Bile reflux gastritis, also known as alkaline reflux gastritis (ARG), refers to the chronic inflammation, erosion, and even ulceration in the gastric mucosa caused by excessive duodenal fluid (including bile, pancreatic, and intestinal fluid) refluxing into the stomach (1). The action component of duodenal reflux fluid is bile acid, which has an accumulative damaging effect on the gastric mucosal barrier and can induce chronic inflammation, erosion, ulcers, gastroesophageal reflux, and even carcinogenesis (2–4). As a common digestive disease, bile reflux gastritis (BRG) accounts for about 22.6% of chronic gastritis (5). Bile reflux gastritis that originated in a non-operative stomach is referred to as primary bile reflux gastritis (PBRG), while BRG that occurred after gastric pylorus surgery is called secondary bile reflux gastritis (SBRG). Endoscopic primary bile reflux is part of the most important diagnostic criteria for PBRG (6, 7). Long-term endoscopic primary bile reflux (EPBR) may also lead to the hyperplasia of gastric epithelial pits and esophageal squamous epithelium, and may even be associated with intestinal metaplasia or cancer (8). However, to date, the etiologies and risk factors of EPBR are not well-understood, especially for gastropathy patients who cannot or will not undergo further endoscopy due to contraindications.

Past two conflicting studies have explored the influence of psychological factors and H. pylori infection on EPBR (4, 5). Another study revealed that EPBR might be involved with sex, age, and fasting time (9). These findings provided a preliminary basis for further research. Our study aimed to further elucidate more possible factors related to the occurrence of EPBR, and eventually, to design a prediction model that provides a valuable evaluation tool for patients with EPBR. The significance of this study is to offer clues for clinical empirical diagnosis and treatment.

In general, the coordinated movement of the stomach and duodenum rarely causes EPBR. However, when the duodenum becomes antiperistaltic and the pyloric closure is incomplete, in the meantime, bile will flow back into the stomach (19). Accompanied by delayed gastric emptying, bile acids continue to interact with the gastric mucosa and finally result in well-recognized damage (20). Any factor that causes gastrointestinal motility disorder and anatomical abnormality can cause pathologic duodenogastric reflux. Endoscopic primary bile reflux was classified as primary and secondary type (21), depending on whether the patient has a gastrectomy history. In addition to other endoscopic features such as the co-existence that changes mucosa: hyperemia, fragility, and erosions, EPBR is one of the mandatory diagnostic criteria for PBRG (6, 7). For patients who cannot or will not undergo endoscopy due to contraindications, the determination of EPBR is particularly critical for clinical empirical treatment. Furthermore, our clinical experience is not identical to the predictors of EPBR reported in most historical studies. Therefore, the purpose of this study was to summarize the predictors and prediction models of EPBR in a real-world setting with a large sample size.

In this retrospective study, 15 clinical parameters that possessed a strong possibility of predicting EPBR were analyzed, and seven risk factors including being male, age ≥45 years old, H. pylori infection, previous medical histories of NSAIDs use, cholelithiasis, erosive gastritis, and MS were accessed for the first time. Furthermore, after validating the regression formula through the ROC and H-L test, the evidence from our retrospective study suggested that the prediction model for EPBR provides a favorable reference for clinical empirical treatment.

As a recognized etiologic agent, H. pylori colonizes the gastric mucosa and causes gastritis, peptic ulcers, and gastric cancer (21, 22). Even now, the relationship between EPBR and H. pylori infection remains controversial (23). Several studies attempted to address the association of EPBR and H. pylori infection with the occurrence and development of chronic gastritis and gastric cancer (9, 14, 24–26). One study implied that bile acid, which continued in gastric juice, had the extraordinary capabilities of promoting ulcer healing and inhibiting the growth of H. pylori (27). In contrast, substantial data believed EPBR to be consistently reduced after successful H. pylori eradication. The H. pylori infection status may affect EPBR by increasing gastrin secretion and altering the duodenal movement (28). This notion meant that the two had a synergistic effect in inducing chronic gastritis (5). A multi-center study of 2,283 subjects from 14 institutions in Japan found that a high concentration of EPBR increased the risk of intestinal metaplasia regardless of the H. pylori infection status (29). Partially contrary to the findings of previous literature reports, our results demonstrated that H. pylori infection and erosive gastritis history coexisted in our prediction model. It is well-known that the prolonged exposure of gastric mucosa to bile acid and H. pylori infection may result in histopathological changes (30, 31). Our study proves to be a likely overlap between H. pylori-associated gastritis and BRG. Consequently, the sensitive identification and appropriate treatment of EPBR should be admitted while considering the presence of H. pylori infection.

Moreover, a history of NSAIDs use, besides H. pylori infection and EPBR, is likewise a common cause of chronic gastritis (32–34). Data from in vivo studies has shown that administration of NSAIDs decreased the prostaglandin concentration in the gastric mucosa but did not increase the mucosal damage in H. pylori-induced gastritis, which is ascribed to the elevated expression of cyclooxygenase-2 (COX-2) induced by H. pylori (8). In our multivariate logistic regression model, H. pylori infection and the history of NSAIDs use were incorporated into the prediction model as risk factors. However, the relationships between H. pylori infection, NSAIDs use, and EPBR in gastric mucosal damage are intricate, which is yet to be clarified by more basic and clinical researches.

During the past few years, several studies have shown that EPBR is more frequent in elderly male patients, which may be associated with an increased rate of gastrectomy and operation of the biliary tract (35). However, a study reported no distinguishable differences in EPBR occurrence between the younger (median age 25 years) and older (median age 51 years) healthy volunteers (36). Another related study believed that the rate of EPBR in women and middle-aged patients was higher than in men and in young and elderly patients (9). Here we demonstrated that EPBR was more common in male patients aged 45 years or older. An appropriate interpretation of the above conclusions imputes to population characteristics or genetic background and synchronously implies that a multi-center prospective study with a larger sample size is needed.

It is currently generally accepted that bile reflux is frequently disclosed in patients with chronic calculous cholecystitis patients (67–80%) and cholecystectomy (89%) (11, 37). Previous studies have evaluated that the predisposition toward EPBR in patients with cholelithiasis can probably be associated with changes in the gut hormone induced by biliary tract disease (12, 38, 39). There was no clear evidence to suggest that EPBR is clinically related to MS patients in previous studies. Meanwhile, in our clinical practice, we realized that EPBR patients are often accompanied by MS. Our results go beyond the previous reports, showing that MS is also a risk factor for EPBR. Existing studies have emphasized that the occurrence of MS is always related to age and gender (40–43). These results underscored the idea that the prevalence of MS tended to be higher with age in women than in men, driven primarily by an increase in abdominal obesity and a decrease in the HDL-C levels (44). Although, whether MS interacts with age, gender, and other factors to play an essential role in EPBR remains undefined. At present, the prevalence of MS continues to rise globally (45), and the frequency of cardio-cerebrovascular events is concerned with MS. Here we demonstrated that EPBR requires more attention instead of just the frequency of cardio-cerebrovascular events associated with MS. In the future, it will be necessary to explore the relationship between MS and EPBR after excluding the other risk factors.

The limitations of the present studies naturally include only a single-center retrospective experience, and more clinical data from other medical institutions for external validation are urgently needed. Meanwhile, gastric cancer may be misdiagnosed as acid reflux, leading to certain false positives in our study, which needs to be paid attention to. Moreover, the diagnosis of EPBR is just configured based on endoscopy without 24 h gastric bilirubin monitoring, and its causal relationship, as well as underlying mechanisms, should be further confirmed through prospective and in-depth studies.

In conclusion, being male, age ≥ 45 years old, H. pylori infection, histories of MS, NSAIDs use, cholelithiasis, and erosive gastritis appear to be the risk factors for EPBR. Meanwhile, this favorable prediction model might be an option for the prediction of EPBR.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.

The studies involving human participants were reviewed and approved by Ethics Committee of Tongji Hospital, School of Medicine, Tongji University. The patients/participants provided their written informed consent to participate in this study.

LC and GZ acquired and analyzed the data and participated in drafting the manuscript. LS, YD, FZ, and CY provided comprehensive case data and analyzed the data. FZ contributed to the concept and design of the work, reviewed, and revised the manuscript. All authors contributed to the article and approved the submitted version.

This work was supported by the State Key Laboratory of Pathogenesis, Prevention, and Treatment of High Incidence Diseases in Central Asia Fund (No.SKL-HIDCA-2021- DX9, Urumqi, China), Xinjiang Uygur Autonomous Region Special Regional Collaborative Innovation Project (Science and Technology Aid Xinjiang program, No. 2021E02075, China), and the Shanghai Key Specialty Construction Project (ZK2019C16).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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