Should we pay more attention to the potential link between Helicobacter pylori and esophageal cancer in Asian countries

Abstract

The presence of Helicobacter pylori (H. pylori) infection has been indicated to have a protective influence on esophageal cancer (EC) in some studies, but its specific impact on the risk of esophageal squamous cell carcinoma and esophageal adenocarcinoma remains inconclusive. This manuscript comment addresses the recent study by López-Gómez et al. Despite it was a retrospective observational study without a control group, this study revealed a notably low prevalence of H. pylori infection among EC patients, indicating a potential association between H. pylori and EC in Spain. It is important to note that the relationship between H. pylori and the risk of EC varies geographically. We also conducted a meta-analysis focusing on this association in Asian populations to offer precise clinical insights. However, no significant correlation between H. pylori infection and EC was identified, suggesting that the perceived protective effect of H. pylori against EC may have been overestimated in the Asian population.

Key Words: Helicobacter pylori; Esophageal cancer; Proton pump inhibitors; Asian; Meta-analysis

Core Tip: Helicobacter pylori (H. pylori) has been implicated in the development of gastric cancer and its eradication is widely accepted as a treatment approach. However, recent research indicates that H. pylori may also play a role in maintaining the balance of gastroesophageal junction cells and could potentially have a protective effect against esophageal cancer (EC). Previous meta-analyses have shown that the relationship between H. pylori and the risk of esophageal squamous cell carcinoma or esophageal adenocarcinoma varies across different regions. This manuscript discusses a recent study by López-Gómez et al. Additionally, an updated meta-analysis focusing on the potential link between H. pylori and EC in Asian populations has been conducted to offer more precise clinical recommendations for countries like China and other Asian nations.

TO THE EDITOR

Helicobacter pylori (H. pylori) is a type of Gram-negative bacterium that has been inhabiting the gastric epithelium of humans for over 58000 years, predating their migration from east Africa[1]. While this bacterium is present in approximately half of the global population, its prevalence in developed nations has been on the decline[2]. In 1994, H. pylori was classified as a group I carcinogen due to substantial evidence linking it to noncardia gastric adenocarcinoma[3]. H. pylori has the capability to induce gastric atrophy in humans, thereby elevating the risk of gastric cancer[4]. The esophageal cancer (EC) comprises two primary histological subtypes: (1) Esophageal squamous cell carcinoma (ESCC); and (2) Esophageal adenocarcinoma (EAC). However, the impact of H. pylori on the risk of developing ESCC and/or EAC remains a topic of ongoing investigation.

H. pylori infection has been suggested to exhibit a “protective effect” against EC. The prevalence of H. pylori has decreased in Western nations since the 20^th century, coinciding with a rise in EC incidence. While prior meta-analyses have examined the association between these factors[5-8], conflicting viewpoints still exist. Currently, the precise relationship between H. pylori and EC remains unclear, with contradictory evidence regarding its potential protective or detrimental impact on EAC.

Recent publications have addressed the correlation between H. pylori and EC, offering new insights for further investigation. However, the specific relationship in Asian regions remains unclear. This manuscript discusses the article by López-Gómez et al[9] and performs a meta-analysis examining the association between H. pylori infection and EC risk in Asian populations. The aim of this manuscript is to provide targeted clinical recommendations for H. pylori eradication therapy in high-risk EC populations in China and other Asian nations.

H. PYLORI AND ESOPHAGEAL CANCER

A study conducted by López-Gómez et al[9] revealed a notably low prevalence of prior H. pylori infection among individuals diagnosed with esophageal carcinoma. Despite being a single-arm retrospective observational study lacking a control group, this research offers insights into a potential link between H. pylori and esophageal carcinoma in Spain from a unique perspective. A previous systematic review and meta-analysis[6] demonstrated a statistically significant relationship between H. pylori and ESCC in Western countries, although this analysis employed a broader definition of H. pylori positivity and included only four studies. Notably, another meta-analysis by Xie et al[7] suggested that H. pylori infection significantly reduced the risk of EAC in Western populations. Various hypotheses have been proposed to explain this association, including alterations in esophageal microbiota due to proton pump inhibitors (PPIs), H. pylori-induced atrophy and loss of acid parietal cells in the antrum, induction of apoptosis in gastric adenocarcinoma cells progressing from Barrett’s esophagus (BE) through the Fas apoptotic pathway, and reduction in ghrelin synthesis leading to secondary effects on central obesity and gastroesophageal reflux disease[10-12].

PPI USE

PPIs are frequently recommended for the treatment of acid-related gastrointestinal disorders and are a component of the multidrug regimen for eradicating H. pylori[13]. However, prolonged use of PPIs could alter the microbial composition in the esophagus, potentially contributing to the development of BE and EC, although conflicting findings have been reported[14]. A recent meta-analysis of 25 cohort studies from 23 publications identified an elevated risk of EC with PPI use[15]. Conversely, a meta-analysis encompassing 65 studies conducted by Zhang et al[16] did not find a significant association between PPI use and EC. Therefore, further robust evidence is required to ascertain the potential role of PPIs in the link between H. pylori infection and EC.

DIFFERENT REGIONS

The prevalence of H. pylori infection varies significantly across different geographical regions. While H. pylori infection has been shown to reduce the risk of EAC in Western populations, no significant association was found in terms of the risk of ESCC when data from Eastern and Western populations were combined. Upon conducting a stratified analysis based on study location, no significant link between H. pylori infection and ESCC risk was observed in Western subjects. However, a notable association between H. pylori infection and a decreased risk of ESCC was identified in East Asian populations[7]. Furthermore, a meta-analysis[17] revealed no significant relationship between H. pylori infection and ESCC risk in the general population, while a lower risk was noted in the Middle East. Another meta-analysis[8] indicated that the presence of H. pylori infection and cytotoxin-associated gene A protein (CagA)-positive strains has been associated with a decreased risk of developing EAC in the general population, while no significant correlation between H. pylori infection/CagA-positive strains and ESCC was detected. It is worth noting that CagA-positive strains may demonstrate a positive correlation with ESCC in non-Asian populations and an inverse correlation in Asian populations.

UPDATED META ANALYSIS

In this manuscript, a meta-analysis was also conducted to examine the relationship between H. pylori infection and EC (EAC and ESCC) in Asian populations. The aim of this updated meta analysis was to offer clinical recommendations regarding H. pylori eradication therapy for high-risk populations of EC in China and other Asian countries. Seven studies conducted in Asian countries were included to investigate the potential link between H. pylori infection and EC (Table 1)[18-26]. The results of the meta-analysis indicated that there was no statistically significant association between H. pylori infection and EC in the Asian population (risk ratio = 0.99, 95%CI: 0.82-1.20, P = 0.92) with significant heterogeneity I² = 91% (Figure 1)[18-26].

Figure 1 Meta-analysis of the association between Helicobacter pylori infection and esophageal cancer studied in Asian countries. A: Forest plot; B: Funnel plot. EC: Esophageal cancer; RR: Risk ratio.

Table 1 Characteristics of included literatures studied in Asian countries.

Ref.	Publication year	Study country	Study type	Study object	Case		Control
					H. pylori +	H. pylori -	H. pylori +	H. pylori -
Wang et al[18]	2003	China	Case-control	ESSC	33	30	145	165
Wu et al[19]	2009	China	Case-control	ESSC	112	205	563	540
Wu et al[20]	2005	China	Case-control	ESSC	28	99	74	97
Kamangar et al[21]	2007	China	Case-control	ESSC	254	81	662	330
Iijima et al[22]	2007	Japan	Case-control	ESSC	60	13	56	17
Hu et al[23]	2009	China	Case-control	ESSC	66	114	102	92
Xue et al[24]	2013	China	Cohort	ESSC	7	3	988	503
Poosari et al[25]	2023	Thailand	Case-control	Esophageal cancer	83	22	40	68
Gao et al[26]	2022	China	Case-control	Adenocarcinoma of the esophagogastric junction	270	345	1221	1857

ESCC: Esophageal squamous cell carcinoma; H. pylori: Helicobacter pylori.

POSSIBLE CAUSES OF HETEROGENEITY

The association between H. pylori infection and EC exhibited significant heterogeneity, as indicated by an I² value of 91%. This variability may be attributed to several factors, including differences in population characteristics, variations in the number of cases and controls, the methodologies employed for H. pylori detection, and the overall study design. We furtherly examined the possible causes of heterogeneity by using subgroup analysis. Subgroup analyses were performed based on different countries in the current investigation (Figure 2), while no significant reduction in heterogeneity was observed within the Asian population, consistent with previous meta-analysis[7]. Thus, further research is necessary to elucidate the underlying causes of this pronounced heterogeneity.

Figure 2 Subgroup analysis evaluating the association between Helicobacter pylori infection and esophageal cancer based on different Asian countries. EC: Esophageal cancer.

CONCLUSION

The relationship between the risk of ESCC/EAC and H. pylori infection demonstrates regional variability. While H. pylori infection may decrease the risk of EC in some countries, the perceived “protective” effect of this association has been found to be overestimated in Asian populations.

ACKNOWLEDGEMENTS

We thanks to Zhang X (Department of Gastroenterology, Lu'an Hospital of Anhui Medical university, Lu'an People's Hospital of Anhui Province) for his strong support in revising this letter.