Functional dyspepsia (FD) is a typical functional gastrointestinal disorders (FGIDs), it refers to a group of clinical symptoms caused by functional disorders of the stomach and duodenum, that are unexplained after a routine clinical evaluation.¹ The main symptoms include one or more of epigastric pain, epigastric burning, postprandial fullness, or early satiation, and may also include epigastric bloating, belching, anorexia, nausea, vomiting, etc. The Rome IV diagnostic criteria divide FD into 3 subtypes of epigastric pain syndrome (EPS), postprandial distress syndrome (PDS), and mixed EPS-PDS subtype based on the main symptoms and possible mechanisms of this disease.^1,2

Studies reported the prevalence of FD is about 4.80-30.00% worldwide.^3,4 Investigations in Asian countries showed the prevalence is around 8.00-23.00%.⁵ In China, FD is also the commonest cause of dyspepsia in population, the prevalence is about 18.40-23.80%.⁵ A large, multi-center, prospective investigation from Guangdong province in China reported the prevalence of FD among outpatients is 16.30% according to the Rome III criteria.⁶ Variation in frequency of FD in different studies might be related to criteria used to diagnose, variation in survey population and environmental factors.^3,5

FGIDs overlap syndrome is quite common in clinic practice, it refers to patients with symptoms related to different gastrointestinal part at the same time, the symptoms of esophagus, stomach, duodenum, colon, anal canal, and other parts could overlap with each other, based on the similar underlying pathophysiological mechanisms of FGIDs (now called disorders of gut-brain interaction), including visceral hypersensitivity and potentially immune dysfunction, dysbiosis and increased mucosal permeability, as well as abnormal gut-brain interaction and socio-psychological factors.^4,7,8 FD as one of the common FGIDs had been reported to overlap with several other common FGIDs, especially the irritable bowel syndrome (IBS), studies from Asia reported the prevalence is about 1.60-49.00% for FD overlap with IBS.⁵ A survey based on Rome IV diagnostic criteria from Western country showed that in clinic population about 66.90% of FD patients had IBS, and about 39.00% of FD patients had functional constipation (FC), while 31.60% of FD patients had IBS and 22.00% of FD patients had FC in general population.²

Gastroesophageal reflux disease (GERD) and FD are the 2 most common upper gastrointestinal disorders with similar symptom clusters of epigastric burning, or postprandial fullness associated with belching, acid eructation and possibly dysphagia.⁹ Although there are separate guidelines for managing each disorder, FD-GERD overlap is very common by shared pathophysiology, including delayed gastric emptying and impaired gastric accommodation.^10,11 A meta-analysis review showed that 7.41% overlap between FD and GERD in the general population, and 31.32% FD with GERD symptoms.¹⁰ Studies from Asia showed the prevalence of FD-GERD overlap is about 20.00-80.00% in different countries and regions.⁹

Several studies showed that FD patients with overlap syndromes have more frequent or severe symptoms, poorer quality of life.¹² They are more likely to experience anxiety, depression, and sleep disorder compared with non-overlap patients.^13,14 Patients with FD overlap have a much more significant symptom burden and consumption of medical resources, compared to patients suffering from FD alone.¹² With the improvement of diagnosis and treatment of FGIDs, FD overlap syndrome have gradually attracted the attention of doctors.

The Rome foundation is the global authority for FGIDs research and education. It updated the diagnostic criteria of FGIDs based on the latest basic research in the field of FGIDs and the findings of evidence-based medical research. In 2016, it issued the latest diagnostic criteria of FGIDs––Rome IV criteria.² Currently, there is a lack of clinical investigation on FD overlap syndrome in China based on the Rome IV criteria. This outpatient population-based study was performed to assess the prevalence of FD (using Rome IV criteria) overlap with GERD, IBS, or FC in 2 tertiary medical centers. Extensive demographic, clinical, social information, anxiety/depression, sleep disorder, and quality of life were investigated to characterize the FD overlap patients compared with FD only patients to identify risk factors for these overlap conditions, meanwhile, to clarify its impact on economic burden and quality of life.

Study Patients

Hangzhou, the capital of Zhejiang province, is a large city of 12.4 million inhabitants in South-East China, of which 99.75% are Han Chinese ethnicity, sociodemographically, its population is representative of the urban Chinese population. Hospitals affiliated to Zhejiang University are the major providers of medical care. Study subjects were prospectively recruited from patients who visited the Gastroenterology Clinic at 2 tertiary medical centers of the First Affiliated Hospital and Sir Run Run Shaw Hospital of Zhejiang University School of Medicine in Hangzhou between September 2019 and December 2020. Consecutive adult patients (age 18-75 years old) with dyspepsia symptoms were further investigated with the Rome IV questionnaires to diagnose FD by staff of the department of Gastroenterology, those who fulfilled the Rome IV criteria of FD were integrated into the study to complete following questionnaires related to the whole gastrointestinal symptoms, psychiatric status, quality of sleep and life, and general personal information. Subjects were excluded with incomplete questionnaires, abdominal operations (except appendectomy), inflammatory bowel disease, pregnant or lactating women, severe systemic diseases, and other organic diseases or psychiatric disorders requiring medication. All patients underwent upper gastrointestinal endoscopy to rule out gastroduodenal ulcers and upper gastrointestinal malignancy. The study protocol was approved by the Ethics Committees of both institutions (Permit No. 20190520-100). Informed consent was obtained from all patients prior to data collection.

Questionnaires

The following questionnaires were used in this study. The Rome questionnaire has been formally translated and validated in Mandarin Chinese. The other questionnaires have also been translated and applied widely in clinical research in China. Their reliability and validity have been tested.^15-17

General personal information

Demographic and lifestyle data of subjects including age, gender, height, weight, marital status, education, profession, exercise, dietary habit, smoking and drinking habit, and medical history of gastroenteritis.

Gastrointestinal symptoms questionnaires

Rome IV questionnaires included FD as well as its subtypes EPS, PDS, and mixed EPS-PDS subtype, IBS, and FC.^2,18 GERD was defined as having typical reflux symptoms that fulfilled the Reflux Disease Questionnaire (RDQ)^19,20 with score ≥ 12 or having endoscopic objective evidence of GERD (reflux esophagitis according to the Los Angeles classification grades C and D were included based on the Lyon Consensus).²¹ In the patients who fulfilled the Rome IV diagnostic criteria of FD, if they also met any of the above diagnoses of IBS, FC, or GERD, those were recorded as FD overlap.

Anxiety and depression questionnaires

Seven-item Generalized Anxiety Disorder Scale (GAD-7) and the Nine-item Patient Health Questionnaire (PHQ-9) questionnaires were investigated, with a cut-off score ≥ 5 for diagnosing borderline neurosis. Anxiety GAD-7 scores were defined as none (0-4), mild (5-9), moderate (10-14), and severe (≥ 15). Depression PHQ-9 scores were defined as none (0-4), mild (5-9), moderate (10-14), moderately severe (15-19), and severe (≥ 20).^22-24

Quality of life

The 36-item Short Form Health Survey (SF-36) measuring 8 health domains: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. Two outcomes are derived from SF-36: average score from 4 physical items (physical functioning, role physical, bodily pain, and general health) represented the Physical Component Summary and average score from 4 mental items (vitality, social functioning, role emotional, and mental health) represented the Mental Component Summary.²⁵

Sleep quality

Pittsburgh Sleep Quality Index (PSQI) is the most commonly used measure of subjective self-report sleep quality. The PSQI consisted of 24 questions. The scores for each component were summed to get a total score (range 0-21), with higher score indicating worse sleep quality. PSQI > 5 was defined as poor sleep quality, while a score ≤ 5 was regarded as good sleep.^26,27

Statistical Methods

Variables were expressed as mean (SD) or median (interquartile values). Proportional differences between FD and FD overlap were compared using Pearson chi-squared test. Continuous, normally distributed data was averaged and analyzed with Student’s t test. The comparison of non-normally distributed data was made with Mann–Whitney U test.

Logistic multivariate regression analyses were conducted to identify independent association of potential risk factors for having FD overlap. Odds ratio with 95% confidence interval was calculated. Categorical variables of gender (male or female), marital status (married, single, divorced, and widowed), body mass index (BMI) (< 24 kg/m² or ≥ 24 kg/m²), education level (≤ high school or ≥ college), occupation type (office work, physical work, house work, and student), cigarette smoking (yes or no), alcohol drinking (yes or no), history of gastroenteritis (yes or no), night shift (yes or no), irregular diet (yes or no), unhealthy dietary habit (yes or no), exercise (yes or no), anxiety (yes or no), depression (yes or no), and sleep quality (good or poor) were created for analyses. Continuous variable of age was converted to 10-year groupings as categorical variables for analyses.

Data analysis performed using the Statistical Package for Social Sciences for Windows (SPSS version 22.0 for Windows; IBM Corp, Armonk, NY, USA). All statistical tests were two-tailed. A P-value < 0.05 was considered statistically significant.

Demographic and Lifestyle Characteristics of Study Patients

A total of 3365 FD patients from gastroenterology outpatient clinic were interviewed. Eighty-four were excluded due to withdrawal of consent or if questionnaires were incomplete or completed incorrectly. Thus, questionnaires from 3281/3365 (97.50%) patients with FD were analyzed.

According to Rome IV criteria questionnaire and RDQ of FD, IBS, FC, and GERD, 1828/3281 (55.71%) patients with FD were diagnosed as FD overlap with GERD, IBS, or FC, 1453/3281 (44.29%) were diagnosed as FD only without overlapping the above diseases. Among the total 3281 patients with FD, 1663/3281 (50.69%) were overlapping with GERD, 704/3281 (21.46%) were overlapping with IBS, 198/3281 (6.03%) were overlapping with FC. The 1091/3281 (33.25%) of patients with FD were overlapping with 1 condition, and 737/3281 (22.64%) with 2 conditions.

The socio-demographic characteristics of FD only and FD overlap patients are presented in Table 1. The average age of FD overlap patients were older than FD only patients (43.34 ± 11.15 vs 42.33 ± 10.27, P = 0.042) , no difference of gender distribution between the 2 groups was found (P > 0.05). FD overlap patients had lower BMI compared with FD only patients (22.22 ± 2.80 vs 23.82 ± 2.63, P < 0.001). FD overlap patients had higher proportion of single/divorced/widowed rate, high education level, being employed, drinking alcohol, history of gastroenteritis, night shift, irregular diet, and unhealthy dietary habit than FD only patients, however, the proportion of exercise and smoking habits as well as BMI were lower in FD overlap patients (P < 0.05).

Table 1 . Distribution of Demographic and General Lifestyle Characteristics of Recruited Patients

Variables	Levels	FD only	FD overlap	P-value
Gender	Male Female	617 (42.46) 836 (57.54)	833 (45.57) 995 (54.43)	0.569
Age (yr)	Mean ± SD	42.33 ± 10.27	43.34 ± 11.15	0.042
BMI (kg/m2)	Mean ± SD	23.82 ± 2.63	22.22 ± 2.80	<0.001
Marital status	Married Single Divorced Widowed	1285(88.44) 132 (9.08) 30 (2.06) 6 (0.41)	1444 (78.99) 200 (10.94) 145 (7.93) 39 (2.13)	<0.001
Education	≤ High school ≥ College	878 (60.43) 575 (39.57)	854 (46.72) 974 (53.28)	<0.001
Job	Office work Physical work House work Student	683 (47.00) 231 (15.90) 507 (34.90) 32 (2.20)	1017 (55.63) 447 (24.45) 341 (18.65) 23 (1.26)	<0.001
Cigarette smoking	No Yes	1202 (82.73) 251 (17.27)	1587 (86.82) 241 (13.18)	0.001
Alcohol drinking	No Yes	1303 (89.68) 150 (10.32)	1546 (84.57) 282 (15.43)	<0.001
History of gastroenteritis	No Yes	1389 (95.60) 64 (4.40)	1644 (89.93) 184 (10.07)	<0.001
Night shift required	No Yes	1316 (90.57) 137 (9.43)	1441 (78.83) 387 (21.17)	<0.001
Irregular diet	No Yes	672 (46.25) 781 (53.75)	389 (21.28) 1439 (78.72)	<0.001
Dietary habit	Like hot food Eating too fast Like dry & hard food Like spicy food Vegetarian diet No special habits	131 (9.02) 138 (9.50) 101 (6.95) 289 (19.89) 54 (3.72) 740 (50.93)	120 (6.56) 444 (24.29) 250 (13.68) 393 (21.50) 100 (5.47) 521 (28.50)	<0.001
Exercise habit	No Yes	566 (38.95) 887 (61.05)	1078 (58.97) 750 (41.03)	<0.001

FD, functional dyspepsia; BMI, body mass index.

Values are presented as n (%).

Different Functional Dyspepsia Subtypes in Functional Dyspepsia Only and Functional Dyspepsia Overlap Patients

All patients were further divided into 3 FD subtypes with the Rome IV criteria, 377/3281 (11.49%) were EPS, 1571/3281 (47.88%) were PDS, and 1333/3281 (40.63%) were mixed EPS-PDS subtype. Among FD only patients, 107 (7.36%) were EPS, 987 (67.93%) were PDS, and 359 (24.71%) were the mixed EPS-PDS subtype. Among FD overlap patients, 270 (14.77%) were EPS, 584 (31.95%) were PDS, and 974 (53.28%) were the mixed EPS-PDS subtype. Mixed EPS-PDS subtype was more prevalent in the FD overlap group than that in the FD only group (P < 0.001, Fig. 1).

Figure 1. Proportion of three functional dyspepsia (FD) subtypes between FD overlap and FD only groups, mixed epigastric pain syndrome (EPS)-postprandial distress syndrome PDS subtype was predominant in FD overlap group (P < 0.001).

Anxiety/Depression, Sleep Quality

FD overlap patients had higher scores of anxiety (8.14 ± 4.23 vs 2.62 ± 3.37) and depression (9.77 ± 4.95 vs 3.23 ± 4.10) compared with FD only patients (both P < 0.001). According to the score of PSQI, the sleep quality of FD overlap patients was worse than FD only patients (6.64 ± 2.75 vs 10.24 ± 3.70, P < 0.05).

Physician Consultations, Economic Burden and Impact on Quality of Life

FD overlap patients had higher frequency of consultation and economic burden compared with FD only group patients. 53.34% FD overlap patients visited physicians 2-5 times, however, majority of FD only patients (60.01%) visited physicians only once in the past year (P < 0.001). The average cost of most FD overlap patients were around 1001-3000 Chinese Yuan during the past year, compared with 501-1000 Chinese Yuan of most FD only patients (P < 0.001) (Table 2). FD overlap patients had poorer quality of life as assessed by SF-36 score (including all the 8 dimensions, physical and mental status) than FD only patients (all P < 0.001, Fig. 2).

Figure 2. The 36-item Short Form Health Survey (SF-36) scores of all domains between functional dyspepsia (FD) overlap and FD only groups, the scores of FD overlap group were much lower than FD only group (*P < 0.001). PF, physical functioning; RP, role physical; BP, bodily pain; GH, general health; VT, vitality; SF, social functioning; RE, role emotional; MH, mental health; PCS, Physical Component Summary, average score from 4 physical items (PF, RP, BP, and GH); MCS, Mental Component Summary, average score from 4 mental items (VT, SF, RE, and MH).

Table 2 . Physician Consultations, Economic Burden of Recruited Patients

Variables	Levels	FD only	FD overlap	P-value
Number of physician consultants in the past year	1 2-5 6-10 > 10	872 (60.01) 528 (36.34) 46 (3.17) 7 (0.48)	418 (22.87) 975 (53.34) 390 (21.33) 45 (2.46)	< 0.001
Average cost in the past year (CNY)	< 500 501-1000 1001-3000 3001-5000 > 5000	481 (33.10) 622 (42.81) 283 (19.48) 55 (3.79) 12 (0.83)	266 (14.55) 598 (32.71) 655 (35.83) 256 (14.00) 53 (2.90)	< 0.001

FD, functional dyspepsia; CNY, Chinese Yuan.

Values are presented as n (%).

Risk Factors of Functional Dyspepsia Overlapping

After multivariate logistic regression controlling for lifestyle and demographic variables: marital status, education level, occupation type, smoking/drinking habit, night shift, irregular diet, unhealthy dietary habit and exercise habit, and significant and independent risk factors for FD overlapping included increasing age, female, low BMI, history of gastroenteritis, anxiety, depression, and poor quality of sleep (P < 0.001) (Table 3).

Table 3 . Risk Factors of Functional Dyspepsia Overlap (Logistic Regression)

Variables	OR	95% CI	P-value
Age (yr)	1.024	1.014-1.035	< 0.001
Gender (female)	1.310	1.058-1.622	0.013
BMIa	0.943	0.924-0.962	< 0.001
History of gastroenteritisb	1.690	1.165-2.451	0.006
Anxietyc	1.465	1.134-1.892	0.003
Depressiond	1.926	1.482-2.502	< 0.001
Quality of Sleep (PSQI)e	2.885	2.220-3.749	< 0.001

^aBody mass index (BMI): categorized as < 24 kg/m² or ≥ 24 kg/m².

^bHistory of gastroenteritis, ^canxiety, ^ddepression: OR for having this condition.

^eQuality of Sleep (Pittsburgh Sleep Quality Index [PSQI]): categorized as good (PSQI score ≤ 5) or poor (PSQI score > 5). OR for poor quality of sleep.

FD, functional dyspepsia; BMI, body mass index.

Adjusted by lifestyle and demographic variables: marital status, education level, occupation type, smoking/drinking habit, night shift, irregular diet, unhealthy dietary habit, and exercise habit.

This outpatient population-based study investigated the prevalence of FD overlap with GERD, IBS, FC using Rome IV criteria, and RDQ in 2 typical tertiary medical centers in a representative large city of Hangzhou in China. Approximately half of the FD patients overlapped with other gastrointestinal disorders, one third of FD patients overlapped with one condition, one in every 5 FD patients overlapped with 2 conditions. FD overlap patients had their demographic and lifestyle characteristics such as higher proportion of single/divorced/widowed rate, high education level, being employed, drinking alcohol, history of gastroenteritis, night shift, irregular diet, and unhealthy dietary habit. Increasing age, female, low BMI, history of gastroenteritis, anxiety, depression, and poor quality of sleep were independent risk factors for FD patients overlapping with other disorders. FD overlap patients had high economic burden and thus poor quality of life.

The prevalence of FD overlapping with other diseases (GERD, IBS, or FC) in the Chinese outpatient clinic population is high (55.71%), there were 50.69% of patients with FD who overlapped with GERD, 21.46% with IBS, and 6.03% with FC. The FD-IBS, FD-FC overlap prevalence were a little lower than Western countries compared with the reported prevalence of clinic population 66.90% and 39.00% respectively using with Rome IV criteria.² The prevalence of FD-IBS overlap in Asian countries was reported as a wide range of 1.60-49.00%.⁵ Previous study in Guangzhou city of China, the prevalence of FD-IBS was about 5.00% in clinic patients using Rome III criteria.²⁸ Prevalence rate of FD-IBS with Rome IV criteria was higher than it in this study. FD-GERD overlap was quite common in clinic, 20.00-80.00% overlap prevalence, most were around 30.00%, reported in Asian countries.⁹ In Western countries reported about 31.32% FD with GERD symptoms.¹⁰ Our study found a slightly higher prevalence of FD-GERD overlap that might be due to we used the RDQ questionnaire based on the symptoms to diagnose GERD. The different prevalence between Eastern and Western countries is uncertain. Environment factors such as diet may partially explain the differences, Western diet with high consumption of wheat, and dairy products, as well as the diet effects on the fecal microbiome, are more likely to develop intestinal symptoms.^29-31 Different culture backgrounds may also contribute to the difference for Asian populations tend to categorize abdominal symptoms as upper gastrointestinal symptoms rather than intestinal symptoms.³²

In this study, FD was further divided into 3 subtypes, PDS is the predominant subtype, it accounted for 47.88% of all the FD patients, followed by mixed EPS-PDS subtype (40.63%), and EPS was the least (11.49%). This was consistent with a previous study from Belgium that PDS (69.00%) group was the largest in FD, followed by mixed type (25.00%), and EPS (7.00%) with Rome IV criteria.³³ However, different from the study of India showed that 64.00% of FD is EPS-PDS overlap with Rome III criteria.³⁴ The difference could be explained by different Rome criteria used, for using the Rome III definition, 31.00% were patients with PDS, 7.00% were patients with EPS, and 62.00% were overlap patients with EPS-PDS in the above Belgium study.³³ In China, a former study with Rome III criteria reported the predominant subtype of FD was EPS (43.00%), followed by mixed EPS-PDS subtype (29.10%) and PDS (27.90%).³⁵ As the same predominant subtype of PDS in our study and the above Belgium study with Rome IV criteria, this might suggest the Rome IV criteria may have better consistency than Rome III criteria on FD subtype diagnosis, it also need to be verified by more studies in the future.

Among the 1828 FD overlap patients in this study, nearly 60.00% (1091/1828) of them overlapping with 1 condition, 40.00% (737/1828) of them overlapping with 2 conditions. A national wide Western general population study reported that among individuals meeting the criteria for 1 or more of the conditions, 30.70% fulfilled the criteria for 2 or all 3 conditions.^36,37 With further analyzing the difference of overlapping prevalence in the 3 subtypes of FD, we found that mixed EPS-PDS subtype was more prevalent in the FD overlap group than EPS or PDS alone. This was consistent with the study from Korea indicated that the IBS-FD group overlap was more likely to have mixed-subtype FD compared with EPS or PDS with Rome III criteria.³⁸ This might imply that mixed EPS-PDS subtype with more symptom clusters was prone to overlap with other gastrointestinal disorders.

For the demographic and lifestyle characteristics in this study, the age of the FD overlap group was older than FD only group patients, they also had lower BMI, higher proportion of divorced rate, high education level, being employed, drinking alcohol, history of gastroenteritis, night shift, irregular diet, and unhealthy dietary habit than FD only patients. As further analyzed by logistic regression showed that increasing age, female, and low BMI were independent risk factors for FD overlap patients. A previous multicenter study from China reported that female sex, divorced or widowed versus married status, and drinking were associated with IBS-FD overlap patients with Rome III criteria.³⁹ Several studies indicated that FGIDs were associated with the marital status of being single or divorced.^40,41 Patients who were divorced or widowed might have more stress, depression, or anxiety than those who were married.⁴² Previous studies had shown various results regarding the association between age, gender or BMI and FD overlap. A study from United States reported no significant differences in age or gender among patients with GERD-FD overlap, GERD only, and dyspepsia only.⁴³ However, study from Vietnam indicated that older age were predominant in GERD-FD overlap, no gender and BMI difference was found,¹¹ female predominance were noted in FGIDs overlap patients in a study from South Korea.⁴⁴ A recent study indicated that waist-to-hip ratio but not BMI was a risk factor for GERD in Vietnamese patients.⁴⁵ Female, being single, lower BMI, and being unemployed were important factors associated with IBS in a study from Iran.⁴⁶ A study from Taiwan also suggested that female gender, lower body weight and BMI were predominant in FD-GERD overlap patients.⁴⁷

The correlation between FD overlapping and education level was unknown, our study found that FD overlap patients had higher education level than FD only patients. A study from Korea showed that 51.00% FGIDs overlap subjects had university education, compared with 31.20% in non-overlap FGIDs group, however, in a population-based study from Mississippi demonstrated that Caucasians with IBS overlapping uninvestigated dyspepsia were likely to be married, live in an urban area, and have low education.⁴⁸ The different demographic characteristics of patients in eastern and western studies might reflect the different culture and social background of the varied study populations from different countries and different diagnostic criteria used. In this study we also found that FD overlap patients had lower proportion of exercise and higher proportion of drinking alcohol, night shift work, irregular diet, and unhealthy dietary habit, this was consistent with other studies,^38-40 suggested that unhealthy lifestyle induced complicated gastrointestinal symptoms.

In this study we found that history of gastroenteritis was a risk factor for FD overlap patients. Currently, there were consensuses that FGIDs could develop after an acute gastroenteritis,^49,50 if the infection involved both the proximal and distal intestine, patients were more likely to develop overlap FGIDs.^51,52 The influence of gastrointestinal infection on the brain-gut axis enteric nervous system interacted with the central nervous system, as emotional and physiological stress that could affect mucosal barrier function, induced visceral hypersensitivity, changed gastric emptying, and intestinal transit, that caused the FGIDs symptoms.⁵³

FD overlap patients had more obvious anxiety, depression, poor quality of sleep than FD only patients, and multivariate logistic regression analysis indicated that they were all the risk factors for FD overlap in this study. A study from Korea reported that anxiety and depression scores were higher in the non-erosive reflux disease (NERD)-FD-IBS overlap group, and FGID symptoms were more frequent and severe in the overlap FGIDs group.⁴⁴ FD Patients with overlapping symptoms had more serious psychological problems than FD only patients, studies from Eastern and Western countries were consistent with that anxiety was an independent factor affecting FD overlap syndromes.^11,44,47,54 Futagami et al⁵⁵ studied FD-NERD-IBS found that patients with overlap had more severe symptoms and greater PSQI scores, and symptoms might be associated with sleep disturbances, compared to patients without overlap.⁵⁵ According to the disordered brain-gut axis interaction, anxiety/depression, sleep disorders, and negative life events might cause more intense somatic pain, more symptom clusters that induced FGIDs overlap.⁵³

As for the prominent physical and psychosocial stressors of FD overlap patients with various symptoms, this study also found that the rate of consultation appeared higher in the overlap group as well as increased economic burden, therefore their quality of life were poor in both physical and mental domains. This result was consistent with other studies either from Western or Eastern countries. A study from United States reported that the rate of consultation appeared higher in the FD-GERD-IBS with constipation/FC overlap groups compared with FD only group.¹² FD-GERD-IBS overlap syndromes had obvious poor quality of life in a Japanese general population study.⁵⁶

This large-scale outpatient study assessed the demographic and lifestyle characteristics and risk factors of FD with Rome IV criteria overlap with GERD, IBS, and FC in 2 representative tertiary medical centers of south-east China, while previous studies were mostly based on Rome II or Rome III. The differences from other studies might be due to the varied study populations from different countries and different diagnostic criteria used. Currently, no large-scale outpatient study in China had been done with the FD overlap using Rome IV criteria yet. Our study suggested a high FD overlap rate in outpatient clinic population using the latest Rome IV criteria, which provided important reference for clinical diagnosis and treatment. Patients with overlapping disorders were also more likely to consult physicians and with high costs, which influenced their quality of life. History of gastroenteritis, anxiety, depression and poor quality of sleep were independent risk factors for FD overlapping. These physical and psychosocial characteristics of FD overlap patients could guide our physicians to better identify and management them in the clinic practice. However, the subjects studied here were from the outpatient clinic, there might be a considerable proportion of patients with FD symptoms in a community who had never consulted to a hospital, as for the inconsistent results of different studies, more cross-cultural studies based on the community population to explore the real facts of demographic and clinical characteristics of FD overlap in Asia and the world are needed.

This research was supported by Zhejiang Provincial Natural Science Foundation of China under Grant No. LY20H030009.

None.

Yan-Qin Long designed the protocol, analyzed the data, and edited the article; Hui-Qin He, Wen-Li Xu, Jing-Jie Wang, and Lu-Xiu Li performed the research with investigation and data entry; Ning Dai, Guo-Dong Shan, and Hong-Tan Chen coordinated the study; and Yan-Qin Long, Ning Dai, and Hong-Tan Chen had primary responsibility for final content. All authors read and approved the final manuscript.