Functional dyspepsia (FD) causes various relatively non-specific symptoms from the upper gastrointestinal (GI) tract; hence, it is underdiagnosed and undermanaged.¹ The pathophysiological mechanisms underlying these symptoms are unclear. On the other hand, many associations have been made with gastric motility disorders² and with visceral hypersensitivity.³ Furthermore, Helicobacter pylori (H. pylori) infections induce gastric inflammation and lowers the pain threshold for gastric distension.⁴ Other causes include altered gut microbiome,⁵ duodenal inflammation,⁶ and psychosocial dysfunction.^7,8 Finally, regarding diagnosis, there is no validated biomarker for a diagnosis of FD. The capsaicin test has shown low diagnostic accuracy in clinical practice because of overlap with other upper gastrointestinal disorders, such as gastroesophageal reflux disease.⁹

The Rome IV criteria show improved specificity for functional dyspepsia (FD).^10-13 The major symptoms of FD include “bothersome” postprandial fullness, epigastric pain, epigastric burning, and early satiation. In addition, the sensation of nausea (but no vomiting) may increase after meals. An FD diagnosis requires that the symptoms be present for at least 3 days per week for 3 continuous months with an onset at least 6 months before the diagnosis. FD can be classified into two subtypes: postprandial distress syndrome (PDS), which involves postprandial fullness and or early satiety; and epigastric pain syndrome (EPS), which is defined as epigastric pain and or stomach burning that is not exclusively postprandial and interferes with typical physical activity.⁸ The various phenotypes of FD and the evolution of ROME criteria from I to IV explain why the prevalence of dyspepsia varies considerably between different populations. Several studies from the past using the Rome I to IV criteria reported a wide range of dyspepsia frequencies. This was attributed to sampling heterogeneity with marked differences in sample size, symptom duration, and methodology used for symptom data collection.¹⁴ Worldwide, FD affects 21% of the general population. The prevalence varies from 5% to 29.5% because of the use of several old definitions, such as upper gastrointestinal symptoms, but the incidence of FD drops dramatically to 7.6% with Rome III criteria.¹⁴

The prevalence of FD in Saudi Arabia, however, is not well characterized. Different definitions have been used in many population studies. Most of these referred to H. pylori-associated dyspepsia. This likely contributes to the epidemiological differences described in several of these studies. The prevalence ranges from 38.5% in the Al Kharj province of central SA,¹⁵ 46.5% in Jazzan province,¹⁶ 66.1% in Taif,¹⁷ 60.1% in Gizan¹⁸ to 86% in Abha, a southern province of Saudi Arabia.¹⁹

In this study, using the Rome IV Criteria for functional GI disorders, this study estimated the prevalence of self-reported symptoms consistent with FD among adults in the general population of SA, to investigate the patient demographics related to these symptoms and better inform current clinical practices.

This study recorded 3,114 potential survey responders who visited the Prince Sattam bin Abdulaziz University Hospital site. Of them, 303 (9.7%) were inconsistent responders and subsequently excluded from the analysis. Of the residual 2,811 participants, 2,279 (81.1%) had no symptoms of dyspepsia based on the Rome IV FD criteria and were classified as controls. The remaining 532 participants (18.9%) fulfilled the criteria for FD symptoms based on the Rome IV diagnostic questionnaire. Responders without and with the Rome IV FD symptoms showed no significant difference (p>0.05) among the regions of SA (Table 1). The average respondent age for individuals with and without FD symptoms was 27 (18-58) and 24 (18-58) years old, respectively (p<0.0001) (Table 1). Slightly more than half of the study population (control group) were women (51%). Moreover, women were significantly more prevalent among the survey participants with FD symptoms (61%) (p<0.0001) (Table 1). The control participants without FD symptoms were similar to those with FD symptoms in terms of smoking habit, marital status, employment, education level, nutritional status, and physical activity (p>0.05) (Table 1).

Regarding comorbidities, the participants reported whether they suffered from diabetes mellitus (14%), hypertension (4%), thyroid disorder (4%), heart disease (1%), headache (25%), and anemia (13%). The most common non-GI symptom was headache (25%). The GI-specific conditions/diseases included hemorrhoids (16%), IBS (17%), anorexia/bulimia (29%), diverticulosis (0.5%) and cholecystitis (34%).

Regarding the participants with FD symptoms, 532 (18.9%) out of 2,811 total responders fulfilled the Rome IV criteria for FD. These subjects were distributed equally between the two major FD subtypes: 222 (7.9%) had PDS; 219 (7.8%) had EP; 91 (3.3%) had the PDS-EPS overlapping variant. The Rome IV FD symptoms were more frequent and significantly different in the central and eastern parts of SA (n=139/675 [21%] and n=124/563 [22%]) than in the rest western (n=127/759 [17%]), northern (n=80/449 [18%]) and southern (n=62/365 [17%]) regions (p<0.001). In addition, the central and eastern region of Saudi Arabia had more frequent self-reports of PDS (67 [10%]) and (62 [11%]) than the western (40 [5%]), northern (30 [7%]) and southern (22 [6%]) regions (p=0.001), (Fig. 1). The frequencies of the EPS and the overlapping variant were distributed equally across all regions of SA (p<0.05) (Fig. 1).

Fig. 2 shows the distribution of FD subtypes in participant dyspeptic patients according to the Rome IV diagnostic criteria between regions across the country. The most common subtypes were PDS, followed by EPS, but the frequency was not significantly different. The overlapping variant frequency was significantly less common than the other subtypes of FD (p=0.001).

IBS and FH were significantly more common in the FD group than in the control group (Table 2). Among the 532 subjects in the FD group, IBS-like symptoms were reported by 44% (232), FH by 19% (102), belching by 8.7% (46), and nausea by 3.1% (17). IBS was significantly more common in the overlapping PDS-EPS variant group (86%, 78/91) than in those with EPS (44%, 97/222) or PDS (26%, 57/219) alone (p<0.05). Similarly, FH was also reported significantly more frequently in the overlapping PDS-EPS variant group (36%, 33/91) than in the EPS (19%, 41/222) and PDS (13%, 28/219) groups (p<0.05). The respondents with FD symptoms were more likely to have higher PHQ-12 somatization and lower QoL scores than the control participants without FD symptoms and those with the overlapping PDS-EPS variant (Table 2). H. pylori-associated dyspepsia was reported in 87/348 H. pylori-positive patients (25%) with sustained symptom resolution after 6 months.

Significant age- and sex-based differences in FD symptoms were identified by comparing the survey responders with FD symptoms with non-FD controls (Table 1). The frequency of FD was significantly higher in the 18-29 years age group (n=381/1,742, 22%) than among those 30-39 years of age (n=113/647, 18%) and 40-58 years of age (n=38/422, 9%) (Fig. 3). Moreover, FD symptoms were associated with sex but not with the education level or relationship status. Female survey responders reported having FD symptoms more frequently than their male counterparts across all age groups (Fig. 3). Finally, there were no significant differences in age, sex, education level, or relationship status between the FD subgroups.

Regarding the management of FD symptoms, most dyspeptic participants (58.4%) reported not using any medication to manage FD symptoms. On the other hand, 22.1% took prescribed medications, while 19.5% took OTC medicine. Moreover, 22.6% of participants who used OTC regimens reported also using herbs to manage their FD symptoms. Those with FD symptoms reported more health care use. These participants also took more medicines and had a lower QoL and higher somatization than those without FD symptoms (p=0.0001) (Table 2). The participants also reported making lifestyle modifications to manage their FD symptoms. In particular, dietary changes, weight loss, and smoking cessation were significantly different compared to the non-dyspeptic control group (Table 2). Responders with FD, who underwent upper gastrointestinal endoscopy (23%), reported peptic ulcer (2%), erosive gastritis (9.8%), and gastritis (22.8%). A normal mucosa was noted in the remaining cases.

This survey provides the first description of the prevalence of FD symptoms and its subtypes using the Rome IV diagnostic criteria in SA. The prevalence of FD was 19%, and the FD subtypes were EPS 43%, PDS 39%, and overlapping variant 18%. FD symptoms were more common in the younger age group than the older age group and among women than men. Aziz et al.²⁴ reported that PDS was the most frequent subtype of FD, representing approximately 60% of the cases in America, Canada, and the UK. Furthermore, the overall prevalence of FD in these countries was 9%. Other studies also found the PDS variant to be the most prevalent in the general population and the overlapping variant to predominate in hospital settings.^25-29 These differences could reflect the different genetic, cultural, socioeconomic, dietary, and environmental factors between the different countries.

More than half the respondents with FD symptoms according to the Rome IV criteria resided in the central and eastern regions of the SA, while less than one-fifth were from each of the remaining geographical regions. In addition, the central and eastern regions of Saudi Arabia had a significantly higher frequency of the PDS subtype (11%) than the other regions (western - 5%, northern - 6%, and southern - 6%). The other two subtypes were similarly distributed across the geographic regions.

This survey showed that responders with FD symptoms had more healthcare use than the non-dyspeptic controls. Only 42% of the participants sought healthcare resources, and 22% received treatment (mostly proton pump inhibitors and prokinetics that are not effective for all subtypes). Dyspeptic patients are usually misdiagnosed with gastroesophageal reflux disease, with only 12.5% receiving an initial FD diagnosis.³⁰ In this study, 58% of respondents did not seek additional healthcare nor receive targeted medications. Of the FD subtypes, the overlapping EPS-PDS variant reported the most healthcare use, the most frequent use of dyspepsia-relevant medications, the highest frequency of overlapping symptoms (e.g., those associated with FH and IBS), the lowest QoL, and the most severe somatization. Overall, the survey specifically tailored for use in the present study effectively revealed differences between the subtypes of FD. On the other hand, there are conflicting data in the literature regarding somatization in FD; some studies report no difference in somatization between subtypes,²⁹ whereas others reported significant differences similar to the present results.^24,25

Regarding medications, the use of antidepressants for PDS is not a treatment option in Saudi Arabia, as described in other studies.^31-34 A meta-analysis found that psychotropic drugs (tricyclic antidepressants, antipsychotics, or both, but not selective serotonin reuptake inhibitors) are effective for PDS.³⁵ In addition, other psychotropic drugs, psychotherapy, and experimental therapies (e.g., rifaximin) are not used. Other treatment options for dyspeptic patients include proton-pump inhibitors, prokinetics, and antibiotics against H. pylori according to the AGA and CAG guidelines, but not antidepressants or anti-anxiety drugs, as stepwise recommended.^21,22 These recommendations apply to EPS, the most prevalent subtype across the country. The findings highlight the importance of not using a therapeutic designated for one disease subtype to treat another subtype, e.g., expecting prokinetics to resolve PDS or proton-pump inhibitors to treat PDS and the overlapping EPS-PDS variant. The prescription of antibiotics to eradicate H. pylori (test and treat strategy) as a first step in managing dyspepsia is helpful, given the high prevalence of H. pylori infection throughout Saudi Arabia.

The H. pylori infection rate (25%) may be lower than in other studies in SA, ranging from 31.8-82.2%^15,16,19,36 due to differences in the age groups involved in the present study compared to the others. The great majority of the survey participants were aged 18-29 years of age. Furthermore, patients with FD symptoms were diagnosed according to the Rome IV diagnostic criteria, not the outdated definitions used in some older studies.

The prevalence of IBS among dyspeptic patients was 44%. A higher prevalence was in overlapping variants, more than 2/3 of dyspeptic patients, and lower (less than 1/5) in IBS with EPS. In population-based studies, the estimated prevalence of IBS among dyspeptic patients ranged between 13% and 29%.³⁷ This might be due to the use of different diagnostic criteria,

Among the dyspeptic participants, gastritis was the most common pathology with a frequency of 23%, which was more or less similar to the results reported in Saudi Arabia and other Arab countries.^16,17,38,39 Studies in the western world reported a higher prevalence of gastritis (62%) among adults.¹⁸ The difference in prevalence between SA and the western world may be due to alcohol, which is not widely consumed in SA.

A few independent factors appear to be associated with the Rome IV-based FD symptoms and subtypes, including co-occurrence of symptoms compatible with FH and IBS, physical QoL, and use of acid-suppressing medications. Similar to the present observations, a long-term follow-up study showed that a poor QoL was associated with FD⁴⁰ and that the co-existence of other functional GI diseases increases the chance of having FD symptoms,^41,42 even though the underlying etiology remains unknown. Another independent factor was somatization, which was positively associated with the PDS and overlapping EPS-PDS variant subtypes, but not EPS, as reported in other studies.^31,43-45

The main limitations of this study were its cross-sectional design and that the data were solely self-reported by the participants. Therefore, the diagnoses could not be confirmed by a clinical evaluation, nor could the endoscopy findings be verified despite the lack of diagnostic yield from performing an endoscopy study in the general population for FD.^26,45 According to the joint ACG and CAG guidelines, because gastric cancer is rare in dyspeptic patients under 60 years of age, they do not routinely recommend upper GI endoscopy as an initial management approach in dyspeptic patients, and the present population sample age was under 60 years of age and mostly younger ages. To address and avoid any potential selection bias, this study used a consistent and systematic methodological approach that was accessible throughout the country. The web-based survey generated new data on the epidemiology of FD subtypes, not overestimated because of outdated definitions of FD or underestimated due to the pitfalls of personal approaches (e.g., face-to-face and telephone interviews).¹⁴

In conclusion, this is the first survey-based study to assess the prevalence of FD symptoms according to the Rome IV diagnostic criteria in the general adult population of Saudi Arabia. An awareness of the epidemiology of FD symptoms, the subtypes, and their distinct therapeutic regimens, and the evolving Rome IV criteria will enable clinical practices to optimize the treatment of this prevalent condition. Improvements in clinical practice rely on the adherence to international guidelines in the diagnosis and management of dyspepsia, which is crucial for improving the QoL and avoiding unnecessary procedures and medications. This is particularly relevant to the PDS subtype for which most therapies are not sufficiently effective.