The Gluten Truth and What is Gluten? Other Things Pediatric GI • A protein found in wheat, barley, rye, oats – Poorly digested by humans – Causes immune reactions in genetically susceptible Kenneth Fine, M.D. individuals – Can become autoimmune In the Beginning… Grains Factors Favoring Grain to Fertile Crescent - 8500 B.C.E. Remain Human Food •Wheat, barley, rye, oats among the first foods to be domesticated • Easily and quickly grown with large yields •Genetically modified its ancestors – Short growing season (few months) Diploid Tetraploid Hexaploid • Seeds could be stored, ground and cooked into good tasting food with high carb/cal availability • Yeast +/- sugar added - baked, fermented, distilled, brewed tasty, pleasurable, addicting food/drink Wild Early Cultivated Modern Ancestors Wheat and Spelt Wheat and Spelt “The Coeliac Affection” Celiac Disease: Described by 100 C.E. The Classic Gluten-Related Aretaeus the “Patients have flatulence and Disease Cappadocian heavy pains of the stomach” • Present in 0.5-1% of Europeans Normal “They are emaciated and and Americans atrophied, pale, feeble, incapable of performing any of their • Gluten-induced immune damage of accustomed work” the small intestine with specific lesion Celiac disease “The stomach labors in digestion • Most often diagnosed by when diarrhea, consisting of intestinal biopsy and blood tests undigested food in a fluid state, seizes the patient” – Most people today do not have the classic syndrome or biopsy Spectrum of SB Histopathology in Celiac Sprue Subtotal VA HLA Genes in Celiac Sprue Normal • Tightly associated with class II alleles HLA-DQ2 90% HLA-DQ8 most of those without DQ2 Total VA Partial Villous Atrophy Celiac Endoscopic Evidence that Celiac Sprue is Abnormalities an Autoimmune Disease • Shares predisposing HLA alleles and is epidem- iologically associated with other autoimmune dz • Antigen Substrate for AEA is a human enzyme – Tissue transglutaminase - responsible for protein crosslinking in response to tissue injury – Can bind gliadin as a substrate (Dieterich et al Nature Med 1996) Duration of Gluten Consumption Main Autoimmune Diseases and Risk of Autoimmune Disease Associated with Celiac Sprue 35% 30% • Diabetes mellitus, type 1 • Rheumatoid arthritis 25% 20% • Dermatitis herpetiformis • Alopecia 15% • Thyroiditis - hypothyroid • Autoimmune hepatitis 10% • Sjogren’s syndrome • Primary biliary cirrhosis 5% 0% • Psoriasis • Sclerosing cholangitis <2 yrs 2-4 yrs 4-12 yrs 12-20 yrs >20 yrs Age at Diagnosis of Celiac Sprue Ventura et al Gastroenterology 1999;117:297 Other Disorders Associated with Microscopic Colitis Gluten Sensitivity Syndrome • Crohn’s disease, Ulcerative colitis • Chronic, watery, non-bloody diarrhea • Chronic diarrhea • Etiology unknown • Gastroesophageal reflux disease • Hepatitis C, many other liver diseases • Normal or near-normal colonoscopic appearance • Female infertility, mother’s of spina bifida • Psychiatric disease, Alcoholism, Depression • Histopathology: LP inflammation, intraepithelial • Iron deficiency anemia lymphocytosis, surface epithelial flattening, • GI cancers/Lymphoma +/- thick subepithelial collagen band Microscopic Colitis MC Possesses Celiac-Like “Collagenous colitis” Normal colon Clinicopathologic Characteristics • Colon biopsy of MC identical to biopsy of CS • 5% of treated CS patients get MC • 75% of MC have celiac genes (DQ2, DQ8) MC • 70% have mild SB damage but rarely CS • Not much more antigliadin antibody in serum than general population; positive titers < CS Stained Fine et al Gastroenterology 1996 Collagen Fine et al Human Pathology 1998 Fine et al Am J Gastro 2000 Small Bowel Enteropathy in Microscopic Colitis With all these similarities to CS suggesting that microscopic colitis patients are gluten-sensitive, why are antibodies to gliadin not detected more often in serum? If an immunologic reaction to gliadin was detectable, it would prove their immunologic gluten sensitivity, and rationalize treatment with a gluten-free diet Follow-up* of 50 Patients with MC Stratification of HLA, SB Bx, AGA Treated with Bismuth Subsalicylate Results in MC by Response to BSS • Well, no further treatment 31 (62%) Response DQ2 or Abnormal Serum Fecal Pattern n 1,3 Small Bowel AGA IgA AGA IgA (13%) • Well, required retreatment x 1 7 Response, 17 11 (65%) 3 (18%) 2 (12%) 3 (18%) no relapse • Relapsed, required adjuvant Rx 10 (20%) Response, 22 22 (100%) 20 (91%) 5 (23%) 12 (55%) relapse No 6 6 (100%) 6 (100%) 1 (17%) 6 (100%) • Continued diarrhea 2 (5%) response Fine et al Gastroenterology 1998 * 15 - 55 months Effect of a GFD in the First 25 MC “Secondary” Gluten-Sensitivity Patients with Relapsing Diarrhea in Microscopic Colitis following Bismuth Subsalicylate • In patients with microscopic colitis, low titers of antigliadin antibodies and mild small Resolution of diarrhea 19 intestinal histopathology occur secondarily to the colonic inflammatory response, rather Improved; less/sporadic diarrhea 4 than the converse No improvement 2 • Dietary gluten in such patients likely fuels the immune fire of the primary colitic disorder Poor Sensitivity of Celiac Blood Problem with Biopsies: Not All Tests with Less Villous Atrophy Gluten-Sensitive People Have Villous Atrophy • Partial villous atrophy - 31% • “Gluten-Sensitive Diarrhea” (Gastroenterology 1980;79:801) • “Gluten-Sensitivity with Mild Enteropathy” (Gastro 1996;111:608) • “Celiac-like Abnormalities in IBS patients” (Gastro 2001;121:1329) • Subtotal villous atrophy - 70% • “Celiac Disease without Villous Atrophy” (Dig Dis Sci 2001;46:879) – Pts. with diarrhea/steatorrhea, anemia, osteoporosis, mouth ulcers • Total villous atrophy - 100% – Small bowel biopsies with γ-δ IEL’s and react to gluten in vitro – All patients became well on a GFD; Sx’s recurred with gluten Rostami et al Am J Gastro 1999;94:888 Dickey W Scand J Gastro 2000;35:181 Tursi A, Am J Gastroenterol. 2001;96:1507-10 Tursi A, J Clin Gastroenterol 2003;36:219-21 Abrams JA, Dig Dis Sci. 2004;49:546-50 Sanders DS, BMJ. 2005;330:775-6 Antigliadin Ab Is Inside the 8yr Prospective Study of Fecal Intestine but not Blood with Mild Testing for Gluten Sensitivity Intestinal Damage • Researchers assessed blood and aspirated small bowel fluid for antigliadin IgA antibody in: • 10,246 pts. collected one stool • Measured fecal antigliadin IgA, ATTA, fecal fat – Celiacs: blood and SB aspirate was positive – Normals: blood and SB aspirate was negative • Buccal swab analyzed for HLA-DQB1 – Celiacs after 1 yr on GFD: blood neg., intestine positive • Questionnaire for clinical data: symptoms, indications • Used intestinal lavage and analysis of rectal effluent • Follow-up symptoms, stool tests to test for the presence of intestinal antigliadin Ab – Called “a relatively non-invasive screening method for early celiac sprue” O’Mahoney et al, Gut 1990 Detection Frequency of AGA Follow-Up: Gluten-Free Diet Rx for Serum vs. Stool Non-Celiac Gluten Sensitivity + Serum AGA + Fecal Patient Group IgG or IgA AGA IgA What improved on a GFD? Asymptomatic volunteers (n=56) 11% 29% – In 6-12 months: IBS-like Abd. Symptoms (n=1280) 12% 62% • All symptoms, subjective assessment of health FH Celiac Disease (n=2151) 14% 64% – In 2-3 years Autoimmune Disease (n=6181) 13% 68% • Fecal antibody levels (indicator of ongoing sensitivity) Microscopic colitis (n=380) 9% 72% • Fecal fat malabsorption (indicator of intestinal dysfunction) Chronic Fatigue (n=141) 10% 63% – Diet had to be 100% strict for malabsorption to resolve Untreated celiac sprue (n=57) 75% 99% AGA = antigliadin antibody # of Symptoms* - Study Onset vs. Subjective Change in Health - 15 Mo. Follow-Up in IBS and MC 15 Mo. Follow-Up vs. Study Onset Treatment n Sx before Sx after P value† Treatment n Better Same Worse 100% Strict GFD 247 4.9 1.0 <0.0001 100% Strict GFD 247 94% 5% 1% <100% Strict GFD 173 4.7 1.4 <0.0001 <100% Strict GFD 173 87% 11% 2% None 77 4.6 4.3 0.30 None 77 6% 93% 1% * Weight loss, fatigue, aphthae, abdominal pain, bloating, dyspepsia, vomiting, diarrhea, or constipation as assessed by questionnaire † Before vs. after in each group; two-tailed paired student’s t-test Improvement of Fecal Anti-Gliadin Improvement of Dietary Fat IgA on GFD - Baseline and 42-Mo. Malabsorption on 100% GFD 42mo 100% GFD <100% GFD No GFD 100% GFD <100% GFD No GFD 80 80 80 900 900 900 800 800 800 70 70 70 U 700 700 700 U 60 60 60 Mean n 600 600 Mean 600 n 50 50 50 Mean Mean i 500 500 426 500 Mean i 40 393 40 40 40 36 Mean t Mean Mean 400 323 t Mean 400 400 30 s 322 300 s 30 30 24 30 300 300 300 20 Mean 20 Mean 20 200 Mean 200 200 11 15 Normal 151 10 10 10 100 100 100 Range P=0.04 P=022 P=0.33 Normal Range P=0.002 P=0.10 P=0.71 0 0 0 0 0 0 Baseline Follow-Up Basel ine Fol l ow-Up Basel ine Fol l ow-Up Baseline Follow-Up Baseline Follow-Up Baseline Follow-Up Reproducibility Studies AGA • Repeated Fecal Antigliadin IgA: Different Stools, Negative Control Groups Same People over days to weeks 120 Group n % negative Babies <10 mos 18 100%* 100 Cow manure 24 100%* 80 Dog Manure 10 100%* 60 Fecal IgG 168 100%† 40 Fecal Antigliadin IgA (Units) IgA Antigliadin Fecal 20 * Fecal Antigliadin IgA † Fecal Antigliadin IgG 0 Non-Celiac Gluten Sensitivity The Non-Celiac Gluten Sensitivity Majority of the Epidemic • Chronic immune “sensitivity” to wheat, barley, rye, oats Whole iceberg increasing, Celiac Disease (0.5-1% ) without celiac-like damage of the small intestine celiac tip smaller 17 million in US, Europe, Mid East Symptomatic Non-Celiac • Makes people ill in many ways: Inflammation, no villous atrophy Gluten Sensitivity (22%) Neuropsychiatric disorders 375 million GS Abdominal symptoms/syndromes Asymptomatic Non-Celiac 47% Autoimmune/asthma disorders Gluten Sensitivity (25% ) Glandular dysfunction 425 million Skin rashes and syndromes At Genetic Risk for • Before 2000, no simple yet sensitive method of Non-Celiac Gluten Sensitivity (47%) diagnosis – Now diagnosable by fecal testing 800 million • blood tests for gluten antibodies insensitive %’s are of a population with a wheat-based diet Celiac vs.