**2. The role of inflammation in functional dyspepsia**

Inflammation has the potential to contribute to the development of FGIDs via the release of specific mediators that impact mechanisms known to play a role in the pathogenesis of these conditions. Acute gastrointestinal inflammation and injury are associated with both peripheral

**Figure 1.** The Biopsychosocial Model of FD

meal. The second subtype, epigastric pain syndrome, was defined as intermittent pain or burning localized to the epigastrium (i.e., not generalized or localized to other abdominal or chest regions) and of at least moderate severity. The Rome III pediatric subcommittee also eliminated the old subtypes, but did not adopt the new adult subtypes because of a lack of existing data to support their existence in children and adolescents. However, recent evidence suggests that the adult subtypes actually may have meaningful associations with mucosal

Most pediatric gastroenterologists may not routinely use Rome criteria and differences exist in how the criteria are interpreted. Nevertheless, there is agreement that a strong majority of children with chronic abdominal pain presenting to pediatric gastroenterology practices fulfill criteria for an FGID, with the two most common being FD and IBS [6-9]. Community preva‐ lence for FD is estimated at 3.5-27% in children/adolescents compared to 20-30% in adults [3,4]. In both pediatric and adult gastroenterology practices, FD frequently overlaps with IBS or gastroesophageal reflux [7,10]. Adult IBS overlap is associated with more psychological dysfunction including anxiety and depression, compared to "pure" FD, but this association does not appear to be present in pediatric overlap [11,12]. Pediatric FD is associated with lower quality of life, increased functional disability, and increased likelihood of meeting criteria for an anxiety disorder relative to healthy children [13]. In adults with FD, the association with anxiety appears to be specific to patients with postprandial distress syndrome, with this relationship also apparent in children/adolescents with symptoms consistent with postpran‐

FD, like all FGIDs, is probably best understood through a biopsychosocial model (see Figure 1). This model states that symptoms are likely the result of varying contributions from, and interactions between, biological/physiological factors (e.g. inflammation, mechanical distur‐ bances, hypersensitivity), psychological factors (e.g. anxiety, depression, somatization), and social factors (e.g. interactions with parents, teachers, or peers). Within this model, there is less emphasis on the "cause" of symptoms than on "contributors" to its emergence and mainte‐ nance. This model would suggest that there is value in identifying and targeting all of the factors which might be contributing to symptom generation in children with FD. It also would suggest that there is value in understanding the mechanisms by which the factors interact with one another, as these mechanisms represent additional opportunities for clinical intervention.

Inflammation has the potential to contribute to the development of FGIDs via the release of specific mediators that impact mechanisms known to play a role in the pathogenesis of these conditions. Acute gastrointestinal inflammation and injury are associated with both peripheral

**2. The role of inflammation in functional dyspepsia**

inflammation and psychosocial functioning in pediatric FD [5].

**1.2. Prevalence and presentation**

30 Dyspepsia - Advances in Understanding and Management

dial distress syndrome [5,14].

**1.3. Etiology**

and central sensitization of the nervous system, which results in visceral hyperalgesia [15]. Neuroplastic changes may occur that affect the response thresholds of enteric nerves, thereby negatively impacting both sensitivity and motility [16]. Both motility and sensitivity responses to acute inflammation in adults generally are reversible; however, animal model responses suggest that, if inflammation occurs in neonates, neuroplastic changes and sensitivity may persist into adulthood [17,18]. Visceral sensitization may be even more relevant in instances where there is chronic inflammation with ongoing mediator release, as there may be subse‐ quent effects on visceral sensitivity that compound and prolong the issue.

The role of inflammation in FD has historically been controversial. However, emerging evidence supports its role as a contributing factor in the biopsychosocial model of FD. In fact, inflammation may be of particular importance in this model, as it interacts with a number of other factors and may actually mediate the relationship between psychologic and physiologic factors. The remainder of this chapter focuses on examination of inflammation within the biopsychosocial model of FD, laying out the current evidence for its prevalence, mechanisms of action, relationship with other important factors, and implications for evaluation and treatment.

**2.3. Eosinophils**

≤20/hpf in the duodenum in 93% [31].

Ethical considerations preclude undertaking studies that assess eosinophil density in healthy pediatric controls. However, the available pediatric literature indicates that it is reasonable to consider eosinophil densities ≥10/hpf in the antrum and >20/hpf in the duodenum to be abnormal. In a pediatric autopsy study, eosinophil density was <10/hpf in the antrum of all subjects and ≤20/hpf in the duodenum of 82%, even though symptoms could not be docu‐ mented [30]. Another study reviewed biopsies from 682 presumably symptomatic children referred for endoscopy, documenting eosinophil density ≤10/hpf in the antrum in 90% and

Inflammation and the Biopsychosocial Model in Pediatric Dyspepsia

http://dx.doi.org/10.5772/56635

33

While certain cut-off points for density seem reasonable, eosinophil density may not be completely informative. Eosinophil biologic activity occurs through mediator release or degranulation, and the effects are generally concentration-dependent. Important to consider is the fact that density and activation are not correlated events [32]. In one study involving 20 children with FD, eosinophil density >20/hpf was present in only 15%; however, moderate to

Adult population studies have demonstrated increased duodenal eosinophil density in those with dyspepsia compared to controls, whereas antral eosinophils did not differ between the groups [34,35]. Higher eosinophil density and a higher prevalence of duodenal eosinophilia (as defined by application of the cut points outlined above) have been specifically associated with the postprandial distress syndrome subtype of FD in adults [36]. Duodenal biopsies from adults with FD also have revealed more extensive degranulation, including documentation of extracellular major basic protein; this corresponds to a similar finding of degranulation and release of major basic protein previously demonstrated in pediatric patients with FD [33,35].

Although no information is available for healthy children, tissue eosinophilia has been evaluated in the broad group of children with chronic abdominal pain, which provides some limited basis for comparison. In a study of 1191 children with chronic abdominal pain, eosinophilia was identified in the antrum or duodenum in 11.4% [37]. In another study, gastric eosinophilia was reported in 19% and duodenal eosinophilia in 32% of children with unspe‐ cified chronic abdominal pain [19]. In contrast, duodenal eosinophilia has been demonstrated

Antral eosinophil density does not appear to have any direct relationship to gastric electro‐ mechanical function in children with FD [28]. However, in patients with elevated mucosal eosinophils, antral CD3+ cell density does correlate with preprandial tachygastria, indicating

There are a number of triggers or inciting events which may initiate an inflammatory response in the gastrointestinal tract, particularly with regard to recruitment and activation of mast cells

extensive degranulation was demonstrated by electron microscopy in 95% [33].

in 79% of children specifically fulfilling FD criteria [38].

that it may result from the interaction between different cell types [28].

**3. Specific Conditions Associated with Mucosal Inflammation**

#### **2.1. Chronic inflammation**

Upper endoscopy is commonly performed in children with chronic abdominal pain in general and children with functional dyspepsia in particular. Histologic inflammation is common in these patients. In children with chronic abdominal pain, esophagitis is common and would implicate gastroesophageal reflux as a contributor or cause of pain [19]. In one study of children with FD, specifically, histologic esophagitis was found in 18%, gastritis in 21%, and duodenitis in 13% [10]. Higher prevalences for gastritis, ranging from 43% to 71%, have been reported by others [20,21]. For the broader group of children with chronic abdominal pain, histologic inflammation has been documented in up to 79%, with an increase in mononuclear cells (indicative of chronic inflammation) in the antrum of 55% and in the duodenum of 16% of these children [19].

Most of these patients have chronic inflammation of which the clinical significance is unknown. Chronic gastritis is not associated with electrogastrographic abnormalities, delayed gastric emptying, or psychologic dysfunction in children with FD [5,22]. Despite this, chronic active gastritis (manifest as lymphocytic and neutrophilic inflammation) has been associated with a higher prevalence of nocturnal pain [21]. Chronic gastritis has been associated with an increased prevalence of postprandial pain [5].

#### **2.2. Mast cells**

Increased mucosal mast cell density has been demonstrated in the gastric corpus and antrum in adults with FD [23,24]. In adults with gastritis, mast cell density is significantly increased and generally correlates with the intensity of the inflammation [25]. Though findings have been variable, increased mast cell density appears isolated to the stomach in adults with FD; increased duodenal mast cell density is more associated with IBS [24,26]. In addition, increased mast cells in the proximal stomach in adults with FD have been associated with hypersensi‐ tivity; these mast cells will degranulate with balloon distension of the proximal stomach [27].

Due to a lack of normal control data, it is not known if gastric mast cells are elevated in pediatric FD. However, antral mast cells do appear to be actively degranulating in children with FD, with a mean degranulation index of 67% and greater than 50% degranulation in over 80% of patients [28]. In children with FD, mast cell density positively correlates with slower gastric emptying and increased gastric dysrhythmia (primarily preprandial bradycardia) in children with FD [28]. Further, this dysrhythmia is associated with increased postprandial pain [29].

#### **2.3. Eosinophils**

The role of inflammation in FD has historically been controversial. However, emerging evidence supports its role as a contributing factor in the biopsychosocial model of FD. In fact, inflammation may be of particular importance in this model, as it interacts with a number of other factors and may actually mediate the relationship between psychologic and physiologic factors. The remainder of this chapter focuses on examination of inflammation within the biopsychosocial model of FD, laying out the current evidence for its prevalence, mechanisms of action, relationship with other important factors, and implications for evaluation and

Upper endoscopy is commonly performed in children with chronic abdominal pain in general and children with functional dyspepsia in particular. Histologic inflammation is common in these patients. In children with chronic abdominal pain, esophagitis is common and would implicate gastroesophageal reflux as a contributor or cause of pain [19]. In one study of children with FD, specifically, histologic esophagitis was found in 18%, gastritis in 21%, and duodenitis in 13% [10]. Higher prevalences for gastritis, ranging from 43% to 71%, have been reported by others [20,21]. For the broader group of children with chronic abdominal pain, histologic inflammation has been documented in up to 79%, with an increase in mononuclear cells (indicative of chronic inflammation) in the antrum of 55% and in the duodenum of 16% of

Most of these patients have chronic inflammation of which the clinical significance is unknown. Chronic gastritis is not associated with electrogastrographic abnormalities, delayed gastric emptying, or psychologic dysfunction in children with FD [5,22]. Despite this, chronic active gastritis (manifest as lymphocytic and neutrophilic inflammation) has been associated with a higher prevalence of nocturnal pain [21]. Chronic gastritis has been associated with an

Increased mucosal mast cell density has been demonstrated in the gastric corpus and antrum in adults with FD [23,24]. In adults with gastritis, mast cell density is significantly increased and generally correlates with the intensity of the inflammation [25]. Though findings have been variable, increased mast cell density appears isolated to the stomach in adults with FD; increased duodenal mast cell density is more associated with IBS [24,26]. In addition, increased mast cells in the proximal stomach in adults with FD have been associated with hypersensi‐ tivity; these mast cells will degranulate with balloon distension of the proximal stomach [27].

Due to a lack of normal control data, it is not known if gastric mast cells are elevated in pediatric FD. However, antral mast cells do appear to be actively degranulating in children with FD, with a mean degranulation index of 67% and greater than 50% degranulation in over 80% of patients [28]. In children with FD, mast cell density positively correlates with slower gastric emptying and increased gastric dysrhythmia (primarily preprandial bradycardia) in children with FD [28]. Further, this dysrhythmia is associated with increased postprandial pain [29].

treatment.

**2.1. Chronic inflammation**

32 Dyspepsia - Advances in Understanding and Management

these children [19].

**2.2. Mast cells**

increased prevalence of postprandial pain [5].

Ethical considerations preclude undertaking studies that assess eosinophil density in healthy pediatric controls. However, the available pediatric literature indicates that it is reasonable to consider eosinophil densities ≥10/hpf in the antrum and >20/hpf in the duodenum to be abnormal. In a pediatric autopsy study, eosinophil density was <10/hpf in the antrum of all subjects and ≤20/hpf in the duodenum of 82%, even though symptoms could not be docu‐ mented [30]. Another study reviewed biopsies from 682 presumably symptomatic children referred for endoscopy, documenting eosinophil density ≤10/hpf in the antrum in 90% and ≤20/hpf in the duodenum in 93% [31].

While certain cut-off points for density seem reasonable, eosinophil density may not be completely informative. Eosinophil biologic activity occurs through mediator release or degranulation, and the effects are generally concentration-dependent. Important to consider is the fact that density and activation are not correlated events [32]. In one study involving 20 children with FD, eosinophil density >20/hpf was present in only 15%; however, moderate to extensive degranulation was demonstrated by electron microscopy in 95% [33].

Adult population studies have demonstrated increased duodenal eosinophil density in those with dyspepsia compared to controls, whereas antral eosinophils did not differ between the groups [34,35]. Higher eosinophil density and a higher prevalence of duodenal eosinophilia (as defined by application of the cut points outlined above) have been specifically associated with the postprandial distress syndrome subtype of FD in adults [36]. Duodenal biopsies from adults with FD also have revealed more extensive degranulation, including documentation of extracellular major basic protein; this corresponds to a similar finding of degranulation and release of major basic protein previously demonstrated in pediatric patients with FD [33,35].

Although no information is available for healthy children, tissue eosinophilia has been evaluated in the broad group of children with chronic abdominal pain, which provides some limited basis for comparison. In a study of 1191 children with chronic abdominal pain, eosinophilia was identified in the antrum or duodenum in 11.4% [37]. In another study, gastric eosinophilia was reported in 19% and duodenal eosinophilia in 32% of children with unspe‐ cified chronic abdominal pain [19]. In contrast, duodenal eosinophilia has been demonstrated in 79% of children specifically fulfilling FD criteria [38].

Antral eosinophil density does not appear to have any direct relationship to gastric electro‐ mechanical function in children with FD [28]. However, in patients with elevated mucosal eosinophils, antral CD3+ cell density does correlate with preprandial tachygastria, indicating that it may result from the interaction between different cell types [28].
