Faculty Bibliography

Inflammatory bowel disease (IBD) is an idiopathic disease thought to be caused by a dysregulated immune response to host intestinal microflora. The role of genetic factors is indicated by familial clustering of cases and higher incidence in monozygotic twins. An interaction between genetic and environmental factors is thought to play a role in the pathogenesis of these disorders. Changes in diet, antibiotic use and intestinal colonization have likely contributed to increased prevalence of inflammatory bowel disease in the past century. Environmental factors or infections are thought to alter the barrier function of the epithelium, leading to loss of immune tolerance to intestinal antigens. This loss of tolerance activates dendritic cells, triggering their transport to mesenteric lymph nodes, where they promote differentiation of naive T cells to TH-1, TH-2, TH-17 cells or T regulatory cells. Production of proinflammatory cytokines and chemokines then follows. Circulating effector and regulatory cells enter the intestine through a highly selective mechanism that involves interaction with the vascular endothelium, diapedesis through the vessel wall and migration to the lamina propria. There are several genes implicated in IBD. Mutations in certain genes can cause defective down regulation of the innate immune response, ineffective clearance of intracellular bacteria and proliferation of both luminal and mucosal-adherent commensal bacteria. IBD is a chronic relapsing inflammatory condition that is immune mediated. Results from research in animal models, human genetics, basic science and clinical trials provide evidence that it is heterogeneous, characterized by various genetic abnormalities, leading to a dysregulated and overly aggressive T cell response to commensal enteric bacteria. Different genetic abnormalities can be characterized as causing defects in mucosal barrier function, immunoregulation or bacterial clearance. Advances in our understanding of the interplay between components of innate and adaptive immune response will be central to future progress.

AIH is characterized by chronic inflammation of the liver, interface hepatitis, hypergammaglobulinemia, and production of autoantibodies. Based on the nature of the serum autoantibodies, two types of AIH are recognized: type 1 (AIH-1), positive for ANA and/or anti-smooth muscle antibody, and type 2 (AIH-2), defined by the positivity for anti-liver kidney microsomal type 1 antibody or for anti-liver cytosol type 1 antibody. AIH demonstrates a female preponderance with the female-to-male ratio of 4:1 in AIH-1 and 10:1 in AIH-2. Several genes confer susceptibility to AIH and influence clinical manifestation, response to treatment, and overall prognosis. Most are located within the human leukocyte antigen (HLA) region, which is involved in the presentation of antigenic peptides to T cells and thus in the initiation of adaptive immune responses. The strongest associations are found within the HLA-DRB1 locus. In patients with increased genetic susceptibility to AIH, immune responses to liver autoantigens could be triggered by molecular mimicry. Because of molecular mimicry, different environmental agents, drugs, and viruses might produce AIH. In AIH, T cells are numerically and functionally impaired, permitting the perpetuation of effector immune responses with ensuing persistent liver destruction. AIH is rare but highly treatable inflammatory condition of the liver. Subclinical and asymptomatic disease is common. AIH therefore needs to be considered in the differential diagnosis of all patients with elevated liver enzymes. Clinical response to immunosuppressive therapy is characteristic and supports the diagnosis.

Eosinophilic esophagitis (EoE) represents a chronic, immune/antigen-mediated esophageal inflammatory disease associated with esophageal dysfunction resulting from severe inflammation. The incidence and prevalence of EoE have been increasing in the past decade; however, the reason for this increase is unclear. There is a chronic inflammatory infiltrate that is present in EoE which promotes inflammation, symptoms, and dysfunction. In addition to eosinophils, interleukin (IL)-5 expressing T cells, B cells, eotaxin-3, IL-13, and IgE-bearing mast cells are present in EoE and are thought to contribute to the disease process. Eosinophils are pro-inflammatory and modulate multiple aspects of the immune response. Eosinophils produce a wide range of inflammatory cytokines, chemokines, granulocyte-monocyte colony-stimulating factors, and tumor necrosis factors. Once activated, eosinophils release granule components, which are toxic to a variety of tissues. Transforming growth factor beta1 is a pro-fibrotic molecule produced by epithelial and inflammatory cells, is overexpressed in EoE, and plays a role in esophageal remodeling. Fibrous remodeling in EoE could be associated with symptoms of dysphagia and may explain and predict future esophageal strictures and dysmotility. EoE is a complex disease involving multiple activation pathways, a large number of cells, and various inflammatory molecules. It, along with other atopic disease, is becoming increasingly prevalent and has an important genetic load and may represent as an immunological tolerance disorder of the GI tract.

The intestinal epithelium plays an active immunologic role in preventing the uptake of foreign antigens. Additionally, the intestinal mucosa is an active site for immune suppression through the development of oral tolerance. Dysfunction of any aspect of the intestinal barrier, such as impairment of intestinal tight junctions, immunologic dysregulation or decreased oral tolerance will lead to overstimulation of the immune system upon exposure to foreign antigens and subsequent unregulated chronic intestinal inflammation. This persistent inflammatory activity may potentially predispose the patient to the development of intestinal autoimmune disease. An active immune response possibly directed against intestinal flora has been postulated to be the underlying etiology for inflammatory bowel disease. Failure of oral tolerance is thought predispose a patient to celiac disease and possibly eosinophilic esophagitis. Additionally, an active immunologic response to absorbed antigen may be the underlying etiology for the development of autoimmune liver disease.

Non-synonymous mutations affecting both alleles of PCSK1 (proprotein convertase 1/3) are associated with obesity and impaired prohormone processing. We report a proband who was compound heterozygous for a maternally inherited frameshift mutation and a paternally inherited 474kb deletion that encompasses PCSK1, representing a novel genetic mechanism underlying this phenotype. Although pro-vasopressin is not a known physiological substrate of PCSK1, the development of central diabetes insipidus in this proband suggests that PCSK1 deficiency can be associated with impaired osmoregulation.

OBJECTIVES/HYPOTHESIS: Extraesophageal manifestations of gastroesophageal reflux (GER) include such signs and symptoms as cough, asthma, respiratory symptoms, hoarseness, and laryngoscopic findings. We reviewed the role of MII-pH monitoring in the evaluation of these findings in children to determine whether there is an association with pathological acid or nonacid reflux. STUDY DESIGN: Retrospective chart review. METHODS: We retrospectively reviewed charts from patients who underwent MII-pH. Inclusion criteria were ages 0 to 21 years with extraesophageal signs or symptom. Data were analyzed using dedicated software and manually reviewed. Reflux composite score was calculated based on DeMeester criteria. Impedance scores were calculated based on adult criteria. Symptom indexes were calculated. RESULTS: A total of 119 MII-pH studies were performed. Of those, 63 studies met inclusion criteria. There were 39 males and 24 females with mean age 7.32 +/- 4.1 years. The most common indication was cough. Six children had pathological GER based on DeMeester score. Using impedance criteria, only 10 of 63 patients had an abnormal evaluation (mean reflux episodes 107). Seven patients (15.2%) were found to have an association between symptom and reflux event. CONCLUSIONS: No association was demonstrated between the extraesophageal signs and symptoms and pathological GER based on DeMeester score or the number of reflux events based on impedance testing.

BACKGROUND: Current treatments of eosinophilic esophagitis (EoE), including restrictive diets or glucocorticoids, provide only transient improvement. Proton pump inhibitor (PPI) use in EoE does not lead to histologic improvement; however, the long-term use of PPI on symptoms and prevention of complications has not been evaluated. OBJECTIVE: To evaluate the use of PPI as maintenance therapy in children with EoE. METHODS: Eosinophilic esophagitis was diagnosed based on initial endoscopic biopsies and persistent eosinophilic inflammation despite PPI therapy. Inclusion criteria included diagnosis of EoE and PPI use as primary maintenance treatment. Patients were excluded if they were treated with dietary or glucocorticoid therapy. Histologic evidence of inflammation as well as degree of subepithelial fibrosis at presentation was compared with most recent biopsies while receiving PPI therapy. RESULTS: Thirty-eight patients (30 males and 8 females; average age 6.7 +/- 5.4 years) fulfilled inclusion criteria. Duration of follow-up was 3.0 +/- 2.4 years. At presentation, vomiting was significantly more frequent in the younger patients, whereas dysphagia occurred more frequently in the older patients. At follow-up, 26 patients were asymptomatic, and the remaining 12 patients' symptoms were significantly improved. No complications of stricture or food impaction were seen. Significant eosinophilic inflammation persisted in 28 patients. No difference in degree of subepithelial fibrosis at diagnosis compared with most recent biopsies. The z-scores of the treated EoE patients significantly improved. CONCLUSION: Patients with EoE treated with PPIs show an improvement in symptoms and z-scores despite persistent eosinophilic inflammation. PPI treatment may be useful maintenance therapy in children with EoE.

BACKGROUND AND AIMS: Increasing use of diagnostic radiography has led to concern about the malignant potential of ionizing radiation. We aimed to quantify the cumulative effective dose (CED) from diagnostic medical imaging in children with inflammatory bowel disease (IBD) and to identify which children are at greatest risk for high amounts of image-related radiation exposure. PATIENTS AND METHODS: A retrospective chart review of pediatric IBD patients seen between January 1 and May 30, 2008 was conducted. The effective dose of radiation received from all of the radiology tests performed during the course of each patient's treatment was estimated using typical effective doses and our institution's computed tomography dose index. A CED >/=50 mSv was considered high. RESULTS: Complete records were available for 257 of 372 screened subjects. One hundred seventy-one had Crohn disease (CD) and 86 had ulcerative colitis (UC). The mean CED was 17.56 +/- 15.91 mSv and was greater for children with CD than for those with UC (20.5 +/- 17.5 vs 11.7 +/- 9.9 mSv, P < 0.0001). Fifteen children (5.8%) had a CED >/=50 mSv, including 14 of 171 (8.2%) with CD and 1 of 86 (1.2%) with UC (P = 0.02). In children with CD, factors associated with high CED per multivariate analysis were any IBD-related surgery (odds ratio 42, 95% confidence interval 8-223, P < 0.0001) and platelet count (odds ratio 16, 95% confidence interval 1.5-175, P = 0.02). CONCLUSIONS: Although all doses of ionizing radiation have some malignancy-inducing potential, a small but important percentage of children with IBD are exposed to particularly high doses of ionizing radiation from diagnostic tests and procedures. Physicians caring for such patients must seek to limit radiation exposure whenever possible to lessen the lifetime risk of malignancy.

BACKGROUND: Poor weight gain and growth can be caused by many medical, nutritional, behavioral, and psychological factors. Crohn disease is one of the more common gastrointestinal etiologies associated with growth failure. The aim of this study is to determine the role of capsule endoscopy (CE) in the evaluation of older children and adolescents who were referred to a pediatric gastroenterology service for a chief complaint of unexplained growth failure. PATIENTS AND METHODS: We retrospectively reviewed the records of children with growth failure undergoing CE between August 2002 and November 2005. Height and weight (expressed as z scores) were recorded at least 6 months before study, at the time of the study, and at least 6 months post study. All of the patients had celiac disease and Crohn disease excluded using standard biochemical, radiologic, endoscopic, and histologic assessment. RESULTS: Seven children (4 males and 3 females) were included in the study-mean age 11.7+/-3.6 years. Indications for CE were growth failure associated with abdominal pain (3 patients), diarrhea and apthous ulcers (2 patients), delayed puberty (1 patient), or a family history of Crohn disease (1 patient). The mean z score for weight at the time of the study was 2.10+/-1.0 and for height was 1.50+/-0.7 All 7 children had normal small bowel series performed before the CE. All had both endoscopically and histologically normal esophagogastroduodenoscopy and colonoscopy. In 4 of 7 patients, multiple small bowel apthous ulcerations consistent with Crohn disease were identified by CE. All 4 patients who had abnormal CE were treated and started gaining weight. The mean z score for weight after 6 months of treatment was 1.35+/-1.2 and for height was 0.50+/-1.7. The mean z score for weight after treatment was significantly improved compared with the mean z score at diagnosis (P<0.05). CONCLUSIONS: In our study, 4 of the 7 older children and adolescents with unexplained growth failure and normal small bowel series were found to have Crohn disease involving the small intestine. In addition, we were able to show the improvement on the mean z score for weight after treatment of small bowel Crohn disease was instituted.