Clinical characteristics and risk factors of refractory gastroesophageal reflux disease: A multicenter cross-sectional study

Abstract

BACKGROUND

Refractory gastroesophageal reflux disease (GERD) constitutes a significant proportion of GERD cases and presents a considerable burden in clinical practice. However, the underlying risk factors contributing to persistent and refractory symptoms and the clinical characteristics of this disease remain poorly understood.

AIM

To investigate the clinical features of refractory GERD and identify the associated risk factors.

METHODS

This is a multicenter cross-sectional study on patients with GERD across 18 medical centers in Shanghai. All participants completed comprehensive questionnaires that assessed their demographic characteristics, lifestyle and dietary habits, clinical manifestations, somatic symptoms, mental and psychological health status, and quality of life. Univariate analysis was performed to identify significant differences between the patients with refractory and non-refractory GERD. Subsequently, stepwise regression analysis was employed to conduct a multivariate binary logistic regression for exploring the association between refractory GERD and various factors, including dietary habits, lifestyle, clinical symptoms, and mental and psychological status.

RESULTS

Our study included 911 patients diagnosed with GERD, of whom 256 (28.1%) had refractory GERD and 655 (71.9%) had non-refractory GERD. Compared to patients with non-refractory GERD, those with refractory GERD are older, have a longer disease duration, and exhibit higher scores for typical reflux symptoms. They are also more likely to present with atypical symptoms, more prone to overeating, more likely to experience somatic symptoms, comorbid anxiety, and depression, and report a lower quality of life. Binary logistic regression analysis identified disease duration and anxiety as significant risk factors and at least 90 minutes of moderate-intensity physical activity per week as a protective factor for refractory GERD.

CONCLUSION

Refractory GERD is associated with a prolonged disease duration, anxiety status, and insufficient physical activity. These findings may afford valuable insights for the clinical management and development of non-pharmacological interventions for refractory GERD.

Key Words: Refractory gastroesophageal reflux disease; Clinical characteristics; Risk factors; Anxiety; Multicenter cross-sectional study

Core Tip: Refractory gastroesophageal reflux disease (GERD) represents a clinically challenging subtype of GERD that remains poorly understood. This cross-sectional study examined data from 256 patients with refractory GERD and 655 patients with non-refractory GERD to identify clinical characteristics and potential risk factors. The results indicate that prolonged disease duration, anxiety, and insufficient physical activity are independent risk factors for refractory GERD. Furthermore, age, overeating, esophageal chest pain, sensation of pharyngeal obstruction, and constipation showed strong correlations with refractory GERD. These findings underscore the presence of distinct, complex pathophysiological mechanisms and clinical features in refractory GERD, along with the role of psychological factors, providing useful insights for long-term management and treatment strategies for refractory GERD.

INTRODUCTION

Refractory gastroesophageal reflux disease (GERD) is a heterogeneous condition characterized by an inadequate or suboptimal response to standard acid-suppressive pharmacotherapy. According to the United Nations, over one billion people worldwide were affected by GERD in 2022[1], and refractory GERD accounted for an estimated 13.2%-54.1% of these cases[2-4].

Unlike patients with GERD who typically respond well to acid-suppressing medications, individuals with refractory GERD experience dual burdens of physical discomfort and psychological distress. Research indicates that these patients have significantly increased rates of visits to primary care providers and emergency departments, and their work performance and sleep quality are markedly impaired[5,6]. Furthermore, the need for repeated medical consultations contributes to a substantial economic burden. Patients with refractory GERD incur medical expenses that are, on average, 7000-10000 United States dollars higher than those who respond effectively to the proton pump inhibitor (PPI) therapy[7,8]. The persistent nature of reflux-related symptoms, combined with the potential adverse effects of prolonged acid suppression, not only compromises the mental health and overall quality of life of patients but may also increase their risk of malignant transformation of the esophageal mucosa[9].

As the number of patients diagnosed with refractory GERD is rising[4], their clinical management is also becoming increasingly challenging, especially in primary care settings such as communities. As a result, researchers have begun to explore possible influencing factors and underlying mechanisms associated with this disease. Existing evidence suggests that lifestyle and dietary habits not only act as significant triggers for GERD symptoms[10,11] but are also closely related to the persistent and recurrent refractory GERD symptoms and poor response to the PPI treatment[12]. Additionally, psychological distress has been identified as a key factor associated with the development of refractory GERD[13,14].

Although the existing literature reports some valuable information on the relationship between refractory GERD and risk factors, there are still major limitations. Specifically, many previous studies have primarily focused on comparing risk factor profiles between different GERD subtypes, particularly between reflux esophagitis and non-erosive reflux disease (NERD)[15], or on contrasting characteristics between patients with GERD and healthy individuals[11]. Some other studies have examined only factors influencing residual symptoms, specifically in patients with NERD[12]. Very few studies are available on refractory GERD. In addition, no cross-sectional investigations on the relationship between refractory and non-refractory GERD are yet available.

This study aims to further investigate the lifestyle habits, dietary habits, clinical manifestations, and psychological status of refractory GERD through a cross-sectional examination at 18 medical centers across Shanghai, China, and identify the independent risk factors of refractory GERD to enhance the awareness of clinicians on refractory GERD.

MATERIALS AND METHODS

Design and participants

From December 2023 to June 2024, outpatients aged 18-80 years diagnosed with GERD were consecutively recruited from 7 municipal or district hospitals and 11 community health service centers in Shanghai. All patients were required to meet at least one of the following criteria before enrollment: Presence of typical clinical manifestations within the past month, including heartburn, esophageal chest pain, and regurgitation; Their reflux diagnostic questionnaire score should be ≥ 12[16], and presence of endoscopic esophageal inflammation (Los Angeles grades B/C/D esophagitis) or pathological gastroesophageal reflux as demonstrated by 24-hour potential of hydrogen-impedance monitoring[17] (acid exposure time ≥ 6% and/or increased number of reflux episodes). Refractory GERD was diagnosed in accordance with the consensus criteria established by European Society of Neurogastroenterology and Motility/American Society of Neurogastroenterology and Motility[18]. It is defined as partially responsive or non-responsive to a stable dose of a PPI/potassium-competitive acid blockers (P-CAB) during a treatment period of at least 8 weeks. The patients were evaluated for achieving a 50% symptom response to a standard dose of PPI/P-CAB for at least 8 weeks. Patients with incomplete or missing data, malignant tumors of the esophagus and stomach, peptic ulcers, hiatal hernia, or upper gastrointestinal surgery, as well as those with communication disorders or mental illnesses who were unable to cooperate with the investigators, were excluded. Incomplete or missing data were defined as the lack of information regarding the core values and absence of key information, including whether the condition was refractory, the duration of the disease, or cases with missing values exceeding 20% in independent variables. Patients who presented with language expression disorders and intellectual disability, those diagnosed with psychiatric conditions such as schizophrenia or bipolar disorder during the consultation, and patients unable to cooperate in completing the case report form were deemed incapable of collaborating with the investigator and were thus excluded from the study.

All participants were informed of the study details. They voluntarily agreed to participate and signed an informed consent form. The study protocol was reviewed and approved by the Ethics Committee of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Affiliated with Shanghai University of Traditional Chinese Medicine (Ethical Review No. 2023-196). The trial was registered with the Chinese Clinical Trial Registry (Registration No. ChiCTR2500096125).

Data collection

All the outpatient physicians who collected the information underwent a standardized training provided by us. We informed the patients about the purpose and procedures of the survey and conducted face-to-face questionnaire interviews. Patients who agreed to participate completed the questionnaires on-site, which were then immediately collected. The questionnaire was composed of four sections. The first section collected demographic information, including age, gender, height, weight, and marital status. The second section focused on lifestyle and dietary habits. The third section assessed clinical symptom characteristics, including both typical and atypical symptoms. The fourth section evaluated somatic symptoms, psychological status, and quality of life.

Lifestyle and dietary habits

The lifestyle questionnaire comprises 10 items assessing the following habits: Staying up late (falling asleep after 2:00), early awakening (waking up more than 30 minutes earlier than usual), frequent dreaming, exercise (engaging in at least 90 minutes of moderate-intensity physical activity per week), smoking (consumption of one or more cigarettes per day for at least one year), and drinking (at least once per week in the past year, with each occasion involving more than 25 g of alcohol for men and more than 15 g for women). The eating habits questionnaire includes 12 items: Eating beyond fullness (habitual eating despite feeling full), skipping breakfast (occurring at least twice per week), and eating before bedtime (within two hours of sleep). Dietary preferences were defined as consuming a specific food type at least three times per week for ≥ 1 year. These included sweet foods (e.g., cakes, cream, and glutinous rice products), greasy foods, raw or cold foods, spicy foods, sour foods (e.g., rice vinegar, citrus fruits, and juices), hot foods (above 65 °C), strong tea (e.g., dark tea with a bitter taste), chocolate, coffee, carbonated beverages, and dairy products.

Clinical manifestations

Typical symptoms of GERD include heartburn, esophageal chest pain, and regurgitation. The severity of each symptom experienced in the past month was assessed using the following scale: 0 (no symptoms), 2 (mild symptoms occasional, occurring approximately once per week), 4 (moderate symptoms intermediate in severity, occurring 2-3 times per week), and 6 (severe symptoms significantly affecting normal daily activities or sleep, occurring 4-7 times per week). Atypical symptoms included nausea, belching, sensation of pharyngeal obstruction, dryness or soreness of the throat, cough, epigastric pain or burning, abdominal distension, poor appetite, constipation, and loose stools. The occurrence of atypical symptoms was evaluated as occurring at least once a week in the past month.

Somatic symptoms, mental and psychological health status, and quality of life

Somatic symptom scale-China: It is a self-report questionnaire developed based on the Shanghai population[19,20]. It has good reliability and validity. This scale consists of 20 brief items and assesses the extent to which patients are bothered by the aforementioned issues over the past six months since they first felt unwell. A score of 36 is the cutoff point for positivity, and a total score of ≥ 36 is considered indicative of the somatic symptom disorder, with higher scores indicating greater severity.

Hospital anxiety and depression scale: This scale comprises two parts: The hospital anxiety and depression scale-anxiety (HADS-A) and the hospital anxiety and depression scale-depression (HADS-D)[13,21]. A total score of 0-7 is considered normal, 8-10 indicates mild anxiety/depression, 11-14 indicates moderate anxiety/depression, and 15-21 indicates severe anxiety/depression.

GERD health-related quality of life: This scale includes 10 items focusing on heartburn, swallowing, and medication efficacy over the past month[22,23]. It has fewer items and exhibits a higher response rate than those exhibited by the somatic symptom scale-China (SSS-CN) and HADS. The total score ranges from 0 to 50 points, with higher scores indicating a poorer quality of life.

36-Item short form survey: This survey comprises nine aspects: Physical functioning, role physical, bodily pain, general health perception, vitality, social functioning, emotional well-being, mental health, and health perception[24,25]. Higher scores indicate a better quality of life.

Statistical analysis

Statistical analysis was conducted using SPSS 27 (IBM). Descriptive analysis of continuous variables was conducted using mean ± SD and median (interquartile range), while categorical variables were expressed as counts and percentages. The Kolmogorov-Smirnov test was used to evaluate normality/non-normality. Univariate analysis was used to compare differences between refractory GERD and non-refractory GERD. Student’s t-test was applied for continuous variables with a normal distribution, while the Mann-Whitney U test was used for non-normal distribution; the χ² test was utilized for categorical variables. Variables with a P value of less than 0.1 in the univariate logistic regression analysis were subsequently included in a multivariate binary logistic regression model for further evaluation. P < 0.05 was considered statistically significant.

RESULTS

Demographic characteristics

Enrollment and group designation are summarized in Figure 1. The baseline demographic characteristics of refractory GERD and non-refractory GERD groups are presented in Table 1. A total of 911 patients with GERD were enrolled, of whom 256 (28.1%) had refractory GERD and 655 (71.9%) had non-refractory GERD. The proportion of female patients was found to be higher in the overall GERD population. The average age of patients with refractory GERD was significantly higher than that of patients with non-refractory GERD (54.79 ± 12.52 vs 52.54 ± 11.94, P < 0.05). Additionally, patients with refractory GERD had a longer mean disease duration (4.12 ± 3.46 vs 3.05 ± 3.01, P < 0.001). No significant differences in gender or body mass index were observed.

Figure 1 Flowchart of patient inclusion. Flow diagram illustrating the selection process for patients with gastroesophageal reflux disease (GERD) in outpatient clinics at multiple hospitals in Shanghai from December 2023 to June 2024. After applying the exclusion criteria, 911 patients with GERD were included in the final analysis, which included 256 patients with refractory GERD and 655 patients with non-refractory GERD. GERD: Gastroesophageal reflux disease; RDQ: Reflux diagnostic; pH: Potential of hydrogen; PPI: Proton pump inhibitor; P-CAB: Potassium-competitive acid blockers.

Table 1 Baseline demographic characteristics of refractory gastroesophageal reflux disease and non-refractory gastroesophageal reflux disease patients, mean ± SD/n (%).

Baseline characteristics	Refractory GERD (n = 256)	Non-refractory GERD (n = 655)	P value
Age (years)	54.79 ± 12.52	52.54 ± 11.94	0.012a
Gender
Male	94 (36.72)	252 (38.47)	0.624
Female	162 (63.28)	403 (61.53)
BMI (kg/m2)	23.33 ± 2.71	23.25 ± 2.44	0.684
Disease duration (years)	4.12 ± 3.46	3.05 ± 3.01	< 0.001c

^aP < 0.05.

^cP < 0.001.

BMI: Body mass index; GERD: Gastroesophageal reflux disease.

Characteristics of clinical manifestations

A comparison of clinical manifestation characteristics, including both typical and atypical symptoms, of the two population groups is shown in Table 2. The esophageal chest pain score was significantly higher in patients with refractory GERD than it was in those with non-refractory GERD. However, no significant difference was found regarding heartburn and regurgitation between the two groups. Our study also found that patients with refractory GERD were more likely to experience atypical symptoms such as a sensation of pharyngeal obstruction and constipation. No significant differences were found regarding the prevalence of nausea, belching, sensation of pharyngeal obstruction, dryness or soreness of the throat, cough, epigastric pain or burning, abdominal distension, poor appetite, or diarrhea between the two groups. Furthermore, an analysis of the number of atypical symptoms revealed that patients with refractory GERD experience a greater burden of atypical symptoms (4.22 ± 2.18 vs 3.77 ± 2.08, P = 0.004).

Table 2 Characteristics of clinical manifestations of refractory gastroesophageal reflux disease and non-refractory gastroesophageal reflux disease patients, mean ± SD/n (%).

Symptom	Refractory GERD (n = 256)	Non-refractory GERD (n = 655)	z/χ2 value	P value
Typical symptoms
Heartburn, median IQR	2 (2.0, 4.0)	2 (0.0, 4.0)	-1.388	0.165
Regurgitation, median IQR	2 (2.0, 4.0)	2 (2.0, 4.0)	-0.55	0.582
Esophageal chest pain, median IQR	2 (0.0, 2.0)	0 (0.0, 2.0)	-2.543	0.011a
Atypical symptoms
Nausea	102 (39.84)	226 (34.50)	2.278	0.131
Belching	150 (58.59)	360 (54.96)	0.985	0.321
Sensation of pharyngeal obstruction	101 (39.45)	199 (30.38)	6.858	0.009b
Dryness or soreness of the throat	105 (41.02)	245 (37.40)	1.014	0.314
Cough	109 (42.58)	243 (37.10)	2.33	0.127
Epigastric pain or burning	109 (42.58)	254 (38.78)	1.109	0.292
Abdominal distension	130 (50.78)	319 (48.70)	0.318	0.573
Poor appetite	124 (48.44)	284 (43.36)	1.92	0.166
Constipation	113 (44.14)	239 (36.49)	4.546	0.033a
Diarrhea	37 (14.45)	99 (15.11)	0.063	0.801
Number of atypical symptoms	4.22 ± 2.18	3.77 ± 2.08	2.901	0.004c

^aP < 0.05.

^bP < 0.01.

^cP < 0.001.

IQR: Interquartile range; GERD: Gastroesophageal reflux disease.

Lifestyle and dietary habits

A χ² test was performed to analyze the lifestyle and dietary habits of patients with refractory GERD and those with non-refractory GERD (Table 3). Compared to patients with non-refractory GERD, those with refractory GERD were more likely to have a dietary habit of overeating (14.84 vs 9.62, P = 0.024). In contrast, a significantly higher proportion of patients in the non-refractory GERD group maintained a lifestyle involving at least 90 minutes of moderate-intensity physical activity per week (26.41 vs 15.63, P = 0.001). Notably, the two groups did not show any significant differences in terms of skipping breakfast, eating before bedtime, picky eating (including sweet foods, greasy foods, raw or cold foods, spicy foods, sour foods, hot foods, strong tea, chocolate, coffee, carbonated beverages, and dairy products), drinking, smoking, staying up late, insomnia, waking up early, or frequent dreaming.

Table 3 Comparison of lifestyle and dietary habits between refractory gastroesophageal reflux disease and non-refractory gastroesophageal reflux disease patients, n (%).

Factors	Refractory GERD (n = 256)	Non-refractory GERD (n = 655)	χ2 value	P value
Dietary habits
Eating beyond fullness	38 (14.84)	63 (9.62)	5.098	0.024a
Skipping breakfast	29 (11.33)	75 (11.45)	0.003	0.958
Eating before bedtime	35 (13.67)	100 (15.27)	0.371	0.542
Sweet food	60 (23.44)	149 (22.75)	0.049	0.824
Greasy food	54 (21.09)	134 (20.46)	0.045	0.831
Raw or cold foods	18 (7.03)	63 (9.62)	1.521	0.218
Spicy foods	69 (26.95)	151 (23.05)	1.528	0.216
Sour foods	25 (9.77)	49 (7.48)	1.287	0.257
Hot foods	37 (14.45)	84 (12.82)	0.424	0.515
Strong tea	41 (16.02)	101 (15.42)	0.05	0.824
Chocolate	23 (8.98)	69 (10.53)	0.487	0.485
Coffee	56 (21.88)	141 (21.53)	0.013	0.909
Carbonated beverages	31 (12.11)	75 (11.45)	0.078	0.780
Dairy products	57 (22.27)	165 (25.19)	0.855	0.355
Lifestyle habits
Smoking	23 (8.98)	80 (12.21)	1.914	0.166
Drinking	47 (18.36)	120 (18.32)	0.001	0.989
Staying up late	37 (14.45)	129 (19.69)	3.394	0.065
Early awakening	44 (17.19)	128 (19.54)	0.666	0.414
Frequent dreaming	49 (19.14)	94 (14.35)	3.191	0.074
Exercise	40 (15.63)	173 (26.41)	11.956	0.001b

^aP < 0.05.

^bP < 0.01.

GERD: Gastroesophageal reflux disease.

Somatic symptoms, mental and psychological health status, and quality of life

Our study compared the somatization symptoms, mental and psychological status, and quality of life of the two groups of participants (Table 4). A statistically significant difference regarding the SSS-CN score was noted between the two groups (28.85 ± 7.68 vs 27.00 ± 6.91, P < 0.001). Regarding the mental and psychological health status, both the HADS-A score (5.30 ± 3.78 vs 3.76 ± 3.74, P < 0.001) and HADS-D score (6.62 ± 4.07 vs 5.07 ± 4.16, P < 0.001) were significantly higher in the refractory GERD group than they were in the non-refractory GERD group. Additionally, in terms of quality of life, patients with refractory GERD had significantly higher GERD health-related quality of life (GERD-HRQL) scores (11.34 ± 6.76 vs 9.66 ± 6.52, P = 0.001), while there was no significant difference in the 36-Item short form survey (SF-36) scores of the two groups (Table 4). Furthermore, our findings indicated that exercise was significantly associated with esophageal chest pain, as well as with the HADS-A, HADS-D, and GERD-HRQL scores (Table 5). Esophageal chest pain was positively correlated with and the sensation of pharyngeal obstruction and constipation were negatively correlated with the SSS-CN, HADS-A, and HADS-D scores (Table 6). In addition, our study indicates that carbonated beverages were positively correlated with the HADS-A and HADS-D scores, and drinking was positively correlated with the SSS-CN score (Table 7).

Table 4 Assessment of somatic symptoms, mental and psychological health status, and quality of life of refractory gastroesophageal reflux disease and non-refractory gastroesophageal reflux disease patients, mean ± SD.

Variable	Refractory GERD (n = 256)	Non-refractory GERD (n = 655)	t value	P value
Somatic symptom
SSS-CN score	28.85 ± 7.68	27.00 ± 6.91	3.512	< 0.001c
Mental and psychological health status
HADS-A score	5.30 ± 3.78	3.76 ± 3.74	5.551	< 0.001c
HADS-D score	6.62 ± 4.07	5.07 ± 4.16	5.075	< 0.001c
Quality of life
GERD-HRQL score	11.34 ± 6.76	9.66 ± 6.52	3.467	0.001b
SF-36 score	114.35 ± 18.70	112.64 ± 18.35	1.255	0.21

^bP < 0.01.

^cP < 0.001.

SSS-CN: Somatic symptom scale-China; HADS-A: Hospital anxiety and depression scale-anxiety; HADS-D: Hospital anxiety and depression scale-depression; GERD-HRQL: Gastroesophageal reflux disease health-related quality of life; SF-36: 36-Item short form survey; GERD: Gastroesophageal reflux disease.

Table 5 Correlation analysis between exercise and other relevant variables.

Variable	Exercise
	r/χ2 value	P value
Esophageal chest pain	-0.158	0.011a
Eating beyond fullness	0.265	0.607
Sensation of pharyngeal obstruction	0.006	0.939
Constipation	0.330	0.566
Disease duration	-0.013	0.831
SSS-CN score	-0.016	0.805
HADS-A score	-0.163	0.009b
HADS-D score	-0.161	0.010a
GERD-HRQL score	-0.224	< 0.001c

^aP < 0.05.

^bP < 0.01.

^cP < 0.001.

SSS-CN: Somatic symptom scale-China; HADS-A: Hospital anxiety and depression scale-anxiety; HADS-D: Hospital anxiety and depression scale-depression; GERD-HRQL: Gastroesophageal reflux disease health-related quality of life.

Table 6 Correlation analysis between clinical manifestations and somatic symptom scale-China score, hospital anxiety and depression scale-anxiety score, and hospital anxiety and depression scale-depression score.

Factors	SSS-CN score		HADS-A score		HADS-D score
	r/ρ value	P value	r/ρ value	P value	r/ρ value	P value
Esophageal chest pain	0.142	0.023a	0.268	< 0.001c	0.187	0.003b
Sensation of pharyngeal obstruction	-0.140	0.025a	-0.184	0.003b	-0.106	0.092
Constipation	-0.260	< 0.001c	-0.223	< 0.001c	-0.148	0.018a

^aP < 0.05.

^bP < 0.01.

^cP < 0.001.

SSS-CN: Somatic symptom scale-China; HADS-A: Hospital anxiety and depression scale-anxiety; HADS-D: Hospital anxiety and depression scale-depression.

Table 7 Correlation analysis between lifestyle and dietary habits and somatic symptom scale-China score, hospital anxiety and depression scale-anxiety score, and hospital anxiety and depression scale-depression score.

Factors	SSS-CN score		HADS-A score		HADS-D score
	r value	P value	r value	P value	r value	P value
Dietary habits
Eating beyond fullness	-0.077	0.22	-0.007	0.905	-0.018	0.778
Skipping breakfast	-0.068	0.278	-0.037	0.557	-0.052	0.408
Eating before bedtime	-0.089	0.154	-0.104	0.097	-0.11	0.078
Sweet food	0.033	0.604	0.098	0.118	-0.007	0.915
Greasy food	0.082	0.189	0.087	0.165	0.029	0.643
Raw or cold foods	-0.063	0.315	0.050	0.423	0.012	0.852
Spicy foods	-0.035	0.580	-0.015	0.816	0.008	0.901
Sour foods	-0.015	0.812	0.065	0.303	0.099	0.115
Hot foods	-0.088	0.162	0.006	0.920	0.0350	0.576
Strong tea	-0.035	0.579	0.046	0.462	-0.004	0.944
Chocolate	-0.033	0.601	0.076	0.227	0.122	0.052
Coffee	-0.035	0.578	0.047	0.452	0.053	0.403
Carbonated beverages	0.115	0.067	0.185	0.003b	0.207	0.001b
Dairy products	-0.053	0.396	0.107	0.086	0.102	0.103
Lifestyle habits
Smoking	0.015	0.808	-0.033	0.600	-0.026	0.676
Drinking	0.199	0.001b	0.027	0.666	0.032	0.607
Staying up late	-0.057	0.362	0.001	0.995	-0.020	0.755
Early awakening	-0.057	0.360	-0.115	0.067	-0.089	0.156
Frequent dreaming	-0.088	0.158	-0.048	0.443	-0.117	0.062

^bP < 0.01.

SSS-CN: Somatic symptom scale-China; HADS-A: Hospital anxiety and depression scale-anxiety; HADS-D: Hospital anxiety and depression scale-depression.

Multivariate binary logistic regression analysis of factors related to refractory GERD

We performed a multivariate binary logistic regression analysis of variables related to refractory GERD (Table 8). Univariate analysis indicated that refractory GERD was associated with age, disease duration, esophageal chest pain, sensation of pharyngeal obstruction, constipation, eating beyond fullness, exercise, and SSS-CN, HADS-A, HADS-D, GERD-HRQL, and SF-36 scores. Multivariate logistic regression analysis, after adjusting for potential confounding variables and conducting multicollinearity analysis, identified disease duration [β = -0.093, odds ratio (OR) = 0.911, 95% confidence interval (CI): 0.872-0.953, P < 0.001] and anxiety (β = -0.100, OR = 0.905, 95%CI: 0.869-0.941, P < 0.001) as significant risk factors for refractory GERD. In contrast, engaging in moderate-intensity physical activity for at least 90 minutes per week was identified as a protective factor (β = 0.585, OR = 1.795, 95%CI: 1.215-2.650, P = 0.003).

Table 8 Multivariate binary logistic regression analysis of factors associated with refractory gastroesophageal reflux disease.

Factors	β	SE	Wald	P value	OR	OR (95%CI)
Age	-0.009	0.006	1.784	0.182	0.991	0.979-1.004
Disease duration	-0.089	0.023	14.943	< 0.001c	0.915	0.874-0.957
Eating beyond fullness	0.362	0.231	2.453	0.117	1.436	0.913-2.260
Exercise	0.588	0.207	8.091	0.004b	1.800	1.201-2.698
Esophageal chest pain	-0.008	0.061	0.018	0.892	0.992	0.879-1.118
Sensation of pharyngeal obstruction	0.232	0.171	1.833	0.176	1.261	0.901-1.763
Constipation	0.135	0.163	0.685	0.408	1.145	0.831-1.576
SSS-CN score	-0.014	0.013	1.239	0.266	0.986	0.961-1.011
HADS-A score	-0.085	0.024	13.122	< 0.001c	0.918	0.877-0.962
GERD-HRQL score	0.006	0.014	0.161	0.689	1.006	0.978-1.034

^bP < 0.01.

^cP < 0.001.

OR: Odds ratio; CI: Confidence interval; SSS-CN: Somatic symptom scale-China; HADS-A: Hospital anxiety and depression scale-anxiety; GERD-HRQL: Gastroesophageal reflux disease health-related quality of life.

DISCUSSION

Refractory GERD has emerged as a major and challenging clinical issue in the field of gastroenterology in recent years. We herein performed a large-scale, multicenter, cross-sectional survey across multiple hospitals and primary community healthcare centers in Shanghai, China, to investigate the clinical characteristics and risk factors associated with refractory GERD. Existing research suggests that the development of refractory GERD involves multiple complex pathophysiological mechanisms, such as visceral hypersensitivity and motility disorders, including transient lower esophageal sphincter relaxations, bile acid and non-acid refluxate exposure, impaired esophageal mucosal barrier function, and dysregulation of the esophageal and intestinal microbiota[12]. However, the factors contributing to refractory GERD have still not been identified, although it has been suggested that refractory GERD may be regulated by multifactorial interactions and complex mechanisms.

Numerous factors are strongly associated with refractory GERD

In our study, the proportion of patients with refractory GERD was 28.1%, which is consistent with the findings of previous prospective studies[26,27]. Age, eating beyond fullness, and clinical symptoms are strongly associated with refractory GERD, suggesting their potential involvement in the pathogenesis of this condition. We found that patients with refractory GERD had a higher age distribution. Numerous prior studies on patients with GERD have demonstrated that both the incidence and overall burden of GERD increase with age, and thus, age is recognized as a significant risk factor[14,28-30]. This trend may be attributed to age-related impairments in anti-reflux mechanisms, such as reduced resting pressure of the upper esophageal sphincter and increased ineffective esophageal motility[31]. However, some studies have reported that age does not significantly influence the severity of esophageal lesions, including changes in esophageal motility and mucosal injury[32,33]. As the disease duration could be an age-related variable, we performed a correlation analysis between age and disease course and found no significant association with refractory GERD.

Compared with patients with non-refractory GERD, those with refractory GERD have higher typical symptom scores of esophageal chest pain and a higher number of atypical symptoms, among which the sensation of pharyngeal obstruction and constipation are the most significant ones. Similar results have been reported by previous studies. It has been previously reported that the non-responsiveness of patients with NERD after taking PPI is related to constipation and that the total symptom score of such patients could significantly decrease after adding prokinetic drugs to their prescription[34]. According to Furuta, the unusual sensation in the throat is a factor impacting the efficacy of rabeprazole (10 mg daily) in patients with GERD[35]. Additionally, studies have shown that patients with refractory GERD with extraesophageal symptoms experience a significant increase in weak acid reflux events[36], which may partially explain why patients with more extraesophageal atypical symptoms cannot benefit from acid-suppressing therapy, further highlighting the involvement of extra-acid mechanisms in this disease. In addition, our findings revealed the esophageal chest pain to be positively correlated with the SSS-CN, HADS-A, and HADS-D scores, whereas the sensation of pharyngeal obstruction and constipation was negatively correlated with these scores. This result suggests that esophageal chest pain, a typical symptom, is significantly influenced by both refractory GERD and psychological factors. In contrast, the other two atypical symptoms may not exert their effects through psychological status or somatization symptoms. This observation further indicates that the contribution and influence of the interaction among multiple factors in the progression of this disease are intricate and multifaceted.

In terms of lifestyle and dietary habits, patients with refractory GERD are more likely to eat beyond fullness. A recent study indicated that eating beyond fullness is the most frequently reported habit and risk factor among individuals experiencing persistent reflux symptoms[37]. In contrast to previous findings that reported numerous predisposing factors regarding the lifestyle and dietary habits of patients with GERD, our study did not find many positive results in terms of such factors in patients with refractory GERD. Additionally, we considered whether poor living habits and dietary patterns play an indirect role in the development of the condition. We found that carbonated beverages have a positive correlation with HADS-A and HADS-D scores, and drinking has a positive correlation with the SSS-CN score. Previous studies have also reported similar results[38,39], that is, frequent consumption of carbonated beverages is associated with higher levels of anxiety and depression. However, drinking does not aggravate somatization symptoms[40]. Thus, it remains unclear whether these factors contribute to refractory GERD by exacerbating anxiety, depression, and somatization symptoms, which requires further in-depth research. This discrepancy suggests that non-lifestyle and non-dietary factors may exert a more pronounced influence on the manifestation of refractory GERD. We hypothesize that patients with refractory GERD, who often experience long-term symptom recurrence, may be more alert to the behaviors that exacerbate or trigger symptoms. Consequently, they may consciously modify their habits to avoid inducing reflux, which could account for the limited number of significant variables identified in our analysis despite the inclusion of numerous relevant factors.

Prolonged disease duration and anxiety are the most significant risk factors for refractory GERD, while regular exercise serves as a protective factor

Our study results indicated that prolonged disease duration is a risk factor for refractory GERD, which is consistent with prior research. Fuchs established a clinical predictive model and reported that the longer the duration of GERD, the higher the frequency of abnormal functional states such as lower esophageal sphincter incompetence and esophageal acid exposure in patients. These disease parameters are causally related to disease progression[41]. However, he did not investigate the relationship between the PPI treatment efficacy and disease duration, nor did he assess the symptom profiles, psychological status, or quality of life of patients. Future studies should incorporate these variables to generate more comprehensive and clinically relevant evidence.

Our study also found that maintaining at least 90 minutes of moderate-intensity physical activity per week is a protective factor against refractory GERD. Mehta conducted a 12-year follow-up study among white women experiencing acid reflux or heartburn at least once weekly and found that moderate-to-vigorous physical activity for at least 30 minutes per day can significantly reduce the risk of GERD symptoms[42]. Furthermore, accumulating more than 150 minutes of physical activity per week is associated with a lower risk of reflux episode occurrence[43,44]. However, the specific mechanism by which exercise alleviates reflux symptoms remains unclear. It may be attributed to the strengthening of the striated muscles of the crural diaphragm through physical activity and the subsequent improvement in the anti-reflux barrier function[10,45]. In refractory GERD, exercise is negatively associated with esophageal chest pain and HADS-A, HADS-D, and GERD-HRQL scores. Research indicates that engaging in brisk walking for 2.5 hours per week may reduce the risk of developing depression by 25%[46]. Exercise can also promote the lactoylation of specific synaptic proteins in the cerebral cortex to alleviate anxiety[47]. These findings suggest that exercise may exert an indirect protective effect, potentially by alleviating anxiety and depression and enhancing the overall quality of life. Thus, regular physical exercise may serve as an effective strategy for reducing the recurrence of reflux symptoms.

Psychological factors have consistently been recognized as significant risk factors for GERD, particularly in cases involving functional esophageal disorders. Patients with GERD often exhibit increased visceral sensitivity, anxiety, depression, and other emotional disturbances[10,48-50]. These psychological conditions may have a bidirectional relationship with GERD, not only elevating the risk of reflux episodes[51] but also directly impacting the quality of life of the patients[52,53]. In this study, after adjusting for confounding variables and conducting a multicollinearity analysis, we identified anxiety as an independent risk factor for refractory GERD, a finding that aligns with previous research. Multiple studies have identified anxiety as a predictive factor for poor response to the PPI therapy[26]. These psychiatric biases can reduce the responsiveness of patients to the PPI treatment[12,13] and increase the frequency of refractory esophageal symptoms[14,54,55]. However, some studies suggest that only higher levels of depression lead to poorer treatment outcomes[56]. In recent years, increasing attention is being given to psychological processes, rather than to physiological parameters, as the primary contributors to symptom severity in patients with refractory GERD[57]. Notably, symptom recurrence in these patients does not appear to be directly linked to reflux events[58], and the role of acid reflux in disease progression has become less prominent. Furthermore, a significant discrepancy exists between the severity of esophageal symptoms and the underlying pathological processes, such as mucosal inflammation or motility disorders. Esophageal hypervigilance and visceral anxiety are considered to be the primary contributing factors[59]. Therefore, investigating the mechanisms linking psychological factors to these conditions may represent an important direction for future research. However, the precise mechanism by which anxiety interacts with this disease remains unclear. It may involve anxiety-induced enhancement of esophageal hyperalgesia and the promotion of central sensitization within the esophagus[60]. Alternatively, it may be associated with the impact of GERD-induced mental disorders on the cerebral cortical structure, potentially mediated through the brain-gut axis by increasing the surface area of the inferior temporal gyrus[61]. Overall, psychological factors appear to contribute to the development of this disease through multiple pathways and perspectives. Psychological disorders such as anxiety not only exacerbate symptoms but also contribute to symptom diversification and complexity.

Limitations and future research

This cross-sectional study investigated factors associated with refractory GERD. However, the specific mechanisms through which these factors influence the efficacy of PPI, as well as the underlying causes of persistent and recurrent symptoms, remain unclear. Moreover, the causal relationships among these variables have not been definitively established, and the role of genetic factors remains uncertain. Therefore, high-quality prospective studies are needed in the future to develop standardized treatment protocols, establish comparative groups, and dynamically evaluate the impact of lifestyle modifications and risk factor interventions to obtain stronger evidence-based medical evidence. Furthermore, this study was conducted in Shanghai, China, which may limit the generalizability of the findings to other ethnic and geographic populations. Therefore, larger-scale, multi-regional studies should be conducted in the future.

CONCLUSION

This study investigated the clinical characteristics and influencing factors of refractory GERD, with a focus on their associations with lifestyle, dietary habits, clinical manifestations, and psychological status. The results demonstrated that refractory GERD is strongly associated with age and the habit of eating beyond fullness behaviors and is more commonly accompanied by atypical symptoms. Notably, our findings identified disease duration and anxiety as independent risk factors and regular physical activity as a protective factor for refractory GERD. The underlying mechanisms linking anxiety to refractory GERD may represent a novel and promising target for therapeutic intervention. These insights are valuable for both physicians and patients, as they facilitate the identification of risk factors and support the development of individualized, comprehensive treatment strategies through lifestyle modifications, psychological counseling, and targeted interventions.