1. Celiac Disease in Children Dascha C. Weir, MD Boston Children’s Hospital Harvard Medical School Gluten Free for Life Conference April 11, 2015

2. Disclosures I have no relevant disclosures

3. Celiac Disease

4. ADULTS CHILDREN and

5. Celiac Disease ADULTS CHILDREN

6. Willem-Karel Dicke Celiac Disease: Roots in Pediatrics Association of Celiac Disease and Gluten NASPGHAN

7. Historical Perspective Definition: “…a condition, seen primarily in infancy and childhood, where there exists a prolonged intermittent diarrheal state resulting in various degrees of malnutrition…that may be reversed and caused to disappear by a specific mode of treatment…the specific carbohydrate diet” 1951

8. “Classical” Celiac Disease Classic Gastrointestinal Manifestations with signs/symptoms of malabsorption Chronic or recurrent diarrhea Abdominal distension Poor appetite Failure to thrive or weight loss Abdominal pain Vomiting Irritability Muscle Wasting Haas, 1951

9. “Classical” Celiac Disease Positive celiac serology and biopsy confirmed celiac disease.

10. Celiac Disease Today Recognized to occur in all age groups: Not just in toddlers and young children At Boston Children’s Hospital: The average age of diagnosis is 10.5 years

11. Celiac Disease Today “Classical” presentation is no longer typical Increasing understanding = increasing rates of diagnosis At Boston Children’s Hospital: Average of 3 new cases diagnosed each week

12. Pediatric Celiac Disease Then NASPGHAN

13. Pediatric Celiac Disease Today ID 9047413 © Godfer | Dreamstime.comGodfer

14. Who Develops Celiac Disease? Slight female predominance (65%) Associated conditions: Autoimmune diseases- Type 1 diabetes mellitus (5-8%) Autoimmune thyroiditis (4%) Genetic disorders - Down syndrome (5%) Williams syndrome Turners syndrome Family members of patients with celiac disease

15. “Non-Classical” Presentation Anemia / Iron deficiency Aphthous stomatitis Arthritis Ataxia Behavioral Problems Constipation Dental enamel defects Depression Dermatitis herpetiformis Epilepsy with intracranial calcifications Headaches Hypotonia Neuropathy Osteopenia/osteoporosis Pancreatic enzyme elevation Pubertal delay Recurrent abdominal pain Short stature Transaminase elevation

16. “Non-Classical” Presentation Anemia / Iron deficiency Aphthous stomatitis Arthritis Ataxia Behavioral Problems Constipation Dental enamel defects Depression Dermatitis herpetiformis Epilepsy with intracranial calcifications Headaches Hypotonia Neuropathy Osteopenia/osteoporosis Pancreatic enzyme elevation Pubertal delay Recurrent abdominal pain Short stature Transaminase elevation

17. “Non-Classical” Presentation Anemia / Iron deficiency Aphthous stomatitis Arthritis Ataxia Behavioral Problems Constipation Dental enamel defects Depression Dermatitis herpetiformis Epilepsy with intracranial calcifications Headaches Hypotonia Neuropathy Osteopenia/osteoporosis Pancreatic enzyme elevation Pubertal delay Recurrent abdominal pain Short stature Transaminase elevation

18. “Non-Classical” Presentation Anemia / Iron deficiency Aphthous stomatitis Arthritis Ataxia Behavioral Problems Constipation Dental enamel defects Depression Dermatitis herpetiformis Epilepsy with intracranial calcifications Headaches Hypotonia Neuropathy Osteopenia/osteoporosis Pancreatic enzyme elevation Pubertal delay Recurrent abdominal pain Short stature Transaminase elevation

19. “Non-Classical” Presentation Anemia / Iron deficiency Aphthous stomatitis Arthritis Ataxia Behavioral Problems Constipation Dental enamel defects Depression Dermatitis herpetiformis Epilepsy with intracranial calcifications Headaches Hypotonia Neuropathy Osteopenia/osteoporosis Pancreatic enzyme elevation Pubertal delay Recurrent abdominal pain Short stature Transaminase elevation

20. “Non-Classical” Presentation Anemia / Iron deficiency Aphthous stomatitis Arthritis Ataxia Behavioral Problems Constipation Dental enamel defects Depression Dermatitis herpetiformis Epilepsy with intracranial calcifications Headaches Hypotonia Neuropathy Osteopenia/osteoporosis Pancreatic enzyme elevation Pubertal delay Recurrent abdominal pain Short stature Transaminase elevation

21. BCH Database 2001-2015 Presenting Symptoms, (n=1520) SymptomPercent Abdominal pain/cramps55.4 Abdominal distension13.5 Diarrhea/loose stools25.1 Constipation/hard stools31.1 Nausea/vomiting22.8 Decreased appetite10.1 Increased fatigue15.1 Weight loss/poor weight gain26.3 Short stature/poor growth15.4 Frequent mouth ulcers 3.9 Joint symptoms 4.9 NO SYMPTOMS7.8 Children under 3 years usually have gastrointestinal symptoms

22. Examples from BCH Celiac clinic 4 year old with abdominal distension.

23. Examples from BCH Celiac clinic 4 year old with abdominal distension. Mild constipation and rare episodic abdominal pain.

24. Examples from BCH Celiac clinic 4 year old with abdominal distension. Mild constipation and rare episodic abdominal pain. Decelerated weight gain.

25. Examples from BCH Celiac clinic 4 year old with abdominal distension. Mild constipation and rare episodic abdominal pain. Decelerated weight gain. Positive celiac serology and biopsy confirmed celiac disease.

26. Examples from BCH Celiac clinic 8 year old with slowing linear growth and weight gain deceleration.

27. Examples from BCH Celiac clinic 8 year old with slowing linear growth and weight gain deceleration. Mild intermittent abdominal pain previously attributed to school anxiety.

28. Examples from BCH Celiac clinic 8 year old with slowing linear growth and weight gain deceleration. Mild intermittent abdominal pain previously attributed to school anxiety. Positive celiac serology and biopsy confirmed celiac disease.

29. Examples from BCH Celiac clinic 14 year old with delayed puberty and poor weight gain. No other signs or symptoms.

30. Examples from BCH Celiac clinic 14 year old with delayed puberty and poor weight gain. No other signs or symptoms. Positive celiac serology and biopsy confirmed celiac disease.

31. Pediatric Complications Nutritional deficiencies Stunted growth Osteopenia Comorbid autoimmune disease Non- responsive celiac disease

32. Persistent Diarrhea + FTT Persistent GI symptoms Short Stature/Delayed Puberty Dental enamel defects Persistent anemia First Degree Relative Diabetes Mellitus Thyroiditis Down Syndrome Turner Syndrome Williams Syndrome

33. Persistent Diarrhea + FTT Persistent GI symptoms Short Stature/Delayed Puberty Dental enamel defects Persistent anemia First Degree Relative Diabetes Mellitus Thyroiditis Down Syndrome Turner Syndrome Williams Syndrome TTG IgA and Total IgA TTG Abnormal? Unlikely CD Consult GI Endoscopic duodenal biopsies Histopathology of CD? Gluten free Diet NO YES

34. Persistent Diarrhea + FTT Persistent GI symptoms Short Stature/Delayed Puberty Dental enamel defects Persistent anemia First Degree Relative Diabetes Mellitus Thyroiditis Down Syndrome Turner Syndrome Williams Syndrome TTG IgA and Total IgA TTG Abnormal? Unlikely CD Consult GI Endoscopic duodenal biopsies Histopathology of CD? Gluten free Diet NO YES

35. Seronegative, IgA sufficient child No further testing unless: -Less than 2 yrs of age -Predisposing diseases -Family predisposition -Severe symptoms -Restricted gluten exposure -Use of immunosuppressive medication With symptoms AND strong clinical suspicion, small intestinal biopsies and HLA testing indicated Consider non-celiac gluten sensitivity

36. Persistent Diarrhea + FTT Persistent GI symptoms Short Stature/Delayed Puberty Dental enamel defects Persistent anemia First Degree Relative Diabetes Mellitus Thyroiditis Down Syndrome Turner Syndrome Williams Syndrome TTG IgA and Total IgA TTG Abnormal? Unlikely CD Consult GI Endoscopic duodenal biopsies Histopathology of CD? Gluten free Diet “Potential” Celiac Review Pathology Monitor Repeat serology Consider repeat biopsy Genetics ? NO YES NO

37. Persistent Diarrhea + FTT Persistent GI symptoms Short Stature/Delayed Puberty Dental enamel defects Persistent anemia First Degree Relative Diabetes Mellitus Thyroiditis Down Syndrome Turner Syndrome Williams Syndrome TTG IgA and Total IgA TTG Abnormal? Unlikely CD Consult GI Endoscopic duodenal biopsies Histopathology of CD? Gluten free Diet “Potential” Celiac Review Pathology Monitor Repeat serology Consider repeat biopsy Genetics ? NO YES NO

38. Potential Celiac Disease Potential Celiac Disease: Individuals with a normal small intestinal mucosa who are at increased risk of developing CD as indicated by positive CD serology Oslo Definitions for coeliac disease and related terms. Gut 2013.

39. Potential CD in children 210 children with potential celiac disease (at least 2 positive TTGs, positive EMA, no villous atrophy and HLA DQ2 or DQ8) 16% had autoimmune disease (T1DM or thyroiditis) 175 were asymptomatic and were kept on a gluten-containing diet Antibodies/clinical symptoms checked every 6 months Small bowel biopsies taken every 2 years Followed for up to 9 years (at least 5 years) with a retention rate of 63% Aurricchio et al. Potential Celiac Children: 9- year Follow-up on a Gluten containing Diet. American Journal of Gastroenterology. April 2014.

40. Potential CD in children Serologic course: 43% persistently elevated 20% became negative 37% with fluctuant levels Histologic course: At 3 years: 86% remained potential At 6 years: 73% remained potential At 9 years: 67% remained potential 33 % developed CD Aurricchio et al. Potential Celiac Children: 9- year Follow-up on a Gluten containing Diet. American Journal of Gastroenterology. April 2014.

41. Persistent Diarrhea + FTT Persistent GI symptoms Short Stature/Delayed Puberty Dental enamel defects Persistent anemia First Degree Relative Diabetes Mellitus Thyroiditis Down Syndrome Turner Syndrome Williams Syndrome TTG IgA and Total IgA TTG Abnormal? Unlikely CD Consult GI Endoscopic duodenal biopsies Histopathology of CD? Gluten free Diet “Potential” Celiac Review Pathology Monitor Repeat serology Consider repeat biopsy Genetics ? NO YES NO

42. Persistent Diarrhea + FTT Persistent GI symptoms Short Stature/Delayed Puberty Dental enamel defects Persistent anemia First Degree Relative Diabetes Mellitus Thyroiditis Down Syndrome Turner Syndrome Williams Syndrome TTG IgA and Total IgA TTG Abnormal? Unlikely CD Consult GI Endoscopic duodenal biopsies Histopathology of CD? Gluten free Diet “Potential” Celiac Review Pathology Monitor Repeat serology Consider repeat biopsy Genetics ? NO YES NO

43. Diagnosis without biopsies? ESPGHAN Guidelines, 2012 GFD without biopsy can be initiated if: -Signs or symptoms suggestive of CD -TTG IgA > 10 times upper limit of normal (200) -EMA positive in second blood sample HLA testing “advisable” to reinforce the diagnosis of CD ESPGHAN Guidelines for the Diagnosis of Coeliac Disease. JPGN. January 2012.

44. Persistent Diarrhea + FTT Persistent GI symptoms Short Stature/Delayed Puberty Dental enamel defects Persistent anemia First Degree Relative Diabetes Mellitus Thyroiditis Down Syndrome Turner Syndrome Williams Syndrome TTG IgA and Total IgA TTG Abnormal? Unlikely CD Gluten free Diet NO Active symptoms consistent with CD Highly Elevated TTG IgA (x10) Positive EMA Consistent HLA typing Close Monitoring GI consultation Consider potential longterm downsides

45. Treatment = Gluten Free Diet

46. Pediatric Considerations

47. Team Approach Social work Pediatric specialized dietician Medical provider Celiac Support Group EDUCATION SUPPORT

48. Historical Wisdom “The Picture of the disease may be the classical one…(emaciation, stunting, large abdomen, irritability and malnutrition) or so slight as to escape the notice for what it is.”

49. Modern Day Wisdom Careful monitoring of growth and development of children Close listening to our children and their parents Recognition of the broad and varied presentations of pediatric celiac disease Appropriate testing of at risk children Decrease the number children with celiac who “escape our notice”

50. Recovery and Health Child and Family- Centered education Ongoing monitoring and support Recognition of the impact of developmental stages on success and quality of life