Celiac Disease: Exploring the Iceberg

1. Celiac Disease:Exploring the Iceberg Stefano Guandalini, M.D. Professor of Pediatrics Chief, Section of Gastroenterology, Hepatology and Nutrition University of Chicago

2. We’ll talk about... • How we define celiac disease • Who gets it and how? • How common it is • What are its clinical manifestations • What conditions can accompany it • Complications • How it is diagnosed and treated

3. Definition Celiac disease is a permanent condition affecting primarily the intestine and caused by an abnormal reaction to gluten occurring in the immune (defense) system of the gut of individuals who possess certain genes. It leads to gastrointestinal and non-gastrointestinal symptoms, but it my as well be asymptomatic. Indeed, celiac disease occurs more often in people who have few or no symptoms!

4. Flattened villi Malabsorption Normal villi Absorption Gluten

5. Where is gluten found?

6. I’m Innocent!! Where is gluten found? The Grass Family - (GRAMINEAE) Subfamily Tribe Festucoideae Zizaneae Oryzeae Hordeae Aveneae Festuceaea Chlorideae wild rice ricewheat oat finger millet teff (ragi) rye barley

7. And what exactly is it? Gluten is made up by Gliadin and Glutenin A (huge!) grain of wheat Some well-identified pieces (called “peptides”)of gliadin are resistant to digestion in the gut and are toxic for celiac patients

8. We’ll talk about... • How we define celiac disease • Who gets it and how? • How common it is • What are its clinical manifestations • What conditions can accompany it • Complications • How it is diagnosed and treated

9. Gluten HLA is not DQ2, DQ8 Who gets celiac disease? Nothing....

10. Other necessary Risk Factors Gluten Infant feeding Infections... HLA is either DQ2 or DQ8 Who gets Celiac Disease? Celiac Disease

11. Breast feeding and celiac disease Odds ratios (95% CI) of effect of breast feeding at the time of gluten introduction on development of CD. Akobeng AK et al., Arch Dis Child 2006

12. Timing of gluten introduction and risk of celiac disease autoimmunity- A prospective study on 1560 children at risk 1307 children followed from birth: 996 for cord blood HLA-DR3 311 for FH of IDDM 253 children enrolled at age 2-3 for FH of IDDM Interviews with telephone questionnaire At age 3, 6, 9, 12, 15 months Same dietary information collected retrospectively Blood drawn for celiac serology (TG2) at 9, 15, 24 m and then annually Blood drawn for celiac serology (TG2) at enrollment and then annually Norris JM et al., JAMA 2005

13. Timing of gluten introduction and risk of celiac disease autoimmunity- A prospective study on 1560 children at risk Norris JM et al., JAMA 2005

14. Does the amount of gluten matter?

15. Amount of gluten at weaning and celiac diseaseThe Swedish experience Ivarsson A et al., Eur J Epidemiol 2003

16. “The rise in incidence was preceded by a twofold increase in the average daily consumption of gluten, and later the decline in incidence coincided with a consumption decrease by one third.” Hernell O et al., Celiac Disease: Effect of Weaning on Disease Risk, 2005

17. Take-home message: celiac disease can be prevented!

18. Does the timing of gluten introduction influence the timing of appearance and/or the presenting symptoms of celiac disease?

19. Breast feeding at time of gluten introduction influences the presenting symptoms of celiac disease P<0.01 % Symptoms at diagnosis Guandalini S., UCCDP – n=92 pts., in press

20. Changing pattern of celiac disease according to age at presentation % Guandalini S., UCCDP – n=92 pts., in press

21. In summary, the role of environmental factors in celiac disease • Breast feeding reduces the risk of celiac disease and/or at least delays its onset. • Introducing gluten at 4-6 months seems to be associated with the lowest risk of celiac disease. • Infants non breast-fed at the time of gluten introduction seem to be more likely to develop typical (GI) celiac disease. • To reduce risk of celiac disease, gluten should be introduced in small amounts. • Intestinal infections – especially by Rotavirus – increase the risk of developing celiac disease

22. We’ll talk about... • How we define celiac disease • Who gets it and how? • How common it is • What are its clinical manifestations • What conditions can accompany it • Complications • How it is diagnosed and treated

23. How common is celiac disease? Currently accepted worldwide Prevalence (in Caucasians): 1% Projected number of celiacs in North America: about 3,000,000 Actual number of known celiacs: about 50,000 For each known celiac there are 53 undiagnosed patients.

24. The Celiac Iceberg Symptomatic Celiac Disease Intestine is damaged Silent Celiac Disease Intestine appears normal Latent Celiac Disease Genetic susceptibility: - DQ2, DQ8 Positive serology

25. We’ll talk about... • How we define celiac disease • Who gets it and how? • How common it is • What are its clinical manifestations • What conditions can accompany it • Complications • How it is diagnosed and treated

26. Clinical Manifestations • Gastrointestinal symptoms/signs (“typical”) • Non-gastrointestinal symptoms/signs (“atypical”) Symptomatic Celiac disease • Celiac Disease may also be associated with other conditions, • and mostly with: • Autoimmune disorders • Some syndromes

27. Gastrointestinal symptoms Most common age of presentation: 6-24 months • Chronic or recurrent diarrhea • Constipation • Anorexia • Failure to thrive or weight loss • Abdominal pain, bloating • Vomiting

28. Typical Celiac Disease

29. London, 1938

30. Children with Celiac Disease

31. Non Gastrointestinal symptoms Most common age of presentation: older child to adult • Dermatitis Herpetiformis • Dental enamel hypoplasia of permanent teeth • Osteopenia/Osteoporosis • Short Stature • Delayed Puberty • Iron-deficient anemia resistant to oral Fe • Liver disease • Arthritis • Neurological problems • Psychiatric Disorders • Women Sub-In-fertility and/or miscarriages and/or low birth babies

32. The list keeps growing • Idiopathic dilated cardiomyopathy • Pancreatitis (ESPGHAN 2007) • Cardiac valves involvement (ESPGHAN 2007)

33. Erythematous macules > urticarial papules > tense vesicles Severe itching Most have no GI symptoms 75% Gluten dependent villous atrophy Serology positive in only 30-40% Dermatitis Herpetiformis

34. It’s not just DH!Other skin disorders possibly associated with celiac disease • Urticaria • Hereditary angioneurotic edema • Cutaneous vasculitis • Erythema nodosum • Psoriasis • Vitiligo • Dermatomyositis • Alopecia aerata… Abenavoli L et al., World J Gastroenterol 2006

35. Dental Enamel Defects Involve the permanent teeth and can be the only presenting sign of Celiac Disease

36. Low bone density (Osteoporosis) Normal Peak Bone Mass can be achieved at puberty by celiac children on a GFD, but only if the diet is strict!

37. Short Stature/Delayed Puberty Can anyone guess how many children who are short have celiac disease as cause of their reduced height? • Short stature in children / teens: ~10% of short children and teens are celiacs • Delayed onset of menstrual periods:  Not uncommon in teen girls with untreated Celiac Disease

38. Anemia • Considered the most common non-GI manifestation in older teenagers and adults • 5-8% of adults with unexplained iron deficiency anemia have Celiac Disease • In children with newly diagnosed Celiac Disease:  Anemia is very common  However, in children presenting with anemia only, celiac disease is not very frequent

39. Liver disease: A study on 14,000 CD patients and 67,000 controls Highly statistically (p<0.001) increased risk for the following conditions in celiac disease (occurring before and after diagnosis) is shown for: • Acute and chronic hepatitis • Primary sclerosing cholangitis • Fatty liver • Liver failure • Liver cirrhosis or fibrosis • Primary biliary cirrhosis Ludvigsson JF et al. Clin Gastroenterol Hepatol 2007

40. Arthritis and Neurological Problems • Arthritis in adults • Fairly common, including those on gluten-free diets • Juvenile chronic arthritis • Up to 3% have Celiac Disease • Neurological problems in teenagers and adults • Cerebellar ataxia (abnormal gait) • Peripheral neuropathies • Epilepsy with cranial calcifications

41. Asymptomatic • Silent:No symptoms Damaged mucosa Positive serology(=elevated celiac antibodies in the blood) Silent Latent • Latent: No symptomsNormal mucosaPositive Serology (=elevated celiac antibodies in the blood)

42. We’ll talk about... • How we define celiac disease • Who gets it and how? • How common it is • What are its clinical manifestations • What conditions can accompany it • Complications • How it is diagnosed and treated

43. Other conditions can be associated with celiac disease The prevalence of Celiac Disease is higher in patients who have the following: • Relative of a celiac person • Certain genetic disorders or syndromes • Other autoimmune conditions

44. Associated Conditions 20 16 12 percentage 8 4 General Population 0 Relatives Down syndrome Thyroiditis IDDM

45. Celiac Disease and Autoimmunity The Prevalence Of Autoimmune Disorders Increases As Diagnosis Is Delayed p = 0.000001 Age at diagnosis (years) Ventura A et al., Gastroenterology 1999

46. We’ll talk about... • How we define celiac disease • Who gets it and how? • How common it is • What are its clinical manifestations • What conditions can accompany it • Complications • How it is diagnosed and treated

47. Refractory celiac disease and related disorders Intestinal lymphoma Reduced life expectancy (if not on the diet!) Major Complications of Celiac Disease

48. Effects of Diagnostic Delay and Adherence to GFD on Mortality in Celiac Patients Corrao et al., Lancet Aug 2001

49. ‘‘The most important diagnostic test in CD is the suspicion of the disease.’’ NIH consensus 2004

50. The role of serology