THE CELIAC PATIENT Carol E. Semrad, M.D. Associate Professor of Medicine The University of Chicago

Celiac Disease Sprue Gluten-enteropathy Celiac sprue Inflammatory disease of the small bowel with a known trigger Same Disease

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) Gliadin (toxic alcohol-soluble fraction) Peptides (33-mer not degraded by human peptidases, contains toxic epitopes) Amino acids (non-toxic to celiac patients) Glutenins (alcohol-insoluble fraction)

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

Modified from Green and Jabri Lancet. 2003:362; Intraepithelial CTL NK-like cells ? ADAPTIVE INNATE Lamina Propria

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)

The clinical presentation of celiac disease is changing Rampertab SD et al., Am J Medicine 2006 Different modes of presentations of celiac disease

Celiac Disease Clinical Presentation Classical Diarrhea Gas/bloating Weight loss Atypical Constipation Dyspepsia Anemia Osteoporosis Rash Neuropathy/ataxia Hepatitis Dental enamel hypoplasia Infertility Silent No sxs/signs Positive Ab Abnormal bx 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 DQ2 A1*05 B1*02 anti-EMA IgA DQ8 A1*03 B1*0302 (anti-DGP) Half DQ2 heterodimer

Antibodies Associated with Celiac Disease IgA Antibody*Sensitivity Specificity Method Anti-gliadin %42-98% ELISA Anti-endomysial 75-98%96-100% Indirect IF Anti-tissue transglutaminase % 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

Normal ScallopedGluten-free diet CELIAC DISEASE Increased IELVillous atrophyRecovering ENDOSCOPY HISTOLOGY

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, B 12, 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% IMPROVE10% FAIL TO IMPROVE (within 2 weeks)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-  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 GliadinSymptomsPermeability Intestinal Biopsy 10 mgNo--Normal 50 mg* 100 mg Yes No -- Normal Minimal changes 500 mgYesIncreased More pronounced changes Catassi et al. GUT 1993; 34: 1515 Ciclitira et al. Clin Sci 1984; 66: 357 Catassi et al. Gastroenterol 2005;128:A253 *capsule of gluten

10 mg gliadin ~ 250 mg wheat flour (less than an 1/8 teaspoon flour)

Are Dietary Oats Tolerated? PATIENT # DISEASE STATUS DIETDURATIONSXS SMALL BOWEL BIOPSY 26 adults (26 control) remission oats (50-70g) gluten-free 6 monthsnosimilar to pre-oat 19 adults (21 control) new oats (50-70g) gluten-free 1 yearnoimproved 23 adults (28 control) 42 children (52 control) remission new oats ad-lib gluten-free oats ad-lib gluten-free 5 years 1 year no improved Janatuinen et al. NEJM 1995;333:1033 Gut 2002; 50: 332 Hogberg et al. Gut 2004;53:649 CELIAC DISEASE