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Volume 10 • Supplement 1 • 2005
H E L I C O B A C T E R
Helicobacter pylori and Non-malignant Diseases
Limas Kupcinskas* and Peter Malfertheiner† *Department of Gastroenterology, Kaunas University of Medicine, Kaunas, Lithuania; †Otto-von-Guericke-Universität, Magdeburg, Zentrum für Innere Medizin, Klinik für Gastroenterologie, Hepatologie und Infectiologie, Magdeburg, Germany A B S T R A C T
This paper reviews new literature data from March in case of low prevalence of the infection. H. pylori 2004 to April 2005 about the association between eradication is of value in chronic NSAID users, but is Helicobacter pylori and non-malignant disease of the insufficient to prevent NSAID-related ulcer disease.
upper gastrointestinal tract. Eradication of H. pylori In developed countries H. pylori eradication does is indicated for all patients with non-malignant diseases not cause gastro-esophageal reflux disease (GORD), associated with this pathogen. However, its effect is however, a negative association between H. pylori and variable, ranging from the highest benefit in the cure GORD does exist, especially in Asia, but the nature of peptic ulcer disease to a small benefit in patients of this relationship should be further clarified.
with non-ulcer dyspepsia. Test and treat strategy is Keywords. Helicobacter pylori, peptic ulcer disease,
still cost-effective for management of patients with gastro-esophageal reflux disease, nonsteroidal anti- uninvestigated dyspepsia. The only limitations of the inflammatory drugs, non-ulcer dyspepsia, uninvest- strategy are the patient’s age and the cost benefit ratio independent of the cag pathogenicity island (PAI).
Peptic Ulcer Disease
The outcome of a H. pylori infection is thought to The role of Helicobacter pylori in peptic ulcer reflect an interplay between the virulence of the disease (PUD) has been well established.
infecting strain, host genetics, and environmental However, in the past year, newer data on this factors. Lu et al. tested whether host genotypes issue were provided. Researchers from Graham’s of the tumor necrosis factor-alpha (TNF-alpha) group identified a H. pylori gene that encompasses promotor single nucleotide polymorphism could both jhp0917 and jhp0918 called dupA (duodenal determine clinical and histological outcomes in ulcer-promoting gene) and is associated with duo- case of H. pylori infection [3]. They revealed that denal ulcer (DU) [1]. dupA was present in 42% both TNF-alpha-1031C and -863A carriers have of DU vs. 21% of patients with gastritis (adjusted increased DU and gastric ulcer (GU) risk in the odds ratio [OR] = 3.1, 95% confidence interval presence of H. pylori infection. As compared to [CI] = 1.7–5.7). dupA is a novel marker associated TNF-α-863CC and -1031TT genotype combina- with an increased risk for DU and reduced risk tions, the ulcer risk in case of H. pylori infection for gastric atrophy and cancer. Its association with was 2.46 (95% CI = 1.32–4.59) for the carriers DU-promoting and -protective effects against with either the -1031C or -863A allele, with an atrophy/cancer was evident in both Asian and increase of up to 6.06 (95% CI = 3.57–10.21) for Western countries. Researchers from the Nether- the individuals harboring both -863A and -1031C lands revealed that H. pylori plasticity region locus alleles. For patients with GU, the 863CC genotype jhp0947–jhp0949 is associated with DU and had a higher rate of intestinal metaplasia than the interleukin-12 production in monocyte cells [2].
-863A carrier. The authors concluded that TNF- The jhp0947–jhp0949 loci might be a novel alpha-1031 and -863 promoter single nucleotide putative H. pylori marker for disease outcome polymorphism should be novel host factors todetermine the risk of peptic ulceration upon Reprint requests to: Limas Kupcinskas, Department of Gastroenterology, Kaunas University of Medicine, Mickeviciaus Str. 9, Kaunas, LT-44307, Lithuania. E-mail: [email protected] within the past century. A large epidemiological 2005 Blackwell Publishing Ltd, Helicobacter, 10 (Suppl. 1), 26–33
H. pylori and Non-malignant Diseases study was carried out in Copenhagen County, for 2–4 more weeks (OR = 1.11; 95% CI = 0.71– Denmark [4]. A random sample of 2416 Danish adults with no history of PUD were enrolled in Maintenance of antisecretory therapy has been a population-based prospective cohort study in the standard long-term treatment for patients with 1983 and 1994. The overall 11-year cumulative bleeding ulcers to prevent recurrent bleeding incidence of PUD was 2.9% (95% CI = 2.2–3.6), even after the discovery of H. pylori. However, i.e. 1.6% (95% CI = 1.1–2.1) for DU, and 1.3% the precise efficacy of H. pylori eradication for (95% CI = 0.8–1.7) for GU. Poor socioeconomic the prevention of rebleeding from peptic ulcer status increased the risk of PUD independently was unknown and the authors of a Cochrane of H. pylori infection (OR = 2.7; 95% CI = 1.1– Collaboration systematic review have shown 6.1) and accounted for 17% of all ulcer cases.
that treatment of H. pylori infection is more High physical activity at work increased the risk effective than antisecretory therapy alone, with of PUD in people infected with H. pylori (OR = or without long-term maintenance antisecretory 2.6; 95% CI = 0.8–8.0). Family history of PUD therapy, in preventing recurrent bleeding from or Lewis blood group antigens did not relate to PU. Consequently, all patients with PU bleeding ulcer incidence. In developing countries, a should be tested for H. pylori infection, and decline of the prevalence of PUD might be the eradication therapy should be prescribed to consequence of the global decreasing prevalence H. pylori-positive patients [7].
The most effective therapy for H. pylori- H. pylori and NSAIDs
associated ulcer disease is bacterial eradication.
More than 15 years of experience were summar- Despite very intense research during recent years, ized in a comprehensive Cochrane Collaboration the relation and interaction of nonsteroidal anti- systematic review, updated in 2004 [5]. Data from inflammatory drugs (NSAIDs) and aspirin with 53 trials were included to compare eradication H. pylori infection in causing upper gastrointestinal therapy to placebo or pharmacological therapies damage remain a very controversial and complex in H. pylori-positive patients. In DU healing, eradication therapy was superior to an ulcer- Greek researchers compared acute upper gas- healing drug (relative risk [RR] of ulcer persisting = trointestinal bleeders taking NSAIDs and non- 0.66; 95% CI = 0.58–0.76) and to no treatment bleeding NSAID users and found that H. pylori (RR = 0.37; 95% CI = 0.26–0.53). In GU healing, infection was the only significant risk factor for no significant differences were detected between upper gastrointestinal bleeding (OR = 1.7; 95% eradication therapy and ulcer healing drugs CI = 1.2–2.5). CagA positivity was not associated (RR = 1.32; 95% CI = 0.92–1.90). In preventing with gastrointestinal bleeding [8]. Another case- DU recurrence, no significant differences were control study was prospectively conducted in 105 detected between eradication therapy and main- H. pylori-negative DU bleeders and the same tenance therapy with ulcer-healing drugs (RR of number of sex- and age-matched H. pylori-positive recurring ulcer = 0.73; 95% CI = 0.42–1.25), but patients. They found that NSAID consumption was eradication therapy was superior to no treatment more common among H. pylori-negative patients (RR = 0.20; 95% CI = 0.15–0.26). In preventing (81%) compared to H. pylori-positive subjects gastric ulcer recurrence, eradication therapy (58.1%, p < .001). H. pylori-negative bleeders was superior to no treatment (RR = 0.28; 95% needed hemostasis more often (55.2% vs. 31.4%, CI = 0.18–0.43). Gisbert and Pajares performed p < .001) or surgical intervention (15.2% vs. 4.8%, a meta-analysis of randomized clinical trials p = .011) and included a greater proportion of comparing the efficacy on ulcer healing of a 7- rebleeding (32.4% vs. 13.3%, p = .001) and a higher day proton pump inhibitor (PPI)-based triple rate of in-hospital mortality (15.2% vs. 3.8%, therapy vs. the same regimen but prolonging the p = .005) [9]. The effect of H. pylori eradication PPI for several more weeks. Authors concluded on gastroduodenal mucosal injury induced by that in patients with PUD and H. pylori infec- taking medium-dose aspirin (300 mg) was invest- tion, prolonging the therapy with PPI after a igated in another study. All subjects underwent triple therapy for 7 days with a PPI and two anti- upper gastrointestinal endoscopy for determina- biotics is not necessary to induce ulcer healing.
tion of H. pylori status and Lanza score. The The mean ulcer-healing rate with a 7-day treat- H. pylori-positive patients were randomized to ment was 91% vs. 92% when PPI was prolonged receive aspirin + eradication therapy or aspirin 2005 Blackwell Publishing Ltd, Helicobacter, 10 (Suppl. 1), 26–33
+ placebo. Endoscopic reassessment was done users. The risk of PU, adjusted for age, gender, 4 months after the onset of aspirin or when H. pylori infection, and antisecretory drug use was symptoms developed. Lanza scores significantly higher in acute (GU: OR = 4.47, 95% CI = 3.19– increased in the placebo group (0.69 ± 0.87 vs.
6.26 and DU: OR = 2.39, 95% CI = 1.73–3.31) 2.25 ± 1.3, p < .0001) and did not change in the than chronic NSAID users (GU: OR = 2.80; 95% H. pylori-eradicated group after aspirin treatment CI = 1.97–3.99 and DU: OR = 1.68; 95% CI = (0.43 ± 0.72 vs. 0.75 ± 0.93, p > .05). The authors 1.22–2.33). PPI treatment was associated with a concluded that H. pylori eradication may prevent reduced risk of PU in both acute (OR = 0.70, 95% medium-dose aspirin-induced gastroduodenal CI = 0.24–2.04) and chronic (OR = 0.32, 95% mucosal injury [10]. A study assessing the CI = 0.15–0.67) NSAID/aspirin users. PPI treat- prevalence of H. pylori infection in patients with ment resulted in an absolute risk reduction of PU perforated PUD, and comparing it with the by 36.6% in acute and 34.6% in chronic NSAID/ prevalence in patients with an uncomplicated ulcer aspirin users. Authors suggested that PPI cotreat- showed that the mean prevalence of H. pylori ment is advisable in symptomatic elderly patients infection in patients with perforated PU is, overall, who need to be treated with NSAIDs or aspirin only about 60%, which contrasts with the 90– even for a short period of time [14].
100% figure usually reported in noncomplicatedulcer disease. However, the most important factor H. pylori and Non-ulcer Dyspepsia
associated with H. pylori-negative perforated PUis NSAID use, and if this factor is excluded, Functional or non-ulcer dyspepsia (NUD) is prevalence of infection is almost 90%, similar to defined as persistent or recurrent pain/discomfort that found in patients with nonperforating ulcer in the upper abdomen, where no structural disease. In the multivariate analysis, NSAID intake explanation for the symptoms is found. Both was the only variable that correlated with PU Maastricht 2–2000 and Maastricht 3–2005 perforation (OR = 3.6; 95% CI = 1.3–10) [11]. A Consensus statements advise the eradication of prospective cohort study evaluating the interac- H. pylori in patients with NUD based on the tion of H. pylori and NSAIDs and how these two evidence of the meta-analysis. Seventeen rand- factors influence the expression of COX-2 mRNA omized controlled trials were included in the in gastric antral, corpus mucosa, and GU found most comprehensive Cochrane Collaboration that H. pylori infection was associated with systematic review updated in 2005. In this study increased COX-2 expression in antral mucosa 14 trials compared antisecretory dual or triple for both NSAID users and non-users. In NSAID therapy with placebo antibiotics (with/without) users, H. pylori infection was not associated antisecretory therapy, and evaluated dyspepsia at with increased COX-2 expression at ulcer edge.
3–12 months [15]. There was an 8% RR reduction H. pylori infection was associated with increased in the H. pylori eradication group (95% CI = 3– COX-2 expression in gastric antral mucosa for 12) compared to placebo. The number needed to both NSAID users and non-users, but not in GU, cure one case of dyspepsia was 18 (95% CI = 12– where the effect of NSAID inhibition plays a major 48). Therefore, H. pylori eradication has a small but role. The authors interpreted indirectly that statistically significant effect on H. pylori-positive H. pylori eradication does not interfere with GU NUD. In addition to symptomatic improvement, healing in NSAID users [12]. A study examining 4–6.2% of patients enrolled in the NUD trials the effect of eradication of H. pylori prior to developed PUD during follow-up in the placebo NSAID use, in H. pylori-infected and H. pylori- group, therefore H. pylori eradication prevents eradicated gerbils, followed by administration of development of PU in NUD patients [15,16].
indomethacin and rofecoxib, showed the reduction Several important clinical studies confirming of gastric damage in Mongolian gerbils cured from the superiority of test and treat strategies in the the infection. Indeed, rofecoxib caused less severe management of NUD were published in 2004.
gastric damage than indomethacin in H. pylori- Lassen et al. assessed the long-term effect of a eradicated gerbils [13]. A very important study test and treat strategy compared with prompt evaluated the risk of PU associated with acute and endoscopy [17]. A total of 500 patients presenting chronic NSAID consumption or aspirin therapy in in primary care with dyspepsia were randomized elderly subjects, and the influence of antisecretory to management by H. pylori testing plus eradica- treatment on this risk. The study included 676 tion therapy or by endoscopy. They concluded elderly NSAID or aspirin users and 2435 non- that on a long-term basis (a median 6.7 years after 2005 Blackwell Publishing Ltd, Helicobacter, 10 (Suppl. 1), 26–33
H. pylori and Non-malignant Diseases randomization; range 6.1–7.3 years), a H. pylori but we do not have enough data to determine a test and the eradication strategy is as efficient as prompt endoscopy for management of dyspeptic In some studies, authors tried to identify sub- patients in primary care and reduces the use of groups of patients with NUD who might show a endoscopy (mean difference 0.62 endoscopies/ major benefit from H. pylori eradication. Finnish person; 95% CI = 0.38–0.86) and antisecretory researchers revealed that antrum-predominant medication (mean difference 102 defined daily gastritis in NUD patients seems to carry an doses/person; 95% CI = 1–205). In contrast, a increased risk for PU [24]. An Italian group found Finnish study of 1552 dyspeptic patients aged that in H. pylori-positive NUD patients during between 25 and 60 years without alarm symptom a 1 year follow-up, DU developed in 12 (22.6%) and followed-up for 2 years, the test-and-treat patients with duodenal colonization and only in strategy did not reduce the number of endoscopies.
two (1.6%) without (OR = 6.29; 95% CI = 2.4– However, this strategy significantly improved dyspeptic symptoms, quality of life, and reducedrisk of development of PUD [16]. Further results H. pylori and GORD
of a large, excellent (CADET) study carried out inCanada, indeed showed that H. pylori eradication During the last year there were ongoing dis- is more cost-effective than short-term omeprazole cussions concerning the relationship between treatment for dyspepsia [18]. In another economic H. pylori infection and gastro-esophageal reflux analysis, a collaborative group has prospectively disease (GORD). The prevalence of H. pylori in registered trials comparing prompt endoscopy GORD patients appears to be lower than in the with a test and treat approach, with the aim of per- general population. Also the prevalence of H. pylori forming an individual patient data meta-analysis is higher in non-erosive disease and gradually of both effect and resource utilization data [19].
decreases in more severe grades of erosive esophag- Five trials were identified, containing 1924 patients itis and Barrett’s esophagus. Although the trend (946 endoscopy; 978 test and treat). The RR of is the same in the countries with a high prevalence remaining symptomatic patients after 1 year was of H. pylori, the proportion of infected patients slightly reduced with endoscopy compared to the is higher in these countries. In a 10-year cross- test and treat (RR = 0.95; 95% CI = 0.92–0.99).
sectional study in the Netherlands, H. pylori was However, the test and treat cost was substantially significantly less often detected in patients with less ($389; 95% CI: $275–$502) per patient.
reflux esophagitis or Barrett’s esophagus compared Thus, H. pylori eradication is an appropriate with the control group, 20 vs. 29% ( p < .001) [26].
option for patients infected with H. pylori and In the ProGORD study, risk factor analysis was uninvestigated/non-ulcer dyspepsia. The test and performed on 2834 non-erosive reflux disease treat strategy is recommended, but may not be (NERD) and 2455 erosive reflux disease (ERD) suitable in older patients. The age limit proposed patients. H. pylori was present in 28.8% and for this strategy by simulation models and expert 25.1%, respectively ( p < .05). Multivariate opinion [20] is 55 years, but it could be decreased analysis revealed that a higher level of education in areas of high gastric cancer incidence. In a study and a positive H. pylori status were associated with from Great Britain, a cohort of 1852 consecutive a lower risk of ERD [27]. Vakil et al. analyzed a gastric cancer cases were investigated, and patient large number of patients with erosive esophagitis age > 55 years (OR = 9.5; 95% CI = 3.8–23.9) was and established that the proportion of H. pylori found to be a significant positive predictor for seropositive- and seronegative-patients for each cancer [21]. However, the study from Germany grade of esophagitis was: grade A, 38%, 36%; grade revealed that in NUD patients without alarm B, 41%, 39%; grade C, 16%, 19%; and grade D, symptoms, increasing the age threshold for prompt 5%, 6%, respectively. The rates of esophagitis endoscopy from 45 to > 50 and > 55 years could healing (with PPI) were not influenced by H. pylori raise the rate of excluded patients with cancer status [28]. The same trend was observed in a from 2.3% to 5.5% and 8.6%, respectively [22].
series of Lithuanian patients, although the absolute As gastric cancer is rare in dyspeptic patients, percentage was higher; the prevalence of H. pylori randomized controlled trials to evaluate different was 81% in NERD, 71.4% in esophagitis grade referral age thresholds are unfeasible. The cost A, 55% in grade B, and 40% in grades C+D [29].
effectiveness of the test and treat strategy decrease In a Japanese study, the overall prevalence of H. where the prevalence of H. pylori is low [23], pylori infection in the reflux esophagitis patient 2005 Blackwell Publishing Ltd, Helicobacter, 10 (Suppl. 1), 26–33
group (24.1%) was significantly lower than in 1.23), but not with regurgitation (OR = 1.05, the control group (71.2%). The prevalence of 95% CI = 0.97–1.14). H. pylori eradication had H. pylori infection in the patients with Barrett’s no effect on the overall prevalence of heartburn esophagus tended to be lower than that in the (OR = 0.99, 95% CI = 0.88–1.12) or regurgitation patients with reflux esophagitis alone (reflux (OR = 1.04, 95% CI = 0.91–1.19) and did not esophagitis alone, 30.0%; short segment Barrett’s improve pre-existing symptoms of heartburn or esophagus, 18.7%; long segment Barrett’s esopha- reflux [35]. In the study from Hong Kong, 236 patients with GORD were randomly assigned Further data addressing the possible negative to omeprazole triple therapy (HpE group) or association between H. pylori infection and eso- omeprazole with placebo. One-year follow-up phageal premalignant diseases and esophageal revealed that H. pylori eradication leads to more adenocarcinoma were also published last year.
Weston et al. found three factors significantly In a randomized controlled trial, Kuipers et al.
associated with index diagnosis of esophageal investigated whether H. pylori eradication influ- high grade dysplasia or adenocarcinoma – large ences gastritis and its sequelae during long-term hiatal hernia, Barrett’s length (longer length), and absence of H. pylori infection [31]. CagA- thirty-one H. pylori-positive GORD patients positive H. pylori strains were associated with with long-term omeprazole maintenance therapy less disease. In Colombian patients with Barrett’s were randomized to either continuous PPI or an esophagus, most were H. pylori-positive, but H. pylori-eradication regimen. Most H. pylori- CagA-positive infections were unusual. The data positive GORD patients had a corpus predominant illustrated how consistent corpus inflammation pangastritis during omeprazole maintenance reduces acid secretion, and prevents Barrett’s therapy. Eradication of H. pylori induced esophagus but only among those with abnormal regression of corpus glandular atrophy. H. pylori gastro-esophageal reflux barriers [32]. A Spanish eradication did not worsen reflux disease or lead to study also provides evidence supporting the a need for increased omeprazole maintenance dose independent protective role of CagA-positive [37]. A randomized controlled trial was carried H. pylori status and IL-1B and ILRN allele out on 157 functional dyspeptic patients, who polymorphisms against GORD [33]. In the meta- were assigned to eradication therapy or placebo analysis, the data on the role of the CagA-positive and followed-up 12 months. Reflux esophagitis H. pylori strains are contradictory. Several studies developed in 6% of the eradication group and in supported the negative association between CagA- 5% of the controls ( p > .05) [38]. A prospective positive H. pylori strains against GORD, but were 1-year follow-up study of 255 patients with not confirmed by others. A multitude of patients DU was also carried out in Lithuania. H. pylori suffer from H. pylori infection and GORD, eradication did not significantly influence the simultaneously. Therefore, further studies are prevalence and incidence of reflux esophagitis, needed to clearly answer the question whether but there was a significantly lower prevalence of infection with CagA-positive H. pylori strains, GORD after successful H. pylori eradication, as which bear a well-documented risk for gastric patients with non-erosive GORD had been cured cancer and PUD, is really helpful against more [39]. In contrast, a Japanese study found that severe reflux esophagitis and, in consequence, 10% of PUD patients developed GORD after a perhaps protective against Barrett’s esophagus cure of H. pylori infection. An age > 70 years and Barrett’s adenocarcinoma [34].
was associated with the development of GORD The data published in 2004–2005 demonstrate [40]. Malfertheiner’s group reported that during that eradication of H. pylori could be differently long-term follow-up after H. pylori eradication, associated with the development of erosive or patients experienced improvement as frequently non-erosive GORD in separate patient subgroups.
as deterioration of reflux symptoms. There Harvey et al. in the population-based study was a tendency towards improvement of reflux (Bristol Helicobacter project) investigated more symptoms if PUD had been the indication for than 10,000 people, of whom the H. pylori- eradication, but towards deterioration in patients positive cases were randomized to placebo or to with initial functional dyspepsia [41]. Raghunath eradication therapy. There was a weak association et al. in a systematic review concluded that there between H. pylori infection and increased pre- is no evidence to indicate that H. pylori eradica- valence of heartburn (OR = 1.14, 95% CI = 1.05– tion in DU disease provokes reflux esophagitis 2005 Blackwell Publishing Ltd, Helicobacter, 10 (Suppl. 1), 26–33
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