Copyright
©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
Non-responsive celiac disease in children on a gluten free diet
Gopal Veeraraghavan, Amelie Therrien, Maya Degroote, Allison McKeown, Paul D Mitchell, Jocelyn A Silvester, Daniel A Leffler, Alan M Leichtner, Ciaran P Kelly, Dascha C Weir
Gopal Veeraraghavan, Division of Gastro-enterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115, United States
Gopal Veeraraghavan, Amelie Therrien, Jocelyn A Silvester, Daniel A Leffler, Ciaran P Kelly, The Celiac Center, Department of Medicine and Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States
Gopal Veeraraghavan, Amelie Therrien, Jocelyn A Silvester, Daniel A Leffler, Alan M Leichtner, Ciaran P Kelly, Dascha C Weir, Celiac Research Program, Harvard Medical School, Boston, MA 02115, United States
Amelie Therrien, Maya Degroote, Allison McKeown, Jocelyn A Silvester, Alan M Leichtner, Dascha C Weir, Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA 02115, United States
Paul D Mitchell, Institutional Centers for Clinical and Translational Research, Boston Children's Hospital, Boston, MA 02115, United States
Daniel A Leffler, Gastrointestinal Therapeutics, Takeda Pharmaceutical International Co, Cambridge, MA 02139, United States
Author contributions: Veeraraghavan G, McKeown A, Degroote M, Silvester JA, Leffler DA, Leichtner AM, Kelly CP and Weir DC contributed planning and/or conducting the study; Veeraraghavan G, Therrien A, Degroote M, McKeown A, Mitchell PD, Silvester JA and Weir DC contributed collecting and/or interpreting data; Veeraraghavan G, Therrien A, Degroote M, Mitchell PD, Silvester JA, Leffler DA, Leichtner AM, Kelly CP and Weir DC contributed drafting the manuscript.
Supported by Boston Children's Hospital and the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, No. P30DK034854, No. K23DK119584 and No. T32DK07760; DG Kinnear Award from the Association Quebecoise des Gastroenterologues du Quebec; and Phase 2 Award from the Fonds de Recherche Sante Quebec.
Institutional review board statement: This study was reviewed and approved by the Institutional Review Board of Boston Children’s Hospital.
Informed consent statement: Patients were not required to give informed consent to the study because this study presented no more than minimal risk to patient privacy and confidentiality.
Conflict-of-interest statement: Leffler DA is employed by Takeda Pharmaceuticals International Co. Kelly CP has acted as a scientific advisor to companies attempting to develop new diagnostic and management approaches for Celiac disease including Cour Pharma, Glutenostics, Innovate, Immunogenx and Takeda. He also acts as Principal Investigator on a research grant on Celiac disease supported by Aptalis. Silvester JA has served on an advisory board for Takeda Pharmaceuticals and has received research funding from Biomedal S.L., Cour Pharma and Glutenostics.
Data sharing statement: No additional data are available.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
http://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Dascha C Weir, MD, Attending Physician, Division of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, 300 Longwood Ave, Boston, MA 02115, United States. dascha.weir@childrens.harvard.edu
Received: December 3, 2020
Peer-review started: December 3, 2020
First decision: December 21, 2020
Revised: January 4, 2021
Accepted: February 1, 2021
Article in press: February 1, 2021
Published online: April 7, 2021
ARTICLE HIGHLIGHTS
Research background
Non-responsive celiac disease (NRCD) is defined as the persistence of symptoms in individuals with celiac disease (CeD) despite being on a gluten-free diet (GFD). There is scant literature about NRCD in the pediatric population.
Research motivation
Addressing an important knowledge gap, this study examines a large cohort of children with CeD providing data on the characteristics, causes and evolution of pediatric NRCD. By characterizing this sub-population of individuals with CeD, we are better equipped to provide clinical guidance and follow-up in those with persistent symptoms.
Research objectives
Through this retrospective cohort study, we sought to determine the incidence, clinical characteristics, and underlying causes of NRCD in children. Additionally, symptom evolution was detailed and compared to identify any potential predictors for NRCD.
Research methods
Retrospective cohort study performed at Boston Children’s Hospital (BCH). Children < 18 years diagnosed with CeD by positive serology and duodenal biopsies compatible with Marsh III histology between 2008 and 2012 were identified in the BCH’s Celiac Disease Program database. Medical records were longitudinally reviewed from the time of diagnosis through September 2015. NRCD was defined as persistent symptoms at 6 mo after the initiation of a GFD, and causes of NRCD as well as symptom evolution were detailed and compared to identify any potential predictors for NRCD.
Research results
Six hundred and sixteen children were included in this retrospective study, of which 91 (15%) met criteria for NRCD, and of this, most were female (77%). Abdominal pain [odds ratio (OR) 1.8 95% confidence interval (CI) 1.1-2.9], constipation (OR 3.1 95%CI 1.9-4.9) and absence of abdominal distension (OR for abdominal distension 0.4 95%CI 0.1-0.98) at diagnosis were associated with NRCD. NRCD was attributed to a wide variety of diagnoses with gluten exposure (30%) and constipation (20%) being the most common causes. 64% of children with NRCD improved on follow-up.
Research conclusions
NRCD after ≥ 6 mo of GFD is frequent among children, especially females, and is associated with initial presenting symptoms of constipation and/or abdominal pain. Gluten exposure is the most frequent cause. Our study highlights the importance of performing a diligent search for the etiologies for NRCD in any celiac child with persistent clinical symptoms despite being on GFD and reinforces the need for close follow up in the first year of a CeD diagnosis.
Research perspectives
Although the use of a large pediatric cohort positively contributes to the breadth of knowledge surrounding NRCD, and inclusion of only children who were diagnosed at BCH reduces referral bias, our cohort may differ from populations in other geographic areas. As such, a future direction of note is to extend this project to include pediatric Celiac Disease Programs across the United States, to assess if geographic location is a factor in the manifestation and characterization of NRCD.
