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Therap Adv Gastroenterol. 2009 May; 2(3): 141–147.
PMCID: PMC3002520

Assessing the Risks and Benefits of Treating Helicobacter Pylori Infection

Introduction

Since the discovery of Helicobacter pylori by Warren and Marshall [Marshall and Warren, 1984] in 1982, much has been learned about this Gram-negative microaerophilic bacterium and its associated pathology. In 1994, the National Institutes of Health recognized that most recurrent duodenal and gastric ulcers were caused by H. pylori and antibiotic treatment was recommended. In the same year, the International Agency for Research on Cancer (IARC) declared H. pylori to be a group I human carcinogen for gastric adenocarcinoma [IARC, 1994]. Since then, physicians have been working diligently in diagnosing and treating H. pylori. Despite the fact that evidence has shown clearly H. pylori to be the culprit for gastritis, peptic ulcers and gastric malignancies including mucosa associated lymphoid tissue (MALT) lymphoma and gastric adenocarcinoma, the effect of H. pylori treatment in patients with gastroesophageal reflux disease remains controversial. In this review, we will discuss the risks and benefits of the treatment of H. pylori in different disease entities. This is summarized in Table 1.

Table 1.
Summary of benefits and risks of H. pylori eradication.

Evidence of the clinical benefits of H. pylori eradication

Gastric and duodenal ulcer

The strong association between H. pylori infection and peptic ulcer disease is unarguable. Meta-analysis studies have showed superior ulcer remission rate for both gastric and duodenal ulcer in patients successfully eradicated of H. pylori infection [Singh and Ghoshal, 2006; Leodolter et al. 2001]. H. pylori eradication therapy was also more superior and cost-effective than maintenance acid suppressive therapy in preventing duodenal ulcer [Ford et al. 2004]. A study by Sharma et al. [2001] also found that H. pylori eradication was more successful in decreasing recurrent gastroduodenal ulcer bleeding compared with ulcer healing treatment alone (17% versus 4% respectively). Maintenance acid suppression therapy was also not necessary after successful H. pylori eradication and ulcer healing [Liu et al. 2003].

MALT lymphoma

Multiple studies have demonstrated a strong association between H. pylori infection and MALT lymphoma [Parsonnet et al. 1994; Wotherspoon et al. 1991]. Both the American College of Gastroenterology (ACG) [Chey and Wong, 2007] and the Maastricht III consensus conference (MCC III) 2006 [Malfertheiner et al. 2007] have proposed H. pylori eradication as the first-line treatment for infected patients with stage I low-grade gastric MALT lymphoma, with favorable long-term outcome. In a large prospective series from Germany [Fischbach et al. 2004], 62% of patients with low-grade gastric MALT lymphoma had complete remission after H. pylori eradication within 12 months. Another study from Taiwan also suggested that anti-H. pylori therapy might be considered as one of the treatment options for early-stage H. pylori-positive gastric diffuse large B-cell lymphoma [L.T. Chen et al. 2005].

Gastric cancer

Gastric cancer is the second most common cause of cancer-related death in the world [Talley et al. 2008]. Both animal and human studies have demonstrated a clear association between H. pylori infection and gastric adenocar-cinoma [Eslick et al. 1999; Huang et al. 1998; Watanabe et al. 1998]. The Cag-A-positive strains of H. pylori further increases the risk for gastric carcinoma over the risk of infection with non-Cag-A strains [Huang et al. 2003]. The IARC estimates that H. pylori causes 36% and 47% of all gastric cancers in developed and developing countries respectively [IARC, 1994]. The epidemiological study EUROGAST included populations from both Asian and Western countries and demonstrated a six-fold increased risk of gastric cancer in H. pylori infected populations compared with uninfected populations [EUROGAST Study Group, 1993]. Furthermore, H. pylori can cause chronic active and atrophic gastritis, both are early steps in the carcinogenesis process [Siurala, 1966]. H. pylori eradication prevents development of these preneoplastic changes of the gastric mucosa, including atrophic gastritis and intestinal metaplasia [Asaka et al. 2001; Ohkuma et al. 2000; Kuipers et al. 1997]. Randomized control studies have shown that regression of these precancerous lesions or a decrease in progression is possible by H. pylori eradication [Zhou et al. 2003]. A study from China over a period of 7.5 years demonstrated that eradication of H. pylori significantly decreased the development of gastric cancer in H. pylori carriers without precancerous lesions [Wong et al. 2004]. Recently the Japanese Gast Study Group found that eradication of H. pylori in 544 patients after endoscopic resection of early gastric cancer significantly reduced the risk of developing metachronous gastric carcinoma [Fukase et al. 2008]. Most of these patients had either intestinal metaplasia or moderate-to-severe gastric atrophy. The risk of subsequent cancer reduced from 4 per 100 every year to 1.4 per 100 every year in the eradication group. The overall consensus is that H. pylori should be eradicated as soon as possible and best before precancerous lesions are present. The 2007 Asia–Pacific Consensus Conference recommended that population-based screening and antibiotic treatment of H. pylori in high-risk regions should be performed [Fock et al. 2008].

Uninvestigated dyspepsia

The MCC III recommended the H. pylori ‘test and treat’ strategy among adult patients under the age of 45 presenting with persistent dyspepsia [Malfertheiner et al. 2007]. The ACG recommended a cut-off age of 55 [Chey and Wong, 2007]. This recommendation is validated by a study in Canada, which concludes that H. pylori eradication has a small but statistically significant effect in H. pylori-positive uninvestigated dyspepsia [Chiba et al. 2002]. Another study from Malaysia also found that H. pylori ‘test and treat’ strategy is more cost effective but less satisfying than prompt endoscopy in the management of young Asian patients with uninvestigated dyspepsia [Mahadeva et al. 2008].

Supportive evidence of clinical benefits for H. pylori eradication

Functional dyspepsia

It remains controversial whether eradicating H. pylori infection is of clinical benefit in patients with functional dyspepsia. Several studies have demonstrated a beneficial effect in terms of symptomatic improvement in H. pylori eradication for functional dyspepsia [McNamara et al. 2002; McColl et al. 1998] but not supported by other studies. The latest meta-analyses, however, have shown a small but statistically significant clinical benefit in a subgroup of patients with functional dyspepsia after eradication of H. pylori infection [Hsu et al. 2001].

Nonsteroidal anti-inflammatory drugs (NSAIDs)

H. pylori infection and NSAIDs independently increase the risk of peptic ulcer bleeding by 1.79- and 4.86-fold respectively and by 6.13-fold when both factors are combined [Huang et al. 2002]. These two risk factors are at least additive if not synergistic in causing pepticulcer bleed. H. pylori eradication was associated with a reduced incidence of peptic ulcer in patients taking NSAIDs (OR 0.43, 95% CI 0.20–0.93) [Vergara et al. 2005]. Both long-term NSAIDs and aspirin users with history of peptic ulcer should be tested for H. pylori and receive eradication therapy if proven positive [Papatheodoridis and Archimandritis, 2005]. Proton pump inhibitor maintenance is necessary after eradication. In naïve NSAID patients, H. pylori eradication may prevent peptic ulcer and bleeding.

Other intestinal and extraintestinal disease

Recent studies have supported an association between H. pylori infection, unexplained iron deficiency anemia [DuBois and Kearney, 2005] and immune thrombocytopenic purpura (ITP) [Gasbarrini et al. 1998]. The MCG III recommended that H. pylori infection should be sought for and treated in patients with unexplained iron deficient anemia and in those with ITP [Tsutsumi et al. 2005]. The Third Chinese National Consensus Report has also added other H. pylori-related gastric diseases such as lymphocytic gastritis, gastric hyperplastic polyps and Menetrier's disease as supportive indications for H. pylori eradication [Hu et al. 2008].

Possible risks of H. pylori eradication

The Blaser's hypothesis

The major concern over a potential negative outcome associated with H. pylori eradication is the risk of provoking gastroesophageal reflux disease (GERD) and esophageal carcinoma. Blaser first raised this concern in 1999 [Blaser, 1999] based on circumstantial evidence that not all H. pylori-infected patients would develop significant clinical consequences in their lifetime and the possible commensal role of H. pylori, since this bacterium was infecting humans 58,000 years ago before migration out of East Africa [Linz et al. 2007]. He suggested that colonization with Cag-positive strains appears protective against proximal diseases including GERD, Barrett's esophagus, and adenocarcinomas of the gastric cardia and lower esophagus. Eradication of H. pylori may remove some beneficial strains and provoke esophageal disease or gastric cancer at the cardia [Hunt, 2001]. This hypothesis was subsequently debated on and the clinical evidence will be discussed [Graham et al. 2007].

GERD

The prevalence of H. pylori in patients with GERD is lower than in those without reflux disease [Metz and Kroser, 1999]. A meta-analysis found that H. pylori-negative status was associated with a significantly increased risk of GERD (pooled OR 1.34, 95% CI 1.15–1.55) [Cremonini et al. 2003]. Despite this, studies did not show H. pylori to have a direct pathogenic effect on GERD. It has no effect on gastroesophageal junction competence [Shirota et al. 1999] and it does not decrease the pressure of the lower esophageal sphincter. There was no significant change in the 24-hour esophageal pH before and after H. pylori eradication [Tefera et al. 1999]. GERD patients who failed H. pylori eradication also relapsed earlier than negative GERD controls and GERD patients who had successful eradication of H. pylori [Schwizer et al. 2001]. An analysis of eight double-blind prospective trials of H. pylori therapy in patients with duodenal ulcer disease confirmed that eradication of H. pylori did not worsen GERD but may improve symptoms in patients with pre-existing GERD [Laine and Sugg, 2002]. Eradication of H. pylori may be associated with a mild worsening of GERD in patients with corpus-predominant gastritis but an improvement in patients with antral-predominant gastritis. Blaser suggested that colonization with the Cag-positive strains may be protective against GERD. Unfortunately, Cag-A-positive strainshave also been associated with gastric adenocarcinoma [Huang et al. 2003].

Barrett's esophagus and esophageal carcinoma

Similar to GERD, a lower prevalence of Barrett's metaplasia and esophageal adenocarcinoma has been described in H. pylori-positive patients [Weston et al. 2000]. However, in a systematic review by Nakajima and Hattori [2004] the expected annual incidence of gastric cancer in patients with corpus atrophy with persistent infection was at least 5.8-fold higher than that for esophageal adenocarcinoma after the eradication of infection at all ages. For patients with underlying reflux esophagitis or Barrett's esophagus, the expected incidence of either gastric or esophageal adenocarcinoma with persistent infection was higher than that of esophageal adenocarcinoma after eradication of infection. This suggests that H. pylori plays an insignificant role in the pathogenesis of Barrett's esophagus and esophageal adenocarcinoma.

Childhood asthma

Two recent studies by Chen and Blaser [2008, 2007] suggested an inverse association of H. pylori infection with childhood asthma and allergic rhinitis. The presence of Cag-A-positive H. pylori strains in a child was inversely related to ever having asthma and this inverse association was stronger than that with adult-onset asthma. The author concluded that childhood acquisition of H. pylori is associated with reduced risks of asthma and allergy. Nevertheless, more prospective studies are needed to demonstrate a causal relationship between H. pylori eradication in childhood and subsequent development of asthma.

Antimicrobial resistance

There is an increasing trend of H. pylori treatment failure with traditional triple therapy containing proton pump inhibitors, amoxicillin, clarithromycin or metronidazole in many parts of the world [Graham and Shiotani, 2008]. Empirical therapies that do not reliably yield a greater than 90% successful rate should not be prescribed. A study has shown that unsuccessful treatments significantly increase resistance [Romano et al. 2008]. It is therefore important to choose the most effective first-line treatment regime in order to avoid treatment failure and subsequent secondary resistances.

Conclusion

The overall evidence strongly supports that the benefits of eradication of H. pylori in indicated patients far outweigh the risks (Table 1). Failure to eradicate H. pylori in patients with peptic ulcer disease is associated with a 60% annual ulcer recurrence rate compared with 10% after eradication and a two to three times increased risk of gastric adenocarcinoma [Marshall, 1994]. We therefore advocate the eradication of H. pylori in indicated patients as listed in the MCC III and ACG guidelines.

Conflict of interest

All authors have no conflicts to disclose.

Contributor Information

Ivan F.N. Hung, Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong.

Benjamin C.Y. Wong, Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong ; kh.ukh@gnowycb..

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