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Celiac Disease

Celiac Disease. Moncton, May 27, 2007. F. Schweiger MD. Celiac sprue - Definiton. Intolerance to gluten proteins from wheat and to related proteins from barley or rye Presents with characteristic histopathological changes of the jejeunal mucosa

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Celiac Disease

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  1. Celiac Disease Moncton, May 27, 2007 F. Schweiger MD

  2. Celiac sprue - Definiton • Intolerance to gluten proteins from wheat and to related proteins from barley or rye • Presents with characteristic histopathological changes of the jejeunal mucosa • Consequences: from asymptomatic to global malabsorption and an increased risk to develop GI malignancies • Manifestation by genetic, environmental,and immunological factors

  3. Mortality of celiac sprue Before introduction of gluten-free diet: 544 children 12 % Hardwick 1939 (malabsorption and infection) After introduction of gluten-free diet (Dickie 1951): 485 children 0.4 % Sheldon 1969 653 adults 2 x increased Logan et al 1989 335 adults on GFD no increase Collin et al 1994

  4. Prevalence of Celiac Disease USA / Canada 1 in 100 Irish 1 in 152 Italians with “dyspepsia” 1 in 103 Swedish blood donors 1 in 256 Brazilians 1 in 680 Baltimore (USA) 1 in 300 • Rare in Afro-Caribbean, Chinese, Japanese • Mild female preponderance (2:1 at most)

  5. Triggers of celiac disease Infectious (viral bacterial) Diatetic (gluten) Genetic HLA-DQ2 Autoimmunity Immune-maturation Th2 Th1 Sprue

  6. Family Gramineae Subfamily Festucoideae Panicoideae Tribe Triticeae Aveneae Oryzeae Andropogoneae Paniceae Subtribe Triticineae Hordeinae Tripsacinae Anthrxoninae Genus Triticum Secale Hordeum Avena Oryza Zea Sorghum Pennisetum Wheat Rye Barley Oats Rice Corn Sorghum Millet

  7. Toxic wheat proteins Glutelins (glutenins of wheat) • Soluble in acids and bases • 45 % Glu Prolamines (gliadins of wheat) • Soluble in 50 – 70 % ethanol • 30 – 56 % Glu, 15 – 30 % Pro • Alpha, beta, gamma, delta gliadins • Toxic peptides: PSQQ, QQQP Gluten

  8. Environmental FactorsOATS • Oats may be tolerated by patients • Oats contain less QQQPF (toxic fraction in wheat gliadin) • Prolamines in oats have less glutamine and proline • Tolerance to oats depends on the amount consumed (less than 40 gm)

  9. Genetic factors • Concordance in monozygotic twins : 75 % • Risk to first degree relatives : 2 – 15 % (10 %) • Risk to 2nd degree relatives : 3 – 5 %

  10. Familial clustering of celiac disease/dermatitis herpetiformis 1.degree relatives number sprue/DH prevalence Parents 521 22 4.2 % Sisters/brothers 368 51 13.8 % Offspring 54 7 12.9 % 2.degree relatives 54 3 5.6 % Total 997 83 8.3 %

  11. Relatives: Who and How to Screen ? • Index case has proven celiac disease • Relative is interested in being screened • Relative is willing to undergo diagnostic testing • Relative is willing to undergo treatment • Relative will derive benefit from treatment • If relative is symptomatic, approach is diagnostic not screening S. Crowe, DDW 2007

  12. Classical presentation of celiac disease1960-ies, Helsinki, Finland Number 53 Age at initial symptoms (months) 7.7 Duration of gluten ingestion (months) 4.3 Age at admission (months) 10.2 Diarrhea 87 % Vomiting 74 % Growth retardation 98 % Weight below 2.5 percentile 70 % Distended abdomen 64 % Acta Ped Scand 1967

  13. Celiac Disease in Adults • 20 % over age 60 • Often mistaken for Irritable Bowel Syndrome • 50 % do not have diarrhea • Iron deficiency anemia most common presentation • Unmasking by gastric surgery • May present as recurrent “canker sores” • Significant fatty stools uncommon • Abdominal pain uncommon

  14. Atypical Presentations (1) • Nonspecific Weight loss, lethargy, fatigue • Hematological bruising (Vitamin K), anemia (iron,folate ,B12) hyposplenism (thrombocytosis) • Neurological cerebellar ataxia, peripheral neuropathy,post/lateral column abnormalities, neuromyopathies, epilepsy (+/-cerebral calcifications) demyelinating CNS lesions

  15. Atypical Presentations (2) • Musculoskeletal Osteoporosis, osteomalacia, #s osteoarthropathy,tetany,weakness dental enamel hypoplasia, • Gynecologic primary or secondary amenorrhea infertility, recurrent abortions • Dermatologic alopecia, follicular keratosis • Psychiatric depression, psychosis, schizophrenia

  16. Atypical Presentations (3) Endocrine : pubertal delay, short stature, 2nd hyperparathyroidism, infertility, impotence, amenorrhea

  17. Dietary Response -? Diagnostic • Placebo response in IBS up to 70 % • Gluten (increased prolamines) is hard to digest • GFD often eliminates other dietary factors • Symptomatic response to GFD, especially a transient response, does not imply the diagnosis of celiac disease

  18. Laboratory tests • Protein: Albumin, globulins, Liver tests • Carbs : glucose, Lactose-H breath test, (D-Xylose) • Fats : (stool for fat), lipid profile, carotene • Minerals : Ca, Mg, P, Fe, ferritin,zinc • Vitamins : RBC folate, B12, Vit A, 25-OH Vitamin D, PT

  19. Serologic Tests for Celiac Disease Serologic Test Sensitivity Specificity PPV NPV percent Anti-EMA (IgA) 85-98 97-100 99 93 IgA antigliadin 75-90 82-95 28-100 65-100 IgG antigliadin 69-85 73-90 20-95 41- 88 tTg (IgA) 92-98 95-98

  20. Epidemiology of Celiac Diseasethe sprue iceberg Clinical CD Abnormal mucosa Silent CD EMA present EMA present Asymptomatic Latent CD Normal mucosa Healthy individuals

  21. The asymptomatic patient • Advantages of screening: • Reduction in risk of enteropathic T-cell lymphoma • Reversal of unrecognized nutritional deficiences • Resolution of mild or unrecognized symptoms • Avoidance of other autoimmune disorders • Improvement of general well-being • Disadvantages of screening: • Lack of motivation to adhere to GFD • Adverse psychological effects Mass screening currently not advocated

  22. Pathology of celiac disease • Length of SB involvement correlates with clinical severity • GFD results in marked improvement beginning distally • Histology is not specific

  23. Causes of villous atrophy • Cow’s milk protein intolerance (children) • Post-gastroenteritis • Giardiasis • Peptic duodenitis (including ZES) • Crohn’s disease • Small intestinal bacterial overgrowth • Eosinophilic enteritis • Radiation or cytotoxic therapy • Tropical sprue • Severe malnutrition • Diffuse small intestinal lymphoma • Graft versus host disease • Hypogammaglobulinemia • Alpha chain disease

  24. Prevalence of autoimmune disease in celiac disease

  25. Dermatitis herpetiformis Insulin-dependent Diabetes Thyroid disease IgA deficiency Epilepsy with cerebral calcifications Inflammatory bowel disease Microscopic colitides IgA mesangial nephropathy Chronic autoimmune hepatitis Sclerosing cholangitis Primary biliary cirrhosis Down syndrome (3-12%) Turner syndrome Rheumatoid arthritis Sarcoidosis Bird fancier’s lung Fibrosing alveolitis Recurrent pericarditis Idiopathic pulmonary hemosiderosis Celiac disease and associated disordersDefinite Association

  26. Dermatitis herpetiformis • Papulovesicular lesions of extensor surfaces, buttocks, trunk, neck and scalp • Intensely pruritic • Early or middle adult life; M = F • 2/3 have patchy enteropathy; tends to be less severe • Less than 10 % have intestinal symptoms • 10 – 40 fold increased risk of lymphoma

  27. Dermatitis herpetiformis • Frequency of Abs to tTG only about 75 % • More than 80 % of pts with DH have sprue • 10 % of celiacs have DH • Tx: Dapsone 1 – 2 mg/kg (does not improve SB) • GFD allows most patients to reduce/stop Dapsone

  28. Celiac disease and type 1 DM Patients (n) Pos (%) Finland children (776) 2.4 Finland adults (195) 4.1 Italy children (498) 3.2 Italy adults (383) 2.6 Italy adults (639) 7.8 Sweden children (436) 4.6 Ireland adults (101) 4.9 UK adults (767) 2.0 Germ/Switz children (1032) 1.2 Australia children (273) 1.8 USA children (211) 1.4

  29. Celiac disease and Osteoporosis • Prevalence of CD is increased in osteoporosis (1.5-3%) Especially in premature osteoporosis/osteomalacia • Newly diagnosed CD : spine 28 % & hip 15 % • Patients with asymptomatic CD have increased risk • Postmenopausal females are at greatest risk

  30. Celiac disease and Osteoporosis • Vitamin D deficiency is common in CD • Bone mineral density increases with GFD, especially in the first year of treatment • Axial bone mass increases more then appendicular BMD

  31. Celiac disease and Osteoporosis • Adequate calcium and vitamin D intake • Regular weight bearing exercises • Smoking cessation; avoid alcohol • Correction of hypogonadism

  32. Celiac Disease and Osteoporosis

  33. Congenital heart disease Lung cavities Sjogren’s syndrome Systemic and cutaneous vasculitis SLE Polymyositis Schizophrenia Myasthenia gravis Iridocyclitis or choroiditis Cystic fibrosis Macroamylasemia Addison’s disease Autoimmune thrombocytopenic purpura Autoimmune hemolytic anemia Celiac disease and associated conditionsPossible association

  34. Celiac Disease and Malignancies 44/105 deaths during 13.5 years in 653 (untreated) patients from Edinburgh, Scotland Risk All malignancies 3 x Lymphoma 30 x Intestinal carcinoma 3 x Esophageal carcinoma 8 x Logan et al, Gastroenterology 1989

  35. Cancer and Celiac Disease 12, 000 celiac patients in Sweden over 30 years: • 6-fold increased risk of lymphoma (18% of all Ca) • Oropharyngeal Ca (SCC) • Esophageal Ca (SCC) • Small bowel Ca • Colon Ca - confined to subjects older than 60 • Primary liver Ca • Reduced occurrence of breast Ca Askling et al. Gastro 2002

  36. Celiac Disease and cancer Strict adherence to a GFD probably reduces the risk of enteropathy-associated T cell lymphoma as well as the other malignancies

  37. Treatment of Celiac Disease • Dietary counseling and strict avoidance of gluten • Initial avoidance of dairy products • Replacements of micronutrients in case of deficiencies • Corticosteroids/azathioprine for celiac crisis or refractory sprue

  38. Treatment of Celiac Disease • Non-compliance is an issue - eating out of home - peer pressure for children - less acceptable taste - accidental ingestion of G. - cost, availability, labelling • Use of oats, wheat starch controversial • GFD reduces risk of malignancy • Unclear how much gluten if any is safe - new FDA guidelines up to 10 mg/day safe ? S. Crowe, DDW 2007

  39. Response to Treatment • Clinical improvement in 2 weeks in 70 %, by 6 weeks in most • Serological improvement by 4 – 6 weeks • Histological improvement in up to 2 years • Gaining weight above ideal BMI • Constipation • Falling off the diet and getting ill again S. Crowe, DDW 2007

  40. Patient on GFD – no Biopsy! Celiac disease is possible and patient willing to undergo a gluten challenge YES, ideally get NO, but wants no further testing if genetic testing genetic testing wants to stay on GFD regardless of testing Challenge if DQ2 or DQ8 Positive; check Abs q 2 m EGD + Bx, if Ab +ve, +ve, increases -ve – not celiac dis. Symptoms develop or likelyhood of CD ? Use GFD for By 6 months suggest G challenge symptom control only S.Crowe, DDW 2007

  41. Gluten Challenge • Gradual increase of gluten in diet up to target (typically 4 slices of bread/day) • Check tTG at 4-6 weeks and at intervals thereafter until positive • Biopsy if diarrhea develops and/or become seropositive • Management if sero-negative at 3-6 months needs to be individualized S.Crowe, DDW 2007

  42. Treatment of celiac disease • Histology may not recover completely despite clinical normalization • Negativation of IgA anti-TTG after 4 – 6 months of a strictly gluten-free diet (GFD) • Diagnosis to be reconsidered when no clinical improvement is reached after 6 – 9 months of a GFD • Risk of malignancy approaches baseline after 5 years of a GFD

  43. Why a Gluten Free Diet ? • Benefits overall cancer risk • Improves unexplained infertility • Improves osteoporosis • Corrects iron deficiency • Improved QOL even for those detected by screening GFD is beneficial for preventing, reversing and/or treating some complications

  44. Summary • Celiac disease is not rare (1 in 100-300) • It can present in many ways iron deficiency anemia, depression, osteoporosis, abnormal liver tests, non-specific or IBS-like symptoms, dyspepsia, DH, recurrent miscarriages, microscopic colitis • Associated with autoimmune diseases • Screening with tTG IgA is best • Confirm diagnosis with duodenal biopsy • Cornerstone of treatment is avoidance of gluten

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