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Jamie S. Barkin, M.D., MACP, MACG, AGAF, FASGE Professor of Medicine University of Miami, Miller School of Medicine Chie PowerPoint Presentation
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Jamie S. Barkin, M.D., MACP, MACG, AGAF, FASGE Professor of Medicine University of Miami, Miller School of Medicine Chie

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Jamie S. Barkin, M.D., MACP, MACG, AGAF, FASGE Professor of Medicine University of Miami, Miller School of Medicine Chie

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  1. CELIAC DISEASE: THE GREAT IMPOSTER Jamie S. Barkin, M.D., MACP, MACG, AGAF, FASGE Professor of Medicine University of Miami, Miller School of Medicine Chief, Division of Gastroenterology Mt. Sinai Medical Center

  2. Introduction • Celiac disease is a genetically-determined autoimmune condition that can present at any age • It is a permanent intolerance to the gliadin fraction of proteins in wheat, barley and rye • Prevalence 1:100 to 1:150 persons • Caucasians are more at risk than other races McGough N, Cummings JH. Proc Nutr Soc 2005;64:434-450 Marmouz F. Eur Ann Allergy & Clin Immunology 2007;39:23-25

  3. Prevalence of Celiac Disease Healthy population - 1:133 1st degree relatives - 1:18 to 1:22 2nd degree relatives - 1:24 to 1:39 Fasano, et al. Arch Intern Med 2003;163:286-92

  4. Celiac Disease Three peaks: • Infancy • Second to third decade of life • Fifth to sixth decade of life Delay in diagnosis – 7 years Ciclitira PJ. Nature Clinical Practice Gastroenterology & Hepatology 2007 (4);9:483

  5. The Celiac Iceberg Manifest mucosal lesion Symptomatic Celiac disease Silent celiac disease Normal mucosa Latent Celiac Disease Genetic susceptibility – DQ2, DQ8 Positive serology (Adapted) CDHNF - NASPGHAN

  6. Stages of Celiac Disease Symptom Serology Histology Latent - + - Silent - + + Diarrhea + + +

  7. Spectrum of Celiac Disease Biopsy Symptoms Malabsorption Villous Atrophy 1% IEL Atypical/Asymptomatic

  8. Does clinical presentation correlate with degree of villous atrophy in patients with celiac disease? • Classical presentation– diarrhea and weight loss symptoms • Atypical or silent presentation – anemia, osteoporosis or dermatitis herpetiformis Aim: To evaluate the correlation between the clinical presentation of patients with celiac disease and the degree of villous atrophy Results: • 499 patients, more of whom had atypical or silent celiac disease than classical presentation – 56% vs. 44% • Clinical presentation did not correlate with the degree of villous atrophy in patients with celiac disease www.nature.com/clinicalpractice/gasthep

  9. Celiac Disease World-Wide • Iran - common finding among patients labeled as irritable bowel syndrome (11%) in Iran • India - common cause of chronic diarrhea both in children and in adults • Central America/Puerto Rico/South America - under-diagnosed

  10. Conditions more common in celiac disease (Adaptation) McGough N, Cummings JH. Proc Nutr Soc 2005;64:434-450

  11. Associations of CD • Hematological: IgA – deficiency, hemolytical anemia, thrombopenic purpura • Nephrological: IgA – nephropathy • Hepatic and digestive: primary biliary cirrhosis, Crohn’s disease and colorectal bleeding • Lupus, Sjögren’s syndrome myasthenia, rheumatoid arthritis, polyarthritis • Atopia, asthma, disease of farmer’s lung or poultry breeders Marmouz F. Eur Ann Allergy & Clin Immunology 2007;39:23-25

  12. Pathophysiology of celiac disease • Malabsorption of nutrients, especially iron, folate, calcium and vitamin D • Increased intestinal permeability may permit entry of other toxins which might induce autoimmune diseases CDHNF - NASPGHAN

  13. Incidence of autoimmune diseases in celiac disease (CD): protective effect of the gluten-free diet AIM: To determine which factors modulate the risk of autoimmune disease and to evaluate the effect of gluten-free diet in 924 celiac patients Results • The cumulative risk of autoimmune disease was 8.1% ±1% at age 15, and 15.7%± 1.5% at age 30 • Factors associated with an increased risk were family history of autoimmunity and diagnosis of CD before age 36 Cosnes J, et al. Clinical Gastroenterology and Hepatology 2008;;6:753-758

  14. Incidence of autoimmune diseases in celiac disease (CD): protective effect of the gluten-free diet (Cont) Results • After CD diagnosis, 55/788 patients developed an autoimmune disease • The cumulative risk of subsequent autoimmune disease was lower in patients compliant to a gluten-free diet vs. noncompliant patients • The incidence of autoimmune diseases was 5.4 per 1000 patient-years during adherence to a gluten-free diet vs. 11.3 per 1000 patient-years during non-adherence to the diet Cosnes J, et al. Clinical Gastroenterology and Hepatology 2008;;6:753-758

  15. Factors in celiac disease • Genetic susceptibility • Immune system • Environment - Gluten in diet

  16. Genetics and pathogenesis of celiac disease • Concordance is 75 – 90% in monozygotic twins and 10 – 20% in dizygotic twins • In first-degree relatives the prevalence is 10% and in second-degree relatives it is 2% • Patients with CD (95%) carry the human leukocyte antigen (HLA, HLA-DQ2 or HLA-DRB*4 DQ8) McGough N, Cummings JH. Proc Nutr Soc 2005;64:434-450

  17. Non-dietary factors • Infections • Viral infections • Sequence homology between -gliadin and adenovirus type 12 & 7, rubella and human herpes-virus 1 • Parasitic infestations • sequence homology between -gliadin and plasmodium yoelli • Other ? CDHNF - NASPGHAN

  18. Dietary Factors • Wheat – (15% protein, 75% starch) Gluten Gliadin Glutenin (alcohol soluble) Prolamine (alcohol insoluble) • Rye prolamines – secalines • Barley prolamines – hordeins • Oats are safe CDHNF - NASPGHAN

  19. Mucosal events • Epithelial cell infiltration • increased IEL’s – (>90% CD8, <10% CD4) • increased mucosal / T cells (nl <10%) • role of / cells in celiac disease is unknown • Mucosal surface alterations • loss of epithelial cells • proliferation of crypt epithelial cells CDHNF - NASPGHAN

  20. Humoral response in celiac disease • Humoral response • Enhanced antibody production • Anti-tissue transglutaminase • Anti-gliadin • ? Other auto-antigens (anti-actin) • Mechanism of antibody production unknown CDHNF - NASPGHAN

  21. Expanded Definition of celiac disease • Celiac disease is an autoimmune condition • Occurs in genetically susceptible individuals • DQ2 and/or DQ8 positive HLA haplotype is necessary but not sufficient • A unique autoimmune disorder because: • Both the environmental trigger (gluten) and the auto-antigen (tissue transglutaminase) are known • Elimination of the environmental trigger leads to a complete resolution of the disease CDHNF - NASPGHAN

  22. Celiac Disease and autoimmunity • Prevalence of autoimmune disorders in celiac disease related to duration of gluten exposure • Diagnosed before 2 years of age: 5% • Age 2-10 years: 17% • Greater than age 10 years: 24% • Increased incidence of autoimmune disease in patients with IDDM and ‘silent’ celiac disease and their first-degree relatives who were EMA+ Ventura et al. Gastro 1999; Not, Diabetologia 2001

  23. Prevalence of celiac disease is higher in other autoimmune conditions CDHNF - NASPGHAN

  24. Visible Iceberg of CD Diarrhea Abdominal pain Weight loss Constipation Bloating

  25. Presenting features of celiac disease • Adults • Diarrhea, altered bowel habit including constipation • Abdominal pain, dyspepsia, bloating • Aphthous ulcers – mouth • Anemia (fe or folate and rarely vitamin B-12) • Weight loss • Dermatitis herpetiformis • Malabsorption, edema • Osteoporosis, low impact fracture McGough N, Cummings JH. Proc Nutr Soc 2005;64:434-450

  26. Invisible Part of the Iceberg • Hematological: iron deficiency anemia • Rheumatologic: demineralization, arthralgias fractures • Neurological: peripheral neuropathy (lack of), epilepsy (and cerebral calcifications) ataxia (vitamin E deficiency?), Migraine • Digestive: stimulating functional, mouth ulcers, unexplained increase of transaminases and rare severe hepatopathy • Gynecological: infertility, amenorrhea, fetal hypotrophy, miscarriages Marmouz F. Eur Ann Allergy & Clin Immunology 2007;39:23-25

  27. Increased overall mortality in adult life Secondary to increased: • Autoimmune diseases • Osteoporosis • Liver diseases • Cancer CDHNF - NASPGHAN

  28. COMPLICATIONS

  29. Potential Nutritional Complications in Untreated Celiac Disease CDHNF - NASPGHAN

  30. Potential Nutritional Complications in Untreated Celiac Disease CDHNF - NASPGHAN

  31. Iron deficiency anemia resistant to oral iron • One of the most common non-GI manifestation in adult studies • 5 – 8% of adults with unexplained iron deficiency anemia have celiac disease • In children with newly diagnosed celiac disease • Anemia is common • Little evidence that celiac disease is common in children presenting with anemia CDHNF - NASPGHAN

  32. Bone Disease in Celiac Disease • Arthritis • Osteoporosis • Osteopenia • Osteomalacia • Rickets CDHNF - NASPGHAN

  33. Bones and Celiac Disease • CD presenting with classic malabsorptive symptoms was the association with bone disease, particularly osteomalacia (Bennet et al, 1932) • Reduced bone mineral density, osteopenia or osteoporosis in 20 – 50% of the patients newly diagnosed with CD (Butcher, et al 1992; Corazza, et al 1995, 1996; Mc Farlane et al, 1995; Kemppainen et al, 1999; Cellier et al 2000; Meyer et al 2001) • The consequences of these bone changes are probably an increase in aches and pains Cont McGough N, Cummings JH. Proc Nutr Soc 2005;64:434-450

  34. Bones and Celiac Disease • Increased fracture is reported , but the risk is small • Patients who presented subclinically with anemia or osteopenia or just on screening, the fracture risk is not increased compared with the controls • BMD does improve with a GFD but may not return to that seen in a matched population (Corraza et al. 1995; McFarlane et al 1995; Sategna-Guidetti et al. 2000; Pazianas et al. 2005)

  35. Risk of cancer in celiac disease (Adaptation) McGough N, Cummings JH. Proc Nutr Soc 2005;64:434-450

  36. “Hepatitis” and Celiac Disease • Evidence for elevated serum transaminases (ALT, AST) in adults with untreated celiac disease • Up to 9% of adults with elevated ALT, AST may have silent celiac disease • Liver biopsies in these patients showed non-specific reactive hepatitis – may simulate NASH • Liver enzymes normalized on gluten-free diet CDHNF - NASPGHAN

  37. Celiac disease screening amongst women of reproductive age • A Swedish cohort study compared 2078 births by women diagnosed with celiac disease prior to or after the birth of an infant with the background child-bearing population Result: • Undiagnosed maternal celiac disease at birth was strongly linked to low or very low infant birth weight, lower placental weights and higher Cesarean section rate Ludvigsson JF et al. Gastroenterology 2005;129:454-463

  38. Dermatitis Herpetiformis • Erythematous macule >urticarial papule > tense vesicles • Severe pruritus • Symmetric distribution • 90% no GI symptoms • 75% villous atrophy • Gluten sensitive Garioch JJ et al. Br J Dermatol 1994;131:822-6 Fry L. Baillieres Clin Gastroenterol 1995;9:371-93 Reunala T, et al. Br J Dermatol 1997;136:315-8

  39. Diagnostic principles of celiac disease • Confirm diagnosis before treating • Diagnosis of celiac disease mandates a strict gluten-free diet for life • following the diet is not easy • QOL implications • Failure to treat has potential long-term adverse health consequences • Increased morbidity and mortality CDHNF - NASPGHAN

  40. Role of serological tests in Celiac Disease • Identify symptomatic individuals who need biopsy • Screening of asymptomatic “at risk” individuals who need a biopsy • Supportive evidence for the diagnosis • Monitoring dietary compliance CDHNF - NASPGHAN

  41. Serological tests • Antigliadin antibodies (AGA) • Antiendomysial antibodies (EMA) • Anti-tissue transglutaminase antibodies (TTG) • First generation (guinea pig recombinant • Second generation (human recombinant) • HLA typing CDHNF - NASPGHAN

  42. Serological Test Comparison Farrell RJ, Kelly CP. Am J Gastroenterol 2001;96:3237-46

  43. Anti-gliadin antibodies (AGA) • Sensitivity and specificity do not exceed 80% • The specificity of AGA IgA is approximately 50% • False positive results can be found in patients with esophagitis, gastroenteritis, inflammatory bowel diseases Basso D, et al Lupus 2006;15:462-465

  44. Serology diagnosis of celiac disease • Tissue transglutaminase is the serological test of choice for the diagnosis of CD • Selective IgA deficiency is found in 2-3% of individuals with CD and affects not only tTg IgA antibodies but also EMA and AGA IgA antibodies • Both IgA and IgG AGA antibodies are present in the sera of patients with CD, although they are not specific because gliadin crosses the normal gut mucosa, and approximately 5 -10% of the healthy population will be positive, particularly older individuals McGough N, et al Proceedings of the Nutrition Society 2005;64;434-450

  45. Biopsy diagnosis of celiac disease Histological Features: • Increased IEL’s (>30/100 enterocytes) • Loss of nuclear polarity • Change from columnar to cuboid • Lamina propria cellular infiltrate • Crypt elongation and hyperplasia • Increased crypt mitotic index • Progressive villous flattening CDHNF - NASPGHAN

  46. Role of “Routine” Small Bowel Biopsy at Endoscopy • Current practices by pediatric GI physicians • Rationale: • Celiac disease is common and endoscopic appearance may look normal • Era of open access endoscopy • Routine biopsy in high-risk groups • Family members • Chronic liver disease • IBS, IDDM, IBD, Sjögren syndrome • Down’s syndrome • Patients with atypical symptoms

  47. Mucosal Differential Diagnosis of Immunopathology • Celiac • Giardiasis • Milk intolerance • Tropical sprue • GVHR Marsh, Gastroenterol 1992;102:330-354

  48. Two main problems when considering screening • ~25 – 30% of individuals with positive screening serological tests may have normal biopsies. It is unclear whether these individuals have early or mild celiac disease, false positive tests or variable production of autoantibody of unclear prognostic value • Compliance with gluten-free diet is poor when symptoms are mild or absent and when diagnosis is made beyond childhood Liu E, et al Clin Gastroenterol Hepatol 2003;(1):356-362

  49. TREATMENT

  50. Gluten-Containing Grains to Avoid CDHNF - NASPGHAN