Transcript Document
THE CELIAC PATIENT Carol E. Semrad, M.D. Associate Professor of Medicine The University of Chicago • • • • Celiac Disease Sprue Gluten-enteropathy Celiac sprue Same Disease Inflammatory disease of the small bowel with a known trigger A Case of “Asymptomatic” Celiac Disease • • • • • • • 50 y.o. woman, Italian/Irish Daughter diagnosed with celiac disease Screening anti-tTG IgA antibody positive Occasional indigestion with pasta meals PMH: Hypothyroidism FH: Parents of short stature Physical examination: obese, height 5’1” Duodenum • Further Studies - Mild anemia, transaminitis, iron deficient - BMD osteopenia • Diagnosis - Celiac disease • Management - Gluten-free diet - Iron therapy - Further evaluation of bone disease - Monitor for improvement Celiac Disease -Trigger Gluten (the protein component of wheat) Glutenins (alcohol-insoluble fraction) Gliadin (toxic alcohol-soluble fraction) Peptides (33-mer not degraded by human peptidases, contains toxic epitopes) Amino acids (non-toxic to celiac patients) Celiac Disease GENES • 95% HLA DQ2 heterodimer alleles DQA1*0501 and DQB1*0201 (20-30% normals carry these alleles) • 5% HLA DQ8 heterodimer alleles DQA1*0301 and DQB1*0302 • Rarely DQ2 half-heterodimer • Non-HLA genes not yet identified ADAPTIVE INNATE Intraepithelial CTL NK-like cells ? Lamina Propria Modified from Green and Jabri Lancet. 2003:362;383-91. Celiac Disease Prevalence in the U.S.A. • Based on GI symptoms 1:4500 • Based on Antibody studies 1:250 (performed in blood donors) ~ 1% of the Caucasian population Classical Celiac Disease (1:4500) Atypical Silent Latent Detected by screening (1:250) Different modes of presentation presentations of celiac disease The clinical of celiac disease is changing Rampertab SD et al., Am J Medicine 2006 Celiac Disease Clinical Presentation Classical Atypical Silent • Diarrhea • Constipation • No sxs/signs • Positive Ab • Gas/bloating • Dyspepsia • Abnormal bx • Weight loss • Anemia • Osteoporosis • Rash • Neuropathy/ataxia • Hepatitis • Dental enamel hypoplasia • Infertility Latent • No sxs/signs • Positive Ab • Normal bx OR CD in remission Celiac Disease Classic, Atypical, Silent Latent Normal Abnormal Celiac Disease Diagnostic Tools Duodenal biopsy Serologies HLA Association anti-tTG IgA, IgG anti-EMA IgA (anti-DGP) DQ2 A1*05 B1*02 DQ8 A1*03 B1*0302 Half DQ2 heterodimer Antibodies Associated with Celiac Disease IgA Antibody* Sensitivity Specificity Method Anti-gliadin 57-100% 42-98% ELISA Anti-endomysial 75-98% 96-100% Indirect IF Anti-tissue transglutaminase 98-100% 97-98%# ELISA *False Negative with IgA deficiency #False Positive tTG in IBD, PBC Positive Predictive Value ~ 100% for EMA 80% for human tTG Fasano, Catassi. Gastro2001:120;636 Carroccio et al. Clin Chem 2002:48;1546 ENDOSCOPY CELIAC DISEASE Scalloped Gluten-free diet Increased IEL Villous atrophy Recovering HISTOLOGY Normal Celiac Disease Who Should Undergo Duodenal Biopsy? • • • • • • High risk with GI symptoms Dermatitis Herpetiformis Unexplained iron deficiency anemia Early osteoporosis/bone fracture Neuropathy/ataxia Positive screening antibody test Celiac Disease Who Should Have Antibody Testing? • Support diagnosis • Screening High risk groups First and second degree relatives Dermatitits Herpeteformis Type I Diabetes Mellitus Autoimmune thyroid disease Irritable Bowel Syndrome Primary Biliary Cirrhosis Turner’s and Down’s Syndrome Celiac disease An approach to antibody screening • tTG IgA antibody and serum IgA level • If positive, confirm with EMA antibody Celiac Disease When is HLA Genotyping Helpful? • Family Members -Negative predictive value • Difficulty in securing a diagnosis - Self-started a gluten-free diet - Equivocal small bowel biopsy findings - Positive antibody with normal biopsy - IgA deficiency Celiac Disease Evaluation • Bone mineral density study - abnormal bone mass in ~ 60% - men > women - if abnormal obtain 25-OH Vit D, PTH, calcium, 24 hour urine calcium • Vitamin/mineral levels in those with evidence of malabsorption/diarrhea - Iron studies and folate - Vitamin A, B12, zinc Celiac Disease Treatment • Life-long strict gluten-free diet - knowledgeable nutritionist - celiac center web sites/support groups (U. Chicago, Columbia, Mayo Clinic, Stanford, U. Maryland, B.I. Boston) • • • • Oats are tolerated by most Daily multiple vitamin and calcium Folic Acid for women of child-bearing age No initial role for bisphosphonates Celiac Disease Monitoring • Resolution of symptoms • tTG antibodies for dietary adherence (? correlation between Ab titer and histology) • Weight (risk for obesity) • Cholesterol level • Bone Mineral Density RESPONSE TO A GLUTEN-FREE DIET 90% IMPROVE (within 2 weeks) 10% FAIL TO IMPROVE Dietary indiscretion Lactose or fructose Intolerance Microscopic colitis Wrong Diagnosis Pancreatic Insufficiency Bacterial overgrowth Refractory sprue Refractory Sprue = Continued symptoms and small bowel atrophy despite a strict gluten-free diet • TYPE I - normal T-lymphocytes population - often responds to steroids, good prognosis • TYPE II -abnormal T cell population (CD3+, CD8-) T-cell receptor- g gene rearrangements often requires parenteral nutrition - progression to lymphoma - poor prognosis - trials with cytotoxic chemo or stem cell transplant - Celiac Disease Long Term Complications • Anemia • Osteoporosis • Intestinal T-cell lymphoma ? Video capsule endoscopy screening • Other Malignancies Gastrointestinal Melenoma Non-Hodgkins Lymphoma Celiac Disease Future Treatments • Bacterial Prolyl Endopeptidase • Genetically altered wheat grain • Specific Inhibitors HLA DQ2 tTG IL15 • Tight junction modulators Summary CELIAC DISEASE • T-cell mediated small bowel mucosa inflammation • Triggered by gluten in the diet in those genetically predisposed • Malabsorption of nutrients • Presents age 2 yrs, young adults, or any age • Diagnosis made by abnormal small bowel biopsy that reverts to normal on a gluten-free diet • Treatment is a life-long strict GF-diet How Much Gluten Is Toxic? CELIAC DISEASE Dose-dependent Effect of Gliadin on Small Bowel Dose of Gliadin Symptoms Permeability Intestinal Biopsy 10 mg No -- Normal 50 mg* Yes -- Minimal changes 100 mg No Normal Minimal changes 500 mg Yes Increased More pronounced changes *capsule of gluten Catassi et al. GUT 1993; 34: 1515 Ciclitira et al. Clin Sci 1984; 66: 357 Catassi et al. Gastroenterol 2005;128:A253 10 mg gliadin ~ 250 mg wheat flour (less than an 1/8 teaspoon flour) CELIAC DISEASE Are Dietary Oats Tolerated? PATIENT # DISEASE STATUS DIET DURATION SXS SMALL BOWEL BIOPSY 26 adults (26 control) remission oats (50-70g) gluten-free 6 months no similar to pre-oat 19 adults (21 control) new oats (50-70g) gluten-free 1 year no improved 23 adults (28 control) remission oats ad-lib gluten-free 5 years no improved 42 children (52 control) new oats ad-lib gluten-free 1 year no improved Janatuinen et al. NEJM 1995;333:1033 Gut 2002; 50: 332 Hogberg et al. Gut 2004;53:649