6/20/2018 Disclosures Celiac Disease • Pentax Research Grant (ergonomics) & Non-Celiac Gluten Sensitivity Amandeep Shergill, M.D., M.S. Associate Clinical Professor of Medicine University of California, San Francisco Director of Endoscopy, San Francisco VA Medical Center Case Scenario Celiac Disease & Non-Celiac Gluten Sensitivity • Celiac Disease • 28 yo female • Pathophysiology • 6 year h/o “IBS”: abd gas, bloating, diarrhea alternating with • Prevalence constipation • Presentation • Tried on multiple medications without relief • Diagnosis • Friend told her she might have Celiac Disease and should get herself • Mortality & Morbidity tested • Treatment • Non-celiac Gluten Sensitivity
6/20/2018 Case Scenario Celiac Disease • “Doc – what is celiac disease? “ • “What is celiac disease?” • Chronic small intestinal immune- mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals Ludvigsson, BMJ 2013. Pathogenesis of Celiac Disease: Pathogenesis of Celiac Disease: Gluten Gluten • Wheat • Wheat • Rye • Rye • Barley • Barley Shan Science 2002
6/20/2018 Pathogenesis of Celiac Disease: Gluten bio.davidson.edu; http://escapinganergy.blogspot.com/2011/05/hold-carrots-vitamin-may- Figure from glutenpost.com exacerbate.html Genetic Factors: HLA-DQ2/HLA-DQ8 Pathogenesis of Celiac Disease Host Triggers -Wheat -HLA:DQ2/DQ8 -Barley -Non HLA genes -Rye Cofactors -Intestinal Infections -Infant feeding practices - 25-30% Caucasian population DQ2/8 positive -Socioeconomic - 4% of DQ2/8 positive individuals exposed to gluten develop CD factors Di Sabatino, Lancet 2009 Kagnoff, Gastro 2005;128:S10-18.; https://commons.wikimedia.org/wiki/File:HLA-DQ2.5_gliadin.PNG
6/20/2018 Incidence of Celiac Disease: active duty US Increasing prevalence over time: military serological studies, 2-4x higher prevalence • Two large Finnish population-based studies • 20y apart • tTG and EMA antibodies • doubling in CD prevalence from 1978– 1980 to 2000– 2001 • American study compared sera collected between 1948 and 1954 with two matched cohorts collected between 1995 - 2003 and between 2006 -2008 respectively • Prevalence of CD was 4x higher in the recent cohorts • Retrospective analysis of matched serum samples taken from US community volunteers in 1974 and 1989 showed a doubling in prevalence “Incidence of CD diagnosis in a healthy US adult population is increasing…and appears higher than other population-based estimates” Khang et al; Aliment Pharmacol Ther 2013; 38: 226-245; Rubio-Tapia Gastro 2009 Riddle AJG 2012 Incidence of Celiac Disease: Pediatrics Lebwhol BMJ 2015 Almallouhi JPGN 2017
6/20/2018 Environmental Risk Factors: Environmental Risk Factors • Infection: • Swedish epidemic: • Rotavirus infection an independent risk factor for celiac disease in • 3x higher CD pediatric onset CD prevalence with • Changes the permeability of and the cytokine balance in the intestinal mucosa change in national • Suggested risk of CD after Campylobacter infection, but not other recommendations foodborne infections. • Infant feeding practices • Breastfeeding • Gluten introduction Tack et al, NatRevGastroHep 2010; Riddle DDS 2013; Riddle AJG 2012; Nadal J Med Ivarsson, Acta Ped 2000; Silano WJG 2010. Micorbiol 2007 Environmental Risk Factors: PreventCD TRIAL: early introduction of gluten Infant feeding • “Failure of oral • Multicenter, randomized, double-blind, placebo-controlled dietary intervention study tolerance to gluten” • ?window of opportunity of first gluten exposure – primary prevention • Potential mechanisms: • Exposing genetically predisposed infants to small quantities of gluten at 16 to 24 weeks of age, preferably while they were still being breast-fed • Immunomodulatory • 944 children: positive for HLA-DQ2 or HLADQ8, at least one first- degree relative with celiac disease. activity breast milk: • 16-24 weeks of age (8 weeks): • bifidobacteria • 475 participants received 100 mg of immunologically active gluten daily • infection • 469 received placebo. • After the intervention, parents were advised to introduce gluten gradually, • Amount of gluten using regular products and standardized recommendations • Primary outcome: frequency of biopsy-confirmed celiac disease at 3 introduced years of age Vriezinga SL et al. N Engl J Med 2014;371:1304-1315. Ivarsson, Best Prac Reas Clin Gastro 2005; Nadal, J Med Microbio 2007; Silano WJG 2010.
6/20/2018 PreventCD TRIAL: early introduction of gluten (16 weeks) Risk of Celiac Disease and Age at Gluten Introduction CELIPREV TRIAL: gluten at 6 vs 12 m • Multicenter, prospective intervention trial comparing early and delayed introduction of gluten to the diet of infants with a familial risk of celiac disease, and followed these children from birth to at least 5 years of age. • 832 newborns: first-degree relative with celiac disease • Randomized to the introduction of dietary gluten: at 6 months (group A) or 12 months (group B). • At 12 months of age, all children began to receive a normal diet containing gluten. • HLA genotype: was determined at 15 months of age • Serologic screening for celiac disease: • evaluated at 15, 24, and 36 months • and at 5, 8, and 10 years • Patients with positive serologic findings underwent intestinal biopsies. • Primary outcome was the prevalence of celiac disease autoimmunity and of * Breast-feeding, regardless of whether it was exclusive or whether overt celiac disease among the children at 5 years of age. it was ongoing during gluten introduction, did not significantly influence the development of celiac disease or the effect of the intervention Lionetti NEJM 2014 VriezingaSL et al. N EnglJ Med 2014;371:1304-1315. CELIPREV TRIALS: gluten at 6 vs 12 m Postponing the introduction of gluten • 2 years of age: Group A vs Group B • Delayed the development of celiac disease • Celiac disease autoimmunity significantly greater (16% vs. 7%, P = • which might reduce the 0.002) negative effect of the disease • Overt celiac disease significant greater on vulnerable organs such as (12% vs. 5%, P = 0.01) the brain. • 5 years of age: between-group • Reduced the prevalence differences were no longer (nonsignificantly) of celiac disease significant for autoimmunity (21% in autoimmunity at any age among group A and 20% in group B, P = children carrying the high-risk 0.59) or overt disease (16% and 16%, HLA genotype P = 0.78 by the log-rank test) • Did not detect an effect of • 10 years: risk of celiac correlated breastfeeding on the with high-risk HLA development of celiac disease Lionetti NEJM 2014 Lionetti NEJM 2014
6/20/2018 GLUTEN INTRODUCTION AND THE RISK OF COELIAC DISEASE: A POSITION PAPER BY THE Breastfeeding during Gluten Introduction EUROPEAN SOCIETY FOR PAEDIATRIC GASTROENTEROLOGY, HEPATOLOGY & NUTRITION • Although breastfeeding should be promoted for its other well-established health benefits, neither any breastfeeding nor breastfeeding during gluten introduction has been shown to reduce the risk of CD. • Gluten may be introduced into the infant’s diet anytime between 4-12 completed months of age. • In children at high risk for CD, earlier introduction of gluten (4 vs. 6 mo or 6 vs. 12 mo) is associated with earlier development of CD autoimmunity (defined as positive serology) and CD, but the cumulative incidence of each in later childhood is similar. • Based on observational data pointing to the association between the amount of gluten intake and risk of CD, consumption of large quantities of gluten should be avoided during the first weeks after gluten introduction and during infancy. However, the optimal amounts of gluten to be introduced at weaning have not been established. Szajewska JPGN 2016 Chmielewska Ann Nutr Metab 2015 Inflammation process and possible routes of probiotic action in the maintenance of CD. In CD Environmental Risk Factors: patients, increased epithelial tight junction permeability (“leaky gut”) favors the entrance of non- well-digested gluten peptides from the lumen to the lamina propria. Microbiome • Children who were born via elective Caesarian section are at increased risk of developing celiac disease, while those born via emergent Caesarian section (and may have had contact with the birth canal) are not • Inverse relationship between Helicobacter pylori colonization and celiac disease • Population-based studies from Sweden have shown that prescription of antibiotics and proton pump inhibitors are each associated with an increased risk of the subsequent development of celiac disease. Luís Fernando de Sousa Moraes et al. Clin. Microbiol. Rev. 2014;27:482-489 Lebwohl CGH 2014; Marild Gastroenterology 2012; Lebwohl Am J Epidemiol 2013; Marild BMC Gastroenterol 2013; Dig Liver Dis. 2013.
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