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Helicobacter pylori infection and current clinical areas of contention

Malfertheiner, Peter; Selgrad, Michael

Current Opinion in Gastroenterology: November 2010 - Volume 26 - Issue 6 - p 618–623
doi: 10.1097/MOG.0b013e32833efede
Stomach and duodenum: Edited by Mitchell L. Schubert
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Purpose of review The indication for Helicobacter pylori (H. pylori) eradication has been extended to few extragastroduodenal diseases. Scientific rigor needs to be applied as the list of clinical manifestations potentially related to H. pylori has disproportionally grown to its scientific evidence. Some potential beneficial aspects of H. pylori in allergic diseases and in the context of obesity are critically addressed in this review. The main challenge, however, continues to be the prevention of gastric cancer by H. pylori eradication. Strategies for identification of individuals and populations at risk are reported as well. A final aspect is dedicated to novel treatment regimens for overcoming the increasing treatment failures with proton pump inhibitor-based triple standards.

Recent findings H. pylori infection is associated with some extragastric diseases such as idiopathic thrombocytic purpura and iron deficiency anemia that benefit from eradication therapy. The inverse relation of H. pylori prevalence and the increase in allergies and obesity, as reported from epidemiological studies, has prompted research for elucidating potential underlying pathophysiological mechanisms. Strategies for gastric cancer prevention include serological screening, which allow adopting eradication therapy in individuals at high risk. New treatments for H. pylori include sequential, bismuth-based quadruple and nonbismuth-based quadruple therapies.

Summary The main clinical challenge remains prevention of H. pylori-related diseases by effective treatment and screening procedures.

Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University of Magdeburg, Magdeburg, Germany

Correspondence to Professor Dr Dres. h. c. Peter Malfertheiner, Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University of Magdeburg, Leipziger Str. 44, D-39120 Magdeburg, Germany Tel: +49 391 6713100; fax: +49 391 6713105; e-mail: peter.malfertheiner@med.ovgu.de

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Introduction

Although basic research on Helicobacter pylori (H. pylori)-related mechanisms of inflammation and carcinogenesis continues to expand, both reporting about fascinating modes of interaction between the microbe and host cells [1,2], the general clinical interest on the H. pylori infection has declined over the past years. Nevertheless, clinical challenges are still on. Standard eradication therapies mark an increased failure rate because of the emerging resistance to antibiotics. Prevention strategies to fight gastric cancer by H. pylori eradication are still not set in place in spite of the overwhelming rationale and strong evidence for such an action [2]. A further issue of contention is whether and which extragastric disease may be causally related to H. pylori infection or whether ‘adapted’ microorganisms to the gastric mucosa may or may not confer some beneficial effects to the host. We address these three clinical areas in the context of the most recent scientific reports.

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Helicobacter pylori and extragastric diseases

A possible association between H. pylori infection and extragastric diseases has been referred to a long list of diseases ranging from neurological disorders, cardiovascular diseases, and skin diseases to mental disorders [3]; it is worth mentioning that even Parkinson disease has been among them. To date, there are, however, only two [idiopathic thrombocytic purpura (ITP) and iron deficiency anemia (IDA)] extragastric diseases with a convincing evidence in context of H. pylori infection. In both of these conditions, H. pylori eradication leads to a clinical benefit. At the other end, however, there are indications for a beneficial role of H. pylori in the intriguing association of the bacteria with allergic diseases and obesity.

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Idiopathic thrombocytic purpura

The role of H. pylori in the pathogenesis of ITP was first described by Gasbarrini et al.[4]. The platelet count in patients with ITP returns to normal levels after H. pylori eradication [5] and this observation has been confirmed and extended. Improvement in platelet count after eradication therapy is obtained as well in adults as in children [6•]. The platelet recovery is a result of the eradication therapy and the eradication of the bacteria is partly explained by the reduction in autoantibody production. Thus, H. pylori assessment should be performed in chronic ITP patients and eradication therapy should be attempted in positive test cases. The recent data support the recommendation first offered in the European guidelines [7].

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Iron deficiency anemia

Several studies have confirmed the link between H. pylori and the pathogenesis of IDA. A recent pooled analysis of eight studies showed that H. pylori eradication therapy can improve IDA, as changes in hemoglobin and serum ferritin concentrations in the eradication groups were higher than those in controls [8]. These studies also demonstrated that H. pylori eradication therapy combined with iron administration is more effective than iron administration alone for the treatment of IDA. A recent meta-analysis of randomized controlled trials showed that treatment of H. pylori infection could be effective in improving anemia and iron status in IDA patients infected by H. pylori, particularly in patients with moderate or severe anemia [9•]. Another meta-analysis on observational studies also confirmed the benefit of eradication therapy in IDA [10].

Different results have been reported concerning IDA in adults compared to children and adolescent patients. In children and adolescents, the balance of iron intake and utilization is much more complex. A finding of particular interest is that the soluble transferrin receptor (sTFR) is significantly elevated in H. pylori-infected children with IDA compared to noninfected children, although serum transferrin and iron show normal levels. For this reason, the sTFR might be a better parameter for the assessment of the iron status in H. pylori-infected children than serum iron or ferritin [11,12]. The current clinical recommendation is to search and treat the H. pylori infection in IDA after exclusion of bleeding sources in the gastrointestinal tract [7].

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Can Helicobacter pylori be beneficial?

Recent findings suggest that H. pylori infection might have some beneficial effects for the development and course of some diseases. Two of those conditions in which H. pylori is proposed to be beneficial are allergic diseases and obesity.

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Asthma, allergy, and atopic diseases

The incidence of asthma and allergic diseases has increased dramatically over the last decades in developed countries. Clinical, epidemiological, and experimental observations indicate that the decrease in infectious diseases, especially those that occur during childhood can influence the development of allergic diseases [13]. Asthma, allergy, and atopic diseases show a negative association with H. pylori. Over the last decades, the prevalence of H. pylori has declined and in contrast the incidence of asthma and related disorders has risen drastically in developed nations. Blaser and colleagues [14–16] reported an inverse correlation between asthma bronchiale and allergy and the prevalence of H. pylori. Colonization with H. pylori, especially with CagA-expressing strains, is inversely correlated with the diagnosis of allergic asthma, supporting the hypothesis that acquisition of H. pylori is associated with a reduced risk of allergic diseases. However, those observations based on epidemiological studies have raised some controversial discussions because of the absence of convincing underlying mechanisms. Some potential mechanisms have recently been studied and proposed as explanation for the inverse relationship of H. pylori with allergic diseases. Allergic diseases are driven by T cells that produce T-helper type 2 (Th2) cytokines and are inhibited by Th1 responses. H. pylori infection activates a Th1 mucosal immune response and the H. pylori neutrophil-activating protein (NAP) appears to play an important modulating role in this process. Furthermore, NAP also inhibits Th2 responses by preventing eosinophilic accumulation in the lung with the associated increase in serum immunoglobulin E (IgE) in a mouse model of allergic asthma [17]. Based on these properties, NAP was identified as a candidate for vaccination as a preventive strategy against allergic diseases and NAP might be a critical molecule of H. pylori with a beneficial effect in allergic diseases [17,18]. Furthermore, the presence of CagA-expressing H. pylori strains in the gastric mucosa leads to a strong gastric recruitment of T-cell populations that might modulate the activity of T cells in other mucosal and cutaneous sites also [19,20].

In conclusion, the development of a vaccine containing microbial products, such as NAP, appears a good candidate for prevention and treatment of allergic diseases. The recent introduction of NAP-containing vaccines in the experimental setting for the prevention of H. pylori infection [21] could ‘theoretically’ provide a protective effect also against allergic diseases.

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Helicobacter pylori and obesity

The incidence of obesity is increasing in developed countries. Among possible related factors reported, changing dietary habits can be held responsible and also H. pylori has been proposed to play a role. H. pylori infection leads to chronic active gastritis in all infected individuals and thereby interferes with the release of gastric hormones, which are involved in the regulation of appetite and food intake. H. pylori infection leads to a decrease in circulating ghrelin through a reduction in ghrelin-producing cells in the gastric mucosa and to an increase in gastric leptin [22,23]. Ghrelin is an important factor in appetite and satiety regulation and after successful eradication of H. pylori, the number of ghrelin-positive cells in the gastric mucosa turns to normal. Based on these observations, weight gain caused by increased appetite after H. pylori eradication has been suggested.

Up to now, the studies analyzing the relationship between H. pylori and obesity are inconclusive. However, in the context of obesity and gut–brain interactions, the role of H. pylori will be better defined in the future.

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Screening and prevention of gastric cancer

Population-based screening for gastric cancer is currently the most effective strategy for primary prevention of gastric cancer. Furthermore, H. pylori eradication holds the potential to prevent gastric cancer development.

The large differences in the incidence of gastric cancer between populations pose a problem for population-based screening. Differences in incidence apart from host genetic factors are related to different H. pylori CagA status and local dietary habits [24].

In Japan and Korea, endoscopy-based population screening has allowed to detect early gastric cancer with the frequent option for endoscopic cancer removal [25,26]. More recently, serological tests have become available to identify patients at risk for gastric cancer development [27].

Serological screening has been implemented in countries at high risk for gastric cancer such as Japan. The infection with H. pylori and consequent atrophic gastritis are recognized as the main risk factors for gastric cancer development [28]. Thus, eradication therapy is likely to be most effective before the development of preneoplastic changes (i.e., gastric atrophy and intestinal metaplasia) [29]. In a recent calculation for a high-risk region in China, an empirically calibrated model of gastric cancer was used to estimate the reduction in lifetime cancer risk, life expectancy and screening, as well as treatment-related costs [30]. Three options have been considered in this model: single lifetime screening at age 20, 30, or 40; single lifetime screening followed by rescreening individuals with negative results; and universal treatment for H. pylori infection at age 20, 30, or 40.

Screening and treatment in individuals at the age of 20 resulted in adequate reduction in the lifetime risk for gastric cancer (men: 14.5%; women 26.6%) with costs below 1500 US$ per life year saved. By application of universal treatment, the risk reduction was even increased by 1.5 and 2.3%, respectively, but the incremental cost–effectiveness rates exceeded 2500 US$ per life year saved. Assessing persons at an older age or rescreening of negative individuals was not cost-effective. However, prospective trials on a global scale are needed to support these theoretical estimations.

The identification of the so-called ‘point of no return’ is critical for an effective prevention of gastric cancer. Several studies over the past years showed conflicting results whether preneoplastic changes (atrophy and intestinal metaplasia among others) might return to normal, remain invariant, or show progress. An indication for H. pylori eradication expected beyond the point of no return, comes from the multicenter Japanese study with a reduction in metachronous gastric cancer after endoscopic detection of early gastric cancer in the onset of patients who received H. pylori eradication [31]. For the prediction of the risk of gastric cancer development and to diagnose atrophic gastritis, serological testing with a combination of pepsinogen I and II, gastrin, and H. pylori antibodies yields accurate results with a high specificity [32,33]. Miki et al.[34] presented long-term results of gastric cancer screening in 101 892 asymptomatic individuals (mean age of 48.7 years) using the pepsinogen method. In their cohort, 125 gastric cancers (80% early-stage gastric cancer) were detected. Furthermore, a recent prospective case cohort study with a follow-up period of 15 years was carried out in China showing that a low pepsinogen I/II ration has the potential to identify individuals with an increased risk for gastric cancer [35••].

However, caution needs to be raised concerning the use of low pepsinogen as an early marker for gastric cancer. Preneoplastic changes generally do not occur in the diffuse-type gastric cancer and, thus, the pepsinogen method seems to be not as useful for this condition.

In conclusion, the serological testing for the simultaneous identification of H. pylori infection by antibody detection and atrophic gastritis is a promising way to predict the risk of gastric cancer and is useful in high-risk regions. However, a specific marker and a global concept for early detection of gastric cancer are still missing. At present, guidelines recommend screening and treating in high-risk gastric cancer areas [36,37].

The implementation of screening and follow-up strategies of patients with already known preneoplastic changes in the gastric mucosa is absolutely required, as recent data from the Netherlands have shown [38,39] that the risk of gastric cancer development in these patients is high. Guidelines for practical implementation of follow-up strategies for these patients are still needed.

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Treatment challenges

The current standard triple therapy for H. pylori eradication based on proton pump inhibitor (PPI) combined with clarithromycin and amoxicillin and/or metronidazole continues to be the first-line option around the globe [7,37,40,41], but faces increasing rates of failure. Several causes have been identified to explain the efficacy loss of PPI triple therapy, including duration of therapy, rapid metabolization of PPI because of (CYP) 2C19 polymorphisms with insufficient control of gastric pH, and a consequent reduction in the antibiotic efficacy [42]. The most important reason for treatment failures, however, is the dramatic increase in antibiotic resistance [43,44]. The primary concern is the clarithromycin resistance, which exceeds by far the 15–20% set as the bar for effectively using clarithromycin as the most potent individual antibiotic in first-line treatment regimen [7,45]. Metronidazole resistance stays constant and up to a metronidazole resistance of 40%, this does not seem to impact on treatment results. Amoxicillin remains virtually unaffected by resistance problems.

The challenge, therefore, is to overcome clarithromycin resistance by either finding an effective substitute among currently available antibiotics or by modifying other complex regimens. Among various attempts to improve the effect of the eradication therapies, three approaches deserve special attention and comments: sequential therapy; quadruple therapies; and levofloxacin as substitute of clarithromycin in PPI triple therapies.

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Sequential therapy

Sequential therapy constantly found superior to conventional triple therapies is an Italian invention and a new variant of a quadruple therapy, composed of 5 days dual therapy with PPI and amoxicillin followed by another 5 days with PPI, clarithromycin, and 5-nitroimidazole [46]. The sequential therapy regimen has now been tested in 13 randomized trials and the therapeutic gain was overall confirmed in respect to the standard triple therapy [47]. Outside Italy, the sequential therapy was also confirmed, though not in controlled trials, to provide high eradication rates [48]. However, it may not work in all geographic areas as a recent not fully published trial from Korea found no superiority of the sequential therapy compared to standard triple therapies. The rationale for the sequential therapy is that within the first 5 days of therapy, clarithromycin-resistant strains are eliminated by PPI-amoxicillin, and the remnant strains are then eradicated by the 5 days triple to follow. Similar results to the sequential therapy have been reported if all four drugs are given simultaneously and this may even shorten the treatment duration to 5 days [49]. For a general recommendation of the sequential therapy, or its quadruple variation as first line, studies from multicenter trials extended to other geographic areas need to be performed.

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Quadruple therapy

The original quadruple therapy based on omeprazole, bismuth subcitrate, metronidazole, and tetracycline (OBMT) is superior to standard triple therapy [50] and already available in the United States in a novel single capsule galenic formulation (bismuth, metronidazole, and tetracycline in one capsule), but currently not available on trade outside the United States. OBMT is the preferred option as second-choice treatment and may be used as first line in areas where clarithromycin resistance exceeds 20% [7]. A recent study from China reported on a new quadruple regimen adding bismuth potassium citrate to the standard therapy, including PPI, clarithromycin, and amoxicillin. This therapy seems to be superior to PPI triple therapy, and combined with the addition of bismuth prolongation of the treatment duration from 7 to 14 days allowed to overcome clarithromycin resistance in 84% of patients [51••]. The complete substitution of clarithromycin as in the OBMT regimen may be even a better choice to evade the problem of clarithromycin resistance [52].

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Novel triple regimen with substitution of clarithromycin

Among classes of antibiotics emerged to be incorporated in triple regimen are fluoroquinolones (levofloxacin, moxifloxacin) and rifabutin. Currently, they are recommended to be incorporated in third-line treatments.

The increasing prevalence of H. pylori-resistant strains to clarithromycin has prompted authors to study the use of levofloxacin as first line. In a direct crossover competition between PPI, amoxicillin, levofloxacin (PPI-AL) with the standard PPI, amoxicillin, clarithromycin (PPI-AC), PPI-AL was inferior by 7% (80.1% PPI-AL vs. 87.4% PPI-AC) [53••].

However, in patients who failed the standard triple in first line, PPI-AL was superior as second line when compared to PPI-AC second line after failure with the levofloxacin-containing triple used in first line.

This study impressively indicates that in the absence of a novel antibiotic, those used as rescue antibiotics (i.e., levofloxacin) cannot be effectively replaced up to first line and selected as first line. In the presence of clarithromycin resistance above 15–20%, treatment should be directed to OBMT and other quadruple therapy solutions.

The development of new molecular tests that allow easy detection and monitoring of the antibiotic resistance in various geographical areas will be crucial for a timely change in the first-line treatment choices in the various regions [54•]. The aspect of proper treatment duration needs to be kept in consideration. Although standard triple therapy does apparently not significantly benefit from treatment prolongation [55], it does matter for quadruple therapy and in all other cases when rescue therapies need to be employed [50,53••].

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Conclusion

We have addressed several areas of H. pylori and related clinical challenges. Improved gastric cancer prevention strategies by early H. pylori detection and eradication have been established in high-risk areas. Currently, meaningful concepts are only available for high-risk regions and a global concept and guidelines for prevention are still missing. The challenge for the treatment of the infection is represented by decreasing eradication rates over the years. New treatment strategies include prolongation or switch of the antibiotics. A safe and effective vaccine for primary prevention would solve most of the current problems. H. pylori infection is related to some specific extragastric diseases and eradication of H. pylori is beneficial also in those conditions. Mechanisms on how H. pylori, the key pathogen for gastroduodenal diseases, affects extradigestive diseases remains intriguing.

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References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest

•• of outstanding interest

Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 665–668).

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Keywords:

gastric cancer screening and prevention; Helicobacter pylori; treatment

© 2010 Lippincott Williams & Wilkins, Inc.