Professor K. Haruma, Division of Gastroenterology, Department of Internal Medicine, Kawaskai Medical School, 557, Matsushima, Kurashiki 701–0192, Japan. E-mail: email@example.com
There is circumstantial evidence that infection with Helicobacter pylori is relatively protective for the occurrence of gastro-oesophageal reflux disease (GERD). It has been suggested that the Japanese population are protected against reflux oesophagitis by their high prevalence of H. pylori associated gastritis. Such gastritis, when becoming chronic, can lead to gastric atrophy, thereby reducing the likelihood of GERD. If this hypothesis is correct, the effects of H. pylori induced gastritis may be an important factor determining the earlier lower prevalence of oesophagitis in Japan, where this infection is especially common. In support of this idea a reduced prevalence of H. pylori infection in Japan, as is now being observed in young Japanese adults, may be, at least in part, responsible for the upsurge in the number of cases of reflux disease in Japan. Concomitantly, H. pylori eradication therapy in patients with gastritis or peptic ulcer disease, which is associated with an increase in gastric acid secretion, may also be at least partly responsible for the increased prevalence of reflux oesophagitis in the Japanese population.
Helicobacter pylori is an important pathogen known to be associated with a number of gastrointestinal diseases including peptic ulcer disease, gastric carcinoma and mucosa-associated lymphoid tissue lymphoma.1 The role of H. pylori infection in gastro-oesophageal reflux disease (GERD) is, however, uncertain.2,3
The falling prevalence of H. pylori infection and related diseases in developed countries during the 20th century has been paralleled by an increase in GERD and its complications.4,5 Furthermore, GERD is uncommon in countries in which most adults are infected with H. pylori.6 In developed countries, approximately 20% of the population are positive for H. pylori infection. In contrast, up to 80% of populations in less-developed countries display evidence of infection with this pathogen.7 In Japan, the prevalence of H. pylori infection was earlier reported to be higher than in other developed countries.8,9 However, recent estimates suggest that the rate of infection is declining;7 in a recent study the prevalence of H. pylori infection in healthy Japanese children was 29% in children aged 15–19 years.10 This value is higher than that found in developed (5–15%) countries, but lower than that reported in developing (30–60%) countries. This changing trend in H. pylori infection may be a critical factor in the increase in incidence of GERD and its complications in Japan in recent years.
Prevalence of h. pylori infection in patients with gerd
Results of studies evaluating the presence of H. pylori infection in patients with GERD are inconsistent, with some reporting an increased prevalence11 and others suggesting a decreased prevalence.12,13 In a meta-analysis of 10 studies conducted in Europe and America, five reported an increased prevalence of H. pylori infection in patients with reflux oesophagitis (mean 37.6%; range 25–60%) compared with healthy controls (mean 22.8%; range 5–35%).14 In the remaining five studies, the prevalence of H. pylori infection was reported to be lower in patients with reflux oesophagitis (mean 42.2%; range 29–76%) than in controls (53%; range 42–82%).15–19
In contrast with the conflicting reports concerning H. pylori in patients with reflux oesophagitis overall, epidemiological data consistently suggest that patients with more severe reflux oesophagitis, including Barrett's oesophagitis, have a lower prevalence of H. pylori than healthy controls or patients with less severe forms of the disease. Data collected from seven studies conducted in Europe, the USA and Japan showed that the overall prevalence of H. pylori infection in patients with Barrett's oesophagus was 23.5% (range 0–38.5%) compared with 34.5% (range 29–41%) in patients with less severe forms of reflux oesophagitis, and 52.3% (range 28.4–76%) in healthy controls.16,20–23
Epidemiological studies conducted in Japan have consistently demonstrated that the prevalence of H. pylori infection in patients with reflux oesophagitis is correlated with the severity of the disease. Shirota et al.24 reported that the prevalence of H. pylori infection in patients with mild and severe reflux disease was significantly (P < 0.05) lower than that in healthy controls (60.7, 47.8, and 14.8%, respectively). Indeed, the level of infection was very low in patients with severe disease. Similarly, only 10.5% of a cohort of Japanese patients with reflux oesophagitis, followed over 2–9 years untreated, progressed to a more severe grade of oesophagitis and none developed Barrett's oesophagus.25 A major risk factor for disease progression was H. pylori infection.
Cross-sectional studies have consistently demonstrated that the prevalence of H. pylori infection increases with age.26,27 In a comparative study of 95 Japanese patients with reflux oesophagitis and 190 healthy controls Haruma et al.23 demonstrated a significantly lower prevalence of infection in the patients (41% vs. 76%, P < 0.01). When these patients were subdivided by age (≤ 59 years; ≥ 60 years) a significant difference in the prevalence of H. pylori infection was found only among patients aged over 60 years of age (29% vs. 85%, P < 0.01). In the same study, gastritis in the antrum and corpus was shown to be significantly milder in elderly patients with reflux oesophagitis than in controls. Atrophic gastritis is closely associated with H. pylori infection9 and gastric acid secretion is known to decrease with the progression of atrophic gastritis.28 Furthermore, several studies have shown that H. pylori infection is less common and atrophic gastritis is less severe in patients with reflux oesophagitis than in those without the disease.29,30 Therefore, it has been hypothesized that H. pylori-associated atrophic gastritis, which is very common in the Japanese population, protects against reflux oesophagitis. In support of this, Haruma et al.23 demonstrated an age-related decrease in gastric acid secretion in H. pylori-positive patients that correlated with the age-related increase in prevalence of gastric mucosal atrophy in this patient group (Figure 1).9 In contrast, in H. pylori-negative patients, gastric acid secretion was maintained with age while atrophic gastritis was extremely rare, irrespective of age, in this patient group.
The effect of h. pylori eradication therapy on the development of gerd
A number of studies have suggested that reflux oesophagitis may develop following H. pylori eradication therapy.31–33 In a retrospective evaluation of 460 patients treated for duodenal ulcer, Labenz et al.31 showed that after 3 years, the estimated incidence of reflux oesophagitis was significantly higher in the 244 patients with successful H. pylori eradication than in the patients with persistent infection (25.9 vs. 12.5%, P < 0.01). In a study conducted in Japan, Hamada et al.32 showed that H. pylori eradication increased the prevalence of reflux oesophagitis in patients with gastritis or peptic ulcer disease. Three years after eradication therapy the incidence of reflux oesophagitis was 18% in treated patients compared with 0.3% in those who had not been treated with eradication therapy (P < 0.01).
The most likely mechanism by which H. pylori is thought to protect against the development of GERD is by decreasing the potency of the gastric refluxate in patients with atrophic gastritis. In patients with gastric acid hyposecretion due to atrophic gastritis, eradication of H. pylori may increase gastric acid secretion and thus promote the development of reflux oesophagitis. This was demonstrated by Haruma et al.34 in a study that measured intragastric acidity in 14 patients who had H. pylori infection and atrophic gastritis, before and after eradication therapy. One year after treatment, H. pylori was successfully eradicated from 13 of the 14 patients. In these patients, median gastric acid pH was significantly reduced (from 5.12 to 2.69) suggesting that gastric acid secretion had increased following eradication therapy. Significant improvements in the histology of the gastric mucosa were reported in parallel with the increase in gastric acidity. These studies support that the incidence of post eradication reflux oesophagitis is correlated with recovery of gastric acid secretion.
One of the unique features of H. pylori is its ability to maintain a neutral pH in the intragastric environment through synthesis of an internal urease that hydrolyses urea releasing ammonia and bicarbonate. The released ammonia acts as an acid neutralizer. This raises the pH of the microenvironment, allowing the H. pylori microorganism to thrive. It has been suggested that the released ammonia may act as a protective factor against the development of reflux oesophagitis in patients infected with H. pylori. This hypothesis was supported by the results of an animal modelling study reported by Hamada.35 In this study, the incidence of reflux oesophagitis was directly correlated with the concentration of infused intragastric ammonia (low; 1.6 × 10−6m; medium 1.6 × 10−5m; high 1.6 × 10−4m). The incidence of reflux oesophagitis was lowest in the high-ammonia group (14%) and increased dose-dependently with increasing ammonia concentrations (medium 29%, low 71%, control [saline infusion] 100%). Thus, the presence of ammonia appears to confer a protective effect. Conversely, decreasing the intragastric ammonia concentration increased susceptibility to the development of reflux oesophagitis.
H. pylori infection may be negatively associated with reflux oesophagitis in the Japanese population. While conflicting evidence has accumulated from Western studies, this association appears to be relatively strong in Japan where there is a relatively high prevalence of H. pylori infection and atrophic gastritis, especially in elderly patients. A reduced prevalence of H. pylori infection in Japan, as is now being seen in younger Japanese adults, may therefore be at least partly responsible for the increased prevalence of reflux oesophagitis. H. pylori eradication therapy may similarly lead to an increased prevalence of reflux oesophagitis in Japan.