In patients with H. pylori-associated PUD, successful eradication is followed by ulcer healing and usually evident clinical improvement. PUD does not relapse and reacquisition of the infection is rare after 5 years of age.31,42,97 Children with abdominal complaints associated with chronic gastritis have a more unpredictable clinical outcome, even if H. pylori is eradicated.73,97
Among long-term complications of H. pylori-associated chronic gastritis, the most important is the multistep disease progression towards gastric atrophy, intestinal metaplasia, dysplasia and gastric cancer.110 In general, this is a rare evolution, affecting no more than 1% of H. pylori-positive patients. This multifactorial process includes host, bacterial and dietary factors.
Family studies have shown that gastric cancer is significantly higher in first-degree relatives of gastric cancer patients.111 Epidemiological case-control and cohort studies have demonstrated that H. pylori is strongly associated with non-cardia gastric carcinoma of both the intestinal and the diffuse type.112,113 An extensive review on this topic showed the best estimate of the relative risk of non-cardia gastric cancer associated with H. pylori infection to be 5.9.113 The odds ratio decreased significantly with aging, from 9.29 in patients with carcinoma at age 20-29 years, to 1 in those older than 70 years of age.112 For some authors, the basis of the genetic predisposition lies either in genetic susceptibility to the infection20 or in mechanisms of DNA repair and carcinogenesis.114 Mutation in p53 is one of the most common genetic alterations found in human cancer, including gastric cancer.115 Inhibition of apoptosis secondary to up-regulation of cyclo-oxygenase 2 by H. pylori-induced inflammation could play a role in inducing intestinal metaplasia. In a subgroup of gastric cancer, as well as in intestinal metaplasia, microsatellite instability, secondary to germline mutation of the DNA mismatch repair genes, has also been demonstrated. The mechanisms inducing intestinal metaplasia and carcino-genesis have recently been reviewed.114
Acid output has long been investigated as a key factor of ulcer development and gastric cancer. Indeed, patients with higher acid output are likely to have antral-predominant gastritis and eventually duodenal ulcer, but they do not show any predisposition towards gastric cancer.116 Patients with lower acid output, on the other hand, are more likely to have a body-predominant gastritis, which predisposes to gastric ulcer and to the multistep progression of disease that, in rare cases, leads to gastric carcinoma. Polymorphisms of the IL-1P promoter have been linked to altered gastric acid secretion and pre-malignant histological features. Severity of the host response to H. pylori infection was related to individual ability to produce IL-1, which has been demonstrated to be a potent inhibitor of gastric acid secretion, as well as a proinflammatory cytokine.117 The histological pathways of H. pylori infection and mechanisms involved in carcinogenesis are shown in Figure 6.8. Genetic as well as acquired (H. pylori-dependent) determinants co-operate, increasing the risk of gastric cancer up to 90-fold in patients with intestinal metaplasia.
Despite the strong causal link between H. pylori and gastric carcinoma, evidence that treatment for H. pylori infection may actually prevent gastric cancer is lacking. The long development time of gastric cancer is the main problem in performing such studies. It has been estimated that a trial with sufficient power to answer the question would have to recruit 100 000 infected subjects with a 20-year follow-up.118 In addition, studies planned to investigate the regression of pre-malignant lesions after eradication gave conflicting results. The progression rate of intestinal metaplasia does not
Prophylactic and therapeutic immunization 89
OR Cancer H. pylori+
duodenal ulcer 0
gastric ulcer 3.4
TGF-alpha f EGFR f yf intestinal metaplasia 6.4 - > 90
Metaplasia —► Dysplasia Cancer (intestinal type)
Antral gastritis (± duodenal ulcer)
Corpus gastritis or pangastritis (± gastric ulcer)
Atrophic gastritis (MAG)
(NAG) non-atrophic gastritis
Cancer (diffuse type)
Figure 6.8 The natural history of Helicobacter pylori infection and associated diseases depends on aging, as well as genetic and bacterial factors (see text). Determinants of diseases are the acid output for the development of peptic ulcer, and the existence of carcinogenetic mechanisms which trigger the multistep gastric carcinogenesis pathway. On the left, are the odds ratios for gastric cancer associated with different clinical pictures. EGFR, epidermal growth factor receptor; MSL, microsatellite instability; TGF, transforming growth factor.
appear to be arrested by eradication; however, eradicating H. pylori leads to resolution of inflammation, elimination of DNA damage and reduction of proliferation, all changes possibly preventing gastric cancer.114
Another malignancy strongly associated with H. pylori infection is gastric B-cell lymphoma, known as MALToma. Even if the stomach is the most common site of the extranodal lymphomas, MALTomas are rare in adults (0.71 cases/100 000 per year in the USA) and definitely exceptional in children. The association of H. pylori infection and MALTomas is based on these considerations: H. pylori is found in more than 90% of cases;119 H. pylori infection precedes the development of the malignancy; and eradicating the infection results in the regression of MALToma in approximately 70% of cases of low-grade disease (stage IE).120 Thus, H. pylori infection in a patient with MALToma is a strong indication for eradication treatment.100 Regression of MALToma after H. pylori eradication was described in a 14-year-old female.121
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