Cheryl E. Gariepy

PEDIATRIC CHRONIC PANCREATITIS IS ASSOCIATED WITH GENETIC RISK FACTORS AND SUBSTANTIAL DISEASE BURDEN

OBJECTIVE To determine the clinical presentation, diagnostic variables, risk factors, and disease burden in children with chronic pancreatitis. STUDY DESIGN We performed a cross-sectional study of data from the International Study Group of Pediatric Pancreatitis: In Search for a Cure, a registry of children with acute recurrent pancreatitis and chronic pancreatitis. Between-group differences were compared using Wilcoxon rank-sum test. RESULTS Among 170 subjects in the registry, 76 (45%) had chronic pancreatitis; 57% were female, 80% were white; median age at diagnosis was 9.9 years. Pancreatitis-predisposing genetic mutations were identified in 51 (67%) and obstructive risk factors in 25 (33%). Toxic/metabolic and autoimmune factors were uncommon. Imaging demonstrated ductal abnormalities and pancreatic atrophy more commonly than calcifications. Fifty-nine (77%) reported abdominal pain within the past year; pain was reported as constant and receiving narcotics in 28%. Children with chronic pancreatitis reported a median of 3 emergency department visits and 2 hospitalizations in the last year. Forty-seven subjects (70%) missed 1 day of school in the past month as the result of chronic pancreatitis; 26 (34%) missed 3 or more days. Children reporting constant pain were more likely to miss school (P = .002), visit the emergency department (P = .01), and experience hospitalizations (P = .03) compared with children with episodic pain. Thirty-three children (43%) underwent therapeutic endoscopic retrograde pancreatography; one or more pancreatic surgeries were performed in 30 (39%). CONCLUSIONS Chronic pancreatitis occurs at a young age with distinct clinical features. Genetic and obstructive risk factors are common, and disease burden is substantial.

Clinical management of motility disorders in children

We review the current clinical evaluation and management of the most common esophageal and gastrointestinal motility disorders in children based on the literature and our experience in a pediatric motility center in the United States. The disorders discussed include esophageal achalasia, pre- and post-fundoplication motility disorders, gastroparesis, motility disorders occurring after repair of congenital atresias, motility disorders associated with gastroschisis, chronic intestinal pseudo-obstruction, motility after intestinal transplantation, motility disorders after colonic resection for Hirschsprungs disease, chronic functional constipation, and motility disorders associated with imperforate anus.

Developmental disorders of the enteric nervous system: Genetic and molecular bases

Nervous control of digestive functions occurs at many levels: the central nervous system, the spinal cord, prevertebral sympathetic ganglia and the enteric nervous system (ENS). The ENS is a collection of neurons within the wall of the entire gastrointestinal tract, associated exocrine glands (salivary glands and the pancreas) and the gallbladder. It modulates and integrates motility (1), microcirculation (2), secretion (3) and immune/inflammatory responses (4). It consists of two major plexuses, the myenteric (Auerbach), the submucosal (Meissner) and associated neural elements connecting the ganglia and projecting to effector systems (muscles, interstitial cells of Cajal, glands, blood vessels and immune cells). The human ENS contains approximately as many neurons as the spinal cord (about 100 million) and is a specialized branch of the peripheral nervous system that can function independently from the central nervous system. The ENS is derived from specific axial levels of the neural crest (NC). Vagal, truncal and sacral NC cells colonize the gut. Vagaland truncal-derived ENS precursors follow a ventral migration pathway, enter the foregut mesenchyme and colonize the developing gut in a rostral-to-caudal progression. Truncal NC gives rise to ganglia in the esophagus and the proximal stomach, whereas the vagal NC gives rise to ganglia throughout the length of the gut. The entire vagal crest colonization process, from NC to rectum is complete by approximately 13 weeks gestation in humans. The colonization of the gut by sacral NC-derived cells and the contribution of these cells to the ENS in mammals are controversial. Some studies indicate that sacral NC cells emigrate from the neural plate early in development and form extraenteric pelvic ganglia. These cells are able to colonize the gut and contribute to the ENS, coincident with the arrival of vagal NC-derived cells (5–8). Other studies suggest that sacral NC cells enter the hindgut mesenchyme several days before the colonization of the hindgut by vagal NC-derived cells and contribute to the ENS (9–12). Whatever the case, only a minority of hindgut neurons seem to be sacral NC-derived, and genetic abnormalities interfering with complete colonization of the gut by vagal NC-derived cells usually leads to complete aganglionosis of the distal colon. By 24 weeks’ gestation, infants seem to have a full complement of ENS neurotransmitters, and at least partial ENS function is established. However, new enteric nerve cells continue to differentiate at least throughout the first couple of years of life, suggesting that the young ENS continues to develop and change. Normal ENS development requires survival of NCderived cells and their coordinated proliferation, movement and differentiation into neurons and glia. All of these processes are influenced by the microenvironment of the developing gut. Defects in the NC-derived cells themselves or alterations in the gut microenvironment may result in abnormal development of the ENS. This review focuses on those disorders of ENS development where a genetic and/or molecular basis is described.

Risk Factors Associated With Pediatric Acute Recurrent and Chronic Pancreatitis: Lessons From INSPPIRE

IMPORTANCE Pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) are poorly understood. OBJECTIVE To characterize and identify risk factors associated with ARP and CP in childhood. DESIGN, SETTING, AND PARTICIPANTS A multinational cross-sectional study of children with ARP or CP at the time of enrollment to the INSPPIRE (International Study Group of Pediatric Pancreatitis: In Search for a Cure) study at participant institutions of the INSPPIRE Consortium. From August 22, 2012, to February 8, 2015, 155 children with ARP and 146 with CP (aged ≤19 years) were enrolled. Their demographic and clinical information was entered into the REDCap (Research Electronic Data Capture) database at the 15 centers. Differences were analyzed using 2-sample t test or Wilcoxon rank sum test for continuous variables and Pearson χ2 test or Fisher exact test for categorical variables. Disease burden variables (pain variables, hospital/emergency department visits, missed school days) were compared using Wilcoxon rank sum test. MAIN OUTCOMES AND MEASURES Demographic characteristics, risk factors, abdominal pain, and disease burden. RESULTS A total of 301 children were enrolled (mean [SD] age, 11.9 [4.5] years; 172 [57%] female); 155 had ARP and 146 had CP. The majority of children with CP (123 of 146 [84%]) reported prior recurrent episodes of acute pancreatitis. Sex distribution was similar between the groups (57% female in both). Hispanic children were less likely to have CP than ARP (17% vs 28%, respectively; odds ratio [OR] = 0.51; 95% CI, 0.29-0.92; P = .02). At least 1 gene mutation in pancreatitis-related genes was found in 48% of patients with ARP vs 73% of patients with CP (P < .001). Children with PRSS1 or SPINK1 mutations were more likely to present with CP compared with ARP (PRSS1: OR = 4.20; 95% CI, 2.14-8.22; P < .001; and SPINK1: OR = 2.30; 95% CI, 1.03-5.13; P = .04). Obstructive risk factors did not differ between children with ARP or CP (33% in both the ARP and CP groups), but toxic/metabolic risk factors were more common in children with ARP (21% overall; 26% in the ARP group and 15% in the CP group; OR = 0.55; 95% CI, 0.31-0.99; P = .046). Pancreatitis-related abdominal pain was a major symptom in 81% of children with ARP or CP within the last year. The disease burden was greater in the CP group compared with the ARP group (more emergency department visits, hospitalizations, and medical, endoscopic, and surgical interventions). CONCLUSIONS AND RELEVANCE Genetic mutations are common in both ARP and CP. Ethnicity and mutations in PRSS1 or SPINK1 may influence the development of CP. The high disease burden in pediatric CP underscores the importance of identifying predisposing factors for progression of ARP to CP in children.

Postnatal intestinal engraftment of prospectively selected enteric neural crest stem cells in a rat model of Hirschsprung disease.

Background  Identification of neuronal progenitor/stem cells in the postnatal gut suggests the development of transplantation approaches to enteric nervous system (ENS) diseases. Many clinical applications would require engrafting large segments of postnatal gut in vivo. We investigated the ability of unselected gut cells vs selected enteric neural crest stem cells (eNCSCs) to engraft and differentiate in the postnatal gut in the Hirschsprung disease (HD, ednrbsl/sl) rat.

Design and Implementation of INSPPIRE

Objectives: Acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) are rare and poorly understood diseases in children. Better understanding of these disorders can only be accomplished via a multicenter, structured, data collection approach. Methods: The International Study Group of Pediatric Pancreatitis: In Search for a Cure (INSPPIRE) consortium was created to investigate the epidemiology, etiologies, pathogenesis, natural history, and outcomes of pediatric ARP and CP. Patient and physician questionnaires were developed to capture information on demographics, medical history, family and social history, medications, hospitalizations, risk factors, diagnostic evaluation, treatments, and outcome information. Information collected in paper questionnaires was then transferred into Research Electronic Data Capture (REDCap), tabulated, and analyzed. Results: The administrative structure of the INSPPIRE consortium was established, and National Institutes of Health funding was obtained. A total of 14 sites (10 in the United States, 2 in Canada, and 2 overseas) participated. Questionnaires were amended and updated as necessary, followed by changes made into the REDCap database. Between September 1, 2012 and August 31, 2013, a total of 194 children were enrolled into the study: 54% were girls, 82% were non-Hispanic, and 72% were whites. Conclusions: The INSPPIRE consortium demonstrates the feasibility of building a multicenter patient registry to study the rare pediatric diseases, ARP and CP. Analyses of collected data will provide a greater understanding of pediatric pancreatitis and create opportunities for therapeutic interventional studies that would not otherwise be possible without a multicenter approach.

Liver fibrosis in adults with Fontan palliation: Do common screening studies predict disease severity?

a Nationwide Childrens Hospital/The Ohio State University, Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, 700 Childrens Drive, Columbus, OH 43205, USA b Wexner Medical Center/The Ohio State University, Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, 370 West 9th Avenue, Columbus, OH 43210, USA c Nationwide Childrens Hospital/The Ohio State University, The Columbus Ohio Adult Congenital Heart Disease Program (COACH), The Heart Center, Division of Pediatric Cardiology, 700 Childrens Drive, Columbus, OH 43205, USA d Wexner Medical Center/The Ohio State University, Department of Internal Medicine, Division of Cardiovascular Medicine, 370 West 9th Avenue, Columbus, OH 43210, USA

Nutrition and Acute Pancreatitis: Review of the Literature and Pediatric Perspectives

Acute pancreatitis is being diagnosed more frequently in pediatrics and there is limited published research to guide management. In contrast, multiple prospective studies in the adult population have resulted in significant changes in the way the disease is managed, especially with regard to severe disease. The nutritional management of pediatric acute pancreatitis appears to lag behind current adult recommendations, likely resulting from a lack of awareness of the adult data, inherent differences between pediatric and adult pancreatitis, and the paucity of research performed in children. The purpose of this review is to examine the adult literature regarding the nutritional management of acute pancreatitis and discuss the possible relevance of this data in the pediatric population.

Direct costs of acute recurrent and chronic pancreatitis in children in the INSPPIRE registry

Objective: To estimate selected direct medical care costs of children with chronic pancreatitis (CP) and acute recurrent pancreatitis (ARP). Methods: We performed a cross-sectional study of data from International Study Group of Pediatric Pancreatitis: In Search for a Cure (INSPPIRE), a multinational registry of children with ARP or CP. We determined health care utilization and estimated costs of hospitalizations, surgical and endoscopic procedures, and medications in our study population. Health care utilization data were obtained from all subjects enrolled in the study, and costs were calculated using national United States costs. Results: We included 224 subjects (median age 12.7 years), 42% of whom had CP. Mean number of hospitalizations, including for surgery and endoscopic retrograde cholangiopancreatography, was 2.3 per person per year, costing an estimated average

The Causal Evaluation of Acute Recurrent and Chronic Pancreatitis in Children: Consensus From the INSPPIRE Group

38,755 per person per year. Including outpatient medications, estimated total mean cost was