Transient Gastric Pressure Elevation Synergizing With Impaired Esophagogastric Junction Barrier Function Plays a Pivotal Role in the Refractory Gastroesophageal Reflux Disease

Abstract

Background/Aims

The pathophysiology of refractory gastroesophageal reflux disease (RGERD), which differs from proton pump inhibitor dependent gastroesophageal reflux disease (DGERD), remains incompletely elucidated. This study aims to compare esophageal motility patterns, transdiaphragmatic pressure gradients (TPG), and reflux profiles between RGERD and DGERD patients, and to delineate dynamic pressure gradient-esophagogastric junction (EGJ) interactions in these patients.

Methods

In this retrospective study, 274 patients who underwent 24-hour impedance-pH monitoring and high-resolution manometry, along with an assessment of proton pump inhibitor responsiveness, were classified as RGERD (32.5%), DGERD (54.4%), or non-GERD (13.1%). Clinical characteristics, TPG, esophageal motility, and reflux metrics were compared between RGERD and DGERD patients. Subgroup analysis excluding hiatal hernia (HH) was conducted to investigate the pathophysiology of RGERD.

Results

The RGERD group exhibited a significantly higher proportion of chest pain compared to the DGERD group. Regarding reflux profiles, RGERD patients without HH (RGERD^HH- group) experienced increased weakly acidic reflux (P < 0.001) and prolonged bolus exposure (P = 0.006) compared to their counterparts (DGERD^HH- group). Mechanistically, the RGERD^HH- group showed reduced lower esophageal sphincter basal pressure (P = 0.010) and EGJ contractile integral (P = 0.005). Notably, following a wet-swallow, the RGERD^HH- group experienced the significant elevation in gastric pressure and TPG. Correlation analyses revealed weakly acidic reflux and bolus exposure were positively correlated with gastric pressure variation, and inversely correlated with lower esophageal sphincter basal pressure.

Conclusions

Transient gastric pressure elevation and compromised EGJ barrier function drive weakly acidic reflux and esophageal bolus exposure. This pressure gradient-barrier mismatch underpins the refractoriness of RGERD.

Introduction

Gastroesophageal reflux disease (GERD) stands as one of the most widespread chronic gastrointestinal diseases, imposing significant clinical, and economic burdens.^1,2 Refractory gastroesophageal reflux disease (RGERD), which is defined by the persistence of reflux symptoms despite the implementation of optimized proton pump inhibitor (PPI) therapy, affects up to 40% of patients with GERD.^3,4 Another subtype of GERD, PPI dependent GERD (DGERD), is characterized by the need for long-term PPI administration to achieve reflux symptom control.⁵ Emerging evidences suggest that distinct pathophysiological mechanisms underlie these 2 subtypes of GERD. RGERD is primarily associated with weakly acidic reflux and visceral hypersensitivity,^6-9 whereas DGERD may be a consequence of rebound acid hypersecretion.¹⁰ However, the specific pathophysiological features of these subtypes, especially esophageal motility patterns, transdiaphragmatic pressure gradients (TPG), and the interactions between dynamic pressure gradient and the esophagogastric junction (EGJ), remain incompletely understood. This lack of understanding poses the significant obstacle to the development of targeted therapeutic strategies.

Currently, understanding pathophysiological mechanisms underlying different GERD subtypes is hampered by four critical gaps. Firstly, there has been an excessive focus on acidic reflux.¹¹ Weakly acidic reflux, which may play a crucial role in provoking reflux symptoms in RGERD,¹² has not been adequately investigated in comparative analyses between different GERD subtypes. Secondly, the assessment of lower esophageal sphincter (LES) pressure is often carried out in isolation, neglecting that adjacent transient pressure fluctuations (eg, post-potable or postprandial gastric pressure variations) may predispose to gastroesophageal reflux as well. Thirdly, many studies have included patients with conditions mimicking GERD, such as esophageal disorders of gut-brain interaction (DGBI) and motility disorders, making it challenging to clearly interpret the underlying pathophysiological mechanisms.¹³ Fourthly, previous studies have often failed to exclude patients with hiatal hernia (HH), which independently disrupts the morphology and pressure gradients of the EGJ, obscuring the intrinsic functional differences between RGERD and DGERD.

Therefore, the objectives of this study are to compare esophageal motility patterns, TPG and reflux profiles between conclusive RGERD and DGERD patients. Specifically, we aim to elucidate the mechanistic roles of dynamic gastric pressure variation and EGJ barrier dysfunction in the pathophysiology of RGERD, with a particular focus on HH-free subgroup.

Materials and Methods

Study Design and Population

This retrospective cohort study consecutively enrolled adult patients (age 18-85 years) who were referred to the Department of Gastroenterology, Peking University Third Hospital from January 2019 to April 2024 due to persistent typical (heartburn, regurgitation, or chest pain) and atypical reflux symptoms. As parts of the routine clinical evaluation, these patients simultaneously underwent 24-hour multichannel intraluminal impedance-pH (MII-pH) monitoring and high-resolution manometry (HRM). Patients were excluded if they had a history of esophageal or gastric surgery, had major comorbidities (eg, systemic sclerosis or achalasia), were pregnant, or had malignancy. The study was conducted in compliance with the Declaration of Helsinki and received approval from the Ethics Committee of Peking University Third Hospital (Approval No. IRB00001052-14056). Prior to undergoing any examination, all patients gave their written informed consent, which had been approved by the Institutional Review Board. This consent explicitly permitted the utilization of their clinical data, as well as data from MII-pH and HRM, for research purpose.

Conclusive GERD was established by three alternative criteria: the detected presence of erosive esophagitis with Los Angeles (LA) grades B-D, Barrett’s esophagus, or peptic esophageal stricture during endoscopy; pathologic acid exposure (acid exposure time [AET] > 4% for the Chinese population^14,15) or total reflux episodes > 80 in 24-hour MII-pH monitoring; a satisfactory response to an empiric PPI trial.^15,16 Based on PPI responsiveness and the criteria for conclusive GERD, patients were classified into three groups: RGERD, patients with conclusive GERD who experienced the limited response to optimized PPI therapy (double dose for at least 8 weeks); DGERD, patients with conclusive GERD who responded to PPI therapy but experienced symptom aggravation early after PPI cessation; non-GERD, patients who presented with reflux symptoms but did not meet any of the diagnostic criterion of conclusive GERD and were further diagnosed with various disorders according to the Rome IV criteria.¹⁷ HH was identified based on the presence of a “double hump” pressure signature at the EGJ during quiet respiration in HRM procedure, with a separation of ≥ 2 cm between the LES and the crural diaphragm peaks.¹⁸

Questionnaires and Clinical Characteristics

All patients were required to complete the following questionnaires: the GERD questionnaire (GerdQ) score is a validated questionnaire consisting of 6 items (4 positive predictors and 2 negative predictors) and is widely used as a screening tool for reflux disease. Patients with a score of ≥ 8 are likely to have GERD.¹⁹ The self-rating depression scale (SDS) and the self-rating anxiety scale (SAS) each contain 20 items to screen for the presence of depression and anxiety, respectively. For both scales, the raw score is converted to an index score by multiplying it by 1.25 then taking the integer. In the Chinese population, a SDS index score of ≥ 53 indicates the presence of depression, while a SAS index score of ≥ 50 indicates the presence of anxiety.^20,21

Demographics and clinical manifestation (typical and atypical symptoms) were obtained from the electronic medical record system. Patients with a body mass index (BMI) of ≥ 24 kg/m² are considered overweight or obese according to the Chinese population standards. Erosive esophagitis with LA grades A-D, Barrett’s esophagus, and peptic esophageal stricture were regarded as positive endoscopic findings.

24-Hour Impedance-pH Monitoring

All patients underwent MII-pH monitoring using an ambulatory monitoring system (Medical Measurement Systems, Enschede, The Netherlands) after overnight fasting for at least 12 hours. They were instructed to stop taking antisecretory or prokinetic drugs for at least 1 week prior to the MII-pH monitoring. The catheter was inserted trans-nasally, and the pH sensor was positioned 5 cm proximal to the LES, which was confirmed by the metrics from HRM. Six impedance probes (Z1 to Z6) were inserted at 17, 15, 9, 7, 5, and 3 cm proximal to the LES in sequence. The tracings of impedance and pH were analyzed using the accompanying analytic software to obtain the following metrics.

According to the property of the refluxate,²² total reflux episodes were divided into 3 subsets: liquid reflux episodes, mixed liquid-gas reflux episodes, and gas reflux episodes. Furthermore, the liquid and mixed reflux episodes were further divided into 3 subsets based on the acidity of the refluxate²³: acidic reflux episodes (pH < 4), weakly acidic reflux episodes (pH 4-7), and weakly alkaline reflux episodes (pH > 7). Both an AET > 4%¹⁴ and a DeMeester score > 14.7²⁴ were considered as indicative of pathologic esophageal acid exposure. A positive symptom-reflux association was considered as either a symptom index of ≥ 50% or a symptom association probability of > 95%.²⁵ In addition, the total esophageal bolus exposure time and its subsets in the upright and supine positions were analyzed separately. The mean nocturnal baseline impedance (MNBI) was manually evaluated. Three 10-minute time periods during the nighttime recumbent period (around 1, 2, and 3 AM) that avoided reflux episodes, swallows, and pH-drops were selected, and the mean baseline impedance from the most distal impedance probe (Z6) within these time periods was defined as MNBI.²⁶

High-resolution Manometry

All patients underwent HRM using a catheter with 36 circumferential solid-state pressure sensors (Sierra Scientific Instruments, Los Angeles, CA, USA) in the supine position. The catheter was inserted trans-nasally, and the pressure sensors were placed at 1-cm intervals, with at least 3 distal pressure sensors located in the stomach. After a 10-minute transition period, patients were instructed to stop swallowing for 30 seconds to assess basal esophageal sphincter pressures, subsequently swallowed 5 mL of water 10 times at 30-second intervals to trace esophageal peristalses. The metrics were manually evaluated according to the Chicago classification version 3.0 criteria.¹⁸ Ineffective esophageal motility was defined as ineffective swallows (weak contraction or failed peristalsis) accounting for ≥ 50% of the total swallows, while absent contractility was defined as 100% failed peristalsis.¹⁸

The esophagogastric junction contractile integral (EGJ-CI) was manually calculated using the distal contractile integral (DCI) tool for 3 consecutive respiratory cycles and then divided by the duration of the respirations.^27,28 The TPG was calculated by subtracting the esophageal pressure (measured at 2 cm proximal to the LES) from the gastric pressure (measured at 2 cm distal to the LES).²⁹ Both gastric pressure and esophageal pressure were obtained from the average pressure in a 30-second period that encompassed all phases of the respiration (mid-respiratory measurement). The TPG before (basal) and after the wet-swallow (post-wet-swallow) were comprehensively evaluated.

Statistical Methods

The original and unprocessed dataset was used for comparative analyses. Continuous variables with a normal distribution (mean ± SD) were analyzed using unpaired t test, while those without a normal distribution (median and interquartile range) were analyzed using the Mann-Whitney test. For categorical variables (number with percentage), Pearson’s chi-square test or Fisher’s exact test was used. The variations in EGJ-CI, TPG, gastric pressure, and esophageal pressure before and after the wet-swallow were analyzed using paired samples test. All analyses were performed using SPSS version 26.0 (IBM Corp, Armonk, NY, USA), and the significance threshold was set at P < 0.05 (two-tailed).

The random forest-based imputation (“missForest” package in R version 4.2.1) was employed to handle the missing values in the dataset. The imputation process did not introduce any statistically significant alteration to the dataset (Supplementary Table 1). Subsequently, the imputed dataset was used for Spearman’s rank correlation analyses between all variables in the entire study population.

Results

A total of 274 patients met the inclusion criteria and were enrolled in the study (the flow diagram is outlined in Fig. 1A). The median age of the patients was 52.0 (39.0-61.3), and 157 (57.3%) of them were male. The study population comprised 89 (32.5%) patients with RGERD, 149 (54.4%) with DGERD, and 36 (13.1%) with non-GERD. Among the non-GERD group, the following disorders were diagnosed: functional heartburn (7, 2.5%), functional chest pain (7, 2.5%), functional dysphagia (2, 0.7%), globus (1, 0.4%), reflux hypersensitivity (1, 0.4%), EGJ outflow obstruction (12, 4.4%), and ineffective esophageal motility (3, 1.1%). The remaining 3 non-GERD patients did not meet any of the above criterion.

Figure 1.

The flow diagram and the proportion of self-reporting reflux symptoms. (A) The flow diagram of this study. (B) Comparisons of self-reporting reflux symptoms between proton pump inhibitor (PPI) dependent gastroesophageal reflux disease (GERD) (DGERD, orange) and refractory GERD (RGERD, blue) patients. ***P < 0.001.

Demographics and Clinical Characteristics

The demographics (age, sex, and BMI) of the patients were comparable between the DGERD and RGERD groups (Table 1). However, the BMI (P = 0.018 for non-GERD vs DGERD, P = 0.010 for non-GERD vs RGERD) and the percentage of male patients (P < 0.001 for each comparison) were significantly lower in the non-GERD group compared to both the DGERD and RGERD groups (Supplementary Table 2). Regarding psychological distress, no significant differences were observed in SAS score, SDS score, or the prevalence rates of anxiety and depression across three groups.

Table 1.

Demographics and Clinical Characteristics of the Proton Pump Inhibitor Dependent Gastroesophageal Reflux Disease and Refractory Gastroesophageal Reflux Disease Groups

Characteristics	DGERD (n = 149)	RGERD (n = 89)	P-value
Age (yr)	52.0 (39.0-61.0)	52.0 (39.0-62.0)	0.939
Sex (male)	94 (63.1)	53 (59.6)	0.587
BMI (kg/m2)	23.0 (20.6-26.0)	23.4 (20.9-26.0)	0.695
Overweight/obesity	63 (42.3)	39 (43.8)	0.817
Positive endoscopic findings	70 (50.0)	38 (45.8)	0.542
SAS score	41.9 (35.0-46.3)	42.5 (35.0-47.5)	0.730
Anxiety	23 (17.7)	10 (13.0)	0.371
SDS score	45.6 (35.0-57.2)	46.3 (37.5-53.1)	0.908
Depression	48 (36.4)	24 (31.2)	0.446
GerdQ score	9.0 (7.0-11.0)	9.0 (7.0-11.0)	0.527

DGERD, proton pump inhibitor dependent gastroesophageal reflux disease; RGERD, refractory gastroesophageal reflux disease; BMI, body mass index; SAS, self-rating anxiety scale; SDS, self-rating depression scale; GerdQ, gastroesophageal reflux disease questionnaire.

Statistics presented as n (%) and median (interquartile range).

The RGERD group had a significantly higher proportion of self-reporting chest pain compared to the DGERD group (Fig. 1B; 44.3% vs 22.1%, P < 0.001). Additionally, the patients with RGERD showed a higher tendency to report belching and globus symptoms compared to those with DGERD, although these differences did not reach statistical significance (belching: 21.6% vs 12.8%, P = 0.073; globus: 29.5% vs 19.5%, P = 0.076). There were no significant differences between the DGERD and RGERD groups in terms of the proportion of positive endoscopic findings, GerdQ scores, or the prevalence rates of other symptoms.

Comparisons of Reflux Profiles and Motility Patterns Between the Dependent Gastroesophageal Reflux Disease and Refractory Gastroesophageal Reflux Disease Groups

The MII-pH metrics are presented in Table 2. Compared to the DGERD group, the RGERD group exhibited increased weakly acidic reflux episodes (P < 0.001) and mixed liquid-gas reflux episodes (P = 0.016). Notably, the bolus exposure time was prolonged in the RGERD group compared to the DGERD group, particularly in the upright position (P = 0.008). The RGERD and DGERD groups exhibited comparable esophageal acid loads, as measured by AET, DeMeester score, and acidic reflux episodes. Additionally, the non-GERD group showed significantly reduced esophageal acid exposure, reflux episodes, and bolus exposure compared to the DGERD and RGERD groups (Supplementary Table 2, P < 0.01 for each comparison). These results indicate that RGERD is characterized by increased weakly acidic reflux and prolonged bolus exposure, rather than elevated esophageal acid exposure. These reflux characteristics may be potential causes of the poor response to acid inhibitor drugs among the patients with RGERD.

Table 2.

Comparisons of Multichannel Intraluminal Impedance-pH Metrics Between the Proton Pump Inhibitor Dependent Gastroesophageal Reflux Disease and Refractory Gastroesophageal Reflux Disease Groups

Metrics	DGERD (n = 149)	RGERD (n = 89)	P-value
AET (%)	2.1 (0.6-5.6)	2.4 (0.6-5.8)	0.531
Pathologic acid exposure	48 (32.2)	33 (37.1)	0.444
Number of long refluxes	1.0 (0.0-2.0)	0.0 (0.0-3.0)	0.993
Longest reflux (min)	5.3 (2.3-13.0)	4.9 (2.4-10.0)	0.671
DeMeester score	7.6 (2.3-18.0)	8.7 (2.5-19.2)	0.627
Total reflux episodes	93.0 (69.0-125.0)	91.0 (77.5-132.5)	0.264
Acidic reflux episodes	31.9 (17.0-51.1)	39.1 (19.2-50.2)	0.252
Weakly acidic reflux episodes	15.2 (7.9-28.0)	22.7 (14.3-32.8)	< 0.001
Weakly alkaline reflux episodes	4.3 (1.0-9.4)	5.3 (1.0-12.5)	0.462
Liquid reflux episodes	16.5 (8.5-30.0)	18.8 (10.9-32.7)	0.229
Mixed reflux episodes	40.1 (25.8-56.9)	47.4 (31.0-67.2)	0.016
Gas reflux episodes	32.5 (18.9-54.2)	27.9 (16.1-48.1)	0.497
Total bolus exposure time (min)	17.0 (10.0-28.5)	21.0 (13.5-34.5)	0.050
Upright bolus exposure time (min)	14.0 (9.0-22.0)	19.0 (11.0-31.5)	0.008
Supine bolus exposure time (min)	2.0 (1.0-4.5)	2.0 (1.0-5.5)	0.476
MNBI (Ohm)	1867.7 (943.7-2574.0)	1561.7 (812.6-2326.6)	0.217
Positive SI/SAP	39 (26.2)	22 (24.7)	0.803

DGERD, proton pump inhibitor dependent gastroesophageal reflux disease; RGERD, refractory gastroesophageal reflux disease; AET, acid exposure time; MNBI, mean nocturnal baseline impedance; SI, symptom index; SAP, symptom association probability.

Statistics presented as n (%) and median (interquartile range).

Regarding HRM metrics (shown in Table 3), basal EGJ-CI and LES basal pressure were slightly lower in the RGERD group compared to the DGERD group, although the differences did not reach statistical significance. No significant differences were observed in the metrics of esophageal body peristalsis or upper esophageal sphincter pressure between the RGERD and DGERD groups. These results demonstrate that the differences between the RGERD and DGERD groups, in terms of esophageal motility, are mainly presented at the EGJ.

Table 3.

Comparisons of High-resolution Manometry Metrics Between the Proton Pump Inhibitor Dependent Gastroesophageal Reflux Disease and Refractory Gastroesophageal Reflux Disease Groups

Metrics	DGERD (n = 149)	RGERD (n = 89)	P-value
Length of esophagus (cm)	24.9 (23.0-26.2)	24.2 (23.0-25.6)	0.350
EGJ
Hiatal hernia	56 (37.6)	25 (28.1)	0.135
Length of LES (cm)	3.2 (2.4-4.0)	3.0 (2.3-3.7)	0.224
Length of intraabdominal LES (cm)	1.5 (0.0-2.3)	1.8 (0.0-2.4)	0.574
LES basal pressure (mmHg)	21.8 (14.9-30.6)	20.9 (14.7-25.8)	0.070
IRP (mmHg)	10.6 (7.7-14.6)	9.5 (7.3-13.2)	0.204
LES relaxation percentage (%)	46.5 (36.0-55.0)	44.0 (35.0-52.0)	0.446
Basal EGJ-CI (mmHg·cm)	67.4 (46.5-99.1)	57.2 (44.6-85.8)	0.114
Post-wet-swallow EGJ-CI (mmHg·cm)	58.4 (31.6-90.3)	57.8 (40.9-82.8)	0.458
EGJ-CI variation (mmHg·cm)	–6.1 (–25.6-9.8)	3.2 (–14.8-12.0)	0.042
TPG
Basal TPG (mmHg)	0.2 (–2.4-3.0)	0.7 (–1.1-4.0)	0.098
Post-wet-swallow TPG (mmHg)	1.4 (–1.7-3.7)	2.2 (0.2-5.1)	0.015
TPG variation (mmHg)	0.4 ± 3.3	0.8 ± 3.7	0.411
Basal gastric pressure (mmHg)	6.6 (4.1-9.3)	6.5 (3.0-9.1)	0.294
Post-wet-swallow gastric pressure (mmHg)	6.4 (4.4-9.5)	6.9 (4.4-9.0)	0.804
Gastric pressure variation (mmHg)	0.1 (–1.8-1.4)	0.7 (–1.8-2.6)	0.205
Basal esophageal pressure (mmHg)	6.6 (3.9-9.1)	5.1 (2.3-7.4)	0.002
Post-wet-swallow esophageal pressure (mmHg)	6.3 (3.8-8.0)	4.2 (2.4-7.0)	0.007
Esophageal pressure variation (mmHg)	–0.3 (–2.2-1.4)	–0.1 (–1.7-1.3)	0.457
UES
UES basal pressure (mmHg)	63.1 (46.3-94.4)	70.6 (45.6-93.3)	0.836
UES relaxation pressure (mmHg)	3.5 (–2.0-8.2)	4.2 (1.0-8.6)	0.145
UES relaxation period (msec)	598.0 (510.0-703.5)	648.0 (507.5-751.0)	0.130
DCI (mmHg·cm·sec)	866.6 (501.1-1447.7)	884.4 (518.8-1361.1)	0.851
CFV (cm/sec)	4.1 (3.3-5.1)	3.9 (3.3-4.7)	0.312
DL (sec)	6.4 (5.7-7.3)	6.4 (5.6-7.0)	0.651
Peristalsis
Weak contraction (%)	8.5 (0.0-27.0)	0.0 (0.0-20.0)	0.595
Fragmented swallow (%)	0.0 (0.0-0.0)	0.0 (0.0-0.0)	0.458
Failed peristalsis (%)	0.0 (0.0-18.0)	0.0 (0.0-18.0)	0.940
Ineffective esophageal motility	43 (28.9)	23 (25.8)	0.615
Absent contractility	0 (0.0)	1 (1.1)	0.374

DGERD, proton pump inhibitor dependent gastroesophageal reflux disease; RGERD, refractory gastroesophageal reflux disease; EGJ, esophagogastric junction; LES, lower esophageal sphincter; IRP, integrated relaxation pressure; EGJ-CI, esophagogastric junction contractile integral; TPG, transdiaphragmatic pressure gradient; UES, upper esophageal sphincter; DCI, distal contractile integral; CFV, contractile front velocity; DL, distal latency.

Statistics presented as n (%), median (interquartile range), or mean ± SD.

Additionally, the RGERD group exhibited a higher post-wet-swallow TPG, which was mainly attributed to lower post-wet-swallow esophageal pressure in this group. Basal and post-wet-swallow gastric pressures were comparable between the RGERD and DGERD groups.

Subgroup Analysis Excluding Hiatal Hernia

Given the well-established and complex impacts of HH on EGJ morphology and pressure gradients, a subgroup analysis excluding HH patients was conducted (shown in Tables 4 and 5, Fig. 2A and 3A). A greater propensity for total reflux episodes was observed in RGERD patients without HH (RGERD^HH– group) compared to their DGERD counterparts (DGERD^HH– group, Fig. 2B). Consistent with the profiles in the entire GERD cohort, the RGERD^HH– group exhibited increased weakly acidic reflux episodes (P < 0.001) and mixed liquid-gas reflux episodes (P = 0.004) compared to the DGERD^HH– group (Fig. 2D and 2E). In addition, both total and upright bolus exposure time were notably prolonged in the RGERD^HH– group (Fig. 2C and 2F; P = 0.006 for total bolus exposure time, P = 0.001 for upright bolus exposure time). Similarly, no significant differences in esophageal acid loads were observed between these 2 subgroups excluding HH.

Table 4.

Hiatal Hernia-free Subgroup Analysis of Multichannel Intraluminal Impedance-pH Metrics

Metrics	DGERDHH– (n = 93)	RGERDHH– (n = 64)	P-value
AET (%)	1.3 (0.4-3.4)	1.7 (0.5-4.3)	0.255
Pathologic acid exposure	19 (20.4)	16 (25.0)	0.499
Number of long refluxes	0.0 (0.0-1.5)	0.0 (0.0-2.0)	0.668
Longest reflux (min)	3.9 (1.6-8.4)	4.3 (1.7-8.2)	0.987
DeMeester score	4.8 (1.8-12.6)	6.5 (2.3-15.2)	0.283
Total reflux episodes	92.0 (70.0-117.5)	94.5 (78.0-151.5)	0.052
Acidic reflux episodes	27.3 (13.3-47.3)	39.6 (18.2-50.3)	0.070
Weakly acidic reflux episodes	15.0 (8.4-26.8)	23.1 (15.4-36.1)	< 0.001
Weakly alkaline reflux episodes	4.3 (1.0-9.7)	6.8 (2.0-15.1)	0.208
Liquid reflux episodes	16.5 (7.2-27.7)	17.5 (9.9-33.1)	0.172
Mixed reflux episodes	38.6 (23.8-51.5)	51.4 (28.7-68.2)	0.004
Gas reflux episodes	32.5 (19.2-51.9)	32.4 (15.3-54.3)	0.885
Total bolus exposure time (min)	14.0 (8.0-24.0)	20.5 (13.0-31.8)	0.006
Upright bolus exposure time (min)	11.0 (7.0-19.0)	18.5 (11.0-29.5)	0.001
Supine bolus exposure time (min)	1.0 (0.0-3.0)	2.0 (1.0-4.0)	0.151
MNBI (Ohm)	2209.7 (1296.3-2686.1)	1949.3 (1415.0-2442.3)	0.181
Positive SI/SAP	23 (24.7)	19 (29.7)	0.491

HH, hiatal hernia; DGERD^HH–, proton pump inhibitor dependent gastroesophageal reflux disease without HH; RGERD^HH–, refractory gastroesophageal reflux disease without HH; AET, acid exposure time; MNBI, mean nocturnal baseline impedance; SI, symptom index; SAP, symptom association probability.

Statistics presented as n (%) and median (interquartile range).

Table 5.

Hiatal Hernia-free Subgroup Analysis of High-resolution Manometry Metrics

Metrics	DGERDHH– (n = 93)	RGERDHH– (n = 64)	P-value
Length of esophagus (cm)	25.7 (24.1-26.7)	24.5 (23.7-25.9)	0.008
EGJ
Length of LES (cm)	3.4 (2.8-4.0)	3.4 (2.5-3.9)	0.398
Length of intraabdominal LES (cm)	2.0 (1.3-2.5)	1.9 (1.4-2.5)	0.618
LES basal pressure (mmHg)	25.4 (18.2-32.8)	22.3 (15.7-26.9)	0.010
IRP (mmHg)	12.5 (8.9-15.4)	10.3 (8.1-13.6)	0.114
LES relaxation percentage (%)	49.0 (38.0-58.8)	47.0 (36.0-52.0)	0.101
Basal EGJ-CI (mmHg·cm)	71.3 (52.5-100.7)	56.9 (38.7-82.8)	0.005
Post-wet-swallow EGJ-CI (mmHg·cm)	64.4 (42.8-94.8)	57.9 (40.6-76.7)	0.326
EGJ-CI variation (mmHg·cm)	–3.0 (–19.8-12.4)	3.4 (−10.5-11.4)	0.193
TPG
Basal TPG (mmHg)	1.0 (–1.8-4.0)	0.4 (–1.7-3.1)	0.713
Post-wet-swallow TPG (mmHg)	1.5 (–1.3-4.0)	1.6 (0.2-4.6)	0.265
TPG variation (mmHg)	0.1 (–1.4-1.9)	1.2 (–1.4-4.2)	0.134
Basal gastric pressure (mmHg)	6.6 (4.4-9.6)	5.4 (2.1-8.2)	0.007
Post-wet-swallow gastric pressure (mmHg)	6.2 (4.1-9.0)	6.1 (4.2-8.6)	0.730
Gastric pressure variation (mmHg)	0.1 (–1.8-1.0)	1.0 (–1.2-2.9)	0.003
Basal esophageal pressure (mmHg)	6.0 ± 3.4	4.3 ± 3.1	0.002
Post-wet-swallow esophageal pressure (mmHg)	5.4 (3.3-7.3)	4.1 (2.3-6.6)	0.047
Esophageal pressure variation (mmHg)	–0.7 (–1.9-1.4)	0.0 (–1.3-1.6)	0.112
UES
UES basal pressure (mmHg)	58.3 (45.7-95.5)	70.2 (47.8-92.7)	0.491
UES relaxation pressure (mmHg)	3.3 ± 6.2	4.5 ± 6.2	0.234
UES relaxation period (msec)	596.0 (524.0-687.5)	664.5 (548.8-773.5)	0.020
DCI (mmHg·cm·sec)	939.3 (563.8-1655.1)	884.4 (537.5-1324.7)	0.329
CFV (cm/sec)	4.1 (3.2-5.2)	3.8 (3.4-4.9)	0.532
DL (sec)	6.5 (5.8-7.4)	6.5 (5.8-7.2)	0.973
Peristalsis
Weak contraction (%)	0.0 (0.0-30.0)	0.0 (0.0-20.0)	0.964
Fragmented swallow (%)	0.0 (0.0-0.0)	0.0 (0.0-0.0)	0.379
Failed peristalsis (%)	0.0 (0.0-10.0)	0.0 (0.0-10.0)	0.471
Ineffective esophageal motility	22 (23.7)	15 (23.4)	0.975
Absent contractility	0 (0.0)	0 (0.0)	-

HH, hiatal hernia; DGERD^HH–, proton pump inhibitor dependent gastroesophageal reflux disease without HH; RGERD^HH–, refractory gastroesophageal reflux disease without HH; EGJ, esophagogastric junction; LES, lower esophageal sphincter; IRP, integrated relaxation pressure; EGJ-CI, esophagogastric junction contractile integral; TPG, transdiaphragmatic pressure gradient; UES, upper esophageal sphincter; DCI, distal contractile integral; CFV, contractile front velocity; DL, distal latency.

Statistics presented as n (%), median (interquartile range), or mean ± SD.

Figure 2.

Reflux profiles in the subgroups excluding hiatal hernia (HH). (A) Spider plot illustrating normalized reflux characteristics in proton pump inhibitor (PPI) dependent gastroesophageal reflux disease (GERD) without HH (DGERD^HH–, orange) and refractory GERD without HH (RGERD^HH-, blue) patients. (B) Total reflux episodes. (C) Total bolus exposure time. (D) Liquid reflux, mixed reflux, and gas reflux episodes. (E) Acidic reflux, weakly acidic reflux, and weakly alkaline reflux episodes. (F) Upright and supine bolus exposure time. AET, acid exposure time; SI, symptom index; SAP, symptom association probability; MNBI, mean nocturnal baseline impedance.

Figure 3.

Esophageal motility and transdiaphragmatic pressure gradient (TPG) in the subgroups excluding hiatal hernia (HH). (A) Spider plot illustrating normalized motility metrics in proton pump inhibitor (PPI) dependent gastroesophageal reflux disease (GERD) without HH (DGERD^HH–, orange) and refractory GERD without HH (RGERD^HH–, blue) patients. (B) Basal esophagogastric junction contractile integral (EGJ-CI). (C) Lower esophageal sphincter (LES) basal pressure. (D-F) Gastric pressure, esophageal pressure, and TPG before (basal) and after (post-wet-swallow) the wet-swallow. (G) High-resolution manometry images before (basal) and after (post-wet-swallow) the wet-swallow. RGERD patients without HH (RGERD^HH–) were characterized by transient gastric pressure elevation following the wet-swallow and compromised esophagogastric junction barrier function. IRP, integrated relaxation pressure; UES, upper esophageal sphincter; DCI, distal contractile integral; CFV, contractile front velocity; DL, distal latency.

In the basal condition, LES pressure (P = 0.010) as well as adjacent esophageal pressure (P = 0.002) and gastric pressure (P = 0.007) were significantly reduced in the RGERD^HH– group compared to the DGERD^HH– group (Fig. 3C-E). Similarly, basal EGJ-CI was notably lower in the RGERD^HH– group as well (Fig. 3B, P = 0.005). These results confirm intrinsic EGJ dysfunction in RGERD, independent of anatomical disruption like HH.

Crucially, gastric pressure variation was significantly higher in the RGERD^HH– group compared to the DGERD^HH– group after the wet-swallow (Table 5, P = 0.003). Additionally, gastric pressure and TPG following the wet-swallow were elevated exclusively in the RGERD^HH– group (Fig. 3D, 3F, and 3G).

Correlation Analyses

The correlations between all variables were analyzed in the entire study population (Fig. 4). The 5 HRM metrics with the strongest correlations with weakly acidic reflux episodes were gastric pressure variation (r = 0.208, P < 0.001), LES basal pressure (r = –0.194, P = 0.001), DCI (r = –0.175, P = 0.004), post-wet-swallow EGJ-CI (r = –0.162, P = 0.007), and basal TPG (r = 0.155, P = 0.010). The 5 HRM metrics with the strongest correlations with total bolus exposure time were LES basal pressure (r = –0.347, P < 0.001), HH (r = 0.290, P < 0.001), integrated relaxation pressure (IRP; r = –0.275, P < 0.001), basal TPG (r = 0.254, P < 0.001), and gastric pressure variation (r = 0.225, P < 0.001). Similarly, the 5 HRM metrics with the strongest correlations with upright bolus exposure time were LES basal pressure (r = –0.347, P < 0.001), IRP (r = –0.290, P < 0.001), HH (r = 0.265, P < 0.001), basal TPG (r = 0.223, P < 0.001), and DCI (r = –0.203, P < 0.001). Upright bolus exposure time was also significantly correlated with gastric pressure variation (r = 0.201, P < 0.001). These results reveal that weakly acidic reflux and esophageal bolus exposure are mechanistically linked to LES basal pressure and gastric pressure variation.

Figure 4.

The Spearman correlation heatmap between all variables in the entire study population. The positive correlation was presented in red, whereas the inverse correlation was presented in blue. The shade of the color corresponded to the strength of the correlation. *P < 0.05, **P < 0.01, ***P < 0.001. BMI, body mass index; GerdQ, gastroesophageal reflux disease questionnaire; SAS, self-rating anxiety scale; SDS, self-rating depression scale; LES, lower esophageal sphincter; IRP, integrated relaxation pressure; UES, upper esophageal sphincter; DCI, distal contractile integral; CFV, contractile front velocity; DL, distal latency; EGJ-CI, esophagogastric junction contractile integral; TPG, transdiaphragmatic pressure gradient; AET, acid exposure time; SI, symptom index; SAP, symptom association probability; MNBI, mean nocturnal baseline impedance.

Discussion

This study identified RGERD as a unique GERD subtype characterized by dual dysregulation: functional incompetence of the EGJ barrier (evidenced by reduced LES basal pressure and EGJ-CI) and dynamic transient gastric pressure elevation post-wet-swallow. The synergy between these motility factors predisposes RGERD patients to weakly acidic reflux and esophageal bolus exposure, even in the absence of HH. Mechanistically, reduced LES pressure compromises the intrinsic “anti-reflux valve” function of the EGJ, while transient gastric pressure spikes—observed exclusively in RGERD^HH– group—create momentary pressure gradients exceeding the impaired EGJ resistance. This dynamic pressure gradient-barrier mismatch aligns with the concept that reflux episodes depend not only on the structural and functional integrity of the EGJ but also on pressure disequilibrium under circumstances such as obesity.¹¹

In this study, the RGERD group exhibited significantly increased weakly acidic reflux episodes compared to the DGERD group, even in their subgroups excluding HH (Tables 2 and 4). As mentioned above, weakly acidic reflux plays a pivotal role in provoking reflux symptoms among the patients with GERD, particularly in those with the RGERD phenotype.^6-8,12 Mechanistically, weakly acidic reflux provokes reflux symptoms mainly through several potential factors: the first is esophageal hypersensitivity to non-acidic refluxate;^6,30 the second is that proteolytic activity of pepsin is still maintained in weakly acidic refluxate.^8,31 These results emphasize that while acid-driven pathophysiology is crucial among the patients with GERD, “non-acid mechanisms” effectively dominate the symptomatology of RGERD.

In addition to increased weakly acidic reflux, prolonged esophageal bolus exposure emerges as another crucial reflux characteristic among the patients with RGERD in this study. Esophageal bolus exposure time correlates with both reflux episodes and esophageal chemical clearance, indicating that it may better reflect the impact of gastroesophageal reflux. A previous study demonstrated that pathologic bolus exposure time, rather than pathologic AET, independently predicted poor pulmonary outcomes and mortality over a 3-year period in idiopathic pulmonary fibrosis patients.³² Furthermore, prolonged bolus exposure time is strongly associated with reflux symptoms provocation. The proportion of non-cardiac chest pain patients with pathologic bolus exposure was significantly higher compared to those with pathologic AET.³³ In addition, bolus exposure time was positively correlated with postoperative resolution of reflux symptoms following laparoscopic fundoplication, outperforming both AET and DeMeester score in diagnostic accuracy for predicting symptom resolution.³⁴ Although progress has been made in elucidating the role of increased weakly acidic reflux and bolus exposure in symptom provocation, the initial motility changes prior to these factors remain poorly understood.

In this study, the correlation heatmap revealed weakly acidic reflux and esophageal bolus exposure were inversely correlated with LES basal pressure and IRP, while positively correlated with HH (Fig. 4). These motility metrics primarily reflect the contractility and morphology of the EGJ, collectively underpinning the competence of anti-reflux valve. The EGJ-CI is a novel metric used to quantify the contractility of the EGJ, assessing both the vigor and length of contraction, independent of respiratory rate.²⁷ Previous studies have revealed EGJ-CI is inversely correlated with AET and reflux episodes.^27,35 In this study, both LES basal pressure and basal EGJ-CI were reduced among the patients with RGERD, particularly in the RGERD^HH– subgroup (Fig. 3B and 3C). These findings indicate that compromised EGJ barrier function predisposes RGERD patients to increased weakly acidic reflux and prolonged esophageal bolus exposure. In contrast to our results, a separate study demonstrated that patients with refractory reflux symptoms exhibited higher EGJ-CI compared to responsive patients, and normal EGJ-CI was linked to an unfavorable PPI response on multivariate analysis.³⁶ Explicably, the discrepancies in findings were attributed to differences in the study population enrolled, and more than half of the patients in that study were diagnosed with reflux hypersensitivity or functional heartburn, conditions characterized by significantly higher EGJ-CI compared to the patients with GERD. This underscores the functional incompetence of the EGJ barrier in “real” RGERD patients.

Crucially, gastric pressure variation also exhibited a positive correlation with weakly acidic reflux and bolus exposure, as depicted in the correlation heatmap. Gastric pressure serves as the impetus for gastroesophageal reflux. A previous study revealed that upright GERD patients exhibited elevated postprandial gastric pressure compared to healthy controls.³⁷ Furthermore, elevated gastric pressure predisposed to transient LES relaxations and reflux episodes.^38,39 In this study, gastric pressure and TPG were elevated following the wet-swallow exclusively in RGERD^HH– group (Fig. 3D and 3F). Generally, gastric pressure experiences dynamic modulation influenced by multiple factors: Firstly, it is affected by the volume, rate and biochemical properties of ingested substances.⁴⁰ Secondly, gastric motility patterns play a crucial role, especially those involving gastric compliance and emptying time.^41,42 Thirdly, the magnitude of intra-abdominal pressure, which is primarily associated with obesity, also impacts gastric pressure.^37,43 In our study, all patients followed a standardized wet-swallow protocol, which involved consuming 5 mL of water 10 times at 30-second intervals during manometry. Furthermore, after the wet-swallow, patients with overweight or obesity exhibited gastric pressure variations that were comparable to those of patients with a healthy weight (Supplementary Table 3). Based on these findings, we hypothesize that gastric motility disorders, particularly delayed gastric emptying, could potentially be a mechanistic contributor to transient gastric pressure elevation in patients with RGERD. However, the inherent limitation of this retrospective cohort study precludes further implementation of objective gastric motility assessments, such as gastric empty scintigraphy and dynamic ultrasonography. Thus, the potential causal relationship between transient gastric pressure elevation and delayed gastric emptying in patients with RGERD still requires further investigation.

MNBI is an objective reflux metric that provides insights into the longitudinal reflux burden, mucosal integrity, and the extent of esophageal mucosal damage.⁴⁴ Specifically, MNBI has been shown to be inversely associated with esophageal acid exposure.⁴⁵ In our study, this relationship is supported by the correlation analysis results, where we found a strong negative correlation between MNBI and esophageal acid exposure metrics (r = –0.740, P < 0.001 for acid exposure time; r = –0.739, P < 0.001 for DeMeester Score). Previous studies have demonstrated that MNBI can effectively discriminate GERD from esophageal DGBI.⁴⁴ However, there is ongoing controversy regarding the predictive efficacy of MNBI in stratifying PPI-responsive and refractory GERD patients.^45,46 In this study, as shown in Tables 2 and 4, the MNBI values were comparable between the RGERD and DGERD groups, which was consistent with the lack of intergroup differences in esophageal acid exposure. These findings suggest that MNBI may lack the discriminatory capacity in distinguishing between RGERD and DGERD subtypes.

The patient-reporting proportion of chest pain was significantly higher in the RGERD group compared to the DGERD group in this study (44.3% vs 22.1%). Esophageal disorders represent the most prevalent source of non-cardiac chest pain, among which GERD is implicated in 35-60% of affected individuals.^47,48 Previous studies demonstrated an elevated proportion of chest pain among patients with refractory reflux symptoms.^4,20 Our results came to the same conclusion in the conclusive GERD population. However, non-GERD patients, encompassing individuals with esophageal DGBI and motility disorders, also exhibited a higher proportion of chest pain (55.6%). Furthermore, the correlation heatmap revealed significantly inverse correlations between chest pain and metrics indicative of esophageal acid load and bolus exposure (Fig. 4). Collectively, these results suggest that the elevated prevalence of chest pain in RGERD patients might be attributed to esophageal hypersensitivity, a key mechanistic contributor to non-cardiac chest pain.⁴⁷

In this study, no statistically significant differences were observed between the RGERD and DGERD groups in term of the prevalence rates and severity of anxiety and depression (Table 1). Previous studies have well established that psychological distress is a major risk factor for the refractory subtype of patients with GERD, with substantial evidences highlighting its significant contribution to the severity of reflux symptoms.^21,49 However, it is crucial to note that the DGERD patients in our study represent a distinct cohort compared to the general PPI-responsive GERD patients enrolled in those previous studies. DGERD patients are characterized by PPI dependence and protracted disease course. Moreover, emerging evidences suggest that psychological factors may play a role in the pathophysiological mechanisms of DGERD.⁵⁰ From both an etiological and clinical perspective, our findings regarding psychological distress are plausible. Nevertheless, prospective studies are warranted to further validate these results.

It is well established that HH exacerbates gastroesophageal reflux through anatomical disruption of the EGJ, leading to increased esophageal acid exposure and reflux episodes.⁵¹ Previous studies have already emphasized the pivotal role of HH in the pathophysiology of refractory reflux symptom.⁴ By rigorously excluding HH cases, this study isolated functional defects of the EGJ from its anatomical disruptions. Our results reveal that functional incompetence and aberrant gastric pressure dynamics are sufficient to provoke refractory symptoms, even in conditions with intact anatomy. These findings challenge the traditional HH-centric paradigm and underscore the critical role of motility-focused evaluations in RGERD patients.

To our knowledge, this is the first study integrating motility patterns, dynamic pressure gradient, and reflux profiles into a coherent pathophysiological model in conclusive RGERD patients. The findings of this study could facilitate bridging existing gaps in the mechanistic understanding of RGERD and proposing potential targeted therapies (e.g., modulation for gastric pressure dynamics, diaphragmatic biofeedback training). In addition, this study challenges the central role of HH in RGERD and advocates for motility-oriented management of RGERD patients. However, this study is hampered by some limitations. Firstly, the retrospective nature of the study represents the predominant limitation, as causality between gastric pressure dynamics and reflux cannot be definitively established. The findings require further validation in prospective investigations. Secondly, the lack of sensory testing precludes assessment for the role of visceral hypersensitivity among RGERD patients.

In conclusion, RGERD is mechanistically distinct from DGERD, characterized by dynamic dissociation between the EGJ barrier and the pressure gradient. These findings strongly support the notion that high-resolution pressure-flow analysis, which depicts the real-time EGJ-pressure gradient-reflux relationships, is important in the management of these patients. A therapeutic strategy targeting dynamic barrier-pressure dysregulation is promising in the future.

Supplementary Materials

Note: To access the supplementary tables and figure mentioned in this article, visit the online version of Journal of Neurogastroenterology and Motility at http://www.jnmjournal.org/, and at http://doi.org/10.5056/jnm25050.