Abstract
Background/Aims
Reflux symptoms frequently present in patients diagnosed with functional dyspepsia (FD). This investigation sought to elucidate the contribution of gastroesophageal reflux in the overlap relationship.
Methods
Consecutive patients presenting with reflux symptoms and/or FD symptoms were prospectively included. Comprehensive assessments, including symptoms evaluation, endoscopy, esophageal functional examinations (high-resolution manometry and reflux monitoring), and proton pump inhibitor (PPI) treatment efficacy evaluation, were conducted in these patients.
Results
The study enrolled 315 patients, 43.2% of which had concurrent FD symptoms and overlapping reflux symptoms. Notably, a mere 28.7% of patients in the overlap symptoms group had objective gastroesophageal reflux disease evidences (the grade of esophagitis ≥ B or the acid exposure time ≥ 4.2%). Functional heartburn was demonstrated to be the main cause of overlapping reflux symptoms (55.1%). Reflux parameters analysis revealed that the reflux burden in the overlap symptoms group paralleled that of the FD symptoms group, with both registering lower levels than the reflux symptoms group (P < 0.05). Furthermore, PPI response rates were notably diminished in the overlap symptoms group (P < 0.001), even for those with objective gastroesophageal reflux disease evidences.
Conclusions
The study illuminated that overlapping reflux symptoms in FD was common. Strikingly, these symptoms primarily diverged from reflux etiology and exhibited suboptimal responses to PPI intervention. These findings challenge prevailing paradigms and accentuate the imperative for nuanced therapeutic approaches tailored to the distinctive characteristics of overlapping reflux symptoms in the context of FD.
Keywords: Dyspepsia, Gastroesophageal reflux, Heartburn, Proton pump inhibitors
Introduction
Functional dyspepsia (FD), characterized by the symptoms of epigastric pain, epigastric burning, postprandial fullness, or early satiety that cannot be explained by organic diseases, is one of the most common digestive tract functional disorder.1 A recent epidemiological study demonstrated that the overall prevalence of FD is 20.8%.2 FD can impair all aspects (physical, mental, and social) of a patient’s life quality.3 Despite its high prevalence and consequential harm, the pathogenesis of FD remains incompletely understood. Current perspectives posit a multifactorial genesis, implicating dysfunction across various domains, including gastrointestinal sensory perception, motility regulation, immune responses, alterations in gastrointestinal microbiota, and the intricate gut-brain axis interactions.1,4
FD often overlaps with other symptoms and diseases. The overlap of FD and reflux symptoms presents a prevalent clinical challenge. A recent meta-analysis demonstrated that approximately 31.3% of FD patients had overlapping reflux symptoms.5 This clinical phenomenon deserves adequate attention, as the quality of lives are significantly more impaired in FD patients with overlapping reflux symptoms than those without.3,6,7 The latest Asia-Pacific guidelines proposed that overlapping reflux symptoms in FD might be reflux-related: impaired gastric motility in FD patients can lead to increased gastric pressure and transient lower esophageal sphincter (LES) relaxations, thereby causing gastroesophageal reflux and eventually reflux symptoms.8 Thus, anti-secretory agents (such as proton pump inhibitor [PPI]) were recommended for these patients.4,8 However, overlapping reflux symptoms can either be caused by gastroesophageal reflux disease (GERD) or by functional esophageal disorders (such as reflux hypersensitive [RH] and functional heartburn [FH]),9 the latter of which poorly responds to PPI treatment.10 There is no direct evidence showing that overlapping reflux symptoms in FD are caused by gastroesophageal reflux.
Further clarifying the causes of overlapping reflux symptoms in FD is important, as it might provide evidence-based medical treatment guidance for these patients. The purpose of this study is to elucidate the specific contribution of gastroesophageal reflux to the overlapping reflux symptoms in FD by using esophageal high-resolution manometry (HRM) and 24-hour pH-impedance monitoring.
Materials and Methods
Study Population and Research Process
The population for this study was derived from a prospective cohort study previously published by our team.11 Consecutive adult outpatients (18-65 years old) who presented with predominant reflux symptoms (heartburn or regurgitation occurring at least 2 days/week and lasting for at least 3 months) and/or FD symptoms (fulfilled the Rome IV criteria12) were prospectively included. The exclusion criteria were as follows: (1) patients with organic lesions such as peptic ulcers or cancers; (2) patients with major motility disorders under HRM examinations; (3) patients who had taken antacids, prokinetics, proton pump inhibitors (PPI) or potassium-competitive acid blockers (P-CAB) 7 days before HRM and reflux monitoring; (4) patients with comorbidities such as severe cardiac or pulmonary diseases, diabetes mellitus, or rheumatic diseases, renal failure, abnormal liver function, etc; (5) patients with a previous history of upper gastrointestinal surgery; and (6) patients who were pregnancy or lactation.
These patients were scheduled to complete baseline demographic data, baseline symptoms (4-point Likert scale and the gastroesophageal reflux disease questionnaire [GerdQ]) and quality of life assessments (the short form [SF] - 36 life quality questionnaire), followed by endoscopic and esophageal functional examinations. After endoscopic and esophageal functional evaluations, patients with esophagitis were given esomeprazole 20 mg twice daily for 8 weeks, while patients without esophagitis were given esomeprazole 20 mg twice daily for 4 weeks. Patients were asked to complete symptom assessments again to evaluate the efficacy of PPI at the end of treatments (Fig. 1).
Figure 1.
Flow chart of the study. FD, functional dyspepsia; PPI, proton pump inhibitor; P-CAB, potassium-competitive acid blocker; bid, twice a day.
This study was approved by the Ethical Review Board of Sun Yat-sen University (IRB No. [2015] 86). Written informed consent was obtained from each participant. The study was registered with ClinicalTrial.gov, number NCT02506634. All authors of this manuscript had access to the study data and had reviewed and approved the final manuscript.
Endoscopy Examination
All patients underwent upper endoscopy examinations in our hospital. The presence and severity of reflux esophagitis (RE) were evaluated based on Los Angeles (LA) classification.13
Esophageal Functional Examination
For HRM examination, the procedure was conducted as previously reported. In brief, the HRM examination process included a 30-second basal pressure recording period, ten 5-mL liquid swallows in the supine position and another 30-second basal pressure recording period, five 5-mL liquid swallows in the upright position.14,15 Distal contractile integral (DCI), distal latency (DL), integrated relaxation pressure (IRP), esophagogastric junction (EGJ) classification, EGJ-contractile integral (EGJ-CI), EGJ pressure, LES length, and esophageal motility diagnosis were all analyzed and recorded by 2 independent certificated investigators according to the Chicago classification version 4.0.16
For reflux monitoring, the procedure was conducted according to Chinese ambulatory reflux monitoring clinical practice guideline.17 Meal periods were excluded. Acid exposure time (AET), DeMeester score, mean acid clearance time, median bolus clearance time, the number of reflux events, the number of proximal reflux events, post-reflux swallow-induced peristaltic wave index (PSPWI), mean nocturnal baseline impedance (MNBI), and symptom association probability (SAP) were analyzed and calculated manually by 2 independent investigators.17 Reflux events were further divided into acid reflux events (pH < 4), weakly acid reflux events (pH = 4-7) and weakly alkaline reflux (pH > 7). SAP was considered positive if the value was ≥ 95%.17 A proximal reflux event was defined as a reflux event with a drop in impedance in either of the 2 most proximal impedance channels.17 AET% was considered pathological if the value was higher than 4.2%.17
Definition and Grouping of Patients
According to symptom spectrum, patients were divided into: (1) the FD symptoms group (FD symptoms that fulfilled the Rome IV criteria); (2) the reflux symptoms group (heartburn or reflux occurring at least 2 day/week and lasting for at least 3 months); and (3) the overlap symptoms group (concurrent FD symptoms and reflux symptoms that fulfilled the criteria of both [1] and [2]).
GERD patients was defined as the patients with the grade of esophagitis ≥ LA B or the AET% ≥ 4.2%.18 For patients with typical reflux symptoms but without objective GERD evidences, RH was considered if they had positive SAP and FH is considered if they had negative SAP.17,18 FD patients were classified into epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS) groups according to the Rome IV criteria.12
Symptom and Treatment Assessment
The frequency and severity of the predominant symptom were assessed on a 4-point Likert scale (frequency: 0, none; 1, 1 day/week; 2, 2-3 day/week; and 3, 4-7 day/week; severity: 0, none; 1, mild; 2, moderate; and 3, severe) both at the time patients were enrolled and at the end of their PPI treatments. A composite symptom score was obtained by multiplying the frequency score by the severity score.11 A response to PPI therapy was considered positive if the predominant symptom composite score during the final week improved by more than 50% from baseline.11
Statistical Methods
Categorical variables were presented in the form of percentages and compared by chi-square tests. According to whether the data was normally distributed, quantitative data was presented as mean (standard deviation) or median (25th, 75th) and compared using one-way ANOVA or Kruskal-Wallis tests. Pairwise comparison was conducted after statistical significant difference was observed among groups. Multivariate stepwise logistics regression was used to explore independent predictors of PPI response (factors with P < 0.1 in univariate analysis were further included in multivariate analysis, and P < 0.05 in multivariate analysis were considered independent factors). The significance level (P-value) was set at 0.05.
Results
Patients’ Distributions
As shown in Figure 2, a total of 315 patients were included, of which 136 were assigned to the overlap symptoms group, 74 to the FD symptoms group, and 105 to the reflux symptoms group, which indicated that up to 64.8% (136/210) of FD patients had overlapping reflux symptoms. In view of the causes of overlapping reflux symptoms, only 28.7% (39/136) of patients in the overlap symptoms group had objective GERD evidences, while FH was demonstrated to be the main cause of overlapping reflux symptoms (75/136, 55.1%).
Figure 2.
Patients’ distribution. FD, functional dyspepsia; GERD, gastroesophageal reflux disease; PPI, proton pump inhibitor; FH, functional heartburn; RH, reflux hypersensitive.
Demographic Characteristics and Esophageal Function Testing in Groups
To explore the direct causes of overlapping reflux symptoms, we systematically compared patients with different symptom spectrum. Baseline characteristics analysis showed that, the GerdQ score was significantly higher in the overlap symptoms group and the reflux symptoms group than that in the FD symptoms group (Table 1).
Table 1.
The Baseline Characteristics of Patients in the Different Symptom Groups
| Characteristics | The overlap symptoms group (n = 136) | The FD symptoms group (n = 74) | The reflux symptoms group (n = 105) | P-value |
|---|---|---|---|---|
| Age (yr) | 39.0 (30.0, 53.0) | 44.0 (29.0, 50.5) | 45.0 (34.0, 56.0) | 0.066 |
| Male (%) | 44.9 | 43.2 | 54.3 | 0.442 |
| BMI (kg/m2) | 21.7 (3.4) | 21.8 (3.0) | 22.4 (3.2) | 0.199 |
| The composite symptom score | 4.0 (4.0, 6.0) | 6.0 (4.0, 6.0) | 6.0 (4.0, 9.0) | 0.102 |
| The GerdQ score | 9.0 (7.0, 11.0) | 6.0 (4.0, 6.0) | 9.0 (8.0, 11.0) | < 0.001 |
| The SF-36 score | 606.0 (478.5, 707.0) | 633.0 (485.5, 695.8) | 606.9 (481.9, 659.4) | 0.558 |
| RE (%) | 0.166 | |||
| Normal | 81.6 | 78.4 | 70.5 | |
| LA-A | 10.3 | 17.6 | 18.1 | |
| LA-B | 8.1 | 4.1 | 10.5 | |
| LA-C | 0.0 | 0.0 | 0.0 | |
| LA-D | 0.0 | 0.0 | 0.9 |
FD, functional dyspepsia; BMI, body mass index; GerdQ, gastroesophageal reflux disease questionnaire; SF-36, short form-36 life quality questionnaire; RE, reflux esophagitis; LA, Los Angeles classification.
Data are presented as median (interquartile range), %, or mean (SD).
For motility parameters, no significant difference was observed in EGJ pressure, EGJ CI, LES length, IRP, DCI, DL, and motility diagnosis among different groups (Table 2). The overlap symptoms group and the FD symptoms group both had a significantly lower proportion of patients with hiatus hernia (EGJ classification II/III) than the reflux symptoms group (Table 2).
Table 2.
The Motility Parameters of Patients in the Different Symptom Groups
| Motility parameters | The overlap symptoms group (n = 136) | The FD symptoms group (n = 74) | The reflux symptoms group (n = 105) | P-value |
|---|---|---|---|---|
| End-expiratory pressure at the EGJ (mmHg) | 10.0 (6.0, 16.0) | 8.0 (4.0, 12.0) | 9.0 (3.0, 14.0) | 0.237 |
| End-inspiratory pressure at the EGJ (mmHg) | 19.0 (12.0, 25.0) | 15.0 (9.8, 20.5) | 16.0 (10.0, 23.0) | 0.228 |
| EGJ CI (mmHg·cm) | 27.2 (14.2, 44.3) | 25.4 (13.3, 34.4) | 25.4 (13.4, 50.1) | 0.870 |
| LES length (cm) | 3.5 (0.9) | 3.8 (0.9) | 3.6 (0.8) | 0.496 |
| IRP (mmHg) | 6.6 (3.8, 9.2) | 6.1 (4.3, 7.6) | 6.8 (3.8, 9.8) | 0.747 |
| DCI (mmHg·s·cm) | 666.3 (305.1, 1326.2) | 486.9 (274.6, 916.2) | 577.0 (248.0, 1225.3) | 0.507 |
| DL (sec) | 6.6 (5.8, 7.3) | 6.9 (6.0, 7.7) | 6.6 (5.9, 7.7) | 0.627 |
| EGJ type (%) | 0.025 | |||
| I | 92.7 | 89.2 | 79.0 | |
| II | 6.6 | 8.1 | 16.2 | |
| III | 0.7 | 2.7 | 4.8 | |
| Motility diagnosis (%) | 0.725 | |||
| Normal | 92.6 | 91.9 | 90.5 | |
| IEM | 7.4 | 6.8 | 8.6 | |
| EGJOO | 0.0 | 1.4 | 1.0 |
FD, functional dyspepsia; EGJ, esophagogastric junction; CI, contraction integral; LES, lower esophageal sphincter; IRP, integrated relaxation pressure; DCI, distal contraction integral; DL, distal contraction integral; IEM, ineffective esophageal motility; EGJOO, esophagogastric junction outflow obstruction.
Data are presented as median (interquartile range), mean (SD), or %.
Reflux parameters analysis showed that the reflux burden (considering parameters like AET%, DeMeester score, mean acid clearance time, and number of acid reflux events) in the overlap symptoms group paralleled that of the FD symptoms group, with both registering lower levels than the reflux symptoms group (Table 3). Only 22.8% of patients in the overlap symptoms group had positive SAP (heartburn/reflux), which was lower than that of patients in the reflux symptoms group, although not reaching statistically significance (Table 3).
Table 3.
The Reflux Parameters of Patients in the Different Symptom Groups
| Reflux parameters | The overlap symptoms group (n = 136) | The FD symptoms group (n = 74) | The reflux symptoms group (n = 105) | P-value |
|---|---|---|---|---|
| AET% | 1.4 (0.4, 4.3) | 0.8 (0.4, 1.9) | 2.5 (0.8, 7.7) | < 0.001 |
| Pathological AET% | 25.0 | 16.2 | 44.8 | < 0.001 |
| DeMeester score | 5.4 (1.8, 13.9) | 3.8 (1.8, 8.6) | 8.5 (4.1, 26.6) | < 0.001 |
| Mean acid clearance time (sec) | 50.0 (22.0, 86.0) | 29.0 (16.5, 60.0) | 72.0 (39.5, 131.3) | < 0.001 |
| Number of total reflux events | 51.0 (36.0, 69.8) | 53.0 (38.5, 68.5) | 59.0 (40.8, 83.3) | 0.096 |
| Number of acid reflux events | 26.0 (10.5, 39.8) | 24.0 (11.0, 37.5) | 31.0 (21.0, 47.0) | 0.011 |
| Number of weakly acidic reflux events | 20.0 (12.0, 35.0) | 23.0 (13.5, 37.0) | 23.0 (10.8, 33.5) | 0.586 |
| Number of weakly alkaline reflux events | 0.0 (0.0, 1.0) | 0.0 (0.0, 1.0) | 0.0 (0.0, 1.0) | 0.592 |
| Number of proximal reflux events | 20.0 (10.0, 35.0) | 18.0 (10.5, 28.0) | 26.0 (13.0, 44.5) | 0.006 |
| Number of proximal acid reflux events | 12.0 (4.0, 22.0) | 9.0 (2.0, 15.5) | 16.0 (7.0, 28.5) | 0.001 |
| Number of proximal weakly acidic reflux events | 6.0 (3.0, 10.0) | 6.0 (3.0, 10.0) | 8.0 (3.0, 13.0) | 0.311 |
| Number of proximal weakly alkaline reflux events | 0.0 (0.0, 0.0) | 0.0 (0.0, 0.0) | 0.0 (0.0, 0.0) | 0.342 |
| Median bolus clearance time (sec) | 10.0 (8.0, 13.0) | 11.0 (9.0, 13.5) | 11.0 (9.0, 13.3) | 0.157 |
| PSPWI (%) | 29.4 (18.2, 41.4) | 30.3 (17.7, 44.6) | 30.2 (20.0, 43.2) | 0.782 |
| MNBI (Ω) | 2417.0 (871.0, 3500.0) | 2800.0 (1575.0, 3555.4) | 1787.0 (694.0, 3500.0) | 0.103 |
| The SAP (heartburn/reflux) positive rate (%) | 22.8 | - | 32.7 | 0.101 |
FD, functional dyspepsia; AET, acid exposure time; PSPWI, post-reflux swallow-induced peristaltic wave index; MNBI, mean nocturnal baseline impedance; SAP, symptom association probability.
Data are presented as median (interquartile range) or %.
The above results suggest that patients with overlap symptoms and patients with pure FD symptoms were very similar in terms of esophageal motility and reflux parameters. In order to figure out what factors determine these patients presented overlapping reflux symptoms or not, multivariate stepwise logistics regression was performed (in patients in the overlap symptoms group and in the FD symptoms group). Baseline characteristics, the composite symptom score, the short form-36 life quality questionnaire (SF-36) score, the presence and severity of esophagitis, motility parameters and reflux parameters were included. However, no independent factor was found to be associated with the presence of overlapping reflux symptoms.
Proton Pump Inhibitor Response
For PPI treatment efficacy, the PPI response rate was significantly lower in the overlap symptoms group and the FD symptoms group than in the reflux symptoms group (43.4% vs 40.5% vs 66.7%; P < 0.001). As for patients in the overlap symptoms group, remarkably, no significant difference was observed in the PPI response rate between patients with objective GERD evidences and patients without (FD + GERD vs FD + FH vs FD + RH = 46.2% vs 41.3% vs 45.5%; P = 0.863).
This study further explored what factors determined these patients’ responding or non-responding to PPI treatment. Baseline characteristics, symptom spectrum, the composite symptom score, the GerdQ score, the SF-36 score, the presence and severity of esophagitis, motility parameters and reflux parameters were included for multivariate stepwise logistics regression analysis. The results showed that BMI, the presence of IEM, and the presence of concurrent FD symptoms and reflux symptoms were independent predictors of PPI response. The likelihood of PPI response increased with the growth of the BMI and the presence of IEM, while decreased with the presence of concurrent FD symptoms and reflux symptoms (Table 4).
Table 4.
Multivariate Stepwise Logistics Regression Analysis of Proton Pump Inhibitor Response
| Multivariate analysis | Parameters | OR (95% CI) | P-value |
|---|---|---|---|
| Step 1 | Constant | 0.027 | 0.001 |
| BMI | 1.186 (1.076, 1.307) | 0.001 | |
| Step 2 | Constant | 0.050 | 0.007 |
| BMI | 1.173 (1.063, 1.293) | 0.001 | |
| Concurrent FD symptoms and GER symptoms | 0.503 (0.282, 0.897) | 0.020 | |
| Step 3 | Constant | 0.502 | 0.008 |
| BMI | 1.167 (1.057, 1.288) | 0.002 | |
| Concurrent FD symptoms and GER symptoms | 0.502 (0.279, 0.901) | 0.021 | |
| IEM | 5.005 (1.030, 24.326) | 0.046 |
BMI, body mass index; FD, functional dyspepsia; GER, gastroesophageal reflux; IEM, ineffective esophageal motility.
Subgroup Analysis
Patients with FD symptoms were further divided into different subtypes based on their symptoms. Thus, patients in the overlap symptoms group were further divided into the EPS + reflux symptoms group (patients with concurrent epigastric pain syndrome and reflux symptoms), the PDS + reflux symptoms group (patients with concurrent postprandial distress syndrome and reflux symptoms), the EPS + PDS + reflux symptoms group (patients with epigastric pain syndrome, postprandial distress syndrome and reflux symptoms), while patients in the FD symptoms group were divided into the EPS symptoms group, the PDS symptoms group, the EPS + PDS symptoms group. Subgroup analysis found that regardless of the FD symptom subtypes, patients with concurrent FD symptoms and overlapping reflux symptoms (the EPS + reflux symptoms group; the PDS + reflux symptoms group; the EPS + PDS + reflux symptoms group) had a comparable reflux burden to patients with pure FD symptoms (the EPS symptoms group, the PDS symptoms group, the EPS + PDS symptoms group), and both were lower than that in the reflux symptoms group. Patients with concurrent FD symptoms subtypes and overlapping reflux symptoms also had lower SAP (heartburn/reflux) positive rates and PPI response rates than patients in the reflux symptoms group (Supplementary Tables 1-3).
Discussion
Overlapping reflux symptoms in FD are particularly common in clinical practice. Further clarifying the causes of overlapping reflux symptoms is a clinically important issue, as it may contribute to the better management of these patients. The current study illuminated that up to 64.8% of FD patients had overlapping reflux symptoms. However, among patients with concurrent FD symptoms and reflux symptoms, only 28.7% had objective GERD evidences. Functional heartburn seemed to be the primary cause of overlapping reflux symptoms. Furthermore, most patients with overlapping reflux symptoms poorly responded to PPI treatments, even for those with objective GERD evidences.
The most widely accepted hypothesis is that overlapping reflux symptoms in FD are cause by gastroesophageal reflux. A study by Bredenoord et al,19 included 214 patients with upper gastrointestinal symptoms. Gastric accommodation was found to be impaired in 47.0% of FD patients, while delayed gastric emptying was found in 13.3% of FD patients.19 Another study by Pauwels et al,20 included 12 GERD patients and 9 healthy controls. The study showed for the first time that the gastric accommodation determines the occurrence of transient LES relaxations and reflux events.20 Putting the circumstantial evidences from the above-mentioned studies together, it seems safe to hypothesize that impaired gastric motility in FD may result in the increased gastric pressure, which leads to the occurrence of gastroesophageal reflux and eventually reflux symptoms. If this hypothesis is valid, acid-suppressing agents should be effective to alleviate overlapping reflux symptoms. However, multiple studies have reported the poor efficacy of PPI treatment in FD patients with overlapping reflux symptoms.21-23 More direct evidences are needed to establish a relationship between overlapping reflux symptoms and gastroesophageal reflux. By using pH-impedance monitoring, the current study showed for the first time that the reflux burden of FD patients with overlapping reflux symptoms was comparable to that of those without. Furthermore, FD patients with overlapping reflux symptoms poorly responded to PPI treatment, even for those with objective GERD evidences. Taken together, these results indicate that overlapping reflux symptoms were mostly unrelated to gastroesophageal reflux. Thus, administering PPI or P-CAB to alleviate overlapping reflux symptoms should be cautious.
Another hypothesis for overlapping reflux symptoms is that they may be caused by the changes of visceral sensitivity induced by psychological conditions. This hypothesis is supported by some previous studies. A study by Colombo et al,24 demonstrated that patients with a positive report of overlapping reflux symptoms had increased sleep disturbances, anxiety, and depression than patients with a negative report. A recent Chinese cross-sectional study included 3281 FD patients, 50.69% of whom overlapped with gastroesophageal reflux symptoms. FD patients with anxiety, depression, and poor sleep quality were found to be more likely to have overlap disorders.25 Although psychological and visceral sensitivity data were not collected in the current study, our study did demonstrate that FH accounted for more than half of the overlap symptoms group. As widely accepted, FH is a functional esophageal disorder that closely related to the psychological condition and visceral sensitivity.26 Therefore, the current study supported that overlapping reflux symptoms may be psychosomatic.
Duodenal eosinophilia infiltration and duodenal hypersensitivity may also contribute to overlapping reflux symptoms.8 However, there are very few studies on duodenal eosinophilia infiltration and duodenal hypersensitivity, all of which are low-level indirect evidences. For duodenal eosinophilia infiltration, Ronkainen et al,27 showed that FD at baseline were associated with an increased risk of developing overlapping reflux symptoms at follow-up with duodenal eosinophilia an independent risk factor for this. For duodenal hypersensitive, Lee et al,28 showed that duodenal acidification might aggravate acid-related symptoms through the induction of hypersensitivity to gastric distension.
The current study also had some limitations. Firstly and most importantly, patients’ psychological conditions (such as anxiety, depression, etc) were not evaluated. This was due to the fact that the population in this study was derived from one of our previous published studies aiming to evaluate the diagnostic value of abdominal symptoms in GERD.11 The lack of evaluation parameters for psychological conditions may explain why this study failed to find any factors independently associated with overlapping symptoms during the multivariate analysis. Secondly, all patients in this study were treated with PPI and not with neuromodulators. Whether neuromodulators are effective to these patients still needs further investigations. Thirdly, gastric motility was not monitored in the current study. Lastly, this study was a single center study in China. All patients were of Chinese linguistic and cultural origin. Whether the results of this study are applicable to other populations needs to be verified by further multi-center studies.
In conclusion, this study illuminated that overlapping reflux symptoms in FD was common. Strikingly, these symptoms primarily diverged from reflux etiology and exhibited suboptimal responses to PPI intervention. These findings challenge prevailing paradigms and accentuate the imperative for nuanced therapeutic approaches tailored to the distinctive characteristics of overlapping reflux symptoms in the context of FD.
Supplementary Materials
Note: To access the supplementary tables mentioned in this article, visit the online version of Journal of Neurogastroenterology and Motility at http://www.jnmjournal.org/, and at https://doi.org/10.5056/jnm24091.
Footnotes
Financial support: The study was supported by the China Postdoctoral Science Foundation (2024M763808); the Postdoctoral Fellowship Program (Grade B) of China Postdoctoral Science Foundation (GZB20240889) and the National Natural Science Foundation of China (82170577).
Conflicts of interest: None.
Author contributions: Songfeng Chen and Xingyu Jia: acquisition of data, analysis and interpretation of data, and drafting of the manuscript; Yinglian Xiao: study concept and design, analysis of data, and finalizing and approving the manuscript; and Qianjun Zhuang, Xun Hou, Kewin T H Siah, Mengyu Zhang, Fangfei Chen, Niandi Tan, and Junnan Hu: acquisition of data, and analysis and interpretation of data.
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