Mast cell activation and clinical outcome in pediatric cholelithiasis and biliary dyskinesia.

BACKGROUND: The current study was undertaken to determine the degree of activation of gallbladder mucosal mast cells, whether mast cell (MC) density or activation differ between patients with and without a positive clinical response to cholecystectomy, and whether either density or activation correlate with gallbladder emptying. RESULTS: Fifteen biliary dyskinesia (BD) and 13 symptomatic cholelithiasis (CL) patients undergoing cholecystectomy were prospectively enrolled. Gallbladder wall MC density (by immunohistochemistry) and activation (by electron microscopy) were determined. Clinical response was evaluated 30 days post-cholecystectomy on a 5-point Likert-type scale. A complete or nearly complete clinical response was seen in 100% of CL and in 87% of BD patients. The overall degranulation indices were 49.4 ± 18.7% for CL patients and 44.2 ± 16.8% for BD patients. Neither MC density nor activation correlated with the gallbladder ejection fraction. A complete clinical response was associated with lower epithelial MC density. CONCLUSION: Cholecystectomy is efficacious in relieving pain in both CL and BD patients. BD and CL are associated not only with increased MC density but a moderate to high degree of MC activation. A possible relationship between MC density and outcome for BD warrants further investigation.

The effect of a meal and water loading on heart rate variability in children with functional dyspepsia.

BACKGROUND: Alteration in autonomic function has been implicated as a possible pathophysiologic mechanism in functional dyspepsia (FD) in adults. METHODS: This was a two-part study. For the first part of the study, nine children with FD and 28 controls underwent heart rate variability (HRV) analysis for 30 min baseline and for 60 min following a test meal. For the second part of the study, eight children with FD and 26 controls underwent HRV analysis for 30 min baseline and for 60 min following rapid water loading. HRV analysis yielded measures for power in the high frequency (HF) band (vagal activity), power in the low frequency (LF) band (mainly sympathetic activity), and LF/HF (sympathovagal balance). RESULTS: HRV parameters did not differ between FD patients and controls in either baseline period or following water loading. Following the meal, HF was higher and LF and LF/HF were lower in FD patients as compared to controls. Baseline LF/HF was positively correlated with the water load volume in controls and negatively correlated with the water load volume in FD patients. CONCLUSION: FD in children is associated with an abnormal autonomic response best demonstrated following a meal. The relationship between baseline sympathovagal balance and water load volume in FD patients is distinctly different from the relationship in control children.

Diagnostic utility of the water load test in children with chronic abdominal pain.

OBJECTIVES: To compare water load test consumption patterns between children with functional gastrointestinal disorders and healthy control children. METHODS: Seventy-one children with recurrent abdominal pain completed the Behavioral Assessment Scale for Children-Self-Report Form and the Questionnaire on Pediatric Gastrointestinal Symptoms during their first visit to a pediatric gastroenterology clinic. Parent- and child-report functional gastrointestinal diagnoses were based on the Questionnaire on Pediatric Gastrointestinal Symptoms scoring criteria, whereas the clinician's diagnosis was based on clinical impression from history and physical examination completed at this visit. Twenty-six healthy children also participated as controls. Statistical comparisons involved Student t tests, whereas receiver operating characteristic curves estimated sensitivity/specificity of the water load test and linear regression determined the amount of variance accounted for in water volume consumption. RESULTS: Children with recurrent abdominal pain, particularly those with a diagnosis of functional dyspepsia, consumed less water than healthy children on the water load test. The water load test demonstrated good specificity, but poor sensitivity, in identifying patients with functional dyspepsia. Clinician evaluation provided the greatest differentiation between functional gastrointestinal disorders on the water load test. CONCLUSIONS: The water load test seems to be a poor diagnostic test for functional dyspepsia because of poor sensitivity. However, future research should examine whether the water load test is identifying a subset of children with functional dyspepsia experiencing a specific mechanosensory dysfunction and whether the water load test can predict clinical response to specific therapeutic interventions.

An evaluation of adult electrogastrography criteria in healthy children.

The current study examined whether electrogastrogram (EGG) recordings obtained from healthy children would be considered normal by standards established for adults and whether EGG patterns differ between children/adolescents and adults. Twenty-eight healthy children (54% females; ages 8-17 years; mean = 12.4 years) were evaluated and compared to 15 healthy adults evaluated previously. EGGs were recorded for 30 min in the fasting state and for 1 hr following a standard meal. For both pediatric and adult participants, there was a significant increase in both the dominant frequency and the dominant power from the pre- to the postprandial period (P < 0.001 for each). Using adult standards, the percentage normal slow waves was > 70% of the recording time in 96% of children in the fasting state and in 100% in the postprandial period. A postprandial power increase was seen in 89% of the children. In conclusion, our data indicate that American Motility Society (AMS) consensus adult criteria for a normal EGG are appropriate to apply to children and adolescents when utilizing methodology and meal challenge similar to those used to establish the adult norms.

Electrogastrography in pediatric functional dyspepsia: relationship to gastric emptying and symptom severity.

OBJECTIVES: The aims of this study were to determine the electrogastrographic patterns in children with functional dyspepsia and to investigate the correlations among electrogastrogram (EGG), gastric emptying (GE), and pain severity. METHODS: We studied 30 children (19 F; mean age 11.4 years) with functional dyspepsia. Electrogastrography was performed for 30 minutes fasting and for 1 hour during a GE test after ingestion of an isotope-labeled solid meal. The percent emptying was measured every 10 minutes for 1 hour after the meal. The dominant frequency of the EGG, the change in the postprandial peak power (deltaP), and percent dysrhythmia during each recording session were calculated. Specific symptoms were graded from 0 (none) to 4 (severe) by the patient. RESULTS: Of 30 patients, 14 (47%) had slow GE, and 15 (50%) had abnormal EGG (dysrhythmia > or = 30% or deltaP < 0). GE was slow in 73% of patients with an abnormal EGG but was slow in only 20% of patients with normal EGG (P = 0.009). GE was negatively correlated with fasting bradygastria (r = -0.383, P = 0.04). Abdominal pain was the most severe dyspeptic symptom, both during fasting and after the meal. Patients with an abnormal EGG had an increased mean pain severity score (3.5 +/- 0.2 vs. 2.5 +/- 0.2, P = 0.002). CONCLUSIONS: Sixty percent of functional dyspepsia subjects had either slow GE or abnormal EGG. Patients with abnormal EGG were more likely to have slow GE. EGG abnormalities were associated with more severe postprandial pain and should be considered a possible mechanism for dyspeptic symptoms.

Mucosal eosinophilia and response to H1/H2 antagonist and cromolyn therapy in pediatric dyspepsia.

Both eosinophils and mast cells have been implicated in the generation of abdominal pain. The purposes of this retrospective study were to determine the prevalence of duodenal eosinophilia in pediatric dyspepsia and to determine the clinical response rate of these patients to combined H1 and H2 receptor antagonist and mast cell stabilizer therapy. Fifty-nine patients (ages 3.5-17.7 years) with dyspepsia undergoing endoscopy were evaluated. All patients had a minimum of 2 forceps biopsies obtained from each of the esophagus, antrum, and duodenal bulb. Routine histologic evaluation was performed and duodenal biopsies were additionally evaluated to determine eosinophil counts. Patients with > 10 eosinophils/hpf were treated with ranitidine and hydroxyzine (H1/H2). Nonresponders were then treated with oral cromolyn. Patients were followed up and response recorded in an abdominal pain database and/or medical chart, which were reviewed for this study. Forty-two patients (71%) had duodenal eosinophilia. Twenty-one (50%) of these were responders to H1/H2. The response rate did not differ between patients with and without noneosinophilic esophagitis, gastritis, or duodenitis, respectively. Two patients were lost to follow-up and considered nonresponders. Seventeen of the remaining 19 (89%) were responders to cromolyn. Overall, the response rate to this treatment pathway was 90%. Duodenal eosinophilia is common in pediatric patients with dyspepsia. These patients appear to be clinically amenable to combination H1/H2 therapy and/or oral cromolyn.

Diagnosing functional abdominal pain with the Rome II criteria: parent, child, and clinician agreement.

OBJECTIVES: To compare the Rome II diagnoses made in children with recurrent abdominal pain by physicians and by parent and child responses on the Questionnaire on Pediatric Gastrointestinal Symptoms. Rates of diagnostic agreement and reasons for disagreement were examined to determine whether changes to the Rome II criteria are needed to improve diagnostic classification. METHODS: One hundred and forty-eight children and their parents or guardians completed the Questionnaire on Pediatric Gastrointestinal Symptoms during their first visit to a pediatric gastroenterology clinic. Parent- and child-report Rome II diagnoses were based on Questionnaire on Pediatric Gastrointestinal Symptoms scoring criteria, whereas the physician's Rome II diagnosis was based on clinical impression from history and physical examination completed at this visit. Statistical comparisons involved Pearson chi tests and Fisher exact tests. Kappa and weighted kappa measured agreement rates. RESULTS: Most children met the criteria for a functional gastrointestinal disorder based on the Rome II criteria. Functional dyspepsia was the most common diagnosis made by all three sources. The percentage of children classified as "no diagnosis" was small and was often a function of symptom duration (especially when diagnosis rested on the child self-report). Diagnostic agreement was fair to moderate. Diagnoses based on parent and child questionnaires agreed more often on functional dyspepsia than irritable bowel syndrome. Diagnostic disagreement was most likely to result from parent and child disagreement on defecation symptoms. CONCLUSIONS: The Rome II classification system shows promise for improving diagnosis, study and treatment of children with recurrent abdominal pain. However, further refinement and clarification of the Rome II criteria for symptom duration and frequency may be needed to improve diagnostic agreement.

Chronic gastritis is not associated with gastric dysrhythmia or delayed solid emptying in children with dyspepsia.

To determine if chronic gastritis (CG) is associated with gastric dysrhythmia or delayed solid emptying in children with dyspepsia, 22 patients (7-15 years of age) with dyspepsia and normal gross endoscopies were studied. Antral biopsies were evaluated for chronic gastritis, and immunohistology was performed to determine densities of CD3+, CD20+, CD25+, and tryptase-positive cells. Electrogastrography (EGG) and gastric scintiscan evaluation were performed within 2-7 days of endoscopy. CG and increased immune cell densities were not associated with altered gastric emptying. Mean CD3+ cell counts were positively correlated with the percentage normal slow waves, and patients with a normal EGG had increased CD3+ cell density. In children with dyspepsia, chronic antral inflammation in the setting of a normal gross endoscopy is not associated with EGG abnormalities or delayed solid emptying. Chronic gastritis and gastric dysrhythmia may simply be two separate and distinct mechanisms resulting in the clinical entity of dyspepsia.

Clinical efficacy and pharmacokinetics of montelukast in dyspeptic children with duodenal eosinophilia.

BACKGROUND: Montelukast, a competitive cysteinyl leucotriene-1 receptor antagonist, reduces airway eosinophilia in asthmatics. We evaluated the effect of this drug in children with eosinophilic duodenitis, defined histologically as duodenal mucosa with peak eosinophil count of more than 10 eosinophils/hpf. METHODS: Forty children and adolescents (6-18 yr) with dyspepsia and duodenal eosinophilia were enrolled in a double blind, randomized, placebo-controlled, cross-over study of monteleukast therapy. Subjects were randomized to receive either 10 mg montelukast or an identical placebo once daily and were evaluated on day 14 for symptomatic and biochemical responses. Subjects were also randomized to one of two blood sampling schemes to evaluate montelukast pharmacokinetics. RESULTS: Using a post treatment global pain assessment, a positive clinical response was observed in 62.1% of patients receiving montelukast compared with 32.4% on placebo (p < 0.02). Pain assessment score deteriorated in 45% of montelukast responders (5/11) after cross-over to placebo and improved in 62% (8/13) of placebo non-responders on cross-over to montelukast. In patients with peak duodenal eosinophil counts between 20-29/hpf (n=19), a positive pain assessment response was observed in 84% of patients receiving montelukast compared to 42% receiving placebo (p < 0.01). Response rate did not differ by age, gender or histologic findings at baseline. Pharmacokinetic analysis yielded parameter estimates for absorption rate constant (Ka), apparent volume of distribution (Vd/F) and elimination rate constant (Kel) of 0.42 h, 0.19 L/kg and 0.26 h, respectively. The relative extent of systemic drug exposure was comparable to that observed in previous pediatric investigations with similar weight-adjusted montelukast doses. Neither dose nor calculated drug exposure were associated with the level of post treatment pain assessment or the change in biochemical markers. CONCLUSIONS: These data suggest a beneficial role for montelukast in the treatment of pediatric patients with dyspepsia associated with duodenal eosinophilia.

Activated duodenal mucosal eosinophils in children with dyspepsia: a pilot transmission electron microscopic study.

BACKGROUND: Activated eosinophils can be identified by electron microscopy (EM) Previous studies have shown EM evidence of eosinophil activation in a variety of gastrointestinal conditions associated with inflammation. The purpose of this study was to evaluate the activation state by EM of duodenal mucosal eosinophils in children who presented with dyspepsia and to determine if eosinophils are activated in patients with normal eosinophil counts on routine histology. METHODS: Twenty patients (ages 7-15 years) with dyspepsia were evaluated. All had normal gross endoscopies and was excluded. Each patient had two endoscopic forceps biopsies taken from both the duodenal bulb (DB) and the second portion of the duodenum (DS) for routine histology to determine eosinophil counts. Two additional biopsies were taken from the adjacent mucosa of each site for EM evaluation. The eosinophil activation state was determined for each specimen and a degranulation index was calculated for DB specimens. RESULTS: On routine histology, peak eosinophil counts were greater than or equal to 20 per hpf in three patients, 11 to 19 per hpf in 12 patients, and less than or equal to 10 per hpf in 5 patients. All patients showed evidence of EM activation on DB specimens and 95% showed activation on DS specimens. The mean degranulation index was 50.5 + 12.0% with 65% of specimens revealing moderate (20 - 60%) degranulation and 30% of specimens revealing extensive (greater than 60%) degranulation. CONCLUSIONS: Eosinophils present in the duodenal mucosa of children with dyspepsia are activated in a significant proportion of patients, even in those with normal eosinophil counts. The degree of degranulation is similar to that seen in other conditions where eosinophils have a pathogenic role.