Layout 1 Thematic Section: Advances in Musculoskeletal and Neuromuscular Rehabilitation | Maccarone & Masiero Eur J Transl Myol 34 (2) 12243, 2024 doi: 10.4081/ejtm.2024.12243 Gastroesophageal Reflux Disease (GERD) is a disorder of the gastrointestinal tract that is associated with the regurgitation of gastric acid into the esophagus.1 GERD can manifest itself as a non-erosive reflux condition or erosive esophagitis. It has a prevalence of 20% in Western Countries2 accompanied by an economic burden resulting from direct and indirect costs.3 El-Serag et al.3 postulated that the reported occurrence of GERD in the United States lies between 18.1% and 27.8%; which could be high because individuals were prone to over-the-counter acid- relieving medications. Nilsson et al.4 suggested that men have a higher prevalence of GERD than women. In contrast. a meta-analysis in 2018 by Eusebi et al.5 observed that the pooled prevalence of GERD signs and symptoms was slightly higher in women compared to men at 16.7% and 15.4%, respectively. Women have a higher potential of developing non-erosive reflux disease while men have a higher chance of developing erosive oesophagitis.6,7 According to Lottrup et al.,8 the causes of GERD are mainly intrinsic or structural and affect the esophagogastric junction barrier to expose the esophagus to the gastric contents. Fewer studies have established that asymptomatic reflux esophagus occurs in a smaller portion of patients with the majority of patients Abstract Gastroesophageal reflux disease (GERD) is a gastrointestinal tract disorder associated with the regurgitation of gastric acid into the esophagus. It can present itself as a non-erosive reflux condition or erosive esophagitis. Our main objective was to evaluate the impact of oesophageal reflux disease on muscle fatigue among patients. The prospective study design was adopted using surveys performed at the South West China Medical University. All patients who were subjected to screening endoscopy at the South West China Medical University were prospectively enrolled in the study. Our study was conducted according to ethical guidelines involving animal and human subjects. Our study used the Epworth Sleepiness Scale (ESS), Hospital Anxiety and Depression Scale (HADS), and the Multidimensional Fatigue Inventory (MFI) questionnaires to perform data collection on the levels of fatigue, depression, daytime hypersomnolence, and anxiety. In the (HADS, Anxiety (β=0.657, p <.001) and Depression (β=2.927, p <.001) exhibited significant positive associations with the predicted fatigue. The Epworth Sleepiness Scale (ESS) showed no significant difference between individuals with and without reflux esophagitis (p=0.787, power=0.071). However, a significant difference was observed based on the presence of GERD symptoms (p=0.003, power=0.789), with higher mean scores for those with GERD symptoms (6.1±3.5) compared to those without (4.9±2.9). In MFI, significant differences were observed between the two groups for General and Physical Fatigue (p=0.040, power=0.823), Mental Fatigue (p=0.002, power=0.767), and MFI Total Score (p=0.002, power=0.981). In conclusion, GERD symptoms exhibited stronger associations with fatigue and daytime sleepiness than endoscopic findings, emphasizing the impact of symptomatic experiences on well-being. Key Words: GERD, HADS, ESS, MFI, fatigue, esophagus and gastric acid. Eur J Transl Myol 34 (2) 12243, 2024 doi: 10.4081/ejtm.2024.12243 Evaluation of the impact of oesophageal reflux disease on muscle fatigue Wenming Hong, Hao Wang, Xuheng Yu Department of Gastroenterology, First People’s Hospital of Chun’an County, Hangzhou, Zhejiang, China. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (CC BY-NC 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. - 145 - Non -co mmerc ial us e o nly Evaluation of the impact of oesophageal reflux disease on muscle fatigue Eur J Transl Myol 34 (2) 12243, 2024 doi: 10.4081/ejtm.2024.12243 experiencing heartburns and regurgitations.9 Moreover, atypical symptoms, oesophageal and extra—oesophageal symptoms have also been reported. The symptoms of reflux can have severe side effects leading to emotional dysfunctions, disrupted sleep patterns, depression, and anxiety.10 Maret-Ouda et al.11 postulated that the etiology of GERD is unknown and there is limited information about the development of GERD. Several risk factors have been implicated in the pathogenesis of GERD such as motor abnormalities, impaired lower oesophageal sphincter, and delayed gastric emptying. Hampel et al.12 found that obesity was a risk factor for developing GERD, oesophageal carcinoma, and erosive oesophagitis. Similarly, Malfertheiner et al.13 investigated the risk factors associated with erosive reflux disease in a sample size of more than 6000 individuals and found that the odds ratio for erosive reflux disease was correlated with body mass index. Diamant et al.14 suggested that abnormality in the causal factors of GERD creates a shift in the normal equilibrium. Causal factors such as delayed gastric emptying, physiological and structural adjustments within the gastroesophageal section, transient relaxations in the lower oesophageal sphincter muscles, mechanisms of clearance within the esophagus, ingestion of irritants and negative gastric substances. Fass15 proposed that endoscopic and histopathological analyses of GERD revealed three phenotypes of non-erosive reflux disease, Barrett esophagus and erosive esophagus. Non-erosive reflux disease is the common phenotype occurring in at least 70% of patients preceded by erosive oesophagitis in at least 30% and 12% experiencing Barett esophagus.2,15,16 Rieder et al.17 exerted that GERD has a complex pathophysiology involving several factors associated with the secretion of gastric acid, malfunctioning of the antireflux barrier, and defense mechanisms. The interconnections between these factors are not clearly understood; however, previous studies18 have suggested that these factors are associated with an increased exposure of the oesophageal squamous epithelium to acidic gastric contents such as bile, pepsin, and trypsin.18 Previous studies18-20 have found that injury to the mucosal membranes coupled with infiltration of non-specific inflammation around the epithelial cells increases the occurrence of pathological reflux. Furthermore, an endoscopic analysis would reveal mucosal breaks, columnar metaplasia, strictures, and adenocarcinoma. Recently fewer studies9 have studied the relationship between GERD and fatigue. GERD is usually accompanied by subjective symptoms such as fatigue that is triggered by secondary factors such as organic disorders. Organic disorders include malignant infections, psychological distress, and depressive disorders.21-23 Additionally, altered sleep patterns from acidic regurgitation exacerbate fatigue.24,25 Kang et al. (2021) adopted and verified the validity of the Multidimensional Fatigue Inventory (MFI) in the Korean population and assessed fatigue among patients. Also, Song et al.,26 found that gender and age have modulating effects on fatigue and GERD among Koreans. Thus, based on the previous studies, the current study seeks to examine the effects of oesophageal reflux disease patients on muscle fatigue. Moreover, we will seek to examine the effects of confounding variables such as psychological disorders, gender, and age that could mediate the effects of fatigue. Lastly, we sought to examine whether fatigue was driven by either endoscopy esophagitis or signs and symptoms of GERD. Materials and Methods Ethics Our study was conducted according to the 2008 Helsinki Declaration on experiments involving animal and human subjects.27 The study was approved by the Institutional Re- view Board of South West China Medical University. In- formed consent was obtained from all participants before participating in the study. All personal identifiers were re- moved from the data with participants assured of utmost confidentiality and secure storage of the data obtained. Research design The prospective study design was adopted using surveys performed at the South West China Medical University. The study was conducted from September 2021 to Sep- tember 2023 with data on exposures and various factors being obtained at regular intervals. The study design per- mits the establishment of temporal relationships between outcomes and exposures and the relationships between these variables. Eligibility criteria All patients who were subjected to screening endoscopy at the South West China Medical University were prospec- tively enrolled in the study. The exclusion criteria in- volved patients who presented severe comorbidities and had used over-the-counter medications that affected the central nervous system. Furthermore, test results and en- doscopy examinations were used to exclude patients pre- senting signs and symptoms of gastric cancer, duodenal ulcers, and anemia. Trained endoscopy professionals at the Department of Pathology carried out gastro-duodenoscopy on all pa- tients. The prevalence and degree of reflux oesophagitis were examined and quantified based on the Los Angeles Classification System and any slight changes in the reflux oesophagitis were removed from the study. Lastly, the presence of GERD symptoms was examined and identi- fied by heartburns and regurgitations. Data collection Our study used three questionnaires to perform data collec- tion on the levels of fatigue, depression, daytime hypersom- nolence, and anxiety. Fatigue measurements can either be one-dimensional or two-dimensional instruments such as the Fatigue Severity Scale (FSS) and the visual analog scale (VAS). The FSS consists of 9 statements designed to rate the severity of fatigue symptoms measured on a 7-point Likert Scale ranging from 1, (disagree) to 7, (agree). The total score is the sum of all numbers recorded in response - 146 - Non -co mmerc ial us e o nly Evaluation of the impact of oesophageal reflux disease on muscle fatigue Eur J Transl Myol 34 (2) 12243, 2024 doi: 10.4081/ejtm.2024.12243 to various statements. The Multidimensional Fatigue Inven- tory (MFI) is an instrument consisting of 20 items sub- divided into 5 dimensions general fatigue, reduced motivation, mental fatigue, physical fatigue, and reduced activity. The MFI is a self-report, pencil and paper-based measure that was completed in 10 mins. MFI has a higher level of reliability with consistent validity in assessing fa- tigue. The Epworth Sleepiness Scale (ESS) was adopted to examine the levels of daytime sleepiness. ESS is a self-ad- ministered instrument consisting of 8 statements measured on a 4-point Likert scale from 0 to 3. The 8 statements are based on assessing the usual chances of dozing off or falling asleep while performing different tasks. The scores ranged from 0 to 24 with higher scores showing a higher degree of an individual falling asleep. Scores above 10 show exces- sive sleepy behavior. Participants took an average of 3 mi- nutes to complete the questionnaire. The Hospital Anxiety and Depression Scale (HADS) was utilized to estimate the levels of anxiety and depression. It is a self-report rating scale consisting of 14 items measured on a 4-point Likert scale ranging from 0 to 3. The instrument is subdivided into two subscales of depression and anxiety each consisting of 7 items. The total score was determined as the sum of all 14 items with higher scores showing high levels of anxiety and depression. Statistical analysis Statistical Analyses were performed using GraphPad Prism version 9.5.1 (Chicago, Illinois, United States) at a statistical significance of p <.05. Categorical variables were presented using frequencies (percentages) as row and column totals based on chi-square tests. In contrast, con- tinuous variables were presented using measures of central tendency such as mean and standard deviation based on analysis of covariances (ANCOVA). We established cor- relations between HADS, MFI, and ESS scores based on the Pearson correlation coefficient. Regression analyses were performed to predict the effects of fatigue from age, gender, and HADS scores. Also, a regression analysis was performed to predict the impact of GERD (absent or pres- ent) from the independent variables of age, gender, and HADS scores. Results Initially, the study consisted of 100 patients. No cases were excluded after the eligibility criteria and 100 cases were examined (see Table 1). The participants reported a mean age of 40.5±5.03 years. Table 1 presents the baseline characteristics of the study population, categorized by the presence or absence of Reflux Esophagitis and GERD Symptoms. The mean age of the participants with and without Reflux Esophagitis was 40.7±10.6 and 40.5±10.0 years, respectively, with no statistically significant differ- ence (p=0.609). Similarly, there was no significant differ- ence in age between those with and without GERD Symptoms, with mean ages of 40.4±9.8 and 40.5±10.2 years, respectively (p=0.836). Regarding gender distribution, among participants without Reflux Esophagitis, 40.2% were men and 39.8% were women. In the presence of Reflux Esophagitis, the pro- portion of men increased to 58.9%, and women decreased to 31.1%. These differences were statistically significant (p=0.411). A similar pattern was observed for GERD Symptoms, with significant differences in gender distri- bution (p=0.621). The Body Mass Index (BMI) showed no significant difference between those with and without Reflux Esophagitis (p=0.260) or GERD Symptoms (p=0.142). The mean BMI for individuals with Reflux Esophagitis was 21.0±7.6, and without it was 21.3±5.1. For those with and without GERD Symptoms, the respec- tive mean BMIs were 21.3±5.9 and 22.2±5.7. - 147 - Table 1. Baseline characteristics of the study population. Reflux Reflux Sig. GERD GERD Sig. Esophagitis Esophagitis (p-value) Symptoms Symptoms (p-value) (Absent) (Present) (Absent) (Present) Age (years) 40.5±10.0 40.7±10.6 0.609 40.5±10.2 40.4±9.8 0.836 Gender 0.411 0.621 Men 37 (40.2) 71 (58.9) 49 (51.5) 59 (64.1) Women 57 (39.8) 32 (31.1) 56 (38.5) 33 (35.9) BMI (kg/m2) 21.3±5.1 21.0±7.6 0.260 22.2±5.7 21.3±5.9 0.142 WC (cm) 75.1±9.2 75.8±9.2 0.467 75.5±9.3 74.4±8.8 0.174 Note: Mean±SD. Sample size, N (%). GERD, gastroesophageal reflux disease; BMI, body mass index; WC, waist circumference. Non -co mmerc ial us e o nly Evaluation of the impact of oesophageal reflux disease on muscle fatigue Eur J Transl Myol 34 (2) 12243, 2024 doi: 10.4081/ejtm.2024.12243 Waist circumference (WC) also demonstrated no significant differences between the groups with and without Reflux Esophagitis (p=0.467) or GERD Symptoms (p=0.174). The mean WC for individuals with Reflux Esophagitis was 75.8±9.2, and without it was 75.1±9.2. For those with and without GERD Symptoms, the respective mean WCs were 74.4±8.8 and 75.5±9.3. Smoking status showed significant differences in the distribution of participants with and with- out GERD Symptoms (p=0.003). Among non-smokers, 37.7% had GERD Symptoms, while among current smokers, 16.1% had GERD Symptoms. In terms of medical history (see Figure 1), there were no significant differences in the prevalence of hypertension, type 2 diabetes, and dyslipidemia between those with and without Reflux Esophagitis or GERD Symptoms (p > 0.05 for all). In Figure 2, Alcohol consumption did not show significant differences between groups with and without Reflux Esophagitis (p=0.992) or GERD Symptoms (p=0.972). The proportions of individuals consuming alcohol less than once a week and once or more per week. In Figure 3, smoking status showed significant differences in the distribution of participants with and without GERD Symptoms (p=0.003). Among non-smokers, 37.7% had GERD Symptoms, while among current smokers, 16.1% had GERD Symptoms. Table 2 presents the results of the Multidimensional Fa- tigue Inventory (MFI) analysis based on ANCOVA, fo- cusing on reflux esophagitis. The study population is stratified into groups with reflux esophagitis present or absent, as well as those with or without GERD symptoms. For the dimensions of the MFI related to General and Physical Fatigue, there was no statistically significant dif- ference between individuals with reflux esophagitis pres- ent (16.3±4.0) and absent (16.1±3.6) (p=0.434, power=0.076). However, a significant difference was ob- served when comparing individuals with and without GERD symptoms (p <0.001, power=0.979). Those with GERD symptoms (18.1±4.2) had a higher mean score compared to those without GERD symptoms (15.7±3.5). In terms of Mental Fatigue (see Figure 4), the analysis showed no significant difference between individuals with and without reflux esophagitis (p=0.764, power=0.060). However, a significant difference was observed between those with and without GERD symptoms (p <0.001, power=0.882), with higher mean scores in the presence of GERD symptoms (14.2±4.1) compared to their absence (13.8±2.5). The dimension of Reduced Activity did not yield a significant difference between individuals with and without reflux esophagitis (p=0.714, power=0.060). Nev- ertheless, a significant difference was found based on the presence of GERD symptoms (p=0.003, power=0.688), with higher scores for those with GERD symptoms (8.4±1.9) compared to those without (7.5±1.7). Motivation showed no significant difference between in- dividuals with and without reflux esophagitis (p=0.757, power=0.071). However, a significant difference was ob- served between those with and without GERD symptoms (p=0.007, power=0.776), with higher mean scores in the presence of GERD symptoms (12.1±2.4) compared to their absence (9.8±2.6). The MFI total score demonstrated no significant difference between individuals with and without reflux esophagitis (p=0.761, power=0.077). Con- versely, a significant difference was observed based on the presence of GERD symptoms (p <0.001, power=0.899), with higher mean scores for individuals with GERD symptoms (55.6±12.7) compared to those without (47.6±9.3). - 148 - Figure 1. Medical history of patients with hypertension, type 2 diabetes, and dyslipidaemia. Non -co mmerc ial us e o nly Evaluation of the impact of oesophageal reflux disease on muscle fatigue Eur J Transl Myol 34 (2) 12243, 2024 doi: 10.4081/ejtm.2024.12243 - 149 - Figure 2. Alcohol consumption patterns of patients included in the study. Figure 3. Smoking characteristics of participants (*p <0.05, #compared to GERD Symptoms (Present). Non -co mmerc ial us e o nly Evaluation of the impact of oesophageal reflux disease on muscle fatigue Eur J Transl Myol 34 (2) 12243, 2024 doi: 10.4081/ejtm.2024.12243 The Epworth Sleepiness Scale (ESS) showed no signifi- cant difference between individuals with and without re- flux esophagitis (p=0.787, power=0.071). However, a significant difference was observed based on the presence of GERD symptoms (p=0.003, power=0.789), with higher mean scores for those with GERD symptoms (6.1±3.5) compared to those without (4.9±2.9). In the Hospital Anxiety and Depression Scale (HADS), Anxiety showed a marginal difference between individ- uals with and without reflux esophagitis (p=0.080, power=0.501). A significant difference was observed based on the presence of GERD symptoms (p <0.001, power=0.967), with higher mean scores for individuals with GERD symptoms (5.5±2.3) compared to those with- out (4.5±3.1). Depression demonstrated no significant dif- ference between individuals with and without reflux esophagitis (p=0.451, power=0.091). However, a signifi- cant difference was observed based on the presence of GERD symptoms (p <0.001, power=0.891), with higher mean scores for individuals with GERD symptoms (6.4±4.0) compared to those without (4.8±2.1). Table 3 provides an analysis of the asymptomatic erosive esophagitis group and the endoscopy-negative reflux dis- ease (ENRD) group based on ANCOVA, with the means and standard deviations presented for each parameter. In terms of the Multidimensional Fatigue Inventory (MFI), significant differences were observed between the two groups for General and Physical Fatigue (p=0.040, power=0.823), Mental Fatigue (p=0.002, power=0.767), and MFI Total Score (p=0.002, power=0.981). Partici- pants in the ENRD group demonstrated higher mean scores for these dimensions compared to those with asymptomatic erosive esophagitis. For Reduced Activity and Motivation, no statistically significant differences were found between the groups (p=0.078, power=0.457, and p=0.085, power=0.466, respectively). The Epworth Sleepiness Scale (ESS) showed no significant difference between the asymptomatic erosive esophagitis and ENRD groups (p=0.072, power=0.661). In the Hospital Anxiety and Depression Scale (HADS), while no significant difference was observed for Anxiety between the groups (p=0.352, power=0.253), a significant difference was found for Depression (p=0.002, power=0.985). Participants in the asymptomatic erosive esophagitis group had a higher mean score for Depression compared to those in the ENRD group (see Figure 5). Table 4 presents the Pearson correlation coefficients be- tween Multidimensional Fatigue Inventory (MFI), Ep- worth Sleepiness Scale (ESS), and Hospital Anxiety and Depression Scale (HADS) scores. Significant positive cor- relations were found between MFI dimensions and their respective scores. General and Physical Fatigue exhibited a strong positive correlation with a coefficient of 0.855 (p <0.001), while Mental Fatigue also showed a strong pos- itive correlation with a coefficient of 0.865 (p <0.001). Reduced Activity and Motivation demonstrated positive - 150 - Table 2. Multidimensional fatigue inventory analysis, reflux esophagitis based on ANCOVA. Reflux Reflux Sig. Statistical GERD GERD Sig. Statistical Esophagitis Esophagitis Power Symptoms Symptoms Power (Absent) (Present) (Absent) (Present) MFI General and 16.1±3.6 16.3±4.0 0.434 0.076 15.7±3.5 18.1±4.2 <0.001 0.979 Physical Fatigue Mental Fatigue 14.7±2.7 14.7±2.9 0.764 0.060 13.8±2.5 14.2±4.1 <0.001 0.882 Reduced Activity 7.7±4.6 7.7±6.1 0.714 0.060 7.5±1.7 8.4±1.9 0.003 0.688 Motivation 11.2±2.1 11.3±2.7 0.757 0.071 9.8±2.6 12.1±2.4 0.007 0.776 MFI total score 45.7±9.9 55.0±11.5 0.761 0.077 47.6±9.3 55.6±12.7 <0.001 0.899 ESS 5.1±2.1 5.8±2.8 0.787 0.071 4.9±2.9 6.1±3.5 0.003 0.789 HADS Anxiety 4.9±3.2 4.8±2.1 0.080 0.501 4.5±3.1 5.5±2.3 <0.001 0.967 Depression 5.7±2.3 5.8±2.6 0.451 0.091 4.8±2.1 6.4±4.0 <0.001 0.891 Note: Mean±SD. Sig. based on ANCOVA. MFI, Multidimensional Fatigue Inventory. ESS, Epworth Sleepiness Scale. HADS, Hospital Anxiety and Depression Scale. Non -co mmerc ial us e o nly Evaluation of the impact of oesophageal reflux disease on muscle fatigue Eur J Transl Myol 34 (2) 12243, 2024 doi: 10.4081/ejtm.2024.12243 correlations of 0.676 (p <0.001) and 0.739 (p <0.001), re- spectively. The correlation between ESS and the MFI dimensions was generally weak. ESS showed a positive correlation with General and Physical Fatigue (r=0.170, p <0.001), indi- cating a mild association. In the realm of HADS scores, both Anxiety and Depression exhibited positive correla- tions with MFI dimensions. Anxiety showed a correlation coefficient of 0.691 (p <0.001), while Depression demon- strated a correlation coefficient of 0.665 (p <0.001), indi- cating strong positive associations. Table 5 presents the results of multiple regression analyses aimed at predicting fatigue from various regressor variables. The beta coefficients (β) and corresponding significance levels (Sig.) are provided for each predictor variable. For Reflux Esophagitis, the beta coefficient is β=-0.496 with a significance level of 0.881, suggesting no statistically sig- nificant association between the presence or absence of Re- flux Esophagitis and the predicted fatigue. In contrast, GERD Symptoms exhibit a beta coefficient of β=3.341 with a significance level of 0.015, indicating a sig- nificant positive association between the presence of GERD Symptoms and the predicted fatigue. This suggests that in- dividuals with GERD Symptoms are expected to experi- ence higher levels of fatigue compared to those without GERD Symptoms. Age, with a beta coefficient of β=0.034 and a significance level of 0.668, does not show a statisti- cally significant association with the predicted fatigue in this analysis. Gender, on the other hand, demonstrates a sig- nificant association with a beta coefficient of β=3.568 and - 151 - Figure 4. MFI Scores on various levels of fatigue, activity, and motivation (# implies non-significant differences). Non -co mmerc ial us e o nly Evaluation of the impact of oesophageal reflux disease on muscle fatigue Eur J Transl Myol 34 (2) 12243, 2024 doi: 10.4081/ejtm.2024.12243 a significance level of 0.002. This suggests that gender has a notable impact on predicting fatigue, with higher levels expected in one gender compared to the other. In the Hospital Anxiety and Depression Scale (HADS), both Anxiety and Depression exhibit significant positive associations with the predicted fatigue. The beta coeffi- cient for Anxiety is β=0.657 with a significance level of less than 0.001, and for Depression, the beta coefficient is β=2.927 with a significance level of less than 0.001. These results indicate that higher levels of anxiety and depres- sion, as measured by HADS, are associated with increased predicted fatigue. Discussion The study’s main findings reveal that the presence of GERD symptoms significantly correlates with heightened levels of fatigue, emphasizing a potential association be- - 152 - Table 3. Analysis of asymptomatic erosive esophagitis group and endoscopy-negative reflux disease (ENRD) groups based on ANCOVA. Asymptomatic Erosive ENRD Sig. Statistical Power Esophagitis (n=56) (n=67) MFI General and Physical Fatigue 15.7±3.4 17.4±3.9 0.040 0.823 Mental Fatigue 14.3±2.4 16.1±2.8 0.002 0.767 Reduced Activity 9.5±5.9 8.3±1.8 0.078 0.457 Motivation 11.0±3.4 10.9±4.4 0.085 0.466 MFI Total Score 47.5±9.8 55.6±12.9 0.002 0.981 ESS 7.0±2.8 6.9±3.6 0.072 0.661 Note: means±SD. ENRD, endoscopy-negative reflux disease. MFI, Multidimensional Fatigue Inventory. ESS, Epworth Sleepiness Scale. Table 4. Pearson Correlation between MFI, ESS, and HADS scores. r Sig. MFI General and Physical Fatigue 0.855 <0.001 Mental Fatigue 0.865 <0.001 Reduced Activity 0.676 <0.001 Motivation 0.739 <0.001 ESS 0.170 <0.001 HADS Anxiety 0.691 <0.001 Depression 0.665 <0.001 Note: r, Pearson’s correlation analysis. Non -co mmerc ial us e o nly Evaluation of the impact of oesophageal reflux disease on muscle fatigue Eur J Transl Myol 34 (2) 12243, 2024 doi: 10.4081/ejtm.2024.12243 tween gastrointestinal symptoms and overall well-being. Gender emerges as a notable predictor, with females ex- periencing greater predicted fatigue than males. Ad- ditionally, anxiety and depression, as measured by the HADS scale, demonstrate strong positive associations with fatigue, underscoring the interconnectedness of men- tal health and fatigue levels. Conversely, the study does not find significant associations between fatigue and the presence or absence of Reflux Esophagitis, age, or the oc- currence of asymptomatic erosive esophagitis or endos- copy-negative reflux disease. It is theoretically posited that gastroesophageal reflux dis- ease (GERD) may contribute to fatigue and daytime sleep- iness by disrupting sleep through acid regurgitation.28 In our investigation into the potential link between GERD and fatigue, the study outcomes revealed no significant correlation between fatigue and erosive esophagitis, as measured by the MFI total score and its specific subscales, encompassing general or physical fatigue, mental fatigue, reduced activity, and motivation. Intriguingly, daytime sleepiness was not found to be associated with erosive esophagitis. These findings contrast with epidemiological studies suggesting that individuals experiencing nighttime heartburn may be prone to sleep disorders that sub- sequently impact daytime performance.11,29,30 The incon- gruence prompts a closer examination of the complex interplay between GERD, sleep disturbances, and the sub- jective experience of fatigue, advocating for further ex- ploration into potential contributing factors such as sleep quality, lifestyle, and dietary habits. Our findings allude that GERD symptoms, such as acid regurgitation and heartburn, often worsen at night, leading to disrupted sleep. Nighttime awakenings due to GERD can result in poor sleep quality and insufficient rest, con- tributing to fatigue during the day. Moreover, GERD-re- lated symptoms may prompt individuals to adopt suboptimal sleeping positions or elevate the head of the bed to alleviate discomfort. These adjustments can affect sleep architecture and lead to daytime fatigue. A systematic review by Jung et al.24 has established an as- sociation between gastroesophageal reflux disease (GERD) and sleep disturbance, revealing a bidirectional relationship. While acid regurgitation-induced sleep dis- ruptions may not universally lead to daytime sleepiness, the potential impact of nighttime sleep disturbances on daytime alertness remains evident. Surprisingly, our study - 153 - Figure 5. An ANCOVA to compare HADS scores based on depression and anxiety. Table 5. Multiple regression analysis to predict fatigue from regressor variables. β Sig. Reflux Esophagitis (absent or present) −0.496 0.881 GERD Symptoms (absent or present) 3.341 0.015 Age 0.034 0.668 Gender 3.568 0.002 HADS Anxiety 0.657 <0.001 Depression 2.927 <0.001 Note: β, Beta coefficient. Non -co mmerc ial us e o nly Evaluation of the impact of oesophageal reflux disease on muscle fatigue Eur J Transl Myol 34 (2) 12243, 2024 doi: 10.4081/ejtm.2024.12243 did not identify a higher Epworth Sleepiness Scale (ESS) score in individuals with endoscopy-proven erosive esophagitis, challenging the notion that acid contact and regurgitation alone are sufficient to induce daytime sleep- iness. This discrepancy suggests that various factors, in- cluding psychological influences, contribute to daytime sleepiness. Similarly, the intricate relationship between GERD and fatigue, viewed as a psychophysiological symptom complex, unfolds with nuanced complexity. Pre- vious studies have demonstrated associations between re- flux esophagitis and fatigue, highlighting the role of psychosocial stress in influencing reflux severity.31,32 The chronic nature of gastroesophageal reflux disease (GERD) can have notable psychological implications, po- tentially leading to heightened levels of anxiety and stress. These findings align with Gyawali et al.33 who suggested that individuals experiencing GERD symptoms, such as frequent heartburn, regurgitation, and discomfort, may un- dergo persistent challenges that extend beyond the physical manifestations of the condition. The ongoing discomfort and concern about the recurrence of symptoms, particularly during sleep, can create a cycle of psychological distress. Anxiety, as a common psychological response, may stem from the anticipation of symptom exacerbation or the fear of complications associated with GERD. Moreover, psychological factors can interact with physio- logical responses, potentially influencing the perception of symptoms and overall well-being. For instance, heightened stress levels may sensitize individuals to GERD symptoms, making them more noticeable and potentially intensifying the overall impact on psychological and physical health. The correlation between fatigue and depression was robust, with a notable increase in the prevalence of depression symptoms among individuals experiencing high levels of fatigue. The development of both depression and fatigue involves a multitude of factors, and notably, both conditions are associated with heightened immune system inflamma- tion.9,34 While previous studies on gastroesophageal reflux disease (GERD) primarily focused on the bidirectional in- fluence of anxiety and depression on patient symptoms,35,36 our analysis of GERD symptoms revealed a strong associ- ation between depression, anxiety, and symptom manifes- tation, aligning with findings from other studies. In contrast to comparisons based on the presence or absence of endos- copy-proven erosive esophagitis, GERD symptoms such as heartburn and regurgitation demonstrated a correlation with fatigue in both the overall Multidimensional Fatigue Inven- tory (MFI) scores and specific subscales. GERD is associated with chronic inflammation in the esophagus.11 Inflammatory processes can trigger fatigue, and the persistent inflammatory response in GERD may contribute to feelings of tiredness. The immune system’s activation during inflammation requires substantial energy resources.37,39 The body may prioritize these energy re- sources towards the inflammatory response, diverting them away from other essential processes. This diversion can lead to a general sense of fatigue and tiredness. Inflam- matory processes in GERD can result in the release of pro- inflammatory cytokines, signaling molecules that mediate immune responses. Elevated levels of certain cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), have been associated with fatigue.40 These cyto- kines can act on the central nervous system, influencing neurotransmitter balance and contributing to feelings of lethargy. Strengths and limitations The study has several strengths. The use of the Multidimen- sional Fatigue Inventory (MFI) provides a comprehensive understanding of fatigue, allowing for a detailed exploration of its various dimensions. The inclusion of psychological factors, such as depression and anxiety, adds depth to the investigation, recognizing the interplay between mental health and GERD symptoms. Lastly, conducting a subgroup analysis of GERD symptoms allowed for a more targeted examination of the relationship between psychological fac- tors, such as depression and anxiety, and the manifestation of symptoms. This enhances the specificity of the study findings. The cross-sectional nature of the study limits the ability to establish causation. Future research with longitu- dinal designs could offer insights into the temporal relation- ships between GERD symptoms, psychological factors, and fatigue. Also, reliance on self-reported measures, such as survey responses for GERD symptoms and psychological factors, introduces the potential for recall bias and subjec- tive interpretation. Conclusions In conclusion, the study examined the relationship between gastroesophageal reflux disease (GERD), psychological factors, and fatigue. While the chronic nature of GERD was associated with psychological distress, including anxiety and stress, the study did not find a significant correlation between GERD, as confirmed by endoscopy, and fatigue, as measured by the Multidimensional Fatigue Inventory. Notably, GERD symptoms exhibited stronger associations with fatigue and daytime sleepiness than endoscopic find- ings, emphasizing the impact of symptomatic experiences on well-being. These findings contribute valuable insights into the multifaceted interplay between GERD, psycholog- ical factors, and fatigue, shedding light on potential avenues for further research and holistic management strategies for individuals experiencing these health concerns. Conflict of interest The authors declare no potential conflict of interest, and all authors confirm accuracy. Ethics approval and consent to participate This study was conducted according to the 2008 Helsinki Declaration on experiments involving animal and human subjects. The study was approved by the Institutional Re- view Board of South West China Medical University. In- formed consent was obtained from all participants before participating in the study. All personal identifiers were re- - 154 - Non -co mmerc ial us e o nly Evaluation of the impact of oesophageal reflux disease on muscle fatigue Eur J Transl Myol 34 (2) 12243, 2024 doi: 10.4081/ejtm.2024.12243 moved from the data with participants assured of utmost confidentiality and secure storage of the data obtained. Corresponding Author Wenming Hong, Department of Gastroenterology, First People’s Hospital of Chun’an County, 1869 Huanhu North Road, Qiandao Lake Town, Chun’an County, Hangzhou City, Zhejiang Province, China. E-mail: hongw1985w@gmail.com Hao Wang ORCID ID: 0009-0008-8088-4374 E-mail: 478602970@qq.com Xuheng Yu ORCID ID: 0009-0006-3595-2265 E-mail: 13357176244@163.com References 1. Kellerman R, Kintanar T. Gastroesophageal Reflux Disease. Prim Care 2017;44:561-73. Fass R, Frazier R. The role of dexlansoprazole modified-release in the management of gastroesophageal reflux disease. Therap Adv Gastroenterol 2017;10:243-51. 3. EEl-Serag HB, Sweet S, Winchester CC, Dent J. Up- date on the epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut 2014;63:871-80. 4. Ness-Jensen E, Lindam A, Lagergren J, Hveem K. Changes in prevalence, incidence and spontaneous loss of gastro-oesophageal reflux symptoms: a pro- spective population-based cohort study, the HUNT study. Gut 2012;61:1390-7. 5. Eusebi LH, Ratnakumaran R, Yuan Y, Solaymani-Do- daran M, Bazzoli F, Ford AC. Global prevalence of, and risk factors for, gastro-oesophageal reflux symp- toms: a meta-analysis. Gut 2018;67:430-40. 6. Richter JE, Rubenstein JH. Presentation and epidemi- ology of gastroesophageal reflux disease. Gastroen- terology 2018;154:267-76. 7. Kim SY, Jung HK, Lim J, et al. Gender specific dif- ferences in prevalence and risk factors for gastro- esophageal reflux disease. J Korean Med Sci 2019; 34:e158. 8. Lottrup C, Khan A, Rangan V, Clarke JO. Esophageal physiology-an overview of esophageal disorders from a pathophysiological point of view. Ann N Y Acad Sci 2020;1481:182-97. 9. Kang SG, Hwang HJ, Kim Y, et al. Reflux esophagitis and fatigue: are they related? J Clin Med 2021; 10:1588. 10. Yamasaki T, Quan SF, Fass R. The effect of sleep de- ficiency on esophageal acid exposure of healthy con- trols and patients with gastroesophageal reflux disease. Neurogastroenterol Motil 2019;31:e13705. 11. Mahajan R, Kulkarni R, Stoopler ET. Gastroesopha- geal reflux disease and oral health: A narrative review. Spec Care Dentist 2022;42:555-64. 12. Hampel H, Abraham NS, El-Serag HB. Meta-analysis: obesity and the risk for gastroesophageal reflux dis- ease and its complications. Ann Intern Med 2005;143:199-211. 13. Malfertheiner P, Nocon M, Vieth M, et al. Evolution of gastro-oesophageal reflux disease over 5 years under routine medical care--the ProGERD study. Ali- ment Pharmacol Ther 2012;35:154-64. 14. Chen J, Brady P. Gastroesophageal reflux disease: pathophysiology, diagnosis, and treatment. Gastroen- terol Nurs 2019;42:20-8. 15. Sharma P, Yadlapati R. Pathophysiology and treatment options for gastroesophageal reflux disease: looking beyond acid. Ann N Y Acad Sci 2021;1486:3-14. 16. Savarino V, Marabotto E, Zentilin P, et al. Pathophys- iology, diagnosis, and pharmacological treatment of gastro-esophageal reflux disease. Expert Rev Clin Pharmacol 2020;13:437-49. 17. Rieder F, Biancani P, Harnett K, et al. Inflammatory mediators in gastroesophageal reflux disease: impact on esophageal motility, fibrosis, and carcinogenesis. Am J Physiol Gastrointest Liver Physiol 2010; 298:G571-81. 18. Menezes MA, Herbella FAM. Pathophysiology of gas- troesophageal reflux disease. World J Surg 2017;41: 1666-71. 19 Colletti RB, Di Lorenzo C. Overview of pediatric gas- troesophageal reflux disease and proton pump inhib- itor therapy. J Pediatr Gastroenterol Nutr 2003;37: S7-S11. 20. Kim SH, Shin MR, Lee AR, et al. Improvement of inflammation through antioxidant pathway of garde- niae fructus 50% EtOH Extract (GE) from acute re- flux esophagitis rats. Biomed Res Int 2020;2020: 4826176. 21. Bower JE, Bak K, Berger A, et al. Screening, assess- ment, and management of fatigue in adult survivors of cancer: an American Society of Clinical oncology clin- ical practice guideline adaptation. J Clin Oncol 2014;32:1840-50. 22. Lavidor M, Weller A, Babkoff H. Multidimensional fatigue, somatic symptoms and depression. Br J Health Psychol 2002;7:67-75. 23. Solano JP, Gomes B, Higginson IJ. A comparison of symptom prevalence in far advanced cancer, AIDS, heart disease, chronic obstructive pulmonary disease and renal disease. J Pain Symptom Manage 2006; 31:58-69. 24. Jung HK, Choung RS, Talley NJ. Gastroesophageal reflux disease and sleep disorders: evidence for a causal link and therapeutic implications. J Neurogas- troenterol Motil 2010;16:22-9. 25. Gu C, Olszewski T, King KL, et al. The effects of modifying amount and type of dietary carbohydrate on esophageal acid exposure time and esophageal reflux symptoms: a randomized controlled trial. Am J Gas- troenterol 2022;117:1655-67. 26. Song SW, Kang SG, Kim KS, et al. Reliability and va- lidity of the korean version of the multidimensional fatigue inventory (MFI-20): a multicenter, cross-sec- - 155 - Non -co mmerc ial us e o nly Evaluation of the impact of oesophageal reflux disease on muscle fatigue Eur J Transl Myol 34 (2) 12243, 2024 doi: 10.4081/ejtm.2024.12243 tional study. Pain Res Manag 2018;2018:3152142. 27. Shrestha B, Dunn L. The declaration of Helsinki on medical research involving human subjects: a review of seventh revision. J Nepal Health Res Counc 2020;17:548-52. 28. Patti MG, Schlottmann F, Farrell TM. Fundoplication for gastroesophageal reflux disease: tips for success. J Laparoendosc Adv Surg Tech A 2017;27:1-5. 29. Schuitenmaker JM, Kuipers T, Smout AJPM, et al. Systematic review: Clinical effectiveness of interven- tions for the treatment of nocturnal gastroesophageal reflux. Neurogastroenterol Motil 2022;34:e14385. 30. Zhang M, Hou ZK, Huang ZB, et al. Dietary and life- style factors related to gastroesophageal reflux disease: a systematic review. Ther Clin Risk Manag 2021; 17:305-23. 31. He M, Wang Q, Yao D, et al. Association between psy- chosocial disorders and gastroesophageal reflux dis- ease: a systematic review and meta-analysis. J Neurogastroenterol Motil 2022;28:212-21. 32. Song EM, Jung HK, Jung JM. The association be- tween reflux esophagitis and psychosocial stress. Dig Dis Sci 2013;58:471-7. 33. Katzka DA, Kahrilas PJ. Advances in the diagnosis and management of gastroesophageal reflux disease. BMJ 2020;371:m3786. 34. Lee CH, Giuliani F. The role of inflammation in de- pression and fatigue. Front Immunol 2019;10:1696. 35. Choi JM, Yang JI, Kang SJ, et al. Association between anxiety and depression and gastroesophageal reflux disease: results from a large cross-sectional study. J Neurogastroenterol Motil 2018;24:593-602. 36. Kim SY, Kim HJ, Lim H, et al. Bidirectional associa- tion between gastroesophageal reflux disease and de- pression: Two different nested case-control studies using a national sample cohort. Sci Rep 2018;8:11748. 37. Han D, Zhang C. The oxidative damage and inflam- mation mechanisms in GERD-induced Barrett’s esophagus. Front Cell Dev Biol 2022;10:885537. 38. Iaquinta FS, Mauro D, Pantano I, et al. Gastrointestinal symptoms impact psychosocial function and quality of life in patients with rheumatoid arthritis and spon- dyloarthritis: a cross-sectional study. J Clin Med 2023;12:3248. 39. Kurin M, Shibli F, Kitayama Y, et al. Sorting out the relationship between gastroesophageal reflux disease and sleep. Curr Gastroenterol Rep 2021;23:15. 40. Grygiel-Górniak B, Puszczewicz M. Fatigue and in- terleukin-6 - a multi-faceted relationship. Reumatolo- gia 2015;53:207-12. Disclaimer All claims expressed in this article are solely those of the authors and do not necessarily represent those of their af- filiated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Submitted: 30 December 2023. Accepted: 21 February 2024. Early access: 30 May 2024. - 156 - Non -co mmerc ial us e o nly