Abstract
Objective
We assessed the factors associated with overlap between functional dyspepsia (FD) and nonerosive reflux disease (NERD) in endoscopy-based Helicobacter pylori-uninfected Japanese health checkup participants.
Methods
We utilized baseline data from 3,085 individuals who underwent upper endoscopy for health screening in a prospective, multicenter cohort study. The participants were asked to complete a questionnaire detailing their upper abdominal symptoms and lifestyle. Anxiety was assessed using the State-Trait Anxiety Inventory (STAI) score. FD, postprandial distress syndrome (PDS), and epigastric pain syndrome (EPS) were defined according to the Rome III criteria. NERD was defined as heartburn or regurgitation ≥1 day/week without erosive esophagitis.
Results
Of the 3,085 participants, 73 (2.4%), 97 (3.1%), and 84 (2.7%) had FD alone, NERD alone, and FD-NERD overlap, respectively. Factors associated with FD-NERD-overlap participants compared with participants with neither FD nor NERD were women [odds ratio (OR): 2.08, 95% confidence interval (CI): 1.24-3.52], body mass index (BMI) <18.5 (OR: 2.87, 95% CI: 1.56-5.07), alcohol consumption ≥20 g/day (OR: 1.85, 95% CI: 1.06-3.15), and a high STAI score (OR: 2.53, 95% CI: 1.62-4.00). Increasing age (OR: 1.06, 95% CI: 1.01-1.11) and EPS symptoms [pure EPS (OR: 3.67, 95% CI: 1.65-8.51) and PDS-EPS overlap (OR: 11.6, 95% CI: 4.09-37.2)] were associated with FD-NERD overlap vs. FD alone. Women (OR: 3.17, 95% CI: 1.47-7.04), BMI <18.5 (OR: 3.03, 95% CI: 1.04-9.90), and acid reflux symptoms ≥2 days a week (OR: 3.57, 95% CI: 1.83-7.14) were associated with FD-NERD overlap vs. NERD alone.
Conclusion
Understanding the clinical features of overlap between FD and NERD will lead to better management.
Keywords: functional dyspepsia, nonerosive reflux disease, overlap, risk factors, health checkup participants
Introduction
Both functional dyspepsia (FD) and gastroesophageal reflux disease (GERD) are common upper gastrointestinal diseases worldwide (1,2). According to the Rome III criteria revised in 2006 (3) and the latest Rome IV criteria revised in 2016 (4), FD is defined as a medical condition that substantially impacts the usual activities of a patient and is characterized by one or more of the following symptoms that are unexplained after a routine clinical evaluation: postprandial fullness, early satiation, epigastric pain, and epigastric burning. FD is divided into two subcategories: postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS). Under the Rome IV criteria, it has been proposed that Helicobacter pylori-associated dyspepsia be considered secondary dyspepsia (4).
GERD is defined in the Montreal definition as a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications (5). GERD is classified into erosive esophagitis (EE) and nonerosive reflux disease (NERD). Compared to EE, NERD is more common in women, exhibits less hiatus hernia and is more likely to be associated with underweight. The pathology of NERD is considered distinct from that of EE (6). Under the Rome IV criteria, NERD is classified into the following three categories: (1) true NERD with abnormal esophageal acid exposure, (2) reflux hypersensitive esophagus with increased esophageal sensitivity but without abnormal esophageal acid exposure, and (3) functional heartburn with symptoms unrelated to gastroesophageal reflux (7).
A recent study revealed that FD and GERD coexist more frequently than would be expected by chance (8). Individuals with both FD and GERD have severe upper abdominal symptoms, which are associated with a decreased quality of life (QOL) (9). In addition, overlap between FD and GERD was associated with a high frequency of proton pump inhibitor (PPI) use (8), a high frequency of sleep disturbance (8,10), a high somatic symptom checklist (SSC) score (8), anxiety (10), depression (10), and smoking (11). Recently, in a long-term follow-up study, overlap between FD and GERD was reported to be associated with greater utilization of health-care resources and a decreased QOL (12). Although pathophysiological mechanisms common to FD and GERD, such as acid exposure in the esophagus, gastric hypomotility, and hypersensitivity, are presumed to be involved in the overlap (13-15), only a few studies have explored the risk factors for FD and GERD with or without their overlap.
Identifying risk factors for overlap between FD and GERD is a clinically important issue, as it may lead to better management of FD and GERD patients. We therefore conducted our assessment using the baseline data of the Upper Gastro Intestinal Disease (UGID) study, which is a five-year cohort study that included 8,888 participants at baseline (16-18). To simplify the investigation of risk factors associated with overlap between FD and GERD, individuals with EE, individuals who were not H. pylori-uninfected based on endoscopic findings, and individuals taking acid secretion inhibitors or gastric medications were excluded from the study population. We aimed to elucidate the factors associated with overlap between FD and NERD in endoscopy-based H. pylori-uninfected Japanese health checkup participants in this cross-sectional study.
Materials and Methods
Participants
This cross-sectional study was based on baseline data from the UGID study, which was a prospective, multicenter five-year cohort study that investigated the prevalence and natural history of gastroesophageal reflux disease and FD (16-18). In the UGID study, individuals ≥18 years old who underwent upper endoscopy as part of a health screening at 7 facilities were enrolled. Of the 8,888 participants enrolled between April 2013 and March 2015, 206 who had postgastrectomy, peptic ulcers, or upper gastrointestinal tract malignancy were excluded from this study. Of the remaining 8,682 participants, 4,484 candidates were considered H. pylori-uninfected based on endoscopic findings and their examination history for H. pylori infection. In addition, the following exclusion criteria were applied: 1) incomplete endoscopic findings (n=16); 2) incomplete data on questionnaire (n=273); 3) treatment with a PPI or histamine type 2-receptor antagonist (H2RA) (n= 189); 4) treatment with a gastromucoprotective or prokinetic agent (n=83); and 5) EE (n=838). The remaining 3,085 participants were included in this study and were classified into the FD alone group, the FD-NERD overlap group, the NERD alone group, and the control group, as appropriate (Fig. 1).
Figure 1.
Flowchart of the study participants. FD: functional dyspepsia, NERD: nonerosive reflux disease. a Endoscopic findings associated with Helicobacter pylori infection of 8,682 participants were as follows: RAC: presence (n=5,294), absence (n=3,284), difficult to determine (n=76), missing data (n=24); endoscopic atrophy: presence (n=3,446), absence (n=5,225), missing data (n=11); overall judgment of H.pylori infection based on endoscopic findings: current infection (n=2,186), past infection (n=1,133), uninfected (n=4,943), difficult to determine (n=398), missing data (n=22). The examination history of H.pylori infection of 8,682 participants was as follows: not examined (n=4,378), positive for infection (n=2,075), negative for infection (n=1,423), not sure (n=730), and missing data (n=76). The treatment history of H.pylori infection of 2,075 positive participants was as follows: not treated (n=315), eradication successful (n=1,468), eradication unsuccessful (n=110), not sure (n=159), and missing data (n=23).
This study was conducted in accordance with the Declaration of Helsinki and its amendments (UMIN-CTR ID: 000022504). The study protocol was approved by the ethics committee at each institution (the ethics committees of Kyoto Second Red Cross Hospital, Yodogawa Christian Hospital, Fukui Red Cross Hospital, Kakogawa Central City Hospital, Kita-harima Medical Center, Saiseikai Nakatsu Hospital and Hotel Okura Kobe Clinic). Written informed consent was obtained from all participants in the study.
Questionnaire
The participants were asked to complete a questionnaire consisting of questions about their upper abdominal symptoms (reflux symptoms, dyspeptic symptoms), height, body weight, smoking history (never, ex-smoker, or current smoker), alcohol consumption (none, ≤20 g/day, 20-60 g/day or >60 g/day), examination history for H. pylori infection (not examined, positivity for infection, negativity for infection, not sure), and treatment history of H. pylori infection (not treated, succeeded in eradication, not succeeded in eradication, not sure). For dyspeptic symptoms of PDS, the frequency of bothersome postprandial fullness and/or early satiation in the past three months was investigated (i.e., never, less than one day a month, one day a month, two to three days a month, one day a week, more than one day a week, or every day). For dyspeptic symptoms of EPS, the frequency of epigastric pain and/or epigastric burning experienced in the past three months was investigated (i.e. never, less than one day a month, one day a month, two to three days a month, one day a week, more than one day a week, or every day). For reflux symptoms, the frequency of heartburn and/or acid regurgitation in the past three months was investigated (i.e., never, less than one day a month, one day a month, two to three days a month, one day a week, more than one day a week, or every day). Anxiety was assessed using the State-Trait Anxiety Inventory (STAI) score (19-21). The STAI (trait) inventory consists of 20 questions (Supplementary material 1), and higher scores indicate a higher level of anxiety. A high STAI score was defined as ≥44 in men and ≥45 in women (22,23). Upper gastrointestinal symptoms were assessed using the Frequency Scale for Symptoms of GERD (FSSG) questionnaire (24,25), which consists of 12 questions related to 7 acid reflux symptoms (RS) and 5 dysmotility-like symptoms (DS) (Supplementary material 2). The use of PPIs, H2RAs, gastromucoprotective or prokinetic agents, nonsteroidal anti-inflammatory drugs (NSAIDs), low-dose aspirin, and oral antidiabetic agents was investigated by the health screening questionnaire used at each institution.
Endoscopic findings
EE was diagnosed based on the presence of endoscopically detectable mucosal breaks and was graded according to the Los Angeles (LA) classification. Hiatal hernia was diagnosed based on proximal dislocation of the esophagogastric junction more than 2 cm above the diaphragmatic hiatus. The status of endoscopic H. pylori infection was assessed by endoscopists based on the presence or absence of the following findings: enlarged folds, nodularity, diffuse redness, regular arrangement of collecting venules (RAC), and endoscopic atrophy; all of these findings are reported to be associated with H. pylori infection in the Kyoto classification (26-28), and participant status was classified as current infection, past infection, uninfected, or difficult to determine. In this study, participants who met all of the following criteria [i.e. RAC (+), no endoscopic atrophy, uninfected by overall judgment] were endoscopically defined as uninfected with H. pylori.
Definitions of FD, PDS, EPS, FD alone, FD-NERD overlap, NERD, NERD alone, and the control group
The FD group was defined as those participants who experienced PDS and/or EPS according to the Rome III criteria (3). PDS was defined as “bothersome postprandial fullness” and/or “early satiation” occurring at least two days a week over the past three months, and EPS was defined as “epigastric pain” or “epigastric burning” occurring at least one day a week over the past three months. The definition of FD did not include an onset of symptoms six months prior to this study. Participants in the FD group were subclassified into the FD alone group and the FD-NERD overlap group according to the absence or presence of NERD, respectively. Participants with heartburn and/or acid regurgitation occurring at least one day a week without EE were defined as having NERD. Participants in the NERD group were subclassified into the NERD alone group and the FD-NERD overlap group according to the absence or presence of FD, respectively. Participants with neither FD nor NERD were defined as the control group.
Statistical analyses
All statistical analyses were conducted using the JMP software program, version 10 (SAS Institute, Cary, USA). Comparisons between the participants with FD, NERD, FD alone, FD-NERD overlap, or NERD alone and the control group as well as between the participants with FD or NERD only and FD-NERD overlap were performed with the chi-square test (or Fisher's exact test, if appropriate) for categorical variables and Student's t-test or the Mann-Whitney U test for continuous variables. Multiple logistic regression analyses to identify factors associated with FD, NERD, FD only, FD-NERD overlap, or NERD only compared to the control group were performed using the following explanatory variables: age, sex, body mass index (BMI; <18.5, 18.5-25, ≥25), current smoking (yes or no), alcohol consumption ≥20 g/day (yes or no), high STAI score (yes or no), and hiatal hernia (yes or no). As the explanatory variables for the multiple logistic regression analyses to identify factors associated with FD-NERD overlap compared with FD only or NERD only, FD subgroup (pure EPS, pure PDS, PDS-EPS overlap) and acid reflux symptoms two or more days a week (yes or no) were additionally used. p<0.05 was considered indicative of statistical significance.
Results
Prevalence of overlap between FD and NERD
Of the 3,085 study participants (1,649 men and 1,436 women, mean age±standard deviation: 48.8±9.1 years old, age distribution: 22 to 81 years old), 73 (2.4%) participants had FD alone, 97 (3.1%) participants had NERD alone, and 84 (2.7%) participants had FD-NERD overlap (Fig. 1). The prevalence of FD and NERD was 5.1% and 5.9%, respectively. A total of 54% of FD participants had overlap of NERD, and 46% of NERD participants had overlap of FD.
As shown in Fig. 2, the total FSSG scores, which reflected the levels of upper gastrointestinal symptoms, were significantly higher in FD-NERD-overlap participants than in participants with FD or NERD alone (FD-NERD overlap 17.6±7.6 vs. FD alone 11.3±5.9 p<0.0001, vs. NERD alone 10.9±6.2 p<0.0001). The FSSG-RS scores (FD-NERD overlap 9.4±4.5 vs. FD alone 4.5±3.5 p<0.0001, vs. NERD alone 5.2±3.4 p<0.0001) and the FSSG-DS scores (FD-NERD overlap 8.2±4.0 vs. FD alone 6.8±3.3 p=0.018, vs. NERD alone 5.8±3.3 p<0.0001) were also significantly higher in FD-NERD-overlap participants than in participants with either disease alone.
Figure 2.
FSSG scores of FD alone, FD-NERD overlap, and NERD alone participants. Total FSSG scores: FD alone (n=71), FD-NERD overlap (n=82), NERD alone (n=94). FSSG-RS scores: FD alone (n=72), FD-NERD overlap (n=82), NERD alone (n=95). FSSG-DS scores: FD alone (n=72), FD-NERD overlap (n=84), NERD alone (n=96). FSSG: frequency scale for symptoms of gastroesophageal reflux disease, FD: functional dyspepsia, NERD: nonerosive reflux disease, RS: reflux symptoms, DS: dysmotility-like symptoms
Factors associated with FD or NERD compared with control participants
Comparisons of the clinical characteristics of the participants with FD and NERD and the control group are shown in Supplementary material 3. In the multivariate analysis, women [odds ratio (OR) 2.01, 95% confidence interval (CI) 1.25-3.25], BMI <18.5 (OR: 2.54, 95% CI: 1.46-4.27), and a high STAI score (OR: 3.85, 95% CI: 2.51-6.05) were found to be risk factors for FD (Table 1). In addition, BMI <18.5 (OR: 2.12, 95% CI: 1.28-3.40), alcohol consumption ≥20 g/day (OR: 2.09, 95% CI: 1.47-2.96), and a high STAI score (OR: 2.06, 95% CI: 1.52-2.81) were found to be risk factors for NERD (Table 1).
Table 1.
Multivariate Analysis of Factors Associated with FD or NERD Participants.
| FD | NERD | |||||||
|---|---|---|---|---|---|---|---|---|
| OR (95% CI) | p value | OR (95% CI) | p value | |||||
| Age | 1.00 (0.98-1.02) | 0.995 | 1.01 (0.997-1.03) | 0.101 | ||||
| Female | 2.01 (1.26-3.25) | 0.0034 | 1.16 (0.81-1.64) | 0.416 | ||||
| BMI 18.5>/18.5-25 | 2.54 (1.46-4.27) | 0.0013 | 2.12 (1.28-3.40) | 0.0044 | ||||
| BMI ≥25/18.5-25 | 0.90 (0.46-1.65) | 0.748 | 1.27 (0.85-1.87) | 0.238 | ||||
| Current smoking | 1.25 (0.67-2.21) | 0.471 | 1.14 (0.73-1.71) | 0.558 | ||||
| Alcohol consumption ≥20 g/day | 1.50 (0.87-2.50) | 0.139 | 2.09 (1.47-2.96) | <0.0001 | ||||
| High STAI score level | 3.85 (2.51-6.05) | <0.0001 | 2.06 (1.52-2.81) | <0.0001 | ||||
| Hiatal hernia | 1.02 (0.61-1.64) | 0.942 | 1.32 (0.93-1.85) | 0.116 | ||||
FD: functional dyspepsia, NERD: nonerosive reflux disease, OR: odds ratio, CI: confidence interval, BMI: body mass index, STAI: State-Trait Anxiety Inventory
Factors associated with FD-NERD overlap compared with control participants
Comparisons of the clinical characteristics of the participants with FD-NERD overlap and the control group are shown in Table 2. The proportion of women, STAI scores, proportion of a high STAI score, and BMI category differed significantly between the FD-NERD overlap and control groups. The multivariate analysis showed that being a woman conferred an increased risk of FD-NERD overlap (OR: 2.08, 95% CI: 1.24-3.52). In addition, BMI <18.5 (OR: 2.87, 95% CI: 1.56-5.07), alcohol consumption ≥20 g/day (OR: 1.85, 95% CI: 1.06-3.15), and a high STAI score (OR: 2.53, 95% CI: 1.62-4.00) were found to be risk factors for FD-NERD overlap (Table 3).
Table 2.
Comparison of Clinical Characteristics between the Participants with FD Alone, FD-NERD Overlap, or NERD Alone and the Control Participants
| Control (n=2,831) | FD or NERD | p value | ||||||
|---|---|---|---|---|---|---|---|---|
| FD alone (n=73) | FD-NERD overlap (n=84) | NERD alone (n=97) | FD alone vs. Control | FD-NERD overlap vs. Control | NERD alone vs. Control | |||
| Age, mean (SD) (years) | 48.9 (9.2) | 45.8 (9.0) | 49.1 (8.0)a | 49.9 (9.5) | 0.0051 | 0.835 | 0.286 | |
| Age group (years) | 0.037 | 0.545 | 0.403 | |||||
| 39≥ (%) | 430 (15.2) | 16 (21.9) | 9 (10.7) | 12 (12.4) | ||||
| 40-49 (%) | 1,149 (40.6) | 37 (50.7) | 38 (45.2) | 35 (36.1) | ||||
| 50-59 (%) | 872 (30.8) | 14 (19.2) | 28 (33.3) | 32 (33.0) | ||||
| 60≤ (%) | 380 (13.4) | 6 (8.2) | 9 (10.7) | 18 (18.6) | ||||
| Female (%) | 1,310 (46.3) | 46 (63.0) | 51 (60.7)d | 29 (29.9) | 0.0046 | 0.0089 | 0.0015 | |
| BMI, mean (SD) (kg/m2) | 22.4 (3.1) | 21.0 (2.7) | 22.0 (3.9) | 23.0 (3.4) | <0.0001 | 0.318 | 0.096 | |
| BMI category | c | 0.0070 | 0.0001 | 0.172 | ||||
| 18.5> (%) | 212 (7.5) | 12 (16.4) | 17 (20.2) | 6 (6.2) | ||||
| 18.5-25 (%) | 2,126 (75.1) | 54 (74.0) | 55 (65.5) | 67 (69.1) | ||||
| 25≤ (%) | 493 (17.4) | 7 (9.6) | 12 (14.3) | 24 (24.7) | ||||
| Current smoking (%) | 414 (14.6) | 8 (11.0) | 14 (15.9) | 17 (17.5) | 0.380 | 0.602 | 0.428 | |
| Alcohol consumption ≥20 g/day (%) | 586 (20.7) | 12 (16.4) | 21 (25.0)b | 38 (39.2) | 0.374 | 0.339 | <0.0001 | |
| Hiatal hernia (%) | 661 (23.4) | 12 (16.4) | 21 (25.0) | 31 (32.0) | 0.167 | 0.725 | 0.0497 | |
| STAI score, mean (SD) | 41.8 (9.7) | 49.8 (9.8) | 47.4 (11.8) | 44.1 (10.9) | <0.0001 | <0.0001 | 0.042 | |
| High STAI score level (%) | 1,084 (38.3) | 52 (71.2) | 50 (59.5) | 48 (49.5) | <0.0001 | 0.0004 | 0.026 | |
| Use of NSAIDs | 19 (0.67) | 1 (1.4) | 1 (1.2) | 0 (0) | 0.400 | 0.444 | 1.00 | |
| Use of low-dose aspirin | 26 (0.92) | 0 (0) | 0 (0) | 2 (2.1) | 1.00 | 1.00 | 0.237 | |
| Use of oral hypoglycemic agents | 51 (1.8) | 0 (0) | 0 (0) | 3 (3.1) | 0.639 | 0.403 | 0.424 | |
| FD subtypes | e | |||||||
| Pure PDS (%) | 44 (60.3) | 23 (27.4) | 0 (0) | |||||
| Pure EPS (%) | 22 (30.1) | 34 (40.5) | 0 (0) | |||||
| PDS-EPS overlap (%) | 7 (9.6) | 27 (32.1) | 0 (0) | |||||
| Frequency of acid reflux symptoms | f | |||||||
| 1 day a week (%) | 0 (0) | 25 (29.8) | 57 (58.8) | |||||
| 2-6 days a week (%) | 0 (0) | 50 (59.5) | 35 (36.1) | |||||
| every day (%) | 0 (0) | 9 (10.7) | 5 (5.2) | |||||
FD: functional dyspepsia, NERD: nonerosive reflux disease, SD: standard deviation, BMI: body mass index, STAI: State-Trait Anxiety Inventory, NSAIDs: nonsteroidal anti-inflammatory drugs
ap<0.05 versus FD alone, bp<0.05 versus NERD alone, cp<0.01 versus NERD alone, dp<0.0001 versus NERD alone, ep<0.0001 versus FD alone, fp<0.0005 versus NERD alone
Table 3.
Multivariate Analysis of Factors Associated with FD Alone, FD-NERD Overlap, or NERD Alone Participants
| FD alone | FD-NERD overlap | NERD alone | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| OR (95% CI) | p value | OR (95% CI) | p value | OR (95% CI) | p value | |||||||
| Age | 0.97 (0.94-0.998) | 0.038 | 1.02 (0.99-1.04) | 0.229 | 1.01 (0.99-1.04) | 0.254 | ||||||
| Female | 1.70 (1.00-2.93) | 0.048 | 2.08 (1.24-3.52) | 0.0051 | 0.68 (0.41-1.11) | 0.126 | ||||||
| BMI 18.5>/18.5-25 | 1.73 (0.85-3.27) | 0.123 | 2.87 (1.56-5.07) | 0.0011 | 1.20 (0.45-2.66) | 0.684 | ||||||
| BMI ≥25/18.5-25 | 0.67 (0.28-1.42) | 0.319 | 1.07 (0.54-1.98) | 0.835 | 1.38 (0.84-2.22) | 0.201 | ||||||
| Current smoking | 0.85 (0.36-1.76) | 0.683 | 1.45 (0.75-2.62) | 0.259 | 0.95 (0.53-1.62) | 0.856 | ||||||
| Alcohol consumption ≥20 g/day | 1.11 (0.55-2.07) | 0.761 | 1.85 (1.06-3.15) | 0.032 | 2.25 (1.43-3.49) | 0.0005 | ||||||
| High STAI score level | 3.88 (2.35-6.64) | <0.0001 | 2.53 (1.62-4.00) | <0.0001 | 1.73 (1.14-2.62) | 0.010 | ||||||
| Hiatal hernia | 0.71 (0.36-1.30) | 0.277 | 1.22 (0.50-1.40) | 0.448 | 1.41 (0.89-2.18) | 0.138 | ||||||
FD: functional dyspepsia, NERD: nonerosive reflux disease, OR: odds ratio, CI: confidence interval, BMI: body mass index, STAI: State-Trait Anxiety Inventory
Factors associated with FD-NERD overlap compared with FD or NERD alone
Compared with the participants with FD alone, those with FD-NERD overlap were older (Table 2). The participants with FD-NERD overlap more often had EPS (pure EPS or PDS-EPS overlap) as the FD subtype, whereas the participants with FD alone more often had pure PDS as the FD subtype (Table 2). In the multivariate analysis, increasing age (OR: 1.06, 95% CI: 1.01-1.11) and EPS symptoms [pure EPS (OR: 3.67, 95% CI: 1.65-8.51) and PDS-EPS overlap (OR: 11.6, 95% CI: 4.09-37.2)] were significant risk factors for FD-NERD overlap compared with FD alone (Table 4).
Table 4.
Multivariate Analysis of Factors Associated with FD-NERD Overlap Participants Compared to FD Alone or NERD Alone Participants
| FD-NERD overlap vs. FD alone |
FD-NERD overlap vs. NERD alone |
|||||||
|---|---|---|---|---|---|---|---|---|
| OR (95% CI) | p value | OR (95% CI) | p value | |||||
| Age | 1.06 (1.01-1.11) | 0.0104 | 1.00 (0.96-1.04) | 0.984 | ||||
| Female | 0.93 (0.38-2.28) | 0.876 | 3.06 (1.37-7.02) | 0.0060 | ||||
| BMI 18.5>/18.5-25 | 2.27 (0.84-6.48) | 0.107 | 3.03 (1.04-9.90) | 0.042 | ||||
| BMI ≥25/18.5-25 | 2.94 (0.87-10.9) | 0.0824 | 1.03 (0.42-2.51) | 0.947 | ||||
| Current smoking | 1.25 (0.40-4.07) | 0.707 | 1.77 (0.72-4.44) | 0.215 | ||||
| Alcohol consumption ≥20 g/day | 2.68 (0.997-7.54) | 0.0508 | 1.13 (0.51-2.54) | 0.762 | ||||
| High STAI score level | 0.60 (0.28-1.27) | 0.184 | 1.42 (0.72-2.83) | 0.311 | ||||
| Hiatal hernia | 1.78 (0.72-4.54) | 0.212 | 0.80 (0.38-1.68) | 0.563 | ||||
| Pure EPS/pure PDS | 3.67 (1.65-8.51) | 0.0013 | ||||||
| PDS-EPS overlap/pure PDS | 11.6 (4.09-37.2) | <0.0001 | ||||||
| Acid reflux symptoms ≥2 days a week | 3.57 (1.83-7.14) | 0.0002 | ||||||
FD: functional dyspepsia, NERD: nonerosive reflux disease, OR: odds ratio, CI: confidence interval, SD: standard deviation, BMI: body mass index, STAI: State-Trait Anxiety Inventory, PDS: postprandial distress syndrome, EPS: epigastric pain syndrome
Compared with participants with NERD alone, the subjects with FD-NERD overlap were more likely to be women, have a lower BMI, and consume less alcohol (Table 2). The participants with FD-NERD exhibited a higher frequency of acid reflux symptoms than those with NERD alone (Table 2). In the multivariate analysis, women (OR 3.06, 95% CI 1.37-7.02), BMI <18.5 (OR: 3.03, 95% CI: 1.04-9.90), and acid reflux symptoms ≥2 days a week (OR: 3.57, 95% CI: 1.83-7.14) were significant risk factors for FD-NERD overlap compared with NERD alone (Table 4).
Discussion
In the present study, the prevalence rates of FD and NERD were 5.1% (157/3,085) and 5.9% (181/3,085), respectively. Overlap of NERD in FD and overlap of FD in NERD were found in 54% and 46%, respectively, and the prevalence of FD-NERD overlap in the study participants was 2.7% (83/3,085).
The prevalence of FD in this study (5.1%) was not lower than the prevalence (1.9%) of FD in Japanese young college students reported in a recent study (29) but was lower than the previously reported prevalence of FD in Japanese health checkup participants, which ranged from 11% to 17% (30,31). The lower prevalence of FD and NERD might be due to the exclusion of individuals with EE and acid secretion inhibitor users, who often have GERD and FD symptoms, as well as the exclusion of H. pylori-infected individuals, in whom FD symptoms can arise. In a recent review, the frequency of overlap of FD symptoms in GERD was reported to be 41.15% (29.46-53.96%), and the frequency of overlap of GERD symptoms in FD was reported to be 31.32% (19.43-46.29%) (13). The relatively high overlap frequencies may have been influenced by the difference in definitions of GERD and FD in this study.
Overlap of FD symptoms in GERD is associated with the frequency of GERD symptoms (9), and the QOL has been reported to be lower in GERD patients with overlap of FD symptoms than in GERD alone patients (12,32,33). In the present study, upper abdominal symptoms as assessed by the FSSG were significantly more frequent in FD-NERD-overlap participants than in FD- or NERD-alone participants, confirming that overlap between FD and NERD is a clinically important condition associated with an increased frequency of upper abdominal symptoms.
In a multivariate analysis comparing FD alone, FD-NERD overlap or NERD alone with non-FD non-NERD, a high STAI score was the only common associated factor. This indicates that trait anxiety as a psychosocial factor is a common risk factor in FD and NERD, consistent with previous reports of psychosocial factor involvement in FD and GERD (10,14,30,34,35). However, there were differences in the degree of involvement of trait anxiety as estimated from the OR of high STAI score, with FD alone having the strongest involvement, followed by FD-NERD overlap, and NERD alone having the weakest.
In an analysis comparing FD-NERD overlap with FD alone, older age was a significant factor associated with FD-NERD overlap. A recent epidemiological study in three countries using the Rome IV criteria reported a young age as a risk factor for FD (36). In the present study, a young age was also a significant risk factor for FD alone compared to non-FD non-NERD, and participants with FD alone were significantly younger than those with FD-NERD overlap.
Regarding FD subtypes, participants with FD-NERD overlap were significantly more likely to have EPS symptoms, such as pure EPS or PDS-EPS overlap, than participants with FD alone. This is consistent with previous reports that abnormal acid reflux observed in FD was associated with epigastric pain, an EPS symptom (37). In cases of FD with PDS-EPS overlap, an association between FD with PDS-EPS overlap and sleep disturbances and a decreased QOL has been reported (38). In addition, a recent epidemiologic study in three countries revealed that heartburn symptoms were more common in FD with PDS-EPS overlap than in FD with pure PDS or pure EPS (36).
Alcohol consumption showed a trend toward an association with FD-NERD overlap compared to FD alone (p=0.0508). Drinking alcohol was a common risk factor for both FD-NERD overlap and NERD alone compared to non-FD non-NERD, indicating the involvement of alcohol consumption in NERD. A recent meta-analysis reported that alcohol consumption is a risk factor for GERD, and the association with alcohol consumption is stronger in reflux esophagitis than in NERD (39).
In an analysis comparing FD-NERD overlap with NERD alone, being a woman was a significant factor associated with FD-NERD overlap. The association of women with FD was reported in a recent Rome IV-based epidemiological study in three countries (36). In the present study, being a woman was associated with both FD alone and FD-NERD overlap. In general, functional gastrointestinal disorders such as FD and irritable bowel syndrome are known to be more common in women than in men (1,40). Although the pathophysiological mechanisms of functional gastrointestinal disorders have not yet been fully elucidated, an increasing number of studies have been reported from the viewpoint of functional gastrointestinal disorders as a disorder of gut-brain interaction (41).
In addition, a low BMI was a risk factor significantly associated with FD-NERD overlap compared to NERD alone. Compared to the control group, a low BMI was significantly associated with FD alone and FD-NERD in a bivariate analysis but was significantly associated only with FD-NERD in a multivariate analysis. The association of a low BMI with FD has been reported in Asian countries (42-44). A study from France revealed that both a low BMI and high BMI were associated with FD symptoms in women (45). A postinfectious onset of FD has been reported to be a risk factor for weight loss (46), but whether or not underweight contributes to the development of FD symptoms is unclear.
In this study, having acid reflux symptoms on two or more days per week was found to be a risk factor associated with FD-NERD overlap. This result is consistent with a previous report that GERD patients with a higher frequency of acid reflux symptoms experienced dyspepsia symptoms more frequently than those with a low frequency of symptoms (9).
The strength of this report was that it involved a relatively large number of participants from a multicenter prospective cohort study. However, several limitations associated with the present study also warrant mention. First, the study participants were health checkup participants, not the general population or patients, and individuals taking gastric medications (including acid secretion inhibitors), individuals with EE, and individuals who were endoscopically infected by H. pylori were excluded. Second, a broad definition of NERD without 24-h pH-impedance testing was used. Third, the presence or absence of H. pylori infection was determined by endoscopic findings and questionnaires, and no biological diagnosis was used.
In conclusion, approximately half of FD and NERD participants had overlap with both conditions, and upper abdominal symptoms were more frequently seen in FD-NERD-overlap participants than in FD alone or NERD alone participants. A high STAI score was a common risk factor for both FD and NERD. Older FD participants and FD-with-EPS-symptoms participants exhibited more NERD overlap, while female NERD participants, those with NERD who were underweight, and those with NERD who had acid reflux symptoms more than two days per week exhibited more FD overlap. Consideration of the clinical features of FD-NERD overlap will lead to better management of FD and NERD patients.
Manabu Murakami and Takeshi Azuma deceased.
The authors state that they have no Conflict of Interest (COI).
Financial Support
This study was funded by a grant provided by the NPO, Gastrointestinal Medical Care Research and Education Center.
Supplementary Material
State-Trait Anxiety Inventory Questionnaire (trait)
Frequency Scale for the Symptoms of GERD Questionnaire
Comparison of clinical characteristics between the participants with FD or NERD and the control participants
Acknowledgement
We are grateful to Ms. Haru Hamanaka, Ms. Yui Hyakuta and Ms. Kana Kawaguchi for their dedicated secretarial assistance. We thank Mr. Masaki Ashida, Mr. Takahide Kudo, and Mr. Takashi Okamoto for their assistance with the statistical analysis. We thank Ms. Junko Otani for her assistance with the database creation. We thank Mr. Katsuya Azuma for his assistance with classifying drugs. We thank Mr. Masayasu Adachi and Mr. Takahiro Hanasaki for their assistance with data collection at Hotel Okura Kobe Clinic.
References
- 1.Ford AC, Marwaha A, Sood R, Moayyedi P. Global prevalence of, and risk factors for, uninvestigated dyspepsia: a meta-analysis. Gut 64: 1049-1057, 2015. [DOI] [PubMed] [Google Scholar]
- 2.Eusebi LH, Ratnakumaran R, Yuan Y, Solaymani-Dodaran M, Bazzoli F, Ford AC. Global prevalence of, and risk factors for, gastro-oesophageal reflux symptoms: a meta-analysis. Gut 67: 430-440, 2018. [DOI] [PubMed] [Google Scholar]
- 3.Tack J, Talley NJ, Camilleri M, et al. Functional gastroduodenal disorders. Gastroenterology 130: 1466-1479, 2006. [DOI] [PubMed] [Google Scholar]
- 4.Stanghellini V, Chan FKL, Hasler WL, et al. Gastroduodenal Disorders. Gastroenterology 150: 1380-1392, 2016. [DOI] [PubMed] [Google Scholar]
- 5.Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R; The Global Consensus Group. The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus. Am J Gastroenterology 101: 1900-1920, 2006. [DOI] [PubMed] [Google Scholar]
- 6.Fass R. Erosive esophagitis and nonerosive reflux disease (NERD). J Clin Gastroenterol 41: 131-137, 2007. [DOI] [PubMed] [Google Scholar]
- 7.Aziz Q, Fass R, Gyawali CP, Miwa H, Pandolfino JE, Zerbib F. Esophageal disorders. Gastroenterology 150: 1368-1379, 2016. [DOI] [PubMed] [Google Scholar]
- 8.Choung RS, Locke GR, Schleck CD, Zinsmeister AR, Talley NJ. Overlap of dyspepsia and gastroesophageal reflux in the general population: one disease or distinct entities? Neurogastroenterol Motil 24: 229-e106, 2012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Gerson LB, Kahrilas PJ, Fass R. Insights into gastroesophageal reflux disease-associated dyspeptic symptoms. Clin Gastroenterol Hepatol 9: 824-833, 2011. [DOI] [PubMed] [Google Scholar]
- 10.Hsu CS, Wen SH, Hung JS, et al. Overlap of dyspepsia in patients with gastroesophageal reflux disease: impact of clinical, metabolic, and psychosocial characteristics. Dig Dis Sci 62: 994-1001, 2017. [DOI] [PubMed] [Google Scholar]
- 11.Fujiwara Y, Kubo M, Kohata Y, et al. Cigarette smoking and its association with overlapping gastroesophageal reflux disease, functional dyspepsia, or irritable bowel syndrome. Intern Med 50: 2443-2447, 2011. [DOI] [PubMed] [Google Scholar]
- 12.Klausen KM, Høgh MB, David M, de Muckadell OBS, Hansen JM. How dyspepsia, gastroesophageal reflux symptoms, and overlapping symptoms affect quality of life, use of health care, and medication - a long-term population based cohort study. Scand J Gastroenterol 56: 753-760, 2021. [DOI] [PubMed] [Google Scholar]
- 13.Geeraerts A, Houtte BV, Clevers E, et al. Gastroesophageal reflux disease-functional dyspepsia overlap: do birds of a feather flock together? Am J Gastroenterol 99: 1167-1182, 2020. [DOI] [PubMed] [Google Scholar]
- 14.Quigley EMM, Lacy BE. Overlap of functional dyspepsia and GERD-diagnostic and treatment implications. Nat Rev Gastroenterol 10: 175-186, 2013. [DOI] [PubMed] [Google Scholar]
- 15.Eusebi LH, Ratnakumaran R, Bazzoli F, Ford AC. Prevalence of dyspepsia in individuals with gastroesophageal reflux-type symptoms in the community: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 16: 39-48.e1, 2018. [DOI] [PubMed] [Google Scholar]
- 16.Mochizuki N, Fujita T, Kobayashi M, et al. Factors associated with the presentation of erosive esophagitis symptoms in health checkup subjects: a prospective, multicenter cohort study. PLoS One 13: e0196848, 2018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Masuda A, Fujita T, Murakami M, et al. Influence of hiatal hernia and male sex on the relationship between alcohol intake and occurrence of Barrett's esophagus. PLoS One 13: e0192951, 2018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Ogisu K, Masuda A, Fujita T, et al. Influence of sex on the association between body mass index and frequency of upper gastrointestinal symptoms. JGH Open 4: 937-944, 2020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Julian LJ. Measures of anxiety: State-Trait Anxiety Inventory (STAI), Beck Anxiety Inventory (BAI), and Hospital Anxiety and Depression Scale-Anxiety (HADS-A). Arthrit Care Res 63: S467-S472, 2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Nakazato K, Mizuguchi T. Development and validation of Japanese version of State-Trait Anxiety Inventory -a study with female subjects. Shinshin-Igaku (Jpn J Psychosom Med) 22: 107-112, 1982. [Google Scholar]
- 21.Spielberger CD, Gorsuch RL, Lushene RE. STAI Manual for the State-trait Anxiety Inventory. Consulting Psychologists Press, California, 1970. [Google Scholar]
- 22.Nakazato K, Shimonaka Y. The Japanese State-Trait Anxiety Inventory: age and sex differences. Percept Mot Skills 69: 611-617, 1989. [DOI] [PubMed] [Google Scholar]
- 23.Mizuguchi T, Shimonaka J, Nakazato K. [Japanese version of STAI State-Trait Anxiety Inventory Form X manual (expanded version)]. Sankyobo, Kyoto, 2012: 9-11 (in Japanese). [Google Scholar]
- 24.Kusano M, Shimoyama Y, Sugimoto S, et al. Development and evaluation of FSSG: frequency scale for the symptoms of GERD. J Gastroenterol 39: 888-891, 2004. [DOI] [PubMed] [Google Scholar]
- 25.Danjo A, Yamaguchi K, Fujimoto K, et al. Comparison of endoscopic findings with symptom assessment systems (FSSG and QUEST) for gastroesophageal reflux disease in Japanese centres. J Gastroenterol Hepatol 24: 633-638, 2009. [DOI] [PubMed] [Google Scholar]
- 26.Toyoshima O, Nishizawa T, Koike K. Endoscopic Kyoto classification of Helicobacter pylori infection and gastric cancer risk diagnosis. World J Gastroenterol 26: 466-477, 2020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Yagi K, Nakamura A, Sekine A. Characteristic endoscopic and magnified endoscopic findings in the normal stomach without Helicobacter pylori infection. J Gastroenterol Hepatol 17: 39-45, 2002. [DOI] [PubMed] [Google Scholar]
- 28.Watanabe K, Nagata N, Nakashima R, et al. Predictive findings for Helicobacter pylori-uninfected, -infected and -eradicated gastric mucosa: validation study. World J Gastroenterol 19: 4374-4379, 2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Yamamoto Y, Furukawa S, Watanabe J, et al. Positive association between sleep disturbance and prevalence of functional dyspepsia in Japanese young people. Dig Dis Sci 67: 3929-3937, 2022. [DOI] [PubMed] [Google Scholar]
- 30.Miwa H, Nagahara A, Asakawa A, et al. Evidence-based clinical practice guidelines for functional dyspepsia 2021. J Gastroenterol 57: 47-61, 2022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Hirakawa K, Adachi K, Amano K, et al. Prevalence of non-ulcer dyspepsia in the Japanese population. J Gastroenterol Hepatol 14: 1083-1087, 1999. [DOI] [PubMed] [Google Scholar]
- 32.Kaji M, Fujiwara Y, Shiba M, et al. Prevalence of overlaps between GERD, FD and IBS and impact on health-related quality of life. J Gastroenterol Hepatol 25: 1151-1156, 2010. [DOI] [PubMed] [Google Scholar]
- 33.Isshi K, Furuhashi H, Koizumi A, Nakada K. Effects of coexisting upper gastrointestinal symptoms on daily life and quality of life in patients with gastroesophageal reflux disease symptoms. Esophagus 18: 684-692, 2021. [DOI] [PubMed] [Google Scholar]
- 34.He M, Wang Q, Yao D, Li J, Bai G. Association between psychosocial disorders and gastroesophageal reflux disease: a systematic review and meta-analysis. J Neurogastroenterol Motil 28: 212-221, 2022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Ford AC, Mahadeva S, Carbone MF, Lacy BE, Talley NJ. Functional dyspepsia. Lancet 396: 1689-1702, 2020. [DOI] [PubMed] [Google Scholar]
- 36.Aziz I, Palsson OS, Törnblom H, Sperber AD, Whitehead WE, Simrén M. Epidemiology, clinical characteristics, and associations for symptom-based Rome IV functional dyspepsia in adults in the USA, Canada, and the UK: a cross-sectional population-based study. Lancet Gastroenterol Hepatol 3: 252-262, 2018. [DOI] [PubMed] [Google Scholar]
- 37.Tack J, Caenepeel P, Arts J, Lee KJ, Sifrim D, Janssens J. Prevalence of acid reflux in functional dyspepsia and its association with symptom profile. Gut 54: 1370, 2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Yamawaki H, Futagami S, Shimpuku M, et al. Impact of sleep disorders, quality of life and gastric emptying in distinct subtypes of functional dyspepsia in Japan. J Neurogastroenterol Motil 20: 104-112, 2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Pan J, Cen L, Chen W, Yu C, Li Y, Shen Z. Alcohol consumption and the risk of gastroesophageal reflux disease: a systematic review and meta-analysis. Alcohol Alcohol 54: 62-69, 2018. [DOI] [PubMed] [Google Scholar]
- 40.Houghton LA, Heitkemper M, Crowell MD, et al. Age, gender, and women's health and the patient. Gastroenterology 150: 1332-1343.e4, 2016. [DOI] [PubMed] [Google Scholar]
- 41.Black CJ, Paine PA, Agrawal A, et al. British Society of Gastroenterology guidelines on the management of functional dyspepsia. Gut 71: 1697-1723, 2022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Beh KH, Chuah KH, Rappek NAM, Mahadeva S. The association of body mass index with functional dyspepsia is independent of psychological morbidity: a cross-sectional study. PLoS One 16: e0245511, 2021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Fujiwara Y, Kubo M, Kohata Y, et al. Risk factors associated with dyspepsia in Japanese adults. J Clin Gastroenterol 45: 567-568, 2011. [DOI] [PubMed] [Google Scholar]
- 44.Yamamoto Y, Furukawa S, Watanabe J, et al. Association between body mass index and functional dyspepsia in young Japanese people. J Neurogastroenterol Motil 28: 276-282, 2022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Pluart DL, Sabaté JM, Bouchoucha M, Hercberg S, Benamouzig R, Julia C. Functional gastrointestinal disorders in 35 447 adults and their association with body mass index. Aliment Pharmacol Ther 41: 758-767, 2015. [DOI] [PubMed] [Google Scholar]
- 46.Schol J, Carbone F, Holvoet L, et al. Postinfectious onset in functional dyspepsia is a risk factor for weight loss. J Gastroenterol 57: 156-163, 2022. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
State-Trait Anxiety Inventory Questionnaire (trait)
Frequency Scale for the Symptoms of GERD Questionnaire
Comparison of clinical characteristics between the participants with FD or NERD and the control participants