. The age of onset, duration of symptoms, and complications of GERD are markers of an increased risk of Barrett's esophagus. In additon, the longer the region of Barrett's mucosa, the higher the risk for the development of dysplasia (33).
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Gastroesophageal reflux disease is the medical term for what we know as acid reflux. Acid reflux occurs when the stomach releases its liquid back into the esophagus, causing inflammation and damage to the esophageal lining. The regurgitated acid most often consists of a few compoundsbr acid, bile, and pepsin.