Background
There are a number of pain-associated functional gastrointestinal disorders (FGIDs) defined by Rome III for children/adolescents, namely irritable bowel syndrome (IBS), functional dyspepsia (FD), abdominal migraines, functional abdominal pain, and functional abdominal pain syndrome [
1]. In adults, there are two recognized FD subtypes, postprandial distress syndrome (PDS; defined by the presence of early satiety preventing completing a normal size meal or fullness following a normal sized meal) and epigastric pain syndrome (EPS; defined by the presence of pain or burning localized to the epigastrium) [
2] These subtypes are not recognized in the pediatric Rome III criteria, although there is some evidence of their existence and indication that the distinction may be clinically meaningful in youth as well [
3,
4]. For example, PDS-related symptoms (i.e., early satiety and/or bloating following a meal) have been associated with increased mucosal mast cells, anxiety, and depression in pediatric FD [
4].
Most children and adolescents with chronic abdominal pain fulfill criteria for an FGID with FD and IBS being the two most common [
1,
5,
6]. These diagnoses form the entry criteria for most abdominal pain studies and therapeutic trials. Utilization of these criteria for research (or clinical practice) presents challenges given some inherent ambiguity in the criteria, inconsistent application of the criteria, and differences in symptom reports between the patients and their parents or guardians [
7]. Additionally, there may be overlap between FGIDs or overlap between FGIDs and other symptoms or conditions which may influence study results or therapeutic response. For adults, FD is well known to overlap with IBS, as well as other conditions such as gastroesophageal reflux disease (GERD) and overactive bladder syndrome (OBS) [
8‐
11]. Overlap syndromes may be associated with greater psychopathology and electromechanical dysfunction [
12,
13]. We have previously found that FD/IBS overlap accounts for 30 % of youth presenting for initial evaluation of chronic abdominal pain [
6]. This represents another area of variability in utilization of Rome criteria as some investigators diagnose overlap FD/IBS while others presumably default to IBS when symptoms of both are present [
7]. Overlap with GERD and OBS has been largely unstudied in a pediatric population. It is important to determine to what degree, if any, individual FGIDs overlap with other syndromes or symptoms in order to understand variability within a diagnostic category which may affect study results or patient outcomes.
The purpose of the current study was to evaluate the frequency of overlap IBS, potential GERD-related symptoms, and OBS-related symptoms, as well as other gastrointestinal and systemic symptoms, in a clinical sample of youth with FD. Additionally, we sought to determine the frequency of PDS and EPS in youth with FD, and whether these subtypes were uniquely related to overlap syndromes or other symptoms.
Discussion
The current study indicates that FD is a heterogeneous condition in children and adolescents. There is significant variability in the presence of gastrointestinal, as well as non-gastrointestinal, symptoms. It is important to understand this variability within diagnostic categories, and also within individual patients as each patient appears to have a somewhat unique symptom profile within the broad category of FD.
Overlap IBS was present in 33 % of the FD patients in the current study. Previously we found IBS overlap in 54 % of patients fulfilling FD criteria [
6]. Consistent with these pediatric findings, IBS overlap has been reported in 33–56 % of adults with FD [
14‐
16]. In adults, IBS occurs more often in those with FD (37 %) as compared to those without FD (7 %) [
12]. IBS has been found to be more common with the PDS subtype in some, but not all, studies in adults [
12,
15]. We found no association between overlapping IBS and PDS; however, the PDS subtype patients were more likely to report the individual symptom of waking at night to have a stool. There was also a trend towards increased reporting of pain improvement with a stool in the PDS subgroup. Associations with EPS could not be assessed given the low EPS frequency. In adults, FD/IBS overlap patients were more likely to be female. (13) We did not find any main effect of gender in our pediatric cohort, however, females 13 years of age and older were more likely to report overlap than were younger females (12 years of age and under).
Evaluating for the presence of GERD overlap in youth with FD presents a challenge, as there is no gold standard test for GERD. Symptoms and available tests lack high sensitivity or specificity. However, the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines concluded, based on expert opinion, that the diagnosis of GERD can be made in adolescents with typical heartburn symptoms [
17]. Heartburn is considered to be a reasonably sensitive indicator of GERD in adults [
18]. Heartburn was reported by 41 % of the patients in the current study. Although a definitive statement isn’t possible, our data suggest that reflux-like symptoms are common in youth with FD. The correlation between reflux-like symptoms and mild histologic esophagitis adds some support for these symptoms being related to GERD in at least some patients. Reported prevalence of GERD in adults with FD has ranged from 13.3 to 56 %, with the prevalence being near 50 % in most studies [
12]. This overlap appears to be greater in those patients with non-erosive GERD (NERD) and, within this group, overlap is greatest among those with heartburn [
8,
9]. It has been suggested that heartburn should be considered an integral part of the dyspepsia complex in adults [
19].
Overactive bladder symptoms were common in FD patients in the current study, with at least one symptom present in 44 %. In adults, OAB is defined as a symptom complex of urinary urgency usually with urinary frequency and nocturia [
10]. The hallmark of OAB in children is urgency. (20) In the current study, urgency was reported by 29 % of the patients. This is similar to the 20.5 % prevalence of OAB in adults with FD [
11]. Pathophysiologic processes implicated in OAB are similar to those that appear relevant to FD (and IBS) including nerve hypersensitivity and mucosal mast cells [
20‐
22].
The FD subtypes, PDS and EPS, are well recognized in adults but were not included in the pediatric FD criteria [
1]. In adults, some studies have shown good separation of PDS and EPS while others have reported significant overlap of the two subtypes [
23]. It appears that separation is better in the general population than in patients who seek medical care [
24]. In one pediatric study, Turco and colleagues evaluated 100 pediatric patients with FD and found EPS alone in 17 %, PDS alone in 47 %, and overlap in 36 %; however, many of these patients crossed over their diagnosis between PDS and EPS over time [
3]. In the current study, 72 % of our pediatric cohort met criteria for PDS, while only 3 % met criteria for EPS. Similar to our previous findings regarding EPS, 52 % of the patients in the current study reported epigastric pain or burning, but only 3 % localized this pain exclusively to the epigastrium, a requirement for diagnosing EPS under the Rome III adult criteria [
4].
Adult data suggests that meal-related symptoms, including pain and nausea, may be the norm in FD [
25]. The PDS subtype did have some associations with other GI symptoms in our pediatric cohort, including increased pain with eating (79 %) and weight loss (36 %), as well as a trend toward increased nausea with eating (70 %). Thus, the consequences of eating may be more widespread than just early satiety. In adult studies, nausea has been reported by 39–65 % of FD patients [
24]. Overall, nausea was reported by 86 % of pediatric patients in the current study with 70 % reporting an increase in nausea with eating. In another pediatric abdominal pain study, nausea was reported by 87 % of subjects who met adult criteria for FD [
26]. Thus, nausea appears to be a common component of FD in both adults and youth. However, nausea may be more associated with PDS than EPS in children [
3]. Nausea is important to consider as it is associated with poor school functioning and greater social disability [
26]. These meal related symptoms may also be associated with nutritional consequences. As noted above, weight loss was common in the current study being reported by 36 % of PDS patients. This is similar to adults where weight loss correlates most strongly with early satiety [
27].
The main strength of the current study is the relatively large population size with symptom reporting performed in a standardized fashion across a wide array of gastrointestinal and non-gastrointestinal symptoms. The main limitation is that the study design did not allow evaluation of the natural history of these symptoms. It is known that symptoms may evolve across time and patients may change FD subtype classification [
3].
Conclusions
In sum, pediatric FD is a heterogeneous syndrome exhibiting variable symptoms from patient to patient with many, but not all, fulfilling criteria for PDS. The clinical presentation of FD also varies with regard to non-FD symptoms, exhibiting significant overlap with IBS as well as symptoms consistent with GERD and OBS. These varying symptom profiles need to be considered in providing care to FD patients. For example, an FD patient with overlap may have a different pathogenic process or respond differently to a treatment regimen than a patient with FD alone or FD with overlap GERD. Likewise, varying symptom profiles need to be accounted for and analyzed in studies involving subjects with FD. Clinical trials need to be designed to fit the patients that are actually encountered, rather than the clean diagnostic boxes we create.
Abbreviations
EPS, epigastric pain syndrome; FD, functional dyspepsia; FGID, functional gastrointestinal disorder; GERD, gastroesophageal reflux disease; hpf, high power field; IBS, irritable bowel syndrome; OBS, overactive bladder syndrome; PDS, postprandial distress syndrome