Benninga, Marc A

Bodewes, Frank A. J. A.

Damen, Gerard M

de Meij, Tim

Escher, Johanna C.

Houwen, RHJ

Kokke, FTM

Schweizer, J.J.

Smits, MJ

Van den Neucker, Anita M.

van der Zee, DC

van Lennep, Marinde

van Wijk, Michiel

Utrecht University Repository

AGAAbstractsSu2062Current Symptoms and Quality of Life in Patients Diagnosed With Achalasiaat a Pediatric Age (0-18yr)Marije J. Smits, Remy Vrijlandt, Marinde V. Lennep, Marc A. Benninga, Michiel P. vanWijkObjectives and study Achalasia is a rare chronic motility disorder with a big impact onQuality of Life (QoL), even in patients treated successfully. We aimed to prospectively assesscurrent symptoms and QoL in patients diagnosed with achalasia in childhood (0-18yr).Methods: Dutch children diagnosed with achalasia between 1990-2013 were contactedeither by telephone or by mail and were asked complete 4 questionnaires. Severity ofachalasia symptoms was assessed using the Eckardt score (suggestive for achalasia when>3) and the Reflux Disease Questionnaire (RDQ, suggestive for gastro esophageal refluxdisease (GERD) when ≥mild heartburn/regurgitation occurred ≥2 days a week). Diseasespecific QoL was assessed with the Achalasia DS-QoL (when <18yr at time of study, 0=worst 100=best) or HRQoL (≥18yr, 0= worst 100=best). General QoL was measured withthe KIDSCREEN-52 (<18yr, T-values over 10 domains relative to healthy norm, higher valuesuggests better QoL) or the SF-36 (≥18yr, 8 domains, 0= worst 100=best QoL per domain)and compared to healthy population norms. Results Seventy-two of 87 (83%) patients wereprospectively reached. Median (inter quartile range, IQR) time since last clinical follow upwas 1.7 years (0.5-6.9 years). Twenty (32%) patients were <18yr. Median Eckardt scorewas 3 (IQR 2-5) with 32 patients (44.5%) having a positive score. Median RDQ score was0.92 (0.10-1.65). GERD was reported relatively more frequent after initial treatment withHeller's myotomy compared to pneumodilation (PD, P=0.04) and median RDQ scores werehigher when initially treated with HM(F) (1.58 (0.96 - 2.71)) compared to ≥1x PD (0.58(0 - 1.58)), P=0.005. Eckardt and RDQ scores were similar for adult and paediatric patients(P=0.980 and P=0.454, respectively). Overall HR-QoL score was 61.3 (48.3-71.0). GeneralQoL (SF-36) in adults (n=52) was lower compared to healthy population norms for 7/8domains, with scores on ‘bodily pain' and ‘general health perceptions' domains (18-25 yr)significantly lower compared to age adjusted norm (P=0.018 and P<0.0001). SF-36 scoreswere similar for patients initially treated with PD or HM. Paediatric achalasia DS-QoL scorewas 17.5 (8-29). Self-reported QoL (KIDSCREEN-52, n=20) was similar to populationnorms. On 2 domains (School Environment, Financial Resources) achalasia patients evenscored better (P=0.038 and P=0.049). Conclusion Almost half of patients with achalasiadiagnosed <18yr still have symptoms suggestive of active disease. This observation stressesthe need for regular clinical follow-up and good transition to the adult gastroenterologist.Disease specific and general quality of life is lower for adult patients compared to paediatricpatients. This suggests that the impact of achalasia increases with duration of disease.Su2063Pediatric Achalasia: Diagnosis, Management and Follow-Up in the NetherlandsMarije J. Smits, Marinde V. Lennep, Marc A. Benninga, Roderick Houwen, Fredericus T.Kokke, David C. van der Zee, F.A.J.A. Bodewes, Anita Van den Neucker, Tim de Meij, J.J.Schweizer, Johanna C. Escher, Gerard Damen, Michiel P. van WijkIntroduction: Pediatric achalasia is a rare esophageal motility disorder. Data on prevalence,incidence, presenting symptoms, treatment success and follow up are scarce. Methods:Medical charts of registered Dutch pediatric achalasia patients (<18yrs) diagnosed betweenJanuary 1990 and December 2013, were retrospectively reviewed for data on presentingsymptoms, treatment, relapses and follow up. Results: In total, 87 Dutch pediatric achalasiapatients (mean age at diagnosis 11.44 +/- 3.43 years, 60% male) were included. Meanincidence was 0.10/100,000 per year (range, 0.03 and 0.21). No significant increase inincidence was observed over the study period. The prevalence of pediatric achalasia in TheNetherlands in 2012 was 0.90/100,000. Presenting symptoms included dysphagia (83%),regurgitation (69%), weight loss (44%) and chest pain (37%). Manometry was incorporatedin diagnostic evaluation in 86%. Eleven (14%) of patients were diagnosed based on bariumswallow and/or upper endoscopy without a documented manometry recording. Initial treat-ment was pneumatic balloon dilation (PD) in 68 (79%) patients and laparoscopic Heller'sMyotomy (HM) in 18 (21%) patients. In 4 patients, achalasia was diagnosed as part of TripleA syndrome. Complications of initital treatment occurred more after HM compared to PD(10/18 vs 1/68 P<0.0001, n=4 perforations). Similarly, complication rate was higher forHM after relapse treatments (20/22 vs 3/135, P<0.0001, n=7 perforations). However, thecumulative amount of complications of re-treatment(s) after initial PD is higher comparedto initial HM (n=21/229 vs n=13/24). Re-treatment was required more often after initial PD(n=59, 88%) compared to initial HM (n=4, 22%), P<0.0001. First re-treatment after initialPD was re-PD in 90% and HM in 10% of patients. After initial HM, first relapse treatmentwas PD in 50% and re-HM in 50%. Median (interquartile range) follow-up after initialtreatment was 3.9 years (1.4 - 10.2). Four years after initial treatment, 46% of patients <18years were lost to follow up. Conclusion: Incidence of pediatric achalasia in the Netherlandsis 0.10/100.000/year. Pneumatic balloon dilation is the predominant initial treatment ofchoice, however high relapse rates indicate the need for prospective studies comparinglaparoscopic Heller's Myotomy and pneumatic balloon dilation for pediatric achalasia. Manypatients are lost to follow up. Considering the long term risks of uncontrolled achalasia,there is a need for a standardized follow up regime to improve clinical outcome and transferto adult care.Su2064Brain Processing of Rectal Sensation in Children With Functional DefecationDisordersIlan J. Koppen, Suzanne M. Mugie, Maartje M. van den Berg, Paul Groot, Michiel B. deRuiter, Liesbeth Reneman, Aart Nederveen, Marc A. BenningaObjectives and Study: The pathophysiology underlying functional defecation disorders(FDD) such as functional constipation (FC) and functional nonretentive fecal incontinence(FNRFI) is poorly understood. Both groups often report fecal incontinence (FI) and a lackof sensation of urge to defecate, although only FC is characterized by low defecationS-588AGA Abstractsfrequency, hard stools and fecal impaction. Impaired brain processing of visceral sensorystimuli might play a role in the loss of rectal sensation in both disorders. The aim of thisstudy was to investigate the cerebral activity in response to rectal distension in childrenwith FNRFI and FC. Methods: 10 patients with FNRFI (8 boys, mean age 13.7 years, range12-17 years) and 15 patients with FC (8 boys, mean age 14.3 years, range 12-18 years)participated. Rectal barostat was performed prior to the fMRI scan. A stepwise pressure-controlled distension protocol was used to determine the pressure threshold for urge sensa-tion. During acquisition of blood oxygenation level-dependent (BOLD) fMRI, subjectsreceived 2 sessions of 5 stimulations consisting of repetitions of 30 seconds of rectal stimula-tion with previous defined threshold pressures, followed by 30 seconds of rest. Images wereacquired on a 3Tesla MRI scanner with an 8-channel SENSE head receive coil. A T2*-weightedecho planar imaging sequence was acquired with: TR/TE=3000/30 ms, slice thickness=3.0mm, voxel size=1.72 x 1.72 x 3 mm, with 40 axial slices covering the whole brain. Analyseswere performed using SPM8 in Matlab, thresholded at p<0.001. Cerebral activation wasdefined as BOLD increase during rectal distension and cerebral deactivation as BOLD decreaseduring rectal distension. Results: Defecation frequency per week was 5.2 for FNRFI patientsand 1.8 for FC patients. The mean number of FI episodes per week was 4.5 for FNRFIpatients and 3.3 for FC patients. FC patients required a mean pressure of 18 mmHg aboveminimal distension pressure (MDP) to provoke urge sensation, for FNRFI patients this was16 mmHg above MDP. During rectal distension, FC patients showed activation in the anteriorcingulate cortex, dorsolateral prefrontal cortex, inferior parietal lobule and putamen. Incontrast, FNRFI patients showed no activation of brain areas during rectal distension.FNRFI patients showed significant deactivation in the hippocampus, parahippocampal gyrus,fusiform gyrus, lingual gyrus, posterior parietal cortex and precentral gyrus. While nosignificant deactivation was detected in FC patients. Conclusion: Children with FNRFIdiffer significantly from children with FC with respect to neural processing of rectal urgesensation in several brain regions. This confirms that FNRFI is a different clinical entitycompared to FC.Su2065Antimicrobial Peptide Cathelicidin Inhibits Obesity in Diabetic Mice ViaInhibition of CD36 Fat Receptor ExpressionDeanna H. Tran, Diana Hoang-Ngoc Tran, S Anjani Mattai, Samantha Ho, Aristea Sideri,Kyriaki Bakirtzi, Iordanis Karagiannidis, David Q. Shih, Simon W. Beaven, Hon Wai KoonBackground: Obesity is a global epidemic. It increases an individual's risk of developingdiabetes, which is associated with debilitating complications. Despite medical advances, anew molecular target that can reflect the severity of obesity and diabetes in diagnosis or actas therapeutic agent is actively sought after. Cathelicidin is an antimicrobial peptide thatpossesses anti-inflammatory properties. Its expression is reduced in the skin of diabeticpatients, but the overall metabolic role of cathelicidin in obesity and diabetes is not under-stood. We hypothesize that cathelicidin expression correlates to obesity and modulates fatmass and hepatic steatosis. Materials and Methods: (Human study) Human serum samplesfrom non-diabetic and type II diabetic male and female patients of ages 18-70 were collectedfrom UCLA. Cathelicidin levels in the serum samples were measured by ELISA. (Animalstudy) c57BL6 male mice were fed with a high fat diet for 8 weeks. After a streptozotocininjection to induce diabetes, the mice were fed with the high fat diet for 3 more weeks.Some groups were injected with cathelicidin and CD36 overexpressing lentiviruses. Fat andlean mass were measured by an EchoMRI machine. Liver steatosis was observed throughMasson Trichrome staining. (In vitro study) Human mesenteric fat adipocytes were isolatedfrom patients undergoing gastrointestinal procedures. Mouse 3T3-L1 differentiated adipo-cytes were used. Results: (Human study) Serum cathelicidin protein levels are significantlyincreased in obese, (BMI >30) non-diabetic patients, compared to non-diabetic patients withnormal BMI values. Meanwhile serum cathelicidin protein levels are significantly lower inobese (BMI >30) type II diabetic patients than those of overweight (BMI 25-29.9) type IIdiabetic patients. (Animal study) Lentiviral overexpression of cathelicidin did not changethe body weight but did reduce hepatic steatosis and decrease fat mass with correspondingincreased lean mass of high fat diet-treated obese and streptozotocin-induced diabetic mice.Cathelicidin overexpression reduced mesenteric fat CD36 receptor mRNA expression andhepatic CD36 protein expression. Such changes were reversed by lentiviral CD36 overexpres-sion. (In vitro study) Exposure of human mesenteric fat adipocytes, mouse 3T3-L1 adipocytes,and human HepG2 hepatocytes to cathelicidin significantly inhibited CD36 mRNA expressionwith reduced fat accumulation. Overexpression of CD36 reversed cathelicidin dependentinhibition of fat accumulation. Summary: Altering levels of circulating cathelicidin mayindicate the development of obesity and diabetes. Cathelicidin inhibits the CD36 fat receptorand fat accumulation in adipocytes and hepatocytes, leading to reduction of fat mass andhepatic steatosis in vivo. Cathelicidin may be a novel therapeutic target against obesity indiabetic conditions.Su2066Immunoneutralization of Gastric Inhibitory Polypeptide (GIP) AttenuatesWeight Gain in MiceMichael O. Boylan, Patricia A. Glazebrook, Milos Tatalovic, M. M. WolfeBackground: Past studies have indicated that GIP functions as an efficiency factor byenhancing both nutrient uptake and storage. Thus, a reduction in GIP signaling shouldprevent the development of obesity in mice fed a high-fat diet (HFD). AIM: To develop asafe and effective biological agent with the capacity to neutralize circulating GIP. Methods:A hybridoma library was created by fusing splenic B cells isolated from mice immunizedwith a GIP fragment to mouse myeloma SP2/0 cells. Supernates from hybridomas werescreened for GIP-specific monoclonal antibodies (mAbs) using a specific ELISA. To identifyGIP-neutralizing mAbs, positive supernates were analyzed with a cell-based reporter assay.The mAbs were then purified using protein A agarose, and their effects on intraperitoneal(i.p.) glucose tolerance, oral glucose tolerance (OGT), and diet-induced weight gain wereevaluated. For i.p. glucose tolerance tests (IPGTTs), mAbs (30 mg/kg body weight [BW])were administered i.p. 60 min before i.p. administration of glucose (18 mmol/kg BW) andhuman GIP (2.5 nmol/kg BW). For OGT tests, mAbs (30 mg/kg BW) were injected i.p.

Pediatric Achalasia: Diagnosis, Management and Follow-Up in the Netherlands

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Pediatric Achalasia: Diagnosis, Management and Follow-Up in the Netherlands

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