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T2076 Spectrum of Gastrointestinal Problems in Children with Electron Transport Chain (ETC) Mitochondrial Disorders
of this study yields preliminary evidence in identifying biomarkers of undiagnosed abdominal pain in children and may further suggest candidate genes for evaluation in the future. Identification of clear biomarkers is needed and represents a significant advance in the evaluation of patients with abdominal pain symptoms. Given the limited sample size further investigation is warranted. Biomarker Expression in Inflammatory and Non inflammatory Groups
AGA Abstracts
glutamate accelerates GE and studied 20 formula fed healthy term infants 1-3 mths in a randomized,double blind,placebo controlled design. The study was approved by IRB and parental consent obtained to perform 2 breath tests while videotaping the subjects. Testmeal was a standard whey formula Nan1®(Nestle) at T1, enriched or not with 20 mg% sodium glutamate (MSG) at T2. Facial reactions were videotaped & event forms filled out. Placebo group:n=10 (8 girls), mean age:9,9+-1,7 wks at T1,mean gestational age 38,1+-1,0wks,birth weight 2844+-430,9g. MSG group:n=10 (6 girls), mean age: 8,4+-2,4 wks at T1,mean gestational age 39,2+-1,8 wks, birth weight 3449+-489,0g. T1/2 at T1& T2 in placebo group were 68,2+-25,0min and 64,1+-31,5min (student t test p=0,36). In the MSG group T1/2 was76,8+-45,6min at T1 and 62,4+-29,1 min after the addition of MSG at T2 (p=0,24). No SAE or any adverse events were reported. One way ANOVA analysis on test meal volume, burping, regurgitation, vomiting,defecation, flatus, stool consistency & crying showed no differences. Videotapes from 18 subjects (8 MSG group) were reviewed by 2 independent experienced speech therapists. Inter-observer reliability on 34 items was over 80% (Chi square analysis). Observation of hedonic, aversive or neutral features were similar at T1&T2 for both groups (Wilcoxon signed-rank test). The observers were unable to detect an ‘umami' reaction while the baby took the bottle containing MSG(5). In conclusion: in healthy infants less than 3 mths 0.02% MSG in standard whey formula does not alter GE. The addition of 0.02% MSG is well tolerated as no AE and no GI symptoms occurred. Observation of gustofacial reflexes reveals no hedonic or aversive reactions, suggesting that these young infants may not have tasted MSG. Whether this finding is relevant in relation to a physiological threshold remains to be demonstrated. (1)Veereman J Pediatr Gastroenterol Nutr 1996; 26: 111. (2)Van Den Driessche J Pediatr Gastroenterol Nutr 1999; 29: 46(3)Staelens S Clinical Nutrition 2008; 27: 264. (4)Zai H Gastroenterology 2006;130:S1736. (5)Steiner Neurosci Biobehav Rev 2001; 25: 53.
T2075 Effect of Medium Chain Triglyceride Enriched Formula On Gastroesophagel Reflux and Gastric Emptying Time in Term Infants Andrea Schwarzer, Stamatiki Kritas, Lisa McCall, Sibylle Koletzko, Geoffrey Davidson, Taher Omari Introduction: The relationship between delayed gastric emptying (GE) and increased gastroesophageal reflux (GER) in infants is unclear, nevertheless strategies that improve GE have been utilised in infants with GER disease. The aim of this study was to measure GER and GE in infants fed a medium chain triglyceride (MCT)-enriched formula which we hypothesized would empty more rapidly from the stomach than the standard long chain triglyceride (LCT)-containing infant formula. Methods: Ten infants (6 male, age 1.6-7.7 months and weight 4.6-6.7 kg) referred for investigation of GER were enrolled. Using a randomized, double-blind, crossover study design, infants were fed an MCT-enriched formula (Caprilon®, SHS International, MCT 75% of total fat) and a standard LCT containing formula (S-26® Newborn, Wyeth, MCT <10% of total fat) over two consecutive days. GER episodes were recorded using a pH-impedance probe which remained in place for 48h and GE of both formulas measured using the 13C-Na octanoate breath test performed on the morning of each study day. Symptoms of cough, regurgitation and irritability/crying were recorded using event markers. Results: The half GE time of standard infant formula was significantly faster than the MCT enriched formula median (IQR) GEt1/2 38.1 min (21.3, 63.9) vs 71.9 min (41.3, 164.6) (p=0.0002). Over the 24h of formula administration, there were no significant differences in esophageal acid exposure (median %time pH<4 5.5% vs 5.7% for standard vs MCT enriched respectively, p=0.9), the frequency of bolus GER episodes (median 32 vs 31 acid GER, p=0.5 and 44 vs 51 weakly acidic GER, p=0.2) or the frequency of symptom episodes (median 20 vs 23 cough, p=0.7, 8 vs 8 regurgitation, p=1.0 and 32 vs 46 crying, p=0.1) Conclusion: Contrary to our hypothesis, GE of MCT-enriched formula was significantly slower than standard LCT containing infant formula suggesting that components, other than the MCT content, may have a profound influence on mechanisms that regulate GE. Despite the marked difference in GE, no change in the rate of GER or typical GER symptoms was observed. This suggests that feed content-based modulation of GE has little impact on GER and it is therefore unlikely to produce a therapeutic benefit in infants with GER disease.
T2072 Dilated Esophageal Epithelial Intercellular Space in Children with NonErosive Reflux Disease Muhammad A. Altaf, Sara Szabo, Colin D. Rudolph, Paula E. North, Pippa M. Simpson, Manu R. Sood BACKGROUND: In a majority of children with gastroesophageal reflux symptoms, endoscopy is normal. In these children with non-erosive reflux disease (NERD), esophageal biopsy histological evaluation is unreliable and non-specific. Dilated intercellular spaces (ICS) and increase in mucosal permeability to acid has been proposed as a reason for heartburn symptoms in adults with NERD. AIMS: To compare the esophageal epithelial intercellular space in children with NERD and asymptomatic controls. METHODS: Esophageal mucosal biopsies were obtained in 39 children, aged 5-18 yrs. Symptoms in children with NERD included retrosternal pain, heart burn, dysphagia and epigastric pain. Children with neurological impairment, eosinophilic, fungal and viral esophagitis were excluded. There were no esophageal erosions on endoscopic evaluation in any of the subjects. All except 2 patients with NERD had failed empiric therapy with proton pump inhibitor prior to endoscopy. Children having endoscopy for reasons other than abdominal or retrosternal pain and inflammatory bowel disease were recruited as controls. The esophageal biopsies were reviewed by a pathologist who selected an area of the basal epithelial layer for electron microscopy (EM) examination. The pathologist was blinded to subject groups. EM photographs were processed at 2000x magnification and Image Pro Plus software was used to measure ICS. Ten different fields were examined and 10 transect lines were drawn at each field to get 100 measurements of ICS for each subject. We used independent student-t test to compare the ICS between the groups. RESULTS: There were 29 subjects in the NERD group with mean (SD) age of 10.8 yr (±2.8 yr) and 10 subjects in the control group with mean (SD) age of 10.2 yr (±3.1 yr). There were 18 females in the NERD and 7 in the control group. The mean ICS in NERD group was 1.17 ±0.2 μm and 0.92 ±0.13 μm in control group (p<0.001). In 3 subjects with erosive esophagitis not included in this abstract, the mean (SD) ICS was 1.23 ±0.16 μm. Light microscopy changes included basal cell hyperplasia in 7, papillary elongation in 8, papillary edema in 5 and inflammatory cell infiltration in 9 patients with NERD. No correlation was found between the light microscopic changes and ICS diameter on EM evaluation. CONCLUSIONS: Children with NERD have dilated ICS similar to what has previously been reported in adults. The cause of the dilated ICS is unclear. It may be due to acid, pepsin or bile induced damage to the esophageal mucosa. Dilation of the ICS may promote symptoms by allowing increased diffusion of acid into the esophageal mucosa with stimulation of the sensory nerves.
T2076 Spectrum of Gastrointestinal Problems in Children with Electron Transport Chain (ETC) Mitochondrial Disorders Jatinder Bhardwaj, Marc Rhoads, Mary Kay Koenig OBJECTIVE and BACKGROUND: Mitochondrial disorders are a recently described group of complex disorders that are rarely described in the literature. There are a multitude of presentations but the organs involved and the spectrum of severity remains undefined. Very few studies give insight into the nutritional and gastrointestinal aspects of the affected children. Patients with mitochondrial Electron transport chain (ETC) complex disorders 14 were reviewed for this study. HYPOTHESIS: We hypothesized that many children with ETC disorders would have gastric emptying delay (gastroparesis) and would require mechanical feeding, but that few would have intestinal failure. MATERIALS AND METHODS: Of a total of 80 patients in a cohort with known or suspected mitochondrial disorders, we identified 20 with proven deficiency of complexes 1-4 of the ETC, over an 18 month period. The mitochondrial disorder was diagnosed employing a complex deficit in biopsied muscle tissue, with corroborating laboratory and imaging studies. A retrospective chart review included nutritional status (age appropriate height, weight (and their percentiles) and the z score assessment), mode of feeding, gastric emptying and antroduodenal motility test results, whenever available. Gastrointestinal complaints were also recorded, including abdominal pain, vomiting, diarrhea, esophageal reflux and constipation. RESULTS: Out of 20 patients, 18 had GI symptoms, with constipation in 6, abdominal pain in 5 and reflux in 4. Eight had weight < 5 percentile for age and 2 had weight for height < 5 percentile. Age adjusted standardized z-scores for weight were less than -2.00 in 5 patients. Additionally 5/5 patients had abnormal gastric emptying scans, and 2 had abnormal antroduodenal motility studies showing neuropathic intestinal pseudoobstruction. Eight (40%) had significant feeding problems requiring formula infusion (4 requiring jejunal and 4 requiring gastrostomy feeding). Two had severe gastrointestinal dysmotility and required TPN for survival. Only 2 patients had no gastrointestinal problems. CONCLUSION: The majority of children with mitochondrial disorders have GI symptoms, and almost half of these have malnutrition requiring mechanical feeding. Half of the tube-fed children required transpyloric feeding because of gastroparesis.
T2074 Immunohistological Differences of Pediatric GI Mucosa in Patients with and Without Inflammation Presenting with Chronic Abdominal Pain. the Quest for Biomarkers Wendy A. Henderson, Ravi Shankar, Tara J. Taylor, Jessica Gill, David Kleiner, Nader N. Youssef Purpose: To compare the expression of interleukin-6(IL-6), mast cells, enterchromaffin cells (EC) and 5-HT in gastrointestinal mucosa in children with chronic abdominal pain with and without evidence of inflammatory gastrointestinal disease. Background: The gastrointestinal pathology in the spectrum of abdominal pain ranging from irritable bowel syndrome to inflammatory bowel disease is poorly understood in children. Methods: Formalin fixed paraffin-embedded gastrointestinal biopsy blocks from patients with inflammatory bowel disease and irritable bowel syndrome (non-inflammatory) (upper GI =15, lower GI =33) were sectioned and stained for IL-6, mast cells, EC cells, and 5-HT. All children had chronic abdominal pain. Biopsy phenotype was confirmed by a pathologist, blinded to patient information. Descriptive statistics and chi-square analysis were used to compare differences between the inflammatory and non-inflammatory groups. Results: The cohort (N=48), age 11.9±2.9 years, 54.2% females, 90% Caucasian, comprised of non-inflammatory (n=26) and inflammatory (n=22) phenotypes. There were significantly increased gastrointestinal mucosal immunoreactivity to IL-6 (p=.004) and EC cells (p=.035) in inflammatory genotypes compared to non-inflammatory. Additionally, we found significantly increased mast cells (p= .049) in non-inflammatory phenotypes compared to inflammatory. Conclusions: The findings
A-633
AGA Abstracts
AGA Abstracts
glutamate accelerates GE and studied 20 formula fed healthy term infants 1-3 mths in a randomized,double blind,placebo controlled design. The study was approved by IRB and parental consent obtained to perform 2 breath tests while videotaping the subjects. Testmeal was a standard whey formula Nan1®(Nestle) at T1, enriched or not with 20 mg% sodium glutamate (MSG) at T2. Facial reactions were videotaped & event forms filled out. Placebo group:n=10 (8 girls), mean age:9,9+-1,7 wks at T1,mean gestational age 38,1+-1,0wks,birth weight 2844+-430,9g. MSG group:n=10 (6 girls), mean age: 8,4+-2,4 wks at T1,mean gestational age 39,2+-1,8 wks, birth weight 3449+-489,0g. T1/2 at T1& T2 in placebo group were 68,2+-25,0min and 64,1+-31,5min (student t test p=0,36). In the MSG group T1/2 was76,8+-45,6min at T1 and 62,4+-29,1 min after the addition of MSG at T2 (p=0,24). No SAE or any adverse events were reported. One way ANOVA analysis on test meal volume, burping, regurgitation, vomiting,defecation, flatus, stool consistency & crying showed no differences. Videotapes from 18 subjects (8 MSG group) were reviewed by 2 independent experienced speech therapists. Inter-observer reliability on 34 items was over 80% (Chi square analysis). Observation of hedonic, aversive or neutral features were similar at T1&T2 for both groups (Wilcoxon signed-rank test). The observers were unable to detect an ‘umami' reaction while the baby took the bottle containing MSG(5). In conclusion: in healthy infants less than 3 mths 0.02% MSG in standard whey formula does not alter GE. The addition of 0.02% MSG is well tolerated as no AE and no GI symptoms occurred. Observation of gustofacial reflexes reveals no hedonic or aversive reactions, suggesting that these young infants may not have tasted MSG. Whether this finding is relevant in relation to a physiological threshold remains to be demonstrated. (1)Veereman J Pediatr Gastroenterol Nutr 1996; 26: 111. (2)Van Den Driessche J Pediatr Gastroenterol Nutr 1999; 29: 46(3)Staelens S Clinical Nutrition 2008; 27: 264. (4)Zai H Gastroenterology 2006;130:S1736. (5)Steiner Neurosci Biobehav Rev 2001; 25: 53.
T2075 Effect of Medium Chain Triglyceride Enriched Formula On Gastroesophagel Reflux and Gastric Emptying Time in Term Infants Andrea Schwarzer, Stamatiki Kritas, Lisa McCall, Sibylle Koletzko, Geoffrey Davidson, Taher Omari Introduction: The relationship between delayed gastric emptying (GE) and increased gastroesophageal reflux (GER) in infants is unclear, nevertheless strategies that improve GE have been utilised in infants with GER disease. The aim of this study was to measure GER and GE in infants fed a medium chain triglyceride (MCT)-enriched formula which we hypothesized would empty more rapidly from the stomach than the standard long chain triglyceride (LCT)-containing infant formula. Methods: Ten infants (6 male, age 1.6-7.7 months and weight 4.6-6.7 kg) referred for investigation of GER were enrolled. Using a randomized, double-blind, crossover study design, infants were fed an MCT-enriched formula (Caprilon®, SHS International, MCT 75% of total fat) and a standard LCT containing formula (S-26® Newborn, Wyeth, MCT <10% of total fat) over two consecutive days. GER episodes were recorded using a pH-impedance probe which remained in place for 48h and GE of both formulas measured using the 13C-Na octanoate breath test performed on the morning of each study day. Symptoms of cough, regurgitation and irritability/crying were recorded using event markers. Results: The half GE time of standard infant formula was significantly faster than the MCT enriched formula median (IQR) GEt1/2 38.1 min (21.3, 63.9) vs 71.9 min (41.3, 164.6) (p=0.0002). Over the 24h of formula administration, there were no significant differences in esophageal acid exposure (median %time pH<4 5.5% vs 5.7% for standard vs MCT enriched respectively, p=0.9), the frequency of bolus GER episodes (median 32 vs 31 acid GER, p=0.5 and 44 vs 51 weakly acidic GER, p=0.2) or the frequency of symptom episodes (median 20 vs 23 cough, p=0.7, 8 vs 8 regurgitation, p=1.0 and 32 vs 46 crying, p=0.1) Conclusion: Contrary to our hypothesis, GE of MCT-enriched formula was significantly slower than standard LCT containing infant formula suggesting that components, other than the MCT content, may have a profound influence on mechanisms that regulate GE. Despite the marked difference in GE, no change in the rate of GER or typical GER symptoms was observed. This suggests that feed content-based modulation of GE has little impact on GER and it is therefore unlikely to produce a therapeutic benefit in infants with GER disease.
T2072 Dilated Esophageal Epithelial Intercellular Space in Children with NonErosive Reflux Disease Muhammad A. Altaf, Sara Szabo, Colin D. Rudolph, Paula E. North, Pippa M. Simpson, Manu R. Sood BACKGROUND: In a majority of children with gastroesophageal reflux symptoms, endoscopy is normal. In these children with non-erosive reflux disease (NERD), esophageal biopsy histological evaluation is unreliable and non-specific. Dilated intercellular spaces (ICS) and increase in mucosal permeability to acid has been proposed as a reason for heartburn symptoms in adults with NERD. AIMS: To compare the esophageal epithelial intercellular space in children with NERD and asymptomatic controls. METHODS: Esophageal mucosal biopsies were obtained in 39 children, aged 5-18 yrs. Symptoms in children with NERD included retrosternal pain, heart burn, dysphagia and epigastric pain. Children with neurological impairment, eosinophilic, fungal and viral esophagitis were excluded. There were no esophageal erosions on endoscopic evaluation in any of the subjects. All except 2 patients with NERD had failed empiric therapy with proton pump inhibitor prior to endoscopy. Children having endoscopy for reasons other than abdominal or retrosternal pain and inflammatory bowel disease were recruited as controls. The esophageal biopsies were reviewed by a pathologist who selected an area of the basal epithelial layer for electron microscopy (EM) examination. The pathologist was blinded to subject groups. EM photographs were processed at 2000x magnification and Image Pro Plus software was used to measure ICS. Ten different fields were examined and 10 transect lines were drawn at each field to get 100 measurements of ICS for each subject. We used independent student-t test to compare the ICS between the groups. RESULTS: There were 29 subjects in the NERD group with mean (SD) age of 10.8 yr (±2.8 yr) and 10 subjects in the control group with mean (SD) age of 10.2 yr (±3.1 yr). There were 18 females in the NERD and 7 in the control group. The mean ICS in NERD group was 1.17 ±0.2 μm and 0.92 ±0.13 μm in control group (p<0.001). In 3 subjects with erosive esophagitis not included in this abstract, the mean (SD) ICS was 1.23 ±0.16 μm. Light microscopy changes included basal cell hyperplasia in 7, papillary elongation in 8, papillary edema in 5 and inflammatory cell infiltration in 9 patients with NERD. No correlation was found between the light microscopic changes and ICS diameter on EM evaluation. CONCLUSIONS: Children with NERD have dilated ICS similar to what has previously been reported in adults. The cause of the dilated ICS is unclear. It may be due to acid, pepsin or bile induced damage to the esophageal mucosa. Dilation of the ICS may promote symptoms by allowing increased diffusion of acid into the esophageal mucosa with stimulation of the sensory nerves.
T2076 Spectrum of Gastrointestinal Problems in Children with Electron Transport Chain (ETC) Mitochondrial Disorders Jatinder Bhardwaj, Marc Rhoads, Mary Kay Koenig OBJECTIVE and BACKGROUND: Mitochondrial disorders are a recently described group of complex disorders that are rarely described in the literature. There are a multitude of presentations but the organs involved and the spectrum of severity remains undefined. Very few studies give insight into the nutritional and gastrointestinal aspects of the affected children. Patients with mitochondrial Electron transport chain (ETC) complex disorders 14 were reviewed for this study. HYPOTHESIS: We hypothesized that many children with ETC disorders would have gastric emptying delay (gastroparesis) and would require mechanical feeding, but that few would have intestinal failure. MATERIALS AND METHODS: Of a total of 80 patients in a cohort with known or suspected mitochondrial disorders, we identified 20 with proven deficiency of complexes 1-4 of the ETC, over an 18 month period. The mitochondrial disorder was diagnosed employing a complex deficit in biopsied muscle tissue, with corroborating laboratory and imaging studies. A retrospective chart review included nutritional status (age appropriate height, weight (and their percentiles) and the z score assessment), mode of feeding, gastric emptying and antroduodenal motility test results, whenever available. Gastrointestinal complaints were also recorded, including abdominal pain, vomiting, diarrhea, esophageal reflux and constipation. RESULTS: Out of 20 patients, 18 had GI symptoms, with constipation in 6, abdominal pain in 5 and reflux in 4. Eight had weight < 5 percentile for age and 2 had weight for height < 5 percentile. Age adjusted standardized z-scores for weight were less than -2.00 in 5 patients. Additionally 5/5 patients had abnormal gastric emptying scans, and 2 had abnormal antroduodenal motility studies showing neuropathic intestinal pseudoobstruction. Eight (40%) had significant feeding problems requiring formula infusion (4 requiring jejunal and 4 requiring gastrostomy feeding). Two had severe gastrointestinal dysmotility and required TPN for survival. Only 2 patients had no gastrointestinal problems. CONCLUSION: The majority of children with mitochondrial disorders have GI symptoms, and almost half of these have malnutrition requiring mechanical feeding. Half of the tube-fed children required transpyloric feeding because of gastroparesis.
T2074 Immunohistological Differences of Pediatric GI Mucosa in Patients with and Without Inflammation Presenting with Chronic Abdominal Pain. the Quest for Biomarkers Wendy A. Henderson, Ravi Shankar, Tara J. Taylor, Jessica Gill, David Kleiner, Nader N. Youssef Purpose: To compare the expression of interleukin-6(IL-6), mast cells, enterchromaffin cells (EC) and 5-HT in gastrointestinal mucosa in children with chronic abdominal pain with and without evidence of inflammatory gastrointestinal disease. Background: The gastrointestinal pathology in the spectrum of abdominal pain ranging from irritable bowel syndrome to inflammatory bowel disease is poorly understood in children. Methods: Formalin fixed paraffin-embedded gastrointestinal biopsy blocks from patients with inflammatory bowel disease and irritable bowel syndrome (non-inflammatory) (upper GI =15, lower GI =33) were sectioned and stained for IL-6, mast cells, EC cells, and 5-HT. All children had chronic abdominal pain. Biopsy phenotype was confirmed by a pathologist, blinded to patient information. Descriptive statistics and chi-square analysis were used to compare differences between the inflammatory and non-inflammatory groups. Results: The cohort (N=48), age 11.9±2.9 years, 54.2% females, 90% Caucasian, comprised of non-inflammatory (n=26) and inflammatory (n=22) phenotypes. There were significantly increased gastrointestinal mucosal immunoreactivity to IL-6 (p=.004) and EC cells (p=.035) in inflammatory genotypes compared to non-inflammatory. Additionally, we found significantly increased mast cells (p= .049) in non-inflammatory phenotypes compared to inflammatory. Conclusions: The findings
A-633
AGA Abstracts