THE INTRIGUING RELATIONSHIP OF HELICOBACTER PYLORI INFECTION AND GASTRO-OESOPHAGEAL REFLUX DISEASE
C. Knippig and P. Malfertheiner
Otto-von-Guericke-Universit¨at Magdeburg, Department of Gastroenterology, Hepatology and Infectiology, Magdeburg, Germany
Introduction
The contrary epidemiological trends of an increase of gastro-oesophageal reflux disease (GORD) and a de- crease of Helicobacter pylori infection have induced the suggestion that Helicobacter pylori is a possible etiologic factor contributing to the increase of GORD pre- valence. These have forwarded several hypothesis to explain the phenomenon, but none is convincing. Fur- thermore eradication of Helicobacter pylori leads to an increase of oesophagitis in patients with ulcer disease as reported by some authors, but not confirmed by others.
Finally there are several implications of Helicobacter pylori infection to gastric physiology that need to be considered in search for a satisfacting explanation.
This article shall give insights into the complex re- lationship of Helicobacter pylori infection with GORD and its implications for the clinical management.
Epidemiology
There is not a gold standard for the definition of GORD[1]. As 24 hour pH-metry studies have shown that only a minority of acid episodes are associated withGORD symptoms and correlate only somewhat with the presence of oesophagitis, definition of GORD has been a point of discussion during the last decade.
The Geneval workshop defined GORD pragmatically as “heartburn symptoms sufficient to impair quality of life” knowing that there is an overlap with the defini- tion of dyspepsia and that this definition will cause confusion between the definition of a disease entitiy and a working diagnostic criteria for clinical use.
Heartburn prevalence ranges from 9% in Europe to 38% in Northern Europe and 42% in the US [2].
Frequency of oesophagitis has been described with a prevalence from 4–76.9% [1]. One of the predispos- ing factors for GORD is the hiatal hernia (Fig. 1),
which can be found in 2.9–20% of patients if it is smaller than 2 cm and from 4.1–40% if the hiatal hernia is more than 2 cm [1].
In patients with reflux symptoms or oesophagitis a lower prevalence of Helicobacter pylori infection was found in some studies, suggesting a possible protective effect of Helicobacter pylori infection [3]–[6]. A syste- matic review evaluating 20 studies found the average prevalence of Helicobacter pylori infection in patients withGORDto be 38% from a world perspective [1], [7]. The pooled estimate of the odds ratio for the pre- valence of Helicobacter pylori in patients with GORD was 0.60 (0.47–0.78 CI, Table 1). However evidence for this protective role was equivocal. Whereas a lower prevalence of Helicobacter pylori infection was found among asian GORDpatients [8], [9], this effect is less prominent in caucasian populations.
These ethnic differences may be attributed to different patterns of Helicobacter pylori gastritis among these populations and therefore may also ex- plain different study results.
Fig. 1. The impact of hiatal hernia in the pathophysiology of GORD (LOS: lower oesophageal sphincter)
gastritis results in hypergastrinaemia and acid hyper- secretion. Corpus predominant or atrophic pangas- tritis lead to decreased acid production and therefor can play a somehow protective role for oesophageal acid exposure ([11]–[13], Figs. 2 and 3).
If Helicobacter pylori is eradicated, gastritis with low acid output is healed leading to higher acid exposure of the esophagus and possibly resulting in GORD [3] if gastro-oesophageal reflux barrier is impaired [14]. As many Helicobacter pylori infected patients without dis- ease have a mixed pattern of gastritis, the elevated gastrin resulting from antral inflammation fails to cause gastric acid secretion because of corpus inflammation.
Clinical observations
The clinical effect of the above described relation- ship has to be analysed under six different aspects:
- The effect of Helicobacter pylori eradication on GORDsymptoms and severity
- The effect of Helicobacter pylori infection and its eradication on proton pump inhibitor (PPI) efficacy
- The effect of Helicobacter pylori infection and its eradication on histology if long term PPItherapy is required for GORDmaintenance therapy
- Helicobacter pylori infection and its role in Barrett’s oesophagus
- The role of cagA-positive-strains in patients with Barrett’s oesophagus
- The role of cagA-positive-strains in patients with oesophageal adenocarcinoma.
Type of gastritis and impact on gastric physiology
One reason for the variable effect of Helicobacter pylori infection and its eradication on acid secretion is the dependence on the type and distribution of gastritis [10]. Non-atrophic predominantly antral
Table 1. Odds ratio for prevalence of Helicobacter pylori in patients with esophagitis [1], [7]
Fig. 2. The pathophysiology of GORD (TLESR: transient lower esophageal sphincter relaxation; LES: lower esophageal sphincter pressure)
Fig. 3. Impact of the pattern of gastritis: antrum predominant gastritis vs. pangastritis
Effect of Helicobacter pylori eradication on GORD symptoms and severity
The actual data range from a more beneficial to an harmful or simply no effect of Helicobacter pylori er- adication on GORD.
The first report of Labenz et al on an increase of the incidence of oesophagitis in ulcer patients after Helicobacter pylori eradication has been confirmed by further studies in patients with corpus predominant gastritis and associated hypochlorhydria. The effect was attributed to the recovery of acid secretion after Helicobacter pylori eradication [15], [16]. Further stu- dies confirmed the increase of gastro-oesophageal re- flux [17], [18] after eradication. A recent prospective, double blind, placebo controlled, randomised trial in- cluding 104 Helicobacter pylori infected GORD pa- tients could show that Helicobacter pylori eradication was the only predictor of treatment failure of GORD. The authors explained the worsening control of reflux disease after Helicobacter pylori eradication with the ammonia production of Helicobacter pylori infection which augments the acid suppressing effect of medi- cation. After successful eradication rebound acid se- cretion on reduced dosage of PPI may have caused relapse of GORD[19]–[21].
Additionaly the resolution of corpus gastritis af- ter successful Helicobacter pylori eradication and re- covery of gastric acid secretion itself [11], [22], [23]
have to be mentioned as the main pathophysiologi- cal factors.
However not all studies could confirm these fin- dings. A prospective, controlled trial could demon-
strate a GORD relapse rate of 83% within one year of follow up independent of Helicobacter pylori status [24]. Additionaly further studies did not find any changes in 24-hour oesophageal acid exposure after successful eradication [24], [25]. A recent prospec- tive randomised study on 231 patients aimed to investigate the influence of Helicobacter pylori erad- ication on gastritis during long term omeprazole therapy for GORD[26] did not find a worsening of reflux disease, nor a need for increased omeprazole maintenance dose.
There are even studies reporting a benefit after Helicobacter pylori eradication: Schwizer et al report of a benefit during a six month follow up in which pa- tients with GORD and persistent Helicobacter pylori infection relapsed earlier than patients in whom Helicobacter pylori had been eradicated [27]. The au- thors explain their result with the pattern of gastritis which functionaly can be linked to normal or in- creased acid secretion, which possible can change to lower acid output following eradication [28]. These results have been confirmed by Kupcinskas et al [29].
The discrepancy of the results of the above men- tioned studies is probably due to different study de- signs, such as inclusion criteria, timing of follow up investigations and ethnic differences in the pattern of Helicobacter pylori gastritis. There are suggestions that the incidence of patients with predominant corpus gastritis is increased in populations with predomi- nantly cagA strains, leading to a worsening of gastro-oesophageal reflux [30], [31]. Although this point is still under discussion, it hints to the impor- tance of respect of ethnicity [32].
Fig. 4. Epidemiology of oesopha- geal adenocarcinoma (from [63])
The effect of Helicobacter pylori on PPI efficacy
More than 70% of patients suffering from GORDare dependent on long term use of acid suppressants [33].
It is well known that Helicobacter pylori infection leads to a higher intragastric pH during PPI treat- ment [19], [20], [34], [35]. Patients with Helicobacter pylori infection treated with pantoprazole have better symptom relief and better healing of severe forms of erosive oesophagitis [36]. These results have been confirmed in a study with 483 patients with uninve- stigated heartburn [37].
However in clinical reality most patients have mild to moderate severity of GORDand in most studies a difference in the efficacy of PPI is neither detectable, nor required [38], [39]. Carlsson and colleagues report- ed from 1350 patients with GORDtreated with ome- prazole similar symptom relief and healing rates in patients with or without Helicobacter pylori infection [40]. These data have been confirmed from other stud- ies [41], [42]. Maintenance dose after healing of ero- sive oesophagitis was independent of Helicobacter pylori status [39].
In summary most treatment trials with PPIdo not show an effect of Helicobacter pylori on symptom re- lief, healing of acute oesophagitis or maintenance treatment of erosive oesophagitis.
The effect of Helicobacter pylori infection and its eradication on histology if long term PPI therapy is required for GORD maintenance therapy
Considering the effect of persistent Helicobacter pylori infection on the type of gastritis under long term PPI therapy Kuipers et al first reported progression of atrophic gastritis in Helicobacter pylori infected pa- tients receiving long term PPI[43].
Atrophic gastritis itself is a well recognised risk factor for gastric cancer in Helicobacter pylori infect- ed subjects. The paper of Kuipers was criticised for weakness in design [44] and his results have not been confirmed in a subsequent randomised trial by Lundell et al [45]. However anxiety did not relieve as Lundell et al also reported of evidence of
accelerated development of moderate and severe atrophy in the Helicobacter pylori infected group on PPItherapy.
Subsequently in a new prospective, randomised trial in 231 patients Kuipers himself could not confirm findings of progression of atrophic gastritis, same as other authors [46]–[49]. However he could demon- strate that corpus gastritis progressed on long term omeprazole treatment if Helicobacter pylori had not been eradicated [50].
As a consequence there is only little evidence that PPItherapy accelerates corpus atrophy in Helicobacter pylori positive patients but PPItherapy moves the pre- dominant type of gastritis from the antrum to the cor- pus. This may be of importance as Uemura et al re- cently showed that the strongest risk factor for cancer is the presence of corpus predominant gastritis [51].
As a consequence recommendation for Helicobacter pylori eradication before prescribing long term PPIis indicated [52].
Helicobacter pylori infection and Barrett’s oesophagus
The definition of Barrett’s oesophagus is a subject of controversy over the last years. It is applied to a columnar-lined oesophagus with biopsy specimens that contain specialized intestinal epithelium. This definition applies to patients with long segment and short segment Barrett’s oesophagus and those with circumferential disease or tongues. Barrett’s oesopha- gus is the consequence of gastroesophageal reflux.
A prospective evaluation of Barrett’s oesophagus in 550 patients found three factors being significantly as- sociated with index diagnosis of Barrett’s high-grade dysplasia or adenocarcinoma: larger size hiatal hernia, Barrett’s length and absence of Helicobacter pylori in- fection [53].
Another study from Japan underlined the protective role of Helicobacter pylori infection in the development of Barrett’s oesophagus especially in the development of long segment Barrett’s oesophagus in 112 reflux pa- tients [54]. This group additionally included endoscopic gastrin test finding that gastric acid hypersecretion may be concerned with the development of Barrett’s oeso- phagus in addition to the absence of Helicobacter pylori.
However there is no evidence that Helicobacter pylori
status itself does affect the presence of Barrett’s compli- cations such as stricture or ulcer [55].
The role of cagA-positive-strains in patients with Barrett’s oesophagus
An important marker of the virulence of Helicobacter pylori strains is cagA encoding the cytotoxin- associated gene protein (cagA) [4]. Almost all Helicobacter pylori isolates from patients with peptic ulcers, atrophic gastritis and gastric cancer are cagA [56]. As there is an inverse relation between carcinoma in the cardia and lower oesophagus and colonization with cagA strains [57] it has been proposed that Helicobacter pylori colonization with especially cagA strains may protect against the development of GORDand its complications.
These suggestions have been underlined by the re- sults of a cross-sectional study in 736 consecutive pa- tients examining the relation between cagA and cagA Helicobacter pylori strains in patients with re- flux oesophagitis and Barrett’s oesophagus [4]. The authors found a significant lower prevalence of Helicobacter pylori (34,9%) in reflux patients than in controls with a prevalence of 59% cagA strains in the control group vs. 35% in the reflux group.
In conclusion cagA strains may on the one side be most harmful by increasing the risk of ulceration and distal cancer but on the other side be most bene- ficial by protecting against reflux oesophagitis and its sequelae. Further studies proved this concept [58].
The role of cagA-positive-strains in patients with oesophageal adenocarcinoma
Different studies hint on a protective role of Helicobacter pylori infection – especially cagA-strains – against the development of oesophageal adenocarcinoma.
The incidence of oesophageal adenocarcinoma increased over the last years [59] reaching 4–12 per 100.000. This is in contrast to the decreasing inci- dence of non-cardia gastric cancer (Fig. 3), [63].
Quddus et al did not find any Helicobacter pylori infected in 19 patients with Barrett’s adenocarcinoma [60]. In a larger study population Helicobacter pylori
again has been identified in significantly higher proportion of patients with benign Barrett’s oeso- phagus than in those with dysplastic Barrett’s oesophagus or Barrett’s adenocarcinoma (34% vs.
17%) [61].
A multicenter study did not find a difference in the prevalence of Helicobacter pylori infection in pa- tients with oesophageal adenocarcinoma when com- pared to age- and sex-matched controls. However infection with the cagA strain of the bacteria resulted in a reduced odds ratio for developing oesophageal adenocarcinoma [57]. These results have been confirmed in a smaller study by Vicari et al [5] and may be explained by Helicobacter pylori induced apoptosis in Barrett derived oesophageal adenocarcinoma cells which is mainly dependent on the presence of the cagA and picB/cagE gene pro- ducts [62].
Conclusion
The interesting pathophysiological interaction between Helicobacter pylori infection, type of gastritis, acid secretion and GORD complicated by weakness of study designs with small numbers of patients should not lead to confusion. The risk of gastric carcinogenesis and peptic ulcer formation against the need for possible higher doses of acid suppressive therapy for symptom control after erad- ication should be balanced carefully and can only lead us to one conclusion: there are more reasons that favour Helicobacter pylori eradication than to le- ave the bug in the stomach of your patients.
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