Usefulness of Single Balloon Enteroscopy in Pediatric Crohn's Disease
1
remission rates, females with UC had a significantly higher rate of corticosteroid use. This finding, if confirmed, may be indicative of more severe disease in females necessitating their use, decreased responsiveness to alternative medications, avoidance of surgery, gender-based bias in management, or other factors. 1158 Changing Trends in Pharmacologic Therapy of Pediatric Crohn's Disease Sylvia Ofei, Ryan Carvalho, Jeffrey S. Hyams, Trudy Lerer, Marc Schaefer, Jason T. Machan, Christine R. Langton, David R. Mack, Jonathan Evans, Marian D. Pfefferkorn, Anne M. Griffiths, Anthony R. Otley, Athos Bousvaros, David J. Keljo, Marsha H. Kay, Maria Oliva-Hemker, Michael Kappelman, Shehzad A. Saeed, Neal S. LeLeiko, Michael C. Stephens, Andrew B. Grossman, James Markowitz, Joel R. Rosh Aim: To characterize trends over the last decade in the treatment of newly diagnosed pediatric Crohn's disease (CD). Methods: Data was obtained from the registry of the Pediatric IBD Collaborative Research Group. Newly diagnosed pediatric CD patients from 22 North Amer- ican centers are enrolled in this observational cohort study. Treatment is determined by the treating physician and not per protocol. In this study, patients with at least one year of follow up who were diagnosed with CD from September 2002-August 2004 (group I) and those diagnosed from September 2007-August 2009 (group II) were included. The use of prednisone, thiopurines (6-MP/AZA), methotrexate (MTX), and biologic therapy within 30 days and 1 year after diagnosis was analyzed. Results: 533 children with CD met inclusion criteria (295 = group I; 238 = group II). At diagnosis, 67% (N=186) of group I and 77% (N=181) of group II had moderate/severe disease activity (p=0.023). No statistical difference was noted for patient demographics including age, gender, and BMI. The table shows the rate of useage (exposure) of the studied medications by 30 days and one year after diagnosis. The use of systemic corticosteroids by 30 days was unchanged between groups. There was a significant increase in the use of methotrexate both at 30 days (group I 1.1% vs. group II 6.1%; p=.002) and by 1 year after diagnosis (group I 6.9% vs. group II 18.0%; p<.001) MTX use in boys (B) by 30d increased significantly (Group I =1.2%vs. Group II = 7.6%, p =.006); girls (G) showed a similar but not statistically significant trend (0.9% vs.4.1% p = NS). By 1 year MTX use in Group 2 was significantly increased in both boys and girls (B 7.5% vs.20.2%, p =.003; G 5.9% vs.14.8%p =.05) There was a significant increase in the use of biologic therapy within 1 year of diagnosis (group I 20.3% vs. group II 30.3%; p= 0.009). There was a notable decrease in the number of patients given 6MP/AZA (77.3 % in group I vs. 60.6% in group II, P<.001) within one year of diagnosis. This decrease was seen in both boys and girls (76.6% vs.58.6B, p=.001; 78.3% vs.63.3%G, p=.02) Conclusion: The use of systemic corticosteroids for induction of remission (use by 30 days) remained steady over the last decade. There was an increase between the two time periods studied in the rate of use of biologic therapy within one year of diagnosis. Both boys and girls showed less 6MP/AZA and more MTX use with this trend being strongest in boys with CD. Whether this reflects concern over the potential risk of lymphoma including Hepatosplenic T-Cell Lymphoma requires further study. 1159 Usefulness of Single Balloon Enteroscopy in Pediatric Crohn's Disease Giovanni Di Nardo, Salvatore Oliva, Federica Ferrari, Ginevra Lastrucci, Valentina Mariani, Claudia Alessandri, Paolo Rossi, Federica Nuti, Marina Aloi, Salvatore Cucchiara Background. Endoscopic visualization of the small bowel (SB) in Crohn's disease (CD), either with wireless capsule endoscopy (WCE) or with balloon assisted techniques is indicated in case of diagnostic uncertainty and when traditional upper gastrointestinal (GI) endoscopy does not account for the clinical activity of the disease. We describe the use of single-balloon enteroscopy (SBE) in consecutive pediatric patients with suspected or established CD. This investigative tool is rarely reported in children. Methods. Thirty patients (age range: 7-18 years) were prospectively investigated: 16 (group A) with suspected CD and unspecific conventional upper and lower GI endoscopy; 14 (group B) with longstanding CD, 13 of which with previous surgery and showing signs unaccountable by conventional endoscopy. All underwent magnetic resonance (MR) and group A also WCE. Results. In group A, SBE allowed to diagnose CD in 12, eosinophilic enteropathy in 2, unspecific abnormalities in 2. Of 10 patients, WCE was diagnostic of CD only in 3, but was suggestive of CD or unspecific in the remaining subjects. In group B, SBE revealed a moderate-to-severe disease activity in most patients, leading to introduction or change in biological therapy, with subsequent marked decrease in the PCDAI. In 1 and 3 patients of group A and group B, respectively, SBE allowed successful dilation of SB strictures. No complications occurred in all investigated subjects. Conclusions. SBE is a useful and safe endoscopic procedure to evaluate SB in pediatric subjects with suspected or established CD. It can allow to achieve a definite diagnosis of CD when the latter is uncertain and may redirect therapeutic choices in selected CD patients. S-197 AGA Abstracts 1160 Glucagon-Like Peptide 2 Induces Neuronal Proliferation via an Activation Dependent, but cAMP Independent Pathway Elaine de Heuvel, Laurie Wallace, Keith A. Sharkey, David L. Sigalet Aim: Glucagon-like peptide 2 (GLP-2) is an intestinal trophic factor which regulates mucosal morphology and integrity of the gut. We have previously shown that enteric neurons express the GLP-2 receptor and that GLP-2 increases the proliferation and the proportion of maturing neurons expressing vasoactive intestinal peptide (VIP) in culture. We hypothesized that these actions are mediated by neuronal activation and intracellular cAMP signaling. Methods: Primary cultures of adult enteric neurons were grown after isolation by microdissection from the colonic submucosal plexus of adult rats (n=25). After isolation, cells were plated onto coverslips and maintained with supplemented Neurobasal-A Media for 8 days. Cells were activated using GLP-2 (10 -8 M), veratridine (VER) (as a +ve control) or sham treated with NaCL for 24 hours, and effects measured by immunohistochemical identification of neurotransmitter expression. Effects on growth were measured after 8 days of treatment by quantifying cell numbers per high powered field. Cells were stained for HuC/D as a pan- neuronal marker, with co-staining for tyrosine hydroxylase (TH) or VIP. To measure cAMP synthesis, cultured neurons were exposed to GLP-2 or forskolin for 0, 10, 30 and 60 minutes after which cells were harvested, lysed, and cAMP content of the cytosol quantified by ELISA. Results: Activation of enteric neurons by 10 -8 M GLP-2 or 30μM veratridine signific- antly increased the % of TH-IR (GLP-2 : 21±6, VER: 16±3 vs controls: 7±2) and VIP-IR neurons (GLP-2 : 40±5, VER: 38±4 vs controls: 8±3) (mean±SD, ANOVA). All of these activations were inhibited by TTX (0.5μM, p<.01). Prolonged treatment with GLP-2 increased the number of HuC+ cells per HPF (GLP-2 : 208±15,vs controls: 100±7% of control). Forskolin (20μM) as an inducer of cAMP synthesis did not alter the proportion of TH-IR or VIP-IR neurons, but did increase cAMP in the cells, whereas GLP-2 had no effect on cAMP levels (p<.0001). Conclusions: Activation of enteric neurons by GLP-2 induces an increase in the proportion of VIP and TH expressing cells, and an increased number of total neurons. These actions are blocked by inhibition of neuronal activation. Unexpectedly, GLP- 2 does not induce cAMP synthesis in cells expressing the native receptor. This study shows that enteric neuronal precursors expressing the native GLP-2 receptor respond to GLP-2 stimulation with an activation dependent, but cAMP independent, alteration in phenotype and cell division rate. Further study is suggested to establish the relevance of this in the regulation of enteric neural plasticity In Vivo. 1161 Glucagon-Like Peptide-1 Modulates Neurally-Evoked Mucosal Chloride Secretion in the Guinea Pig Ileum In Vitro Sara Baldassano, Guo-Du Wang, Jackie D. Wood Background and Aims: Glucagon-like peptide-1 (GLP-1) is a gut-derived incretin hormone secreted from intestinal endocrine L-cells in response to food ingestion. The physiological effects of GLP-1 are multiple, including its ability to enhance satiety, reduce food intake and influence gastric reservoir and antral motor functions. Moreover, GLP-1 acts at the G protein-coupled receptor, GLP-1R, to stimulate insulin release from the pancreas. On the other hand, little is known about its role in the neural control of mucosal secretory physiology. Therefore, our aim was to investigate involvement of GLP-1 in control of intestinal mucosal secretory behavior by the enteric nervous system. Methods: Mucosal preparations from guinea pig ileum were mounted in Ussing flux chambers for measurement of short-current (Isc) as a surrogate for chloride secretion. ELISA was used to study the effects of GLR-1R activation on neurotransmitter release. Expression of GLP-1R in guinea pig ileum was assessed with immunohistochemistry. Results: Application of GLP-1 (0.1 nM -1 μM ) to either serosal or mucosal sides of the preparations evoked no change in baseline Isc. Transmural electrical field stimulation (EFS) evoked a typical biphasic increase in Isc with an initial rapidly rising phase followed by a sustained phase. GLP-1 (0.1 nM -1 μM) in the serosal side of the chamber produced a concentration-dependent reduction in the EFS-evoked biphasic responses. The action of GLP-1 was suppressed by exendin (9-39) (10 nM), a GLP-1 antagonist. To investigate putative neuronal mechanisms for the inhibitory action of GLP-1, we tested the effect of GLP-1 (0.1 nM -1 μM) in the presence of tetrodoxin, scopolamine, hexamethonium, or the peptide type 1 receptor (VPAC1) antagonist. Tetrodoxin (1μM) or scopolamine (1μM) abolished or reduced the inhibitory action of GLP-1 on EFS-evoked increases in Isc, while hexamethonium (100μM) or VPAC1 receptor antagonist (1 μM) had no effect. We measured acetylcholine (ACh) release after EFS, in the presence or absence of GLP-1. GLP-1 (10 nM) significantly reduced the amount of ACh release and the effect was greatly suppressed by pre-treatment with exendin (9-39) (10nM). In the submucosal plexus, GLP-1R-immunoreac- tivity (-IR) was expressed in 66.91% of choline acetyltransferase-IR neurons, 60.60% of neuropeptide Y-IR neurons, 54.8 % of somatostatin-IR neurons and 42.00% of vasoactive intestinal peptide-IR neurons. Conclusion: These data suggest that GLP-1R is expressed in guinea pig submucosal neurons and its activation leads to a decrease in neurally evoked epithelial chloride secretion through suppression of ACh release from secretomotor neurons. Acknowledgment: NIH 2R01DK037238-22A1, 1-year funding under the American Recovery and Reinvestment Act. 1162 Glucagon-Like Peptide-2 Induces Rapid Adaptation and Improves Function of the Remnant Intestine Following Intestinal Resection in Preterm Neonates Andreas Vegge, Thomas Thymann, Barbara Stoll, Pernille Lund, Niels Qvist, Bolette Hartmann, Jacob Jelsing, Palle B. Jeppesen, Jens J. Holst, Per T. Sangild Introduction: Short bowel syndrome (SBS) is a frequent complication after intestinal resection in preterm infants suffering from necrotizing enterocolitis (NEC). We hypothesized that exposure to elevated levels of the intestino-trophic hormone glucagon-like peptide-2 (GLP- 2) will improve intestinal structure and function in the period immediately following massive intestinal resection in preterm neonates. Methods: Preterm pigs (a well recognized model of infant NEC) were fed colostrum for 48 hours before undergoing resection of 50% of the AGA Abstracts
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Transcript of Usefulness of Single Balloon Enteroscopy in Pediatric Crohn's Disease
remission rates, females with UC had a significantly higher rate of corticosteroid use. Thisfinding, if confirmed, may be indicative of more severe disease in females necessitating theiruse, decreased responsiveness to alternative medications, avoidance of surgery, gender-basedbias in management, or other factors.
1158
Changing Trends in Pharmacologic Therapy of Pediatric Crohn's DiseaseSylvia Ofei, Ryan Carvalho, Jeffrey S. Hyams, Trudy Lerer, Marc Schaefer, Jason T.Machan, Christine R. Langton, David R. Mack, Jonathan Evans, Marian D. Pfefferkorn,Anne M. Griffiths, Anthony R. Otley, Athos Bousvaros, David J. Keljo, Marsha H. Kay,Maria Oliva-Hemker, Michael Kappelman, Shehzad A. Saeed, Neal S. LeLeiko, Michael C.Stephens, Andrew B. Grossman, James Markowitz, Joel R. Rosh
Aim: To characterize trends over the last decade in the treatment of newly diagnosed pediatricCrohn's disease (CD). Methods: Data was obtained from the registry of the Pediatric IBDCollaborative Research Group. Newly diagnosed pediatric CD patients from 22 North Amer-ican centers are enrolled in this observational cohort study. Treatment is determined by thetreating physician and not per protocol. In this study, patients with at least one year offollow up who were diagnosed with CD from September 2002-August 2004 (group I) andthose diagnosed from September 2007-August 2009 (group II) were included. The use ofprednisone, thiopurines (6-MP/AZA), methotrexate (MTX), and biologic therapy within 30days and 1 year after diagnosis was analyzed. Results: 533 children with CD met inclusioncriteria (295 = group I; 238 = group II). At diagnosis, 67% (N=186) of group I and 77%(N=181) of group II had moderate/severe disease activity (p=0.023). No statistical differencewas noted for patient demographics including age, gender, and BMI. The table shows therate of useage (exposure) of the studied medications by 30 days and one year after diagnosis.The use of systemic corticosteroids by 30 days was unchanged between groups. There wasa significant increase in the use of methotrexate both at 30 days (group I 1.1% vs. groupII 6.1%; p=.002) and by 1 year after diagnosis (group I 6.9% vs. group II 18.0%; p<.001)MTX use in boys (B) by 30d increased significantly (Group I =1.2%vs. Group II = 7.6%,p =.006); girls (G) showed a similar but not statistically significant trend (0.9% vs.4.1% p =NS). By 1 year MTX use in Group 2 was significantly increased in both boys and girls (B7.5% vs.20.2%, p =.003; G 5.9% vs.14.8%p =.05) There was a significant increase in theuse of biologic therapy within 1 year of diagnosis (group I 20.3% vs. group II 30.3%; p=0.009). There was a notable decrease in the number of patients given 6MP/AZA (77.3 %in group I vs. 60.6% in group II, P<.001) within one year of diagnosis. This decrease wasseen in both boys and girls (76.6% vs.58.6B, p=.001; 78.3% vs.63.3%G, p=.02) Conclusion:The use of systemic corticosteroids for induction of remission (use by 30 days) remainedsteady over the last decade. There was an increase between the two time periods studiedin the rate of use of biologic therapy within one year of diagnosis. Both boys and girlsshowed less 6MP/AZA and more MTX use with this trend being strongest in boys with CD.Whether this reflects concern over the potential risk of lymphoma including HepatosplenicT-Cell Lymphoma requires further study.
1159
Usefulness of Single Balloon Enteroscopy in Pediatric Crohn's DiseaseGiovanni Di Nardo, Salvatore Oliva, Federica Ferrari, Ginevra Lastrucci, ValentinaMariani, Claudia Alessandri, Paolo Rossi, Federica Nuti, Marina Aloi, Salvatore Cucchiara
Background. Endoscopic visualization of the small bowel (SB) in Crohn's disease (CD),either with wireless capsule endoscopy (WCE) or with balloon assisted techniques is indicatedin case of diagnostic uncertainty and when traditional upper gastrointestinal (GI) endoscopydoes not account for the clinical activity of the disease. We describe the use of single-balloonenteroscopy (SBE) in consecutive pediatric patients with suspected or established CD. Thisinvestigative tool is rarely reported in children. Methods. Thirty patients (age range: 7-18years) were prospectively investigated: 16 (group A) with suspected CD and unspecificconventional upper and lower GI endoscopy; 14 (group B) with longstanding CD, 13 ofwhich with previous surgery and showing signs unaccountable by conventional endoscopy.All underwent magnetic resonance (MR) and group A also WCE. Results. In group A, SBEallowed to diagnose CD in 12, eosinophilic enteropathy in 2, unspecific abnormalities in2. Of 10 patients, WCE was diagnostic of CD only in 3, but was suggestive of CD orunspecific in the remaining subjects. In group B, SBE revealed a moderate-to-severe diseaseactivity in most patients, leading to introduction or change in biological therapy, withsubsequent marked decrease in the PCDAI. In 1 and 3 patients of group A and group B,respectively, SBE allowed successful dilation of SB strictures. No complications occurred inall investigated subjects. Conclusions. SBE is a useful and safe endoscopic procedure toevaluate SB in pediatric subjects with suspected or established CD. It can allow to achievea definite diagnosis of CD when the latter is uncertain and may redirect therapeutic choicesin selected CD patients.
S-197 AGA Abstracts
1160
Glucagon-Like Peptide 2 Induces Neuronal Proliferation via an ActivationDependent, but cAMP Independent PathwayElaine de Heuvel, Laurie Wallace, Keith A. Sharkey, David L. Sigalet
Aim: Glucagon-like peptide 2 (GLP-2) is an intestinal trophic factor which regulates mucosalmorphology and integrity of the gut. We have previously shown that enteric neurons expressthe GLP-2 receptor and that GLP-2 increases the proliferation and the proportion of maturingneurons expressing vasoactive intestinal peptide (VIP) in culture. We hypothesized thatthese actions are mediated by neuronal activation and intracellular cAMP signaling. Methods:Primary cultures of adult enteric neurons were grown after isolation by microdissectionfrom the colonic submucosal plexus of adult rats (n=25). After isolation, cells were platedonto coverslips and maintained with supplemented Neurobasal-A Media for 8 days. Cellswere activated using GLP-2 (10-8M), veratridine (VER) (as a +ve control) or sham treatedwith NaCL for 24 hours, and effects measured by immunohistochemical identification ofneurotransmitter expression. Effects on growth were measured after 8 days of treatment byquantifying cell numbers per high powered field. Cells were stained for HuC/D as a pan-neuronal marker, with co-staining for tyrosine hydroxylase (TH) or VIP. To measure cAMPsynthesis, cultured neurons were exposed to GLP-2 or forskolin for 0, 10, 30 and 60 minutesafter which cells were harvested, lysed, and cAMP content of the cytosol quantified byELISA. Results: Activation of enteric neurons by 10-8M GLP-2 or 30μM veratridine signific-antly increased the % of TH-IR (GLP-2 : 21±6, VER: 16±3 vs controls: 7±2) and VIP-IRneurons (GLP-2 : 40±5, VER: 38±4 vs controls: 8±3) (mean±SD, ANOVA). All of theseactivations were inhibited by TTX (0.5μM, p<.01). Prolonged treatment with GLP-2 increasedthe number of HuC+ cells per HPF (GLP-2 : 208±15,vs controls: 100±7% of control).Forskolin (20μM) as an inducer of cAMP synthesis did not alter the proportion of TH-IRor VIP-IR neurons, but did increase cAMP in the cells, whereas GLP-2 had no effect oncAMP levels (p<.0001). Conclusions: Activation of enteric neurons by GLP-2 induces anincrease in the proportion of VIP and TH expressing cells, and an increased number of totalneurons. These actions are blocked by inhibition of neuronal activation. Unexpectedly, GLP-2 does not induce cAMP synthesis in cells expressing the native receptor. This study showsthat enteric neuronal precursors expressing the native GLP-2 receptor respond to GLP-2stimulation with an activation dependent, but cAMP independent, alteration in phenotypeand cell division rate. Further study is suggested to establish the relevance of this in theregulation of enteric neural plasticity In Vivo.
1161
Glucagon-Like Peptide-1 Modulates Neurally-Evoked Mucosal ChlorideSecretion in the Guinea Pig Ileum In VitroSara Baldassano, Guo-Du Wang, Jackie D. Wood
Background and Aims: Glucagon-like peptide-1 (GLP-1) is a gut-derived incretin hormonesecreted from intestinal endocrine L-cells in response to food ingestion. The physiologicaleffects of GLP-1 are multiple, including its ability to enhance satiety, reduce food intakeand influence gastric reservoir and antral motor functions. Moreover, GLP-1 acts at the Gprotein-coupled receptor, GLP-1R, to stimulate insulin release from the pancreas. On theother hand, little is known about its role in the neural control of mucosal secretory physiology.Therefore, our aim was to investigate involvement of GLP-1 in control of intestinal mucosalsecretory behavior by the enteric nervous system. Methods: Mucosal preparations fromguinea pig ileum were mounted in Ussing flux chambers for measurement of short-current(Isc) as a surrogate for chloride secretion. ELISA was used to study the effects of GLR-1Ractivation on neurotransmitter release. Expression of GLP-1R in guinea pig ileumwas assessedwith immunohistochemistry. Results: Application of GLP-1 (0.1 nM -1 μM ) to either serosalor mucosal sides of the preparations evoked no change in baseline Isc. Transmural electricalfield stimulation (EFS) evoked a typical biphasic increase in Isc with an initial rapidly risingphase followed by a sustained phase. GLP-1 (0.1 nM -1 μM) in the serosal side of the chamberproduced a concentration-dependent reduction in the EFS-evoked biphasic responses. Theaction of GLP-1was suppressed by exendin (9-39) (10 nM), a GLP-1 antagonist. To investigateputative neuronal mechanisms for the inhibitory action of GLP-1, we tested the effect ofGLP-1 (0.1 nM -1 μM) in the presence of tetrodoxin, scopolamine, hexamethonium, or thepeptide type 1 receptor (VPAC1) antagonist. Tetrodoxin (1μM) or scopolamine (1μM)abolished or reduced the inhibitory action of GLP-1 on EFS-evoked increases in Isc, whilehexamethonium (100μM) or VPAC1 receptor antagonist (1 μM) had no effect. We measuredacetylcholine (ACh) release after EFS, in the presence or absence of GLP-1. GLP-1 (10 nM)significantly reduced the amount of ACh release and the effect was greatly suppressed bypre-treatment with exendin (9-39) (10nM). In the submucosal plexus, GLP-1R-immunoreac-tivity (-IR) was expressed in 66.91% of choline acetyltransferase-IR neurons, 60.60% ofneuropeptide Y-IR neurons, 54.8 % of somatostatin-IR neurons and 42.00% of vasoactiveintestinal peptide-IR neurons. Conclusion: These data suggest that GLP-1R is expressed inguinea pig submucosal neurons and its activation leads to a decrease in neurally evokedepithelial chloride secretion through suppression of ACh release from secretomotor neurons.Acknowledgment: NIH 2R01DK037238-22A1, 1-year funding under the American Recoveryand Reinvestment Act.
1162
Glucagon-Like Peptide-2 Induces Rapid Adaptation and Improves Function ofthe Remnant Intestine Following Intestinal Resection in Preterm NeonatesAndreas Vegge, Thomas Thymann, Barbara Stoll, Pernille Lund, Niels Qvist, BoletteHartmann, Jacob Jelsing, Palle B. Jeppesen, Jens J. Holst, Per T. Sangild
Introduction: Short bowel syndrome (SBS) is a frequent complication after intestinal resectionin preterm infants suffering from necrotizing enterocolitis (NEC). We hypothesized thatexposure to elevated levels of the intestino-trophic hormone glucagon-like peptide-2 (GLP-2) will improve intestinal structure and function in the period immediately following massiveintestinal resection in preterm neonates. Methods: Preterm pigs (a well recognized modelof infant NEC) were fed colostrum for 48 hours before undergoing resection of 50% of the
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