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

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 and eosinophils. These include stress/anxiety, infection (including H. pylori), and allergy, as detailed below.

#### **3.1. Stress/Anxiety**

The involvement of inflammation in the biopsychosocial model is best illustrated by examining the stress response. Corticotropin releasing hormone (CRH), produced by the hypothalamus (as well as immune cells including lymphocytes and mast cells) is a major mediator of the stress response in the hypothalamic-pituitary-adrenal axis and, subsequently, within the brain-gut axis. CRH has central nervous system (CNS) effects which may alter central processing of nociceptive messages, leading to anxiogenic and depressive effects. The stress response also results in physiologic effects which may be relevant to FGIDs, including inflammation and alterations of sensorimotor function such as altered gastric accommodation, gastric dysmotil‐ ity, and visceral hypersensitivity.

The relationship between the CNS and gastrointestinal pathophysiology appears bidirectional. In a rodent model, gastric irritation in the neonatal period induces a long lasting increase in depression- and anxiety-like behaviors. This, in turn, is associated with an increased expres‐ sion of CRH in the hypothalamus and increased sensitivity of the hypothalamic-pituitaryadrenal axis to stress [39]. CRH stress systems may be activated by afferent nerves from inflamed sites or via cytokines including TNF-α, IL-1, IL-6, and IL-12 [40]. The majority of studies support an enhanced hypothalamic-pituitary-adrenal axis in at least some adults with IBS, although results have been variable [41-45].

Corticotropin releasing hormone receptors are widely expressed including within the gastro‐ intestinal tract and immune cells. Mast cells express both CRH1 and CRH2 receptor subtypes at their surface [46]. Most of the inflammatory cell actions, including those on mast cells, occur via CRH2 receptors. Once mast cells are activated, they release mediators which recruit and activate eosinophils. Both of these cell types are interactive in a bi-directional fashion with T helper cells (Th; see Figure 2).

Once activated by CRH, mast cells may release pre-formed and newly synthesized cytokines, including interleukins (IL-4, IL-5, IL-6) and tumor necrosis factor (TNF-α) among others [50,51]. In adults, there is selective luminal release of tryptase and histamine from jejunal mast cells under cold stress; the magnitude of release is similar to that induced by antigen exposure in food allergic patients [52]. Once released, mast cell and eosinophil mediators can stimulate afferent nerves sending a "pain" message, sensitize afferent nerves resulting in visceral hypersensitivity, and alter electromechanical function (see Figure 2). Histamine also can stimulate afferent sensory nerves via H2 receptors [53]. Consistent with this, experimental anxiety decreases gastric compliance and accommodation and increases epigastric symptom

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35

**Figure 2.** The Relationship between CRH Activation and Inflammatory Cells in FD Symptom Generation

FD has been reported at a higher prevalence following both bacterial and parasitic infections [55]. It seems likely that FD may also be induced by viral gastroenteritis similar to what has been reported with IBS. In a large cohort of adults that were evaluated 8 years after bacterial

scores during a standard nutrient challenge [54].

**3.2. Infection**

In addition to this indirect pathway, there also may be a direct effect for CRH on eosinophils. In a rodent model, psychologic stress results in eosinophils expressing CRH [47]. CRH is not expressed on eosinophils in the intestines of the mice except under psychologic stress and decreases after the stress is removed, with the reversion requiring longer periods of time as the length of the stressor increases [47]. A high correlation exists between anxiety scores and mucosal eosinophil density in children with FD [48]. Antral mast cell density also correlates with anxiety scores in children with FD [5]. Stress appears to shift the relative proportion and trafficking of T helper lymphocytes towards a Th2 or "allergic" phenotype [40]. This shift is driven by central and peripheral CRH, catecholamines, and histamine via H2 receptors. The Th2 phenotype is associated with release of IL-4, IL-10, and IL-13, which stimulate growth and activation of mast cells and eosinophils [40]. Shifting from a Th1 to a Th2 response may be the mechanism through which low grade inflammation leads to visceral sensitivity and motility disturbances; eosinophils and mast cells represent the key effector cells [49].

**Figure 2.** The Relationship between CRH Activation and Inflammatory Cells in FD Symptom Generation

Once activated by CRH, mast cells may release pre-formed and newly synthesized cytokines, including interleukins (IL-4, IL-5, IL-6) and tumor necrosis factor (TNF-α) among others [50,51]. In adults, there is selective luminal release of tryptase and histamine from jejunal mast cells under cold stress; the magnitude of release is similar to that induced by antigen exposure in food allergic patients [52]. Once released, mast cell and eosinophil mediators can stimulate afferent nerves sending a "pain" message, sensitize afferent nerves resulting in visceral hypersensitivity, and alter electromechanical function (see Figure 2). Histamine also can stimulate afferent sensory nerves via H2 receptors [53]. Consistent with this, experimental anxiety decreases gastric compliance and accommodation and increases epigastric symptom scores during a standard nutrient challenge [54].

#### **3.2. Infection**

and eosinophils. These include stress/anxiety, infection (including H. pylori), and allergy, as

The involvement of inflammation in the biopsychosocial model is best illustrated by examining the stress response. Corticotropin releasing hormone (CRH), produced by the hypothalamus (as well as immune cells including lymphocytes and mast cells) is a major mediator of the stress response in the hypothalamic-pituitary-adrenal axis and, subsequently, within the brain-gut axis. CRH has central nervous system (CNS) effects which may alter central processing of nociceptive messages, leading to anxiogenic and depressive effects. The stress response also results in physiologic effects which may be relevant to FGIDs, including inflammation and alterations of sensorimotor function such as altered gastric accommodation, gastric dysmotil‐

The relationship between the CNS and gastrointestinal pathophysiology appears bidirectional. In a rodent model, gastric irritation in the neonatal period induces a long lasting increase in depression- and anxiety-like behaviors. This, in turn, is associated with an increased expres‐ sion of CRH in the hypothalamus and increased sensitivity of the hypothalamic-pituitaryadrenal axis to stress [39]. CRH stress systems may be activated by afferent nerves from inflamed sites or via cytokines including TNF-α, IL-1, IL-6, and IL-12 [40]. The majority of studies support an enhanced hypothalamic-pituitary-adrenal axis in at least some adults with

Corticotropin releasing hormone receptors are widely expressed including within the gastro‐ intestinal tract and immune cells. Mast cells express both CRH1 and CRH2 receptor subtypes at their surface [46]. Most of the inflammatory cell actions, including those on mast cells, occur via CRH2 receptors. Once mast cells are activated, they release mediators which recruit and activate eosinophils. Both of these cell types are interactive in a bi-directional fashion with T

In addition to this indirect pathway, there also may be a direct effect for CRH on eosinophils. In a rodent model, psychologic stress results in eosinophils expressing CRH [47]. CRH is not expressed on eosinophils in the intestines of the mice except under psychologic stress and decreases after the stress is removed, with the reversion requiring longer periods of time as the length of the stressor increases [47]. A high correlation exists between anxiety scores and mucosal eosinophil density in children with FD [48]. Antral mast cell density also correlates with anxiety scores in children with FD [5]. Stress appears to shift the relative proportion and trafficking of T helper lymphocytes towards a Th2 or "allergic" phenotype [40]. This shift is driven by central and peripheral CRH, catecholamines, and histamine via H2 receptors. The Th2 phenotype is associated with release of IL-4, IL-10, and IL-13, which stimulate growth and activation of mast cells and eosinophils [40]. Shifting from a Th1 to a Th2 response may be the mechanism through which low grade inflammation leads to visceral sensitivity and motility

disturbances; eosinophils and mast cells represent the key effector cells [49].

detailed below.

**3.1. Stress/Anxiety**

ity, and visceral hypersensitivity.

34 Dyspepsia - Advances in Understanding and Management

helper cells (Th; see Figure 2).

IBS, although results have been variable [41-45].

FD has been reported at a higher prevalence following both bacterial and parasitic infections [55]. It seems likely that FD may also be induced by viral gastroenteritis similar to what has been reported with IBS. In a large cohort of adults that were evaluated 8 years after bacterial dysentery, an increased prevalence of FD was found compared to non-infected controls [56]. Consistent with the biopsychosocial model, anxiety and depression were independent risk factors for developing post-infectious FD [56]. In another study, 82 adults were identified with persistent abdominal symptoms following *Giardia* infection; 24.3% of these met criteria for FD, while 80.5% met criteria for IBS [57]. Over half of these patients reported exacerbation due to specific foods and nearly half reported exacerbations with physical or mental stress [57]. Rates of post-infectious FD appear similar in pediatric populations. In a study of 88 children with a previous positive bacterial stool culture, FD was present in 24% and IBS in 87% [58]. Fifty-six percent of these patients reported the onset of abdominal pain after the acute infection.

reporting an inverse relation between severity of symptoms and gastric inflammation [72]. H. pylori colonization in children is associated with increased mucosal lymphocytes, plasma cells, neutrophils, and eosinophils, which decrease with eradication [20]. H. pylori colonization may also be associated with increased antral mast cell density, though this may be H. pylori strain specific [73]. In the setting of nodular gastritis associated with HP colonization, eosinophils may be of particular significance. Nodularity is associated with the presence and density of eosinophils [74]. Patients with nodular gastritis have a higher incidence of FD symptoms which resolve with eradication therapy and improvement of gross endoscopic appearance [70]. Even in the absence of nodularity, H. pylori colonization is associated with increased antral eosinophils, as well as increased gastric fluid eosinophil cationic protein indicating eosino‐ philic activation [20,75,76]. These findings suggest a possible pathophysiologic role for eosinophils in contributing to symptoms in patients with H. pylori colonization or possibly

Inflammation and the Biopsychosocial Model in Pediatric Dyspepsia

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

37

Similar to post-infectious FD, H. pylori may be associated with electromechanical dysfunction which, in turn, can contribute to FD symptom generation. Though studies are conflicting, H. pylori has not consistently been associated with delayed gastric emptying or visceral hyper‐ sensitivity [77]. However, treatment with a prokinetic was found to be as effective as eradica‐ tion at 12 months [78]. H. pylori also has been associated with an abnormal electrogastrogram that normalized in 83% with eradication [79]. H. pylori does not appear to have any effect on

The role of allergy in the development of FD has not been greatly studied. However, allergy may be important given the observed increases in, and activation of, mast cells and eosinophils in FD. FGIDs occur more commonly in children with a history of cow's milk allergy as infants [80]. In children with FD in association with cow's milk allergy, mucosal application of cow's milk is associated with increased eosinophils and mast cells, as well as rapid degranulation, within 10 minutes of application [81]. In addition, cow's milk exposure is associated with increased mast cells within 5 μm of nerves [81]. Adult FD patients with a history of allergy have increased duodenal eosinophil density [36]. In addition, lymphoid hyperplasia is significantly more frequent in children with abdominal pain associated with food allergies [19]. Lymphoid hyperplasia is associated with food hypersensitivity although this reaction may be local reactivity only as it is associated with normal skin prick tests and normal serum IgE levels

Food allergy, similar to post-infectious FD and H. pylori colonization, also may cause electro‐ mechanical dysfunction. Exposure to cow's milk in allergic FD children resulted in increased bradygastria [81]. In infants with cow's milk allergy, exposure results in gastric arrhythmias

Whether food allergy accounts for a substantial portion of children with FD is not clear. One study found no significant increase in immunoreactivity to common food allergens in FD children with duodenal eosinophilia, although it is possible that the reaction was localized to the mucosa [85]. It is also possible that environmental allergens may be playing a role. Antigen

following eradication.

accommodation [60].

**3.3. Allergy**

[82,83].

and delayed gastric emptying [84].

Post-infectious FD appears to represent an impaired ability to terminate the inflammatory response after the offending pathogen has been eliminated, but also may involve neuroplastic changes in visceral and central afferent pathways as it is associated with impaired accommo‐ dation and increased sensitivity to distension [59-61]. Post-infectious FD patients frequently demonstrate histologic duodenitis, with a severe grade in 57% [62]. Post-infectious FD is associated with increased macrophages and may be associated with increased CD8+ cells [62, 63]. Findings regarding CD8+ cells however have been variable [62,63]. Duodenal eosinophilia has also been described in post-infectious FD [49]. In addition, gastric mast cells are signifi‐ cantly increased in post-infectious FD as compared to healthy controls [64]. Post-infectious FD is associated with increased gastric release of histamine and 5HT, as well as increased number of mast cells within 5 μm of nerve fibers as compared to healthy controls or patients with FD that is not post-infectious [64].

*H. pylori.* The role of Helicobacter pylori (H. pylori) in FD remains incompletely defined and, as such, deserves particular attention within the scope of infectious organisms. Given that most people never demonstrate symptoms at all when colonized with H. pylori, it is possible that H. pylori has little to no contributory value for a significant subset of the population with FD. However, it is possible that H. pylori may generate symptoms as a primary chronic infection or, alternatively, patients may experience post-infectious FD once H. pylori has cleared in the much the same way as seen in other bacterial and parasitic infections.

Several studies have demonstrated efficacy in reducing FD symptoms with H. pylori eradica‐ tion; however, others have found only a moderate (but statistically significant) effect or no clinical benefit to eradication at all [65-69]. A Cochrane review concluded that eradication was significantly better than placebo [69]. Response rates may be dependent on the specific symptom. For example, one study documented a positive response to H. pylori eradication, but only for the symptoms of epigastric pain and burning, indicating that efficacy may be restricted to patients with the epigastric pain syndrome subtype of FD [67]. A large number of patients with FD continue to experience symptoms following H. pylori eradication. These may be patients in whom H. pylori had no pathologic role, or may represent a group of patients who should be classified as post-infectious FD given that complete resolution of submucosal inflammation requires a prolonged period [70].

H. pylori colonization is generally associated with gastric and duodenal histologic inflamma‐ tion. Histologic duodenitis has been associated with more severe symptoms when histologic gastritis also is present [71]. However, this finding has not been consistent, with others actually reporting an inverse relation between severity of symptoms and gastric inflammation [72]. H. pylori colonization in children is associated with increased mucosal lymphocytes, plasma cells, neutrophils, and eosinophils, which decrease with eradication [20]. H. pylori colonization may also be associated with increased antral mast cell density, though this may be H. pylori strain specific [73]. In the setting of nodular gastritis associated with HP colonization, eosinophils may be of particular significance. Nodularity is associated with the presence and density of eosinophils [74]. Patients with nodular gastritis have a higher incidence of FD symptoms which resolve with eradication therapy and improvement of gross endoscopic appearance [70]. Even in the absence of nodularity, H. pylori colonization is associated with increased antral eosinophils, as well as increased gastric fluid eosinophil cationic protein indicating eosino‐ philic activation [20,75,76]. These findings suggest a possible pathophysiologic role for eosinophils in contributing to symptoms in patients with H. pylori colonization or possibly following eradication.

Similar to post-infectious FD, H. pylori may be associated with electromechanical dysfunction which, in turn, can contribute to FD symptom generation. Though studies are conflicting, H. pylori has not consistently been associated with delayed gastric emptying or visceral hyper‐ sensitivity [77]. However, treatment with a prokinetic was found to be as effective as eradica‐ tion at 12 months [78]. H. pylori also has been associated with an abnormal electrogastrogram that normalized in 83% with eradication [79]. H. pylori does not appear to have any effect on accommodation [60].

#### **3.3. Allergy**

dysentery, an increased prevalence of FD was found compared to non-infected controls [56]. Consistent with the biopsychosocial model, anxiety and depression were independent risk factors for developing post-infectious FD [56]. In another study, 82 adults were identified with persistent abdominal symptoms following *Giardia* infection; 24.3% of these met criteria for FD, while 80.5% met criteria for IBS [57]. Over half of these patients reported exacerbation due to specific foods and nearly half reported exacerbations with physical or mental stress [57]. Rates of post-infectious FD appear similar in pediatric populations. In a study of 88 children with a previous positive bacterial stool culture, FD was present in 24% and IBS in 87% [58]. Fifty-six percent of these patients reported the onset of abdominal pain after the acute infection.

Post-infectious FD appears to represent an impaired ability to terminate the inflammatory response after the offending pathogen has been eliminated, but also may involve neuroplastic changes in visceral and central afferent pathways as it is associated with impaired accommo‐ dation and increased sensitivity to distension [59-61]. Post-infectious FD patients frequently demonstrate histologic duodenitis, with a severe grade in 57% [62]. Post-infectious FD is associated with increased macrophages and may be associated with increased CD8+ cells [62, 63]. Findings regarding CD8+ cells however have been variable [62,63]. Duodenal eosinophilia has also been described in post-infectious FD [49]. In addition, gastric mast cells are signifi‐ cantly increased in post-infectious FD as compared to healthy controls [64]. Post-infectious FD is associated with increased gastric release of histamine and 5HT, as well as increased number of mast cells within 5 μm of nerve fibers as compared to healthy controls or patients with FD

*H. pylori.* The role of Helicobacter pylori (H. pylori) in FD remains incompletely defined and, as such, deserves particular attention within the scope of infectious organisms. Given that most people never demonstrate symptoms at all when colonized with H. pylori, it is possible that H. pylori has little to no contributory value for a significant subset of the population with FD. However, it is possible that H. pylori may generate symptoms as a primary chronic infection or, alternatively, patients may experience post-infectious FD once H. pylori has cleared in the

Several studies have demonstrated efficacy in reducing FD symptoms with H. pylori eradica‐ tion; however, others have found only a moderate (but statistically significant) effect or no clinical benefit to eradication at all [65-69]. A Cochrane review concluded that eradication was significantly better than placebo [69]. Response rates may be dependent on the specific symptom. For example, one study documented a positive response to H. pylori eradication, but only for the symptoms of epigastric pain and burning, indicating that efficacy may be restricted to patients with the epigastric pain syndrome subtype of FD [67]. A large number of patients with FD continue to experience symptoms following H. pylori eradication. These may be patients in whom H. pylori had no pathologic role, or may represent a group of patients who should be classified as post-infectious FD given that complete resolution of submucosal

H. pylori colonization is generally associated with gastric and duodenal histologic inflamma‐ tion. Histologic duodenitis has been associated with more severe symptoms when histologic gastritis also is present [71]. However, this finding has not been consistent, with others actually

much the same way as seen in other bacterial and parasitic infections.

inflammation requires a prolonged period [70].

that is not post-infectious [64].

36 Dyspepsia - Advances in Understanding and Management

The role of allergy in the development of FD has not been greatly studied. However, allergy may be important given the observed increases in, and activation of, mast cells and eosinophils in FD. FGIDs occur more commonly in children with a history of cow's milk allergy as infants [80]. In children with FD in association with cow's milk allergy, mucosal application of cow's milk is associated with increased eosinophils and mast cells, as well as rapid degranulation, within 10 minutes of application [81]. In addition, cow's milk exposure is associated with increased mast cells within 5 μm of nerves [81]. Adult FD patients with a history of allergy have increased duodenal eosinophil density [36]. In addition, lymphoid hyperplasia is significantly more frequent in children with abdominal pain associated with food allergies [19]. Lymphoid hyperplasia is associated with food hypersensitivity although this reaction may be local reactivity only as it is associated with normal skin prick tests and normal serum IgE levels [82,83].

Food allergy, similar to post-infectious FD and H. pylori colonization, also may cause electro‐ mechanical dysfunction. Exposure to cow's milk in allergic FD children resulted in increased bradygastria [81]. In infants with cow's milk allergy, exposure results in gastric arrhythmias and delayed gastric emptying [84].

Whether food allergy accounts for a substantial portion of children with FD is not clear. One study found no significant increase in immunoreactivity to common food allergens in FD children with duodenal eosinophilia, although it is possible that the reaction was localized to the mucosa [85]. It is also possible that environmental allergens may be playing a role. Antigen exposure in adults with birch pollen allergy results in an increase in mucosal major basic protein positive eosinophils and IgE-bearing cells, as well as in FD symptoms, in the majority of patients [86]. Information in this area remains quite limited.

of a variety of mediators with downstream effects. In one open-label observational study of children with FD in association duodenal eosinophilia, resolution of pain was demonstrated with use of oral cromolyn in 89% of patients who had previously failed to respond to H2 and combined H1/H2 antagonism [91]. There have been no other pediatric or adult studies on the use of mast cell stabilizers in patients with FD. Benefit has been demonstrated in adults with IBS and may be related to blocking allergic or immunologic reactions to foods [92-94]. Ketotifen, specifically, has been shown to significantly decrease pain in adults with IBS and to increase the threshold for discomfort in patients with visceral hypersensitivity [95]. Ketotifen also acts as an H1 antagonist, so the effects may not be directly, or completely, related to mast

Inflammation and the Biopsychosocial Model in Pediatric Dyspepsia

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

39

*Antihistamine Medications and Proton Pump Inhibitors (PPI).* Acid reduction remains the most common treatment prescribed empirically by pediatric gastroenterologists for children with FD [9]. While there are numerous adult studies to support this practice, pediatric studies are limited. In children with chronic abdominal pain, famotidine (H2 recptor antagonist - H2RA) was superior to placebo in global improvement, with clear benefit to those with FD [96]. In a large pediatric study, omeperazole was shown to have a very modest advantage in the relief of all symptoms as compared to either famotidine or ranitidine; however, there was no significant difference between the three with regard to resolution of abdominal pain, epigastric

In adults, H2 antagonism has been shown to improve at least some symptoms associated with FD, including abdominal pain, indigestion, belching, and gastroesophageal reflux symptoms [98,99]. H2 antagonists have been shown to be superior to prokinetic medications and short term use of an anxiolytic [100,101]. A meta-analysis evaluating the use of PPIs in adult FD determined that they were superior to placebo in symptom reduction [102]. Studies of omeperazole, lansoprazole, and pantoprazole have demonstrated a modest superiority to placebo in symptom reduction which is limited to patients with ulcer-like or reflux-like FD [103-105]. Whether PPIs are superior to H2 antagonism is not completely clear. Omeperazole was found to have a modest increase in efficacy as compared to ranitidine at 4 weeks (51% vs.

Given the response to PPIs, it would appear that at least some of the clinical improvement from H2 antagonism or PPIs is related directly to acid suppression. A significant portion of responders may derive benefit from treatment of overlap GERD, or possibly from peptic gastritis or duodenitis. Conversely, the benefit may be due to removing exposure to acid in patients with acid hypersensitivity. PPIs do not appear to have other benefits with regard to

The benefit of H2 antagonism may be unrelated to acid reduction, at least in part. Histamine has direct gastric myogenic actions, modulates afferent enteric nerve excitability, and acts as an immunomodulating agent [53,107-111]. There may be additional benefit from H1 antago‐ nism, as well. Combining an H1 antagonist with an H2 antagonist has been reported to relieve symptoms in 50% of children with FD associated with duodenal eosinophilia and in 79% of adults with FD associated with increased antral mast cell density who had previously failed to respond to acid reduction therapy [91,112]. H1 receptors affect smooth muscle contraction

cell stabilization.

pain, nausea, or vomiting specifically [97].

36%), but there was no additional benefit at 6 months [101].

gastric emptying or myoelectrical function [106].

### **4. Implications for Care**

#### **4.1. Evaluation**

The current approach to the pediatric FD patient has not been thoroughly studied. Based on existing small studies in children and large studies in adults, however, it appears reasonable to treat empirically with acid reducing medications and proceed with endoscopy with biopsies for non-responders. There may be value in evaluating mucosal biopsies for eosinophil density, particularly those obtained from the duodenum. A reasonable standard would be to consider antral eosinophil density >10/hpf and duodenal eosinophil density >20/hpf as abnormal. Despite current information implicating a role for mucosal mast cells, particularly in the antrum, it is less clear if there is value in determining mast cell density. The latter would require special immunohistochemical stains and the standard for normal is even less well defined than for eosinophils.

#### **4.2. Treatment**

Medications targeting mast cells or eosinophils could offer benefit by decreasing either cell density or activation. Such agents include corticosteroids and mast cell stabilizers. In addition, medications potentially could provide relief by targeting receptors for specific mediators once released by either cell. Although there is no current means for identifying the specific media‐ tors generating symptoms in a particular patient, antagonists are available for some mediators, such as histamine, cysteinyl leukotrienes, and TNF- α. Finally, other treatments exist that may provide relief by targeting other factors, such as CRH, that may play an important role in activation and/or maintenance of inflammation. Consistent with a biopsychosocial model, combining treatments that address inflammation from different perspectives ultimately should be most beneficial.

*Corticosteroids.* Corticosteroids have not been evaluated in treating FD, but are commonly used in the treatment of eosinophilic gastroenteritis, although there are no placebo-controlled studies evaluating efficacy. The extensive side effect profile represents a significant draw back in considering their use long term. Budesonide may represent a safer alternative. Budesonide is a synthetic corticosteroid with high topical activity and substantial first pass elimination, limiting systemic exposure [87]. The literature regarding budesonide and eosinophilic gastroenteritis is limited, consisting of only case reports where budesonide therapy has been reported to be effective against eosinophilia in the duodenum and jejunum [88-90].

*Mast Cell Stabilizers.* Mast cell stabilizers, including cromolyn and ketotifen, would represent an attractive potential therapy given data implicating mast cells in the generation of FD symptoms as previously discussed. These agents would have the potential to prevent release of a variety of mediators with downstream effects. In one open-label observational study of children with FD in association duodenal eosinophilia, resolution of pain was demonstrated with use of oral cromolyn in 89% of patients who had previously failed to respond to H2 and combined H1/H2 antagonism [91]. There have been no other pediatric or adult studies on the use of mast cell stabilizers in patients with FD. Benefit has been demonstrated in adults with IBS and may be related to blocking allergic or immunologic reactions to foods [92-94]. Ketotifen, specifically, has been shown to significantly decrease pain in adults with IBS and to increase the threshold for discomfort in patients with visceral hypersensitivity [95]. Ketotifen also acts as an H1 antagonist, so the effects may not be directly, or completely, related to mast cell stabilization.

exposure in adults with birch pollen allergy results in an increase in mucosal major basic protein positive eosinophils and IgE-bearing cells, as well as in FD symptoms, in the majority

The current approach to the pediatric FD patient has not been thoroughly studied. Based on existing small studies in children and large studies in adults, however, it appears reasonable to treat empirically with acid reducing medications and proceed with endoscopy with biopsies for non-responders. There may be value in evaluating mucosal biopsies for eosinophil density, particularly those obtained from the duodenum. A reasonable standard would be to consider antral eosinophil density >10/hpf and duodenal eosinophil density >20/hpf as abnormal. Despite current information implicating a role for mucosal mast cells, particularly in the antrum, it is less clear if there is value in determining mast cell density. The latter would require special immunohistochemical stains and the standard for normal is even less well defined than

Medications targeting mast cells or eosinophils could offer benefit by decreasing either cell density or activation. Such agents include corticosteroids and mast cell stabilizers. In addition, medications potentially could provide relief by targeting receptors for specific mediators once released by either cell. Although there is no current means for identifying the specific media‐ tors generating symptoms in a particular patient, antagonists are available for some mediators, such as histamine, cysteinyl leukotrienes, and TNF- α. Finally, other treatments exist that may provide relief by targeting other factors, such as CRH, that may play an important role in activation and/or maintenance of inflammation. Consistent with a biopsychosocial model, combining treatments that address inflammation from different perspectives ultimately

*Corticosteroids.* Corticosteroids have not been evaluated in treating FD, but are commonly used in the treatment of eosinophilic gastroenteritis, although there are no placebo-controlled studies evaluating efficacy. The extensive side effect profile represents a significant draw back in considering their use long term. Budesonide may represent a safer alternative. Budesonide is a synthetic corticosteroid with high topical activity and substantial first pass elimination, limiting systemic exposure [87]. The literature regarding budesonide and eosinophilic gastroenteritis is limited, consisting of only case reports where budesonide therapy has been

*Mast Cell Stabilizers.* Mast cell stabilizers, including cromolyn and ketotifen, would represent an attractive potential therapy given data implicating mast cells in the generation of FD symptoms as previously discussed. These agents would have the potential to prevent release

reported to be effective against eosinophilia in the duodenum and jejunum [88-90].

of patients [86]. Information in this area remains quite limited.

**4. Implications for Care**

38 Dyspepsia - Advances in Understanding and Management

**4.1. Evaluation**

for eosinophils.

**4.2. Treatment**

should be most beneficial.

*Antihistamine Medications and Proton Pump Inhibitors (PPI).* Acid reduction remains the most common treatment prescribed empirically by pediatric gastroenterologists for children with FD [9]. While there are numerous adult studies to support this practice, pediatric studies are limited. In children with chronic abdominal pain, famotidine (H2 recptor antagonist - H2RA) was superior to placebo in global improvement, with clear benefit to those with FD [96]. In a large pediatric study, omeperazole was shown to have a very modest advantage in the relief of all symptoms as compared to either famotidine or ranitidine; however, there was no significant difference between the three with regard to resolution of abdominal pain, epigastric pain, nausea, or vomiting specifically [97].

In adults, H2 antagonism has been shown to improve at least some symptoms associated with FD, including abdominal pain, indigestion, belching, and gastroesophageal reflux symptoms [98,99]. H2 antagonists have been shown to be superior to prokinetic medications and short term use of an anxiolytic [100,101]. A meta-analysis evaluating the use of PPIs in adult FD determined that they were superior to placebo in symptom reduction [102]. Studies of omeperazole, lansoprazole, and pantoprazole have demonstrated a modest superiority to placebo in symptom reduction which is limited to patients with ulcer-like or reflux-like FD [103-105]. Whether PPIs are superior to H2 antagonism is not completely clear. Omeperazole was found to have a modest increase in efficacy as compared to ranitidine at 4 weeks (51% vs. 36%), but there was no additional benefit at 6 months [101].

Given the response to PPIs, it would appear that at least some of the clinical improvement from H2 antagonism or PPIs is related directly to acid suppression. A significant portion of responders may derive benefit from treatment of overlap GERD, or possibly from peptic gastritis or duodenitis. Conversely, the benefit may be due to removing exposure to acid in patients with acid hypersensitivity. PPIs do not appear to have other benefits with regard to gastric emptying or myoelectrical function [106].

The benefit of H2 antagonism may be unrelated to acid reduction, at least in part. Histamine has direct gastric myogenic actions, modulates afferent enteric nerve excitability, and acts as an immunomodulating agent [53,107-111]. There may be additional benefit from H1 antago‐ nism, as well. Combining an H1 antagonist with an H2 antagonist has been reported to relieve symptoms in 50% of children with FD associated with duodenal eosinophilia and in 79% of adults with FD associated with increased antral mast cell density who had previously failed to respond to acid reduction therapy [91,112]. H1 receptors affect smooth muscle contraction and visceral sensitivity [53]. In addition, some benefit from H1 antagonism may be due to an anxiolytic effect [113].

eosinophilia [131]. Children receiving medication plus biofeedback-assisted relaxation training demonstrated better outcomes with regard to pain intensity, duration of pain episodes, and global clinical improvement as compared to children receiving medications

Inflammation and the Biopsychosocial Model in Pediatric Dyspepsia

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41

Current evidence implicates inflammation, particularly mast cells and eosinophils, in the pathophysiology of FD. FD in adults is associated with an increase in antral mast cell density and an increase in duodenal eosinophil density; elevated duodenal eosinophil density is frequently present in children with FD. Active degranulation of both cell types in children with FD suggests a pathophysiologic role. In children with FD, higher antral mast cell density is associated with gastric electromechanical dysfunction, psychologic dysfunction, and symp‐ toms consistent with the postprandial distress syndrome subtype of FD defined for adults. Duodenal eosinophil density appears associated with anxiety in children with FD, but relationships with electromechanical dysfunction appear less direct. Both mast cells and eosinophils may have key roles in conditions that are associated with FD, including anxiety, infection (including H. pylori), and allergy. Ultimately, inflammation appears to be of particular importance in FD. Inflammation interacts with a number of other factors and may

There may be efficacy in utilizing medications directed at inflammation, particularly mast cells and eosinophils. Most reports on treatment response consist of case series using H1/H2 antagonists, mast cell stabilizers, and anti-TNF-α. Consistent with a biopsychosocial model, some evidence exists to suggest that combining treatments targeting different components of the model that may influence inflammation can increase rates of symptom resolution in pediatric FD. There remains a need for placebo-controlled trials of the various medications and other treatments targeting inflammation which have been suggested to have efficacy, both alone and in thoughtful combination. Treatment for pediatric FD must continue to evolve if we are to prevent the significant downstream costs to the individual and society and, in this

even mediate the relationship between psychologic and physiologic factors.

and Craig A. Friesen2

1 Division of Developmental & Behavioral Sciences, The Children's Mercy Hospitals & Clin‐

2 Division of Gastroenterology, Hepatology, & Nutrition, The Children's Mercy Hospitals &

goal, inflammation appears an important primary target.

alone [131].

**5. Conclusions**

**Author details**

Jennifer Verrill Schurman1

ics, Kansas City, MO, USA

Clinics, Kansas City, MO, USA

*Cysteinyl Leukotriene (cysLT) Antagosists.* CysLTs are another potential therapeutic target. The pattern of eosinophil degranulation in pediatric FD is consistent with the release of major basic protein, which is known to enhance the synthesis of cysLT; cysLT, in turn, stimulates smooth muscle contraction and recruitment of eosinophils [114]. CysLTs have been shown to alter mast cell function. CysLTs can induce IL-5 and TNF-α production in primed mast cells, an effect blocked by cysLT inhibition [115]. Leukotrienes (LTs) have the potential to increase intestinal sensory nerve sensitivity during inflammation. CysLTs have been shown to stimulate enteric neurons and to have a pro-contactile effect on the esophagus, stomach, small intestine, colon, and gallbladder [116-123].

Montelukast, a cysLT receptor antagonist, was superior to placebo with regard to relief of pain in a double-blind, placebo-controlled, cross-over trial of children with FD associated with duodenal eosinophilia [124]. The response rate was 84% in patients with eosinophil densities between 20 and 29/hpf versus 42% receiving placebo. A second study confirmed this high response rate [125]. In the latter study, the short term clinical response did not result from a decrease in eosinophil density or activation. This suggests that the effect of montelukast may be mediated through an enteric nerve effect on motility or sensitivity, something that remains to be demonstrated.

*Anti-TNF-α.* TNF-α would represent another potential therapeutic target. Mast cells are an important source of intestinal mucosal TNF-α in humans. CysLTs induce TNF-α production. TNF-α can recruit and prolong survival of eosinophils, as well promote a Th2 response depending on other chemokines present in the microenvironment [126-128]. Serum TNF-α concentration prior to treatment correlates negatively with the subsequent clinical response to montelukast in pediatric FD associated with duodenal eosinophilia, indicating that TNF-α may represent an alternative pathway for symptom generation in these patients. Although there are no controlled studies, anti-TNF-α has been reported to be effective in a series of children with resistant eosinophil disease, including patients with FD [129].

*Biofeedback-Assisted Relaxation Training.* The biopsychosocial model and CRH physiology would suggest a potential role for CRH antagonism or for controlling CRH secretion by controlling anxiety and the stress response. There are no previous studies evaluating CRHantagonists in FD. Stress management would have the potential to control CRH secretion and, thereby, decrease inflammation. Biofeedback is a technique where individuals are trained to relieve physical or emotional symptoms using signals from their bodies that are displayed visually or aurally. It can be paired with relaxation training to yield biofeedback-assisted relaxation training. Biofeedback-assisted relaxation training may be considered as a solo therapy or, consistent with the biopsychosocial model, a stronger effect may occur in combin‐ ing relaxation with medications targeting biologic factors such as inflammation. The combi‐ nation of biofeedback-assisted relaxation training and fiber is superior to fiber alone in children with non-specific abdominal pain [130]. The effect of biofeedback-assisted relaxation training on inflammation has not been studied directly, but biofeedback-assisted relaxation training has been studied as adjunctive treatment in children with FD in association with duodenal eosinophilia [131]. Children receiving medication plus biofeedback-assisted relaxation training demonstrated better outcomes with regard to pain intensity, duration of pain episodes, and global clinical improvement as compared to children receiving medications alone [131].

### **5. Conclusions**

and visceral sensitivity [53]. In addition, some benefit from H1 antagonism may be due to an

*Cysteinyl Leukotriene (cysLT) Antagosists.* CysLTs are another potential therapeutic target. The pattern of eosinophil degranulation in pediatric FD is consistent with the release of major basic protein, which is known to enhance the synthesis of cysLT; cysLT, in turn, stimulates smooth muscle contraction and recruitment of eosinophils [114]. CysLTs have been shown to alter mast cell function. CysLTs can induce IL-5 and TNF-α production in primed mast cells, an effect blocked by cysLT inhibition [115]. Leukotrienes (LTs) have the potential to increase intestinal sensory nerve sensitivity during inflammation. CysLTs have been shown to stimulate enteric neurons and to have a pro-contactile effect on the esophagus, stomach, small intestine, colon,

Montelukast, a cysLT receptor antagonist, was superior to placebo with regard to relief of pain in a double-blind, placebo-controlled, cross-over trial of children with FD associated with duodenal eosinophilia [124]. The response rate was 84% in patients with eosinophil densities between 20 and 29/hpf versus 42% receiving placebo. A second study confirmed this high response rate [125]. In the latter study, the short term clinical response did not result from a decrease in eosinophil density or activation. This suggests that the effect of montelukast may be mediated through an enteric nerve effect on motility or sensitivity, something that remains

*Anti-TNF-α.* TNF-α would represent another potential therapeutic target. Mast cells are an important source of intestinal mucosal TNF-α in humans. CysLTs induce TNF-α production. TNF-α can recruit and prolong survival of eosinophils, as well promote a Th2 response depending on other chemokines present in the microenvironment [126-128]. Serum TNF-α concentration prior to treatment correlates negatively with the subsequent clinical response to montelukast in pediatric FD associated with duodenal eosinophilia, indicating that TNF-α may represent an alternative pathway for symptom generation in these patients. Although there are no controlled studies, anti-TNF-α has been reported to be effective in a series of children

*Biofeedback-Assisted Relaxation Training.* The biopsychosocial model and CRH physiology would suggest a potential role for CRH antagonism or for controlling CRH secretion by controlling anxiety and the stress response. There are no previous studies evaluating CRHantagonists in FD. Stress management would have the potential to control CRH secretion and, thereby, decrease inflammation. Biofeedback is a technique where individuals are trained to relieve physical or emotional symptoms using signals from their bodies that are displayed visually or aurally. It can be paired with relaxation training to yield biofeedback-assisted relaxation training. Biofeedback-assisted relaxation training may be considered as a solo therapy or, consistent with the biopsychosocial model, a stronger effect may occur in combin‐ ing relaxation with medications targeting biologic factors such as inflammation. The combi‐ nation of biofeedback-assisted relaxation training and fiber is superior to fiber alone in children with non-specific abdominal pain [130]. The effect of biofeedback-assisted relaxation training on inflammation has not been studied directly, but biofeedback-assisted relaxation training has been studied as adjunctive treatment in children with FD in association with duodenal

with resistant eosinophil disease, including patients with FD [129].

anxiolytic effect [113].

40 Dyspepsia - Advances in Understanding and Management

and gallbladder [116-123].

to be demonstrated.

Current evidence implicates inflammation, particularly mast cells and eosinophils, in the pathophysiology of FD. FD in adults is associated with an increase in antral mast cell density and an increase in duodenal eosinophil density; elevated duodenal eosinophil density is frequently present in children with FD. Active degranulation of both cell types in children with FD suggests a pathophysiologic role. In children with FD, higher antral mast cell density is associated with gastric electromechanical dysfunction, psychologic dysfunction, and symp‐ toms consistent with the postprandial distress syndrome subtype of FD defined for adults. Duodenal eosinophil density appears associated with anxiety in children with FD, but relationships with electromechanical dysfunction appear less direct. Both mast cells and eosinophils may have key roles in conditions that are associated with FD, including anxiety, infection (including H. pylori), and allergy. Ultimately, inflammation appears to be of particular importance in FD. Inflammation interacts with a number of other factors and may even mediate the relationship between psychologic and physiologic factors.

There may be efficacy in utilizing medications directed at inflammation, particularly mast cells and eosinophils. Most reports on treatment response consist of case series using H1/H2 antagonists, mast cell stabilizers, and anti-TNF-α. Consistent with a biopsychosocial model, some evidence exists to suggest that combining treatments targeting different components of the model that may influence inflammation can increase rates of symptom resolution in pediatric FD. There remains a need for placebo-controlled trials of the various medications and other treatments targeting inflammation which have been suggested to have efficacy, both alone and in thoughtful combination. Treatment for pediatric FD must continue to evolve if we are to prevent the significant downstream costs to the individual and society and, in this goal, inflammation appears an important primary target.

## **Author details**

Jennifer Verrill Schurman1 and Craig A. Friesen2

1 Division of Developmental & Behavioral Sciences, The Children's Mercy Hospitals & Clin‐ ics, Kansas City, MO, USA

2 Division of Gastroenterology, Hepatology, & Nutrition, The Children's Mercy Hospitals & Clinics, Kansas City, MO, USA

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**Chapter 4**

**Functional Dyspepsia and** *Helicobacter pylori* **Infection**

*Helicobacter pylori* (*H. pylori*) was first observed over 100 years ago yet its association with clinical diseases was not fully understanding until 1982 when Marshall and Warren identified and subsequently cultured the gastric bacterium. At their first attempt to culture the bacteria was not successful. Colonies finally grew when they accidentally left some culture plates over the Easter holiday. Dr. Barry Marshall subsequently inoculated himself with culture broth containing more than 1 billion organism to prove that this bacterium would cause peptic ulcers supporting Koch's postulate. He developed acute gastritis 1 week after the inoculation. *H. pylori* is a microaerophilic, spiral shaped, gram negative bacterium measuring about 3.5 microns in length and 0.5 microns in width. In vitro, this bacterium is a gradually growing organism that can be cultured on blood agar incubated at 37ºC in a microaerophilic condition (5% oxygen) for 4-7 days. The colony of this bacteria is tiny, uniformly sized and translucence

*H. pylori* is a Gram-negative, spiral shaped, bacterium about 3.5 microns long and 0.5 microns wide. (fig 2B). This bacterium uses its 2-7 unipolar flagella to escape the harsh luminal acidity by burrowing into the mucus layer that covers the gastric mucosa and so reside in close proximity to the more neutral pH of the epithelial cell surface of the gastric mucosa. It can convert from a highly motile, helical (spiral) shape to a more dormant coccoidal form, perhaps a survival benefit depending upon its local environment. Being microaerophilic, *H. pylori* requires oxygen. *H. pylori* is biochemically characterized as positive for catalase, oxidase, and urease. The urease enzyme, which has been located on the surface of the bacteria, is important and likely to be vital for bacterial survival and colonization in the highly acidity milieu of the stomach. Urease breaks down the luminal urea normally produced by the gastric mucosa,

> © 2013 Vilaichone and Mahachai; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

Ratha-korn Vilaichone and Varocha Mahachai

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/56652

**1. Introduction**

(fig 2A).

yielding carbon dioxide and ammonia.
