New Insights on Gluten Sensitivity Sheila E. Crowe, MD, FRCPC, FACP, FACG, AGAF Department of Medicine University of California, San Diego Page 1 1
low fat diet low carb diet gluten free diet low fat diet low carb diet gluten free diet The market for gluten-free food and beverage products grew at a compound annual growth rate of 28 percent from 2004 to 2008, to finish with almost $1.6 billion in retail sales. By 2012 sales were expected to reach $2.6 billion. Sales are now predicted to be $1.68 billion in the USA and $3.38 billion worldwide by 2015 (Reuters on line, Sept 2012) Page 2 2
3 Adapted from Boyce JA et al. JACI.2010;126(6):1105 Gluten Sensitivity Due to Celiac Disease (CD) Oslo Definitions A chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals Non-Celiac Gluten Sensitivity (NCGS) One or more immunological, morphological and/or symptomatic alterations triggered by gluten ingestion in individuals in whom celiac disease has been excluded Ludvigsson, J et al, Gut, 62(1):43-52; 2013 Page 3
Dietary grains with increased gluten, increased wheat in diets worldwide Other environmental Microbiota Fasano et al, Arch Int Med, 163:286, 2003 Rubio-Tapa et al, Gastroenterology, 137: 88, 2009 AGA Technical Review, Gastroenterology, 131:1981, 2006 Virta et al, Scand J Gatroenterol, 44:933, 2009 Rubio-Tapia, Am J Gastroenterol, 2012 1 Campanella et al, Scand J Gastroenterol, 43:1311, 2008 2 Sainsbury, A., et al, Clin Gastroenterol Hepatol, 11:359, 2013 Page 4 4
5 1. Cooper, BT, et al, Gastroenterol, 79; 801, 1980 2. Digiacomo DV et al, Scand J Gastroenterol, 48:921, 2013 3. Sabatino, AD & Corazzo, GR, Ann Intern Med, 156, 309: 2012 4. Massari, S, et al, Ine Arch Allergy Immunol, 155;389, 2011 Elevated AGA IgA, IgG (up to 50% +AGA IgG) 1, 5 No specific HLA association Some studies suggest gluten may activate the innate immune system (IL-8, IFN-γ, etc) in NCGS 2 Increased permeability, mucosal inflammation, eosinophils 5, basophil activation but not found in a recent study 3 Other proposed mechanisms include immune complex, autoimmune, microbiota, wheat amylase trypsin inhibitors 4, toxicity, false neurotransmitters, leaky gut. 1. Volta, U et al, J Clin Gastroenterol, 46: 680, 2012 2. Sabatino, AD & Corazzo, GR, Ann Intern Med, 156: 309, 2012 3. Bucci C, et al, Clin Gastro Hepatol, in press (2013) 4. Junker, Y etal, J Exp Med, 209: 2395, 2013 5. Carroccio, A et al, Am J Gastroenterol, 107:1898, 2012 Page 5
Fermentation Page 6 6
Wahnschaffe et al, Gastroenterology, 121: 1329, 2001 Sanders et al, Lancet, 358: 1504, 2001 Ladabaum et al, Aliment Pharmacol Ther 19:1199, 2004 Ford, et al, Arch Int Med 13:651, 2009 Page 7 7
Vasquez-Roque, et al, Gastroenterol, 144:903, 2013 Vasquez-Roque, et al, Gastroenterol, 144:903, 2013 Page 8 8
J. Biesiekierski, et al, Gastroenterol, 145:320, 2013 J. Biesiekierski, et al, Gastroenterol, 145:320, 2013 Page 9 9
10 Risk of celiac disease and HLA status DR3- or DR5/7-90-95% DR4-5-10% Only HLA DQ2 or DQ8 positive subjects are at risk of getting celiac disease Necessary for celiac disease but not sufficient General population < 1.0% DQ2 homozygous 31X DQ2/DQ8 positive 14X DQ8 homozygous 10X DQ2 heterozygous 10X DQ8 heterozygous 2X DQ2 and DQ8 negative - < 0.1X Helpful test for its NPVabsence excludes celiac disease but not NCGS Pietzak, M, Clin Gastro & Hepatol, 7:996, 2009 Page 10
Sugal, E, et al, Digestive & Liver Disease, 42:352, 2010 Crowe, SE. In The Clinic : Celiac Disease, Ann Int Med,2011 154:ITC5-14, Celiac disease is possible & patient is willing to undergo gluten challenge? Up to 6 to 12 months on GFD check serology and consider EGD + Bx Yes, get genetic testing Challenge if HLA DQ2 or 8 positive Check Ab q1-2 months up to 6 months No but wants genetic testing for sake of children No further evaluation if they will still stay on GFD regardless of evaluation and will not have children tested EGD + Bx if Ab +, symptoms develop, or by 3-6 months Positive increases likelihood of celiac disease, encourage gluten challenge Negative not celiac disease,? use GFD for symptom control only Page 11 11
12 Gradual increase of gluten up to target (ideally 10g equivalent of 4 slices bread/ day but varies by patient) One study showed that a 14-day 3 g challenge was sufficient to induce serologic and histologic changes 1 Check TTG IgA q2-6 weeks until positive EGD/biopsy if diarrhea develops and/or seropositive Management if still seronegative at 3 to 6 months needs to be individualized but typically involves EGD/biopsy now or after longer gluten challenge 1 Leffler, D, et al, Gut, 2012 Type of ARF Immune mediated Tissue damage Genetic factors Wheat hypersensitivity IgE-mediated Transient Yes Celiac disease T cell mediated Persistent with gluten ingestion Non-celiac gluten sensitivity Wheat starch intolerance Innate immune? Other mechanisms Microscopic Yes Not known Non-immune Not apparent Seemingly not Page 12
Boettcher, E, & Crowe, SE, Am J Gastroenterol, 108:728; 2013 Page 13 13