Helicobacter pylori: present status and future prospects in Japan

Most new H. pylori infections occur in children; however, in the absence of specific clinical signs associated with infection, the mode of transmission is difficult to define. Vomitus, saliva, and feces are the presumed sources of direct transmission, particularly in crowded housing conditions. Generally, infection correlates inversely with socioeconomic conditions,23 with lifetime infection rates in affluent countries dropping toward 10%, while rates in countries with emerging economies approach 80%–90%.16,24,25 Most infected individuals experience asymptomatic gastritis, although recurrent gastroduodenal ulceration may occur in 10%–15% of the infected population. The incidence of gastric cancer is lower, with approximately 1%–5% of infected individuals developing adenocarcinoma and even fewer experiencing gastric MALT lymphoma.1,2,26‐29

The most investigated of these toxins stem from a segment of bacterial DNA referred to as the cag pathogenicity island (cag PAI). The presence of the cag PAI is usually associated with presence of the s1m1 (more harmful) subtype of the vacuolating cytotoxin VacA. Genes within the cag PAI encode proteins such as CagE, an ATPase that drives a type IV secretion apparatus that allows bacterial macromolecules, especially CagA toxin, to translocate into the host cell.3,30 The intact cag PAI of H. pylori plays a significant role in the pathogenesis of gastritis in humans, since H. pylori carrying the cag PAI is associated with increased chemokine expression in gastric mucosal specimens31 and stronger inflammation.

CagA is injected into epithelial cells by the type IV secretory system, possibly as a mechanism to reduce the stress of gastric acid on the bacterium, since its transcription is increased at low pH.32 VacA is a pore-forming protein, which causes epithelial cells to vacuolate in vitro. Retrospective analyses of samples from gastric cancer patients have suggested an association with the cagA ⁺/vacA ⁺-positive genotype.33 Further studies have confirmed that a risk for both cancer and peptic ulcer is associated particularly with the cagA/vacA s1m1 genotype, but rarely with strains carrying the vacA s2m2 polymorphism.34,35 However, the cagA gene does not act alone, because delivery of the CagA protein into epithelial cells appears to be dependent on a secretion system encoded for by the adjacent cluster of genes, the cag PAI.36 After the CagA protein is injected into the host cell cytoplasm, it is tyrosine phosphorylated by host Src kinases and subsequently changes the epithelial morphology.37‐41 CagA in strains from distinct geographic populations appears to be phosphorylated to a different degree, resulting in graded effects on intracellular signaling.42,43

Oxygen-derived free radicals, which are released from activated neutrophils, are considered to be one of the potential toxic factors involving H. pylori-induced gastric mucosal injury, since H. pylori exhibits chemotactic activity for neutrophils.44,45 Neutrophil infiltration of the gastric mucosa leads to development of the initial lesion in H. pylori-associated gastritis and remains a hallmark of active bacterial infection. In response to the activation of neutrophils, NADPH oxidase (Nox) in the neutrophils’ cell membranes becomes activated; an electron transfer takes place from NADPH in cells to oxygen inside and outside of cells, and the oxygen molecules that receive an electron become superoxide radicals (O₂ ⁻), which are rapidly converted to hydrogen per oxides (H₂O₂) by spontaneous dismutation, or to enzymatic superoxide dismutase (SOD) and hydroxyl radicals (^•OH), which are formed nonenzymatically in the presence of Fe²⁺. In neutrophils, myeloperoxidase (MPO) also results in the formation of a potent oxidant, the hypochlorous anion (OCl⁻), from H₂O₂ in the presence of Cl⁻. This hypochlorous anion reacts with ammonia, derived from urea by H. pylori-associated urease, and yields cytotoxic oxidant, monochloramine (NH₂Cl) 46 with its lipophilic property, allowing it to freely penetrate biological membranes to oxidize intracellular components47 (Fig. 2).

8-Hydroxy-2-deoxyguanosine (8-OHdG) is one of the most abundant lesions in DNA induced by reactive oxygen species.48 It results from an attack by a singlet hydroxyl or oxygen radical on guanine (Fig. 2). Patients with cagA-positive H. pylori strains have higher 8-OHdG levels than both cagA-negative and H. pylori-negative patients.49 The cagA-positive patients are characterized by greater oxidative DNA damage overall and at a younger age, in the presence of multifocal atrophy.49

The preferred animal model for studying H. pylori gastritis is the Mongolian gerbil (Meriones unguiculatus).50‐53 In one study, gerbils infected with a mutated strain lacking cagE exhibited a substantially reduced severity of gastritis.54 Gastric ulceration developed in all of the gerbils infected with the wild-type strain but in none of those infected with the cagE mutant strain. In addition, intestinal metaplasia and gastric cancer developed in some gerbils with wild-type infection but not in animals infected with the cagE-negative mutant.54 These findings were confirmed by showing that the repaired cagE-positive H. pylori strain induced severe gastric inflammation, gastric mucosal atrophy, and gastric ulcer formation.55 Recently, the nucleotide sequences of cDNAs encoding preproghrelin, a precursor of ghrelin (an appetite-promoting endocrine peptide produced mainly from A-like cells in the gastric fundus)52,56 and sonic hedgehog, a morphogen that may regulate and organize fundic gland epithelial differentiation, have been identified in the Mongolian gerbil.53,57 Preproghrelin and sonic hedgehog mRNA expression is significantly reduced in the gastric mucosa of Mongolian gerbils with persistent H. pylori colonization.52,53

After reaching the mucosa and attaching by means of its lectins, H. pylori applies toxin to the gastric mucosa (Fig. 3). Then, the cells change their morphology and migrate, some detach, and sometimes apoptosis occurs. The healing process involves proliferation of adjacent, more healthy cells. Gastric epithelial cell turnover is regulated by the balance between cell death (apoptosis) and cell proliferation (Fig. 3). Such a regulated cell turnover by apoptosis and proliferation is essential for maintaining healthy gastric mucosal integrity. Some cells differentiate into intestinal tissue, a transformation called intestinal metaplasia. This may be somewhat protective in that H. pylori is unable to attach to these cells, allowing inflammatory processes to become quiet in these areas. However, extensive metaplasia is associated with decreased acid secretion, which may allow other commensal bacteria to colonize and carcinogen formation to occur. Proliferation by itself is not carcinogenic, but mutagens, such as monochloramine, may be formed in the presence of ammonia and hypochlorous anion. These cause errors in transcription to occur.

At an earlier phase after bacterial inoculation, an initial transient enhancement of cell apoptosis (2–4 weeks) and a later increase in cell proliferation (16–20 weeks) occur in the H. pylori-colonized gastric mucosa of gerbils.58 While the level of apoptosis increases as H. pylori-evoked gastric mucosal inflammation advances in mice, the enhanced level of apoptosis is significantly attenuated in H. pylori-colonized gastric mucosa of gerbils with enhanced inflammation and epithelial proliferation in the gastric mucosa during longer term colonization,59 suggesting a possible link between attenuated gastric mucosal apoptosis and a specific carcinogenesis in gerbils after H. pylori colonization.60,61

The strongest association of H. pylori infection is with peptic ulcer disease;62 95% of duodenal ulcers and 70% of gastric ulcers are related to H. pylori infection. Several cohort studies have estimated that the lifetime risk of ulcer disease in H. pylori-positive subjects is three to ten times that in H. pylori-negative subjects.63 Introduction of H. pylori eradication regimens has completed the evidence for a causal relation between H. pylori and peptic ulcer disease because H. pylori eradication has been shown to strongly reduce the risk of ulcer recurrence.64 In prospective controlled studies of duodenal ulcer recurrence, ulcers recurred in 55%–86% of patients in H. pylori-positive cohorts, in contrast to a rate of 3%–21% in H. pylori-negative (successfully eradicated) cohorts65‐70 (Table 1). Gastric ulcers typically recurred in 46%–71% of patients in H. pylori-positive cohorts, contrasting with ulcer recurrence rates of 10% or less in H. pylori-negative (successfully eradicated) cohorts71‐76 (Table 2).

The meta-analytic results of a North American study by Laine et al.70 have shown that H. pylori eradication markedly decreases ulcer recurrence. Nevertheless, ulcers recurred in 20% of patients in these studies within 6 months, despite a successful cure of infection and no reported use of nonsteroidal anti-inflammatory drugs (NSAIDs), suggesting that non-H. pylori, non-NSAID ulcers may be more common in the United States than previously believed.

According to a recent systematic review of 56 randomized controlled trials of treatment for peptic ulcer disease in H. pylori-positive adults,77 a 1 to 2 weeks’ course of H. pylori eradication therapy is an effective treatment. Namely, in duodenal ulcer (DU) healing, eradication therapy was superior to several weeks of ulcer healing drugs [34 trials, 3910 patients, relative risk (RR) of ulcer persisting = 0.66] or no treatment (2 trials, 207 patients, RR = 0.37). In gastric ulcer (GU) healing, no significant differences were detected between eradication therapy and administration of an ulcer healing drug (14 trials, 1572 patients, RR = 1.25). For preventing DU recurrence, no significant differences were detected between eradication therapy and maintenance therapy with an ulcer healing drug (4 trials, 319 patients, RR = 0.73), but eradication therapy was superior to no treatment (27 trials, 2509 patients, RR = 0.20). For preventing GU recurrence, eradication therapy was superior to no treatment (11 trials, 1104 patients, RR = 0.29).

The incidence of peptic ulcers has steadily decreased in Western countries in the last two decades. The decreasing prevalence of peptic ulcers is thought to result both from contraction of the formerly large pool of patients with recurrent ulcer disease by H. pylori eradication at first presentation and from the decreasing prevalence of H. pylori infection in the population.24,78,79 The latter is related to several factors, such as improved hygiene and living conditions, decreased family sizes, and the use of antimicrobial therapy for other purposes.

Helicobacter pylori and NSAIDs are the two major causes of peptic ulcer disease. Their potential interaction in the induction of ulcer disease remains controversial. A thorough analysis of interaction data has revealed that the ulcer-inducing effects of both risk factors are cumulative.80 Eradication of H. pylori in chronic NSAID users does no harm, and in some studies has decreased the incidence of ulcer disease. In a study from Hong Kong, patients starting with NSAID maintenance therapy were randomized to eradication therapy or placebo. After 6 months of follow-up, the incidence of ulcers was 12.1% in the eradication group and 34.4% in the placebo group (P = 0.0085). The corresponding probabilities of complicated ulcers after 6 months were 4.2% and 27.1% (P = 0.0026), respectively.81 These data show that, at least in an Asian population, screening and treatment for H. pylori infection significantly reduces the risk of ulcers in patients starting long-term NSAID treatment, but also that eradication alone is insufficient to totally prevent ulcers and ulcer complications. In several studies, H. pylori eradication was inferior to omeprazole maintenance treatment for prevention of recurrent NSAID-associated ulcer bleeding.82,83 An overall synthesis of these data suggests that NSAIDs and H. pylori are independent, but not necessarily additive, causes of peptic ulcer. The wise choice might be to address both issues in all patients with ulcer complications: supplement NSAID users at risk with a second agent, consider the option of selective cyclooxygenase-2 (cox-2) inhibitors, and eradicate H. pylori as well.

Recently, the “Rome III” classification for functional gastrointestinal disorders was defined.84 In this classification, functional dyspepsia (FD) is included in the subcategory of functional gastroduodenal disorders.85 Four types of functional gastroduodenal disorders are distinguished: FD [B1, comprising postprandial distress syndrome (B1a) and epigastric pain syndrome (B1b)]; belching disorders (B2); functional nausea and vomiting disorders, functional vomiting, and cyclic vomiting syndrome (B3); and rumination syndrome (B4).85,86

Of patients with functional dyspepsia, 30%–60% carry H. pylori, but this prevalence is not much different from that in the unaffected population.87 Various studies have focused on the effect of H. pylori eradication in patients with both functional and uninvestigated dyspepsia. A meta-analysis of 13 randomized studies of nonulcer dyspepsia showed that when dyspepsia outcomes are dichotomized into minimal/resolved versus same/worse symptoms, H. pylori eradication is associated with an 8% RR reduction compared with placebo.88 The calculated number-needed-to-treat to cure one case of dyspepsia is 18. Apart from the focus on cure of symptoms, cost efficiency is also an issue when treating large groups of patients. Given this reported number-needed-to-treat, it remains unclear whether H. pylori eradication is a cost-effective strategy. In a Canadian primary care study, however, H. pylori eradication was reported to be more cost-effective after 1 year of follow-up than empirical diagnosis and treatment.89,90 In another interesting study, Sonnenberg and Townsend91 found that, for some reason, expenditure on many other aspects of health care decreased after patients had eradicated H. pylori.

Another Cochrane meta-analysis compared treatment strategies for uninvestigated dyspepsia.92 Individual strategies consisted of initial pharmacological therapy (with endoscopy for treatment failures), early endoscopy, testing for H. pylori and endoscopy only for those testing positive, or H. pylori eradication therapy with or without prior testing. The analysis showed that proton-pump inhibitors (PPIs) are effective in the treatment of dyspepsia. Early investigation by endoscopy or H. pylori testing benefited some patients with dyspepsia but was not cost-effective as part of an overall management strategy.92 A meta-analysis of five studies comparing prompt endoscopy followed by targeted treatment versus an H. pylori test-and-treat strategy without further investigation reported that endoscopy was associated with a small symptom benefit at 1 year (RR, 0.95), but this strategy was not cost-effective.93 In summary, H. pylori play a role in the etiology of dyspeptic symptoms; thus, H. pylori test-and-treat strategies are effective for a subgroup of patients with dyspepsia. For patients with uninvestigated dyspepsia, an H. pylori test-and-treat strategy is an appropriate option, although empirical acid-suppressive therapy can be more efficient in populations with a low H. pylori prevalence. Also, in patients with investigated FD, H. pylori eradication is a relevant option. In both situations, patients must be aware that symptom resolution may take months after completion of therapy.

Thirty years ago, Correa et al.94 proposed that gastritis could progress to gastric cancer, which made the identification of H. pylori as a major cause of gastritis even more relevant. Chronic H. pylori-induced inflammation can eventually lead to loss of the normal gastric mucosal architecture, with destruction of gastric glands and replacement by intestinal metaplasia. This process of atrophic gastritis and intestinal metaplasia occurs in approximately half of the H. pylori-colonized population, first in those subjects and at those sites where inflammation is most severe.95 Because not everyone infected with H. pylori develops gastric cancer, several modifiers have been identified. Currently, the perception is that gastric cancer arises from multiple “hits,” which include oxidative stress and environmental toxins, which increase mutation rates. Diet, bacterial factors, and genes regulating the host response likely affect the degree of oxidative stress and DNA damage.96 Host polymorphisms in the regions controlling interleukin (IL)-1 have been reported to be associated with an increased incidence of hypochlorhydria and gastric cancer,97‐102 probably because these regions regulate the inflammatory response to bacterial infections. Areas of gland loss and intestinal metaplasia extend with time multifocally, and although they do not give rise to any specific symptoms, they increase the risk for gastric cancer by five-to 90-fold, depending on the extent and severity of atrophy.103

Evidence that H. pylori increases the risk of gastric cancer development via the sequence of metaplasia and atrophy originates from various studies that showed that H. pylori-positive subjects develop these conditions far more often than do uninfected controls.104 This finding is supported by data that show geographical associations between the prevalence of H. pylori and the incidence of gastric cancer.105,106 On the basis of these findings, it has been estimated that H. pylori colonization increases the risk of gastric cancer approximately tenfold, and H. pylori has been designated a class I carcinogen by WHO.107 Later case-control studies that looked more extensively into signs of previous H. pylori infection in gastric cancer patients and controls re ported even higher odds ratios, up to 68, for development of distal gastric cancer in the presence of H. pylori infection.108 This result is supported by data from animal models, most notably the Mongolian gerbil model, in which H. pylori infection induces atrophic gastritis and gastric dysplasia.60,61,109 The risk of development of atrophy and cancer in the presence of H. pylori is again related to host and bacterial factors, which influence the severity of the chronic inflammatory response and the amount of gastric mucosa involved. As such, the risk is increased not only in subjects colonized with cagA-positive strains110,111 but also in those with a genetic predisposition to higher IL-1 production in response to colonization.97 In the developed world, 60% to 80% of gastric cancers are therefore related to the long-term presence of H. pylori.

Interestingly, the incidence of gastric cancer has significantly decreased over the past decades in Western countries. This decrease preceded the aforementioned decrease in the prevalence of H. pylori. As a slow process over decades, however, this decrease is not relevant to an individual subject who is H. pylori-positive. Furthermore, in spite of the decline in gastric cancer incidence in Western countries, gastric cancer is still the fourth most common cancer in the world, as its incidence remains very high in large areas of the world, particularly in parts of East Asia and South America.112 Much research now focuses on the cancer-preventive effect of H. pylori eradication, aimed at both the general population and patients with preneoplastic conditions, particularly atrophic gastritis and intestinal metaplasia. In the case of the latter, several placebo-controlled randomized studies have now reported that H. pylori eradication can induce to some extent regression of atrophy.113‐117 The effect of these interventions on gastric cancer prevention is, however, less obvious than the historical cancer incidence might suggest. In several studies, H. pylori eradication had in the first years of follow-up no significant effect on gastric cancer incidence.114,116,118 In all of these studies, the difference between the eradication and placebo groups with respect to the incidence of gastric cancer in the first 4 to 12 years after treatment was not significant. The striking observation in all of these studies, however, was that those gastric cancers that occurred after eradication treatment were confined to those subjects who already had atrophic gastritis and intestinal metaplasia at baseline, suggesting that the major cancer-preventive effect of H. pylori eradication is to be expected in subjects without those precancerous conditions; patients with those conditions may at least in part have already passed the point of no return. If confirmed by other studies, this result means that the observed regression of the severity of atrophy is of no direct relevance with respect to cancer risk. One study differed from the others in that it did observe a significant preventive effect of H. pylori eradication on gastric cancer development.119 The investigators monitored 1120 patients in a nonrandomized study for a mean of 3.4 years (range, 1–8 years) after H. pylori eradication treatment. Gastric cancer developed in 8 of 944 patients cured of infection and in 4 of 176 who had persistent infection (P = 0.04). The remarkable observation was that gastric cancers occurred only in patients with previous gastric ulcers and not in those who had duodenal ulcers (P = 0.005).119 This result is consistent with the hypothesis that gastric ulcer patients, in contrast to duodenal ulcer patients, are characterized by reduced gastric acid secretion, corpus-predominant gastritis, and accelerated progression toward atrophic gastritis and intestinal metaplasia. Similarly, previous studies have also shown that gastric ulcer patients are at higher risk for gastric cancer than are duodenal ulcer patients.26 The above-mentioned preventive studies, taken together, described cancer development in 29 (1.5%) of 1896 subjects receiving placebo and in 25 (0.9%) of 2754 subjects receiving eradication treatment, corresponding to an odds ratio of 0.54 for cancer development after H. pylori eradication compared with placebo, suggesting that H. pylori eradication may decrease the risk for development of distal gastric cancer. Further studies are being performed in this field, the results of which will allow a more precise determination of the cancer-preventive effect of H. pylori eradication, of whether atrophy and metaplasia are conditions beyond the point of no return, and of the side effects and costs of such preventive measures.

The Japan Collaborative Cohort Study Group for Evaluation of Cancer Risk reported that women with a family history of gastric cancer and H. pylori infection were associated with a 5.1-fold greater risk for gastric cancer compared with women without a family history of gastric cancer and who did not have H. pylori infection.120 In contrast, family history and H. pylori infection were not found to be significant risk factors for gastric cancer in male patients in their report, where the investigation of H. pylori infection was performed only by using H. pylori antibodies. Recently, results of a large nested case-control study within a prospective cohort have been reported in Japan.121 Among 123 576 subjects that were followed up from 1990 to 2004, 511 gastric cancer cases matched to 511 controls were used in this analysis. The adjusted odds ratio of gastric cancer associated with H. pylori infection was 5.1. In addition, if anti-CagA positivity was used as an indicator of previous or current infection, the risk was reached 12.5.

Nearly all MALT lymphoma patients are H. pylori positive,122 and H. pylori-positive subjects have a significantly increased risk for the development of gastric MALT lymphoma.123 Because of diagnostic controversies and the relative rarity of this disorder, the exact incidence in H. pylori-positive subjects is unknown, but MALT lymphomas occur in fewer than 0.1% of H. pylori-positive subjects.124 Randomized trials to determine the effect of H. pylori eradication in MALT lymphoma patients are therefore not feasible, but various case series have reported that eradication can lead to complete remission in patients with low-grade gastric MALT lymphoma.125‐128 Overall, approximately 60%–80% of these patients reach complete remission following H. pylori eradication, some 10% continue to have signs of minimal residual disease, and the remainder show no response or disease progression. The variation in response among different series may be due in part to different criteria for the diagnosis of MALT lymphoma, potentially including some patients with benign lymphoid aggregates. Of those who initially reach complete remission after H. pylori eradication, 10%–35% show recurrent disease during further follow-up. For that reason, long-term follow-up of MALT lymphoma patients is mandatory.129 A major predictor of the response appears to be the presence of a t(11;18) (q21;q21) translocation. This translocation is associated with API2-MALT1 fusion, the former being involved in regulation of apoptosis and the latter resembling a caspase-like protein, with an as yet unknown biological function. Together, the fusion leads to suppression of apoptosis. Several studies have reported that MALT lymphomas with this translocation respond only rarely or not at all to H. pylori eradication.130,131

Gastroesophageal reflux disease (GERD) has long been considered to occur independently of H. pylori colonization; that is, it occurs with the same frequency and severity in H. pylori-positive and -negative subjects. This opinion is based on cross-sectional observations that suggest that the prevalence of H. pylori among GERD patients is similar to that among controls.132 However, further studies have suggested that H. pylori might protect against the development of GERD and by that means might be of benefit to its hosts. This slowly emerging concept derives from repeated observations of a low prevalence of H. pylori among GERD patients, particularly of the more virulent strains;133 reciprocal time and geographical trends for H. pylori prevalence compared with the incidence of GERD and its complications; a potentially increased incidence of GERD after H. pylori eradication;134 and the recognition that H. pylori-induced corpus gastritis reduces acid secretion. However, no evidence suggests that H. pylori eradication has a considerable impact on either the new development of GERD,135 the worsening of preexisting GERD when treatment has been withdrawn during disease remission,136 or preexistent GERD in remission during PPI maintenance therapy.113,117 Together, these data show that although epidemiologic data suggest that there may be an inverse relation between H. pylori and GERD, the risk for new development or worsening of preexistent GERD is not an issue when deciding whether to treat H. pylori.

Diagnostic methods for H. pylori infection are categorized as invasive or noninvasive tests.137 Invasive tests involve endoscopic biopsy of gastric mucosal samples, whereas noninvasive tests do not require an endoscopic procedure. The invasive tests are histology,138 rapid urease test (RUT),139 and microaerobic bacterial culture.17 The advantage of the RUT is that it is inexpensive, easy-to-use, and rapid. The advantages of culture are its specificity of 100% (direct demonstration of the presence of H. pylori) and that it allows further characterization of the organism (determining its sensitivity to antibiotics, investigating its virulence factors, etc). Noninvasive tests are the urea breath test,140 antibody tests of sera141‐143 or of urine,144,145 and the H. pylori stool antigen test.146‐149

During the 20 years since the World Gastroenterology Organization (WGO-OMGE) consensus conference, international or domestic consensus conferences for H. pylori eradication have been held all over the world, including in Europe, America, and Asia (Fig. 4). Most recently, on 22 November 2006, the Japanese Society for Helicobacter Research held a “Current Consensus—2006” (Management of H. pylori infection in Japan) meeting in Tokyo. In this consensus meeting, one of the main topics was whether Japan will become the first H. pylori-free country.

Originally, in 1988, Marshall et al.66 reported that H. pylori had been eradicated in 27% of a colloidal bismuth substrate (CBS)/placebo group and in 70% of a CBS/tinidazole group. Furthermore, when H. pylori persisted, 61% of duodenal ulcers healed and 84% relapsed, whereas when H. pylori was cleared, 92% of ulcers healed and only 21% relapsed during the 12-month follow-up period.66

According to a randomized, double-blind, placebo-controlled study performed by Lind et al.,150 787 patients with proven duodenal ulcer disease were randomized to treatment twice daily for 1 week with omeprazole, 20 mg (O), plus either placebo (P) or combinations of two of the following antimicrobials: amoxicillin, 1 g (A), clarithromycin, 250 or 500 mg (C250, C500), or metronidazole, 400 mg (M). Their eradication rates for the all-patients-treated analysis were 96%, OAC500; 95%, OMC250; 90%, OMC500; 84%, OAC250; 79%, OAM; and 1%, OP. These results suggest that omeprazole-based triple therapies given twice daily for 1 week produce high eradication rates, are well-tolerated, and are associated with high patient compliance.

In terms of second-line treatment, Matsuhisa et al.151 examined the eradication rate of a PPI, amoxicillin, and metronidazole (PPI/AM) regimen in 228 patients with H. pylori infection, in whom the first-line therapy with a PPI, amoxicillin, and clarithromycin administered for 1 week had failed. Their eradication rates for PPI/AM(500) and PPI/AM(750) were 90.6% and 88.6%, respectively, suggesting that PPI/AM administered for 1 week may be a highly effective second-line regimen.

In terms of third-line regimens, Gisbert et al.152 performed a third eradication treatment with levofloxacin (500 mg), amoxicillin (1 g), and omeprazole (20 mg), each twice daily for 10 days (n = 100), which resulted in per-protocol and intention-to-treat eradication rates of 66% and 60%. Although such fluoroquinolone-based rescue therapy constitutes an encouraging empirical third-line strategy after multiple previous H. pylori eradication failures,152 a high resistance rate (47.9%) to fluoroquinolone has been observed in H. pylori strains from Japanese patients after unsuccessful H. pylori eradication. Therefore, the choice of this antibiotic for the third-line treatment should be made only after drug susceptibility testing.153,154

Side effects of H. pylori eradication are reported in up to 50% of patients taking the triple agent regimen.155,156 The adverse effects are usually mild; fewer than 10% of patients stop treatment due to side effects.155 The common side effects are dysgeusia and diarrhea. Amoxicillin can cause diarrhea or an allergic reaction with skin rash. Clarithromycin can cause dysgeusia, vomiting, nausea, abdominal pain, and rarely QT prolongation. Metronidazole can cause seizures, peripheral neuropathy, and a disulfiram-like reaction with ethanol, and it can increase the toxicity of anticoagulants, lithium, and phenytoin. Acute gastrointestinal mucosal lesions have been demonstrated to be an adverse event after eradication therapy. Acute duodenal erosions were observed in 13.5% of patients who received eradication therapy;157 erosions were transient and asymptomatic in the early phase after eradication. Acute gastric erosions showed the same clinical characteristics, but acute gastric ulcers with severe symptoms rarely occurred. The acute mucosal lesions that occurred were probably attributable to an increase in acid secretion associated with the resolution of gastric mucosal inflammation.6 On the other hand, the occurrence of mild reflux esophagitis at a late phase after eradication is controversial. Helicobacter pylori infection is an environmental factor that has declined as GERD has increased.158 However, a systematic review159 of randomized trials did not show any role of H. pylori eradication in causing GERD. There was no increase in reflux symptoms in almost 3000 patients with H. pylori infection who were randomly assigned eradication therapy compared with placebo.160,161

Cells of the gastric mucosa undergo constant renewal, the rate depending on the health of the tissue. The current evidence162 suggests that a single stem cell in every gastric gland indirectly gives rise to a clone of differentiated cells, by production of committed progenitor cells. It is most likely that this stem cell occupies a niche in the isthmus composed of mesenchymal cells and extracellular matrices. This environment regulates the function of the epithelial stem cell via mesenchymal-epithelial cross talk. Recent studies in gnotobiotic mouse models of chronic atrophic gastritis163 have shown that parietal cell loss results in amplification of multi- and oligopotential gastric stem cells, which express sialylated glycan receptors recognized by H. pylori adhesions, SabA,164 HpaA,165 and HP0721.166 DNA microarray studies indicate that 6%–7% of H. pylori genes are differentially expressed in response to a shift in pH from 7 to 5.167 A large group of genes downregulated at pH 5, in particular, encode outer membrane proteins, including Hop family members that are predicted to be outer membrane porins and adhesins. Loss of acid-producing parietal cells increases bacterial adhesin expression and increases the proportion of stem cells with adhesin receptors.168 Another very provocative study suggests that in the mouse model of gastric cancer evoked with Helicobacter felis (cat Helicobacter), infection arises because malignant stem cells emerge from a pool of bone marrow cells that are recruited into areas of chronic gastritis.169

Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease that leads to thrombocytopenia as a result of increased thrombocytolysis due to the appearance of autoantibodies to platelets. The acute type frequently occurs in children, often preceded by a viral infection. It develops rapidly and shows spontaneous remission. Chronic-type ITP occurs most commonly in adults and reportedly correlates with H. pylori infection. In 1988, Gasbarrini et al.7 reported that H. pylori eradication therapy to eight patients with H. pylori-positive ITP improved thrombocytosis after the therapy. Veneri et al.,171 who administered H. pylori eradication therapy to 43 patients with H. pylori-positive ITP, reported the therapy to be successful in 41 of the 43 and recognized continuous improvement in 20 (48.8%) of these 41 patients on long-term observation. According to another report by the same authors,172 the frequencies of HLA-DRB 111, HLA-DRB 114, and HLA-DQB 103 as host factors were high in H. pylori-positive ITP, while the frequency of HLA-DRB 103 as a host factor was higher in the H. pylori-negative ITP group than in the H. pylori-positive ITP group, and HLA-DQB 103 showed favorable platelet reactivity after eradication therapy in H. pylori-positive ITP.172 Inaba et al.173 administered H. pylori eradication therapy to 35 patients with chronic ITP (25 H. pylori-positive ITP patients and 10 H. pylori-negative ITP patients), and succeeded in eradicating the bacteria in all of the patients with H. pylori-positive ITP. They reported that the platelet count was improved in 11 (44%) of the 25 patients, while the platelet count was unchanged in the 10 H. pylori-negative ITP patients. We also administered bacterial eradication therapy to 37 patients with chronic ITP (26 H. pylori-positive ITP and 11 H. pylori-negative ITP patients) and succeeded in eradicating the bacteria in all of the H. pylori-positive ITP patients; we found the platelet count to be improved in 16 (62%) of the 26 patients with H. pylori-positive ITP, while the platelet count was unchanged in the 11 patients with H. pylori-negative ITP.12 In other words, there was no improvement with bacterial eradication in H. pylori-negative ITP, and the effects of the antibacterial agent itself in terms of increasing the platelet count was negligible.

Many other reports show a relation between H. pylori infection and human diseases such as iron-deficiency anemia8,174‐181 and chronic urticaria.182‐184