Helicobacter pylori Infection in Gastroesophageal Reflux Disease in the Asian Countries

Helicobacter pylori infection, a common infection in many countries, is related to the clinical course of upper gastrointestinal diseases. Gastroesophageal reflux disease (GERD) is a common esophageal disease in Western countries and its prevalence is increasing in Asian countries. The pathophysiology of GERD is multifactorial. Although no single factor has been isolated as the cause of GERD, a negative association between the prevalence of H. pylori and the severity of GERD, including Barrett's esophagus, has been demonstrated in epidemiological studies. The high prevalence of H. pylori infection affects the incidence of GERD in Asian countries. In the subjects with East Asian CagA-positive strains, acid injury may be minimized by hypochlorhydria from pangastritis and gastric atrophy. Additionally, host genetic factors may affect the development of GERD. The interactions between genetic factors and the virulence of H. pylori infection may be the reason for the low prevalence of GERD in Asian countries. H. pylori eradication is not considered pivotal in GERD exacerbation based on evidence from Western studies. A recent meta-analysis demonstrated that eradication therapy of H. pylori was related to a higher risk of developing de novo GERD in Asian studies. H. pylori infection remains an inconclusive and important issue in GERD in Asian countries.


Introduction
The prevalence of gastroesophageal reflux disease (GERD) in the general population has been estimated to be 10-20% [1][2][3][4]. Conversely, most Asian population-based studies have reported a lower prevalence of less than 10% [3][4][5][6]. In epidemiological studies, H. pylori and GERD have been found to be negatively associated and strongly related to cytotoxin-associated gene product-(CagA-) positive strains of H. pylori [7]. However, an increasing prevalence of GERD and decreasing prevalence of H. pylori have been reported in Asian countries [8], which is in agreement with a previous report of no increase in the prevalence of GERD symptoms with age [4]. GERD markedly reduces patients' quality of life and imparts a significant economic burden on the healthcare system [9][10][11]. Therefore, decreasing the prevalence of H. pylori infection is an important issue in GERD, especially in Asian populations. In addition, H. pylori eradication has been presumed to exacerbate GERD due to improvement of gastritis and the recovery of hypochlorhydria; several studies have been conducted to clarify this controversy.

Gastric Acidity and H. pylori
Gastric acid plays a key role in the etiology of GERD and is an element of the disease that may be modified by H. pylori infection. Gastric secretion can increase, decrease, or remain steady depending on the pattern of H. pylori-related inflammation [12]. The major components of acid secretion in patients with H. pylori infection include the density of H. pylori colonization, its distribution, and the severity of the mucosal inflammatory response to the infection. Patients with a duodenal ulcer and H. pylori infection have antrumpredominant gastritis, which leads to hypergastrinemia and acid hypersecretion. In contrast, patients with gastric ulcer or gastric cancer present mainly with corpus-predominant gastritis or pangastritis, which is characterized by intense destruction or atrophy of acid-secreting glands. Patients who have corpus-predominant gastritis or pangastritis also show gastric acid hyposecretion [13,14]. Bacterial virulence and host inflammatory responses are important in determining patterns of acid secretion and gastritis. East Asian CagA-positive strain of H. pylori induces primarily corpuspredominant gastritis or pangastritis with hypochlorhydria. And, East Asian CagA-positive strain is strongly associated with gastric cancer. A Japanese study revealed different sequences of CagA between the regions where gastric cancer is prevalent or not. The authors defined the East Asian CagApositive strains which showed the specific repeat sequences located in the 3 region of cagA gene. In the study, most CagA-positive strains in Asian countries were East Asian CagA-positive strains and most CagA-positive strains in Western countries were Western CagA-positive strains [15]. In Asian populations with East Asian CagA-positive strains, acid injury may be minimized by hypochlorhydria from pangastritis and gastric atrophy. Additionally, host genetic factors may affect the development of GERD. IL-1B and IL-1RN genetic polymorphisms are inversely associated with the risk of GERD in H. pylori-infected subjects because their specific genotypes are linked to corpus atrophy, gastric cancer, and hypochlorhydria [16][17][18][19][20]. Thus, such specific genotypes, including the IL-1B-511-T, IL-1B-31-C, and IL-1RN-1 alleles, can be considered protective against GERD. In particular, the subjects with IL-1B-511 T allele is accentuated in the presence of H. pylori infection due to high gastric mucosal IL-1 levels [20,21]. However, other investigators have reported contradictory results that IL-1B-511-T allele was associated with reflux esophagitis [22]. These opposite results suggest ethnic differences regarding IL-1 genetic polymorphisms and levels of gastric mucosal IL-1 . Additionally, several genetic risk factors for GERD, including polymorphisms in G-protein beta 3 subunit gene (GNB3) [23], IL-10 [24], CYP2C19 [25], glutathione S-transferase P1 [26,27], cyclin D1 [28], and DNA repair genes [29], may be involved.
The interactions between genetic factors and the virulence of H. pylori infection may be the reason for the low prevalence of GERD in Asian countries [16-18, 20-22, 27, 29].

Epidemiological Evidence of a Link between
H. pylori Infection and GERD Table 1 shows recent epidemiological reports of an inverse relationship between H. pylori infection and reflux esophagitis or Barrett's esophagus in the western countries and East Asian countries [30][31][32][33][34][35]. This negative association was also evident in patients with severe GERD and H. pylori infection with virulent CagA-positive strains in Western countries [36,37].

Proton Pump Inhibitors (PPIs) in GERD Patients with H. pylori Infection
Long-term maintenance therapy of proton pump inhibitors (PPIs) for GERD induces gastritis and progression of gastric atrophy and intestinal metaplasia to gastric adenocarcinoma in patients with H. pylori infection [46,47]. These patterns are significantly associated with the CagA-positive strains [48]. Current guidelines, including the Asia-Pacific Consensus for H. pylori infection, recommend H. pylori eradication in GERD patients requiring long-term PPIs [49]. However, there is no evidence that H. pylori eradication reduces the risk of gastric adenocarcinoma in patients with this condition.

H. pylori Eradication in GERD
Despite the inverse relationship between H. pylori and GERD in cross-sectional studies, the results are less consistent in prospective studies of H. pylori eradication in patients with GERD. Early studies revealed that H. pylori eradication was positively associated with reflux esophagitis or GERD symptoms in patients with gastric and duodenal ulcer diseases [50,51]. Hiatal hernia, corpus gastritis, and CagA-positive H. pylori strains have been reported to be risk factors for newly developed reflux esophagitis after H. pylori eradication [51,52]. However, other studies have shown improvement of reflux symptoms after H. pylori eradication in patients with peptic ulcer disease and nonulcer dyspepsia [53,54]. The Maastricht IV Consensus Report suggested that H. pylori eradication does not exacerbate preexisting GERD or affect treatment efficacy [55]. A recent meta-analysis demonstrated that eradication therapy of H. pylori was related to a significantly higher risk of developing de novo GERD in Asian studies [42]. In contrast, no such risk has been reported by Western studies [43][44][45]. Table 2 shows the summaries of the results of meta-analyses. However, this remains an inconclusive issue in Asian countries. For example, two largescale cohort studies in Korea produced inconsistent results [56,57] (3) Control (18) GERD: gastroesophageal reflux disease. analyzing the results of studies of H. pylori eradication in GERD patients. To date, cohort studies and randomized controlled trials of the effects of H. pylori eradication on GERD are inconclusive. The decreasing prevalence of H. pylori and the recovery of acid secretion capacity after eradication in patients with CagA-positive H. pylori and corpus gastritis are possible causes of the higher prevalence of GERD in Asian countries. These issues necessitate a more detailed study.

Conflict of Interests
The authors declare that there is no conflict of interests regarding the publication of this paper.

Authors' Contribution
Su Jin Hong wrote the paper; Sang Woo Kim revised the paper.