1. Case Discussion John F. Pohl MD Assistant Professor of Pediatrics Section of Pediatric Gastroenterology Scott and White Hospital Texas A&M Health Science Center Temple, Texas

2. Dr. PohlDr. Gupta

3. Pertinent History 5 year old male with 2 year history of intermittent vomiting of a cyclic nature (CVS?) 2 prior episodes of dehydration requiring hospitalization. Previous Giardia infection (pertinent?) Brother with “wheat allergy” and Giardia infection Mother with IBS. Father and paternal relatives with stomach problems and wheat allergy.

4. Pertinent History Serum bicarbonate 16 Urine organic acid screen: Increased 3-hydroxybutyric and acetoacetic acid consistent with physiologic ketosis or disorder of fatty acid oxidation. Urine analysis: Sp. gravity 1.032, pH 5.5, 4+ ketones, negative blood / glucose / protein / nitrite / leukocyte esterase / bilirubin. 0 RBCs, 0 WBCs, 0 bacteria. MRI: Scattered areas of increased signal intensity on the FLAIR images particularly noted in the subcortical white matter regions. During the work-up, an upper endoscopy was performed.

5. Duodenum Normal appearing villi

6. Duodenum Lymphoid aggregate Increased inflammatory cells in crypt region

7. Shortened villi

8. Giardia

9. Follow-up Patient’s brother was known to have celiac sprue. Patient’s father, although never officially tested, had gone on a strict wheat free diet and had resolution of symptoms. This patient’s celiac titer: Anti-endomysial antibody 1 : 80 (normal <1:5) Tissue transglutaminase antibody 1.1 (normal <1)

10. Introduction AKA, “Sprue” or “gluten-sensitive enteropathy” First described around 200 AD. “Sprue” was used in 18 th century (Dutch, “aphthous disease”). Samuel Gee: “On the Coeliac Affection” (1888). Dicke and Der Kamer: Identified alcohol soluble fraction of wheat gluten (gliadin) and similar residues in related barley, rye, and oats as being the damaging agents (1950-53).

11. Definition of Celiac Disease Permanent intolerance to dietary wheat gliadins. Produces intestinal lesions in genetically- susceptible individuals. Immunologic and genetic basis. Relatively common. Has an broad phenotype: IBS / chronic diarrheaKwashiorkor, ascites, FTT

12. Epidemiology Prevalence seems to have changed. 1950 – 1970: Prevalence increased (or ↑d use of endoscopic biopsy?) 1970 – Present: Large decline in prevalence in Europe. WHY? 1. Prolonged breast feeding 2. Low allergen formula 3. Less AGE in infants Age at which diagnosis is made is increasing. IBS / chronic diarrheaKwashiorkor, ascites, FTT >

13. Epidemiology Old data of US incidence – 1:6000. Recent large scale serologic screen of blood donors in United States – 1:250 Maki and Collin (1997): The “celiac iceberg” Diagnosed CD Latent CD

14. Pathogenesis – Family history Prevalence in 1 st degree relatives up to 10% (screening of relatives is ESSENTIAL). Concordance in monozygotic twins: 75%.

15. Pathogenesis - Immunity Celiac is an immune mediated small bowel enteropathy. Due to gluten-sensitive T-cells. Increased numbers of CD8 T-lymphocytes in mucosa

16. Pathogenesis - Immunity Antigen Class II HLA APC cellsT-cells (lamina propria) ↑ IL-2, cytokines, IL-6, TNF  T-cell & Macrophage proliferation Mucosal injury Gliadin protein fraction of wheat, rye, barley, and probably oats

17. Early Presentation Classically presents at 6-18 m of age once gluten is introduced. Chronic diarrhea / rectal prolapse FTT “Celiac crisis” – diarrhea with dehydration “Celiac personality” Kwashiorkor Developmental delay Constipation (<10%) Bruising, rickets, hematoma formation

19. Celiac Disease From Atlas of Pediatric Physical Diagnosis, 2 nd ed., BJ Zitelli editor. Mosby-Wolfe, 1992.

20. Late Presentation School age or later (even adulthood) Mild, chronic diarrhea Occasional constipation Lactose intolerance Dental enamel hypoplasia Kwashiorkor less likely Osteopenia / osteoporosis Short stature Unexplained microcytic (Fe) / macrocytic (folic acid) anemia Can be asymptomatic!

21. “Atypical” Presentation Unexplained short stature Aphthous stomatitis Enamel hypoplasia Infertility Unexplained anemia Unexplained ↑SGOT/SGPT (cirrhosis / AIH) Osteoporosis Alopecia Peripheral neuropathy / central CNS changes Lymphoma

22. Laboratory Features Gliadin IgA/IgG Reticulin IgA Endomysial IgA Tissue Transglutaminase IgA 3-5% of celiac patients are IgA deficient! IgA deficiency: False-negatives None of the tests have 100% sensitivity and specificity (false-negatives / false-positives). Increased rate of Giardia

23. Laboratory Features Antigliadin antibody Antigliadin IgG: sens. 90-100%, spec. 60%. Antigliadin IgA: sens. 60-100%, spec. 86-100% Ab titers and sensitivity of IgG and IgA tend to decrease as patient’s age increases (>3yrs old).

24. Laboratory Features Antiendomysium antibody (IgA) Sensitivity: close to 100% Specificity: close to 100% Antibody to unknown antigen

25. Laboratory Features Tissue transglutaminase antibody (TTG ) Probably the sole autoantigen recognized by the antiendomysium Ab. High affinity for gliadin proteins Almost 100% sensitivity and specificity Now the antibody test of choice.

26. Diagnostic Testing Once antibody tests positive, duodenal biopsy is key to diagnosis (absolute 100% sensitivity and specificity). Hyperplastic crypts Increased mitotic figures Villi flattened / gone Dense lymphocytic infiltrate with plasma cells Disaccharidases: Brush border hydrolases are decreased, especially lactase (lactose intolerance).

27. Diagnostic Test There is a spectrum of insult… There is always a lymphocytic infiltrate that goes away with dietary manipulation. Villi presentAbsent villi

28. Endoscopic Celiac Disease

29. Untreated Celiac Disease

30. Treated Celiac Disease

31. Treatment Removal of gluten is essential!

32. Treatment Behavioral disturbances resolve quickly. Immediate weight gain with complete correction in one year. Developmental delay corrects in 1-2 months. Stools return to normal in a few weeks. Abdominal distention resolves in a few months. Villi resume normal architecture in one year. “Safe” gluten intake < 50mg/day A dedicated nutritionist is imperative.

33. Treatment Gluten challenge (older diagnostic criteria) Done after 6 years of age. Done to confirm long-lasting nature of disease (adopted in 1970). Allow 5-10 g gluten daily (2 pieces of bread) for 1-12 months once patient is healthy. Problem with technique: 3 procedures to confirm diagnosis. ESPGAN (1990): revised diagnostic criteria for celiac.

34. Treatment New criteria (children > 2 yrs): Histologically similar to celiac disease at time of diagnosis. Clinical recovery is evident after gluten removal. Ab levels return to normal after diet restriction. If these criteria cannot be fulfilled, classic gluten challenge is necessary. Careful! Over half of relapsing patients are only detected by biopsy alone (they look normal).

35. Associated Diseases Higher incidence of autoimmune diseases overall than the normal population. May be due to the shared HLA haplotypes between diseases. Seems to be related to duration of gluten exposure.

36. Associated Diseases Hemochromatosis Type I Diabetes Mellitus Autoimmune thyroid disease Addison disease Autoimmune thrombocytopenia Sarcoidosis Autoimmune hepatitis CNS disease (seizures, CNS calcifications) Dermatitis herpetiformis Primary biliary cirrhosis Lymphoma (risk 25-125X risk of general pop.) Trisomy 21 (4-17% with celiac disease)

37. IDDM Barera, et al, Pediatr, 2002 (Italy) Investigated prevalence of celiac disease in pediatric patients (8.6 ±4.6 yrs) with IDDM. 60% -- had celiac disease at time of IDDM diagnosis. Prevalence of celiac disease approximately 20X higher than general population. SHOULD WE SCREEN OUR DIABETICS???

38. What about the MRI changes in this patient?

39. Another Example of CNS Findings Calcification

40. Celiac Disease and CNS Findings PRESENTATIONS: Headaches / migraines Cerebellar ataxia Epilepsy Myoclonic ataxia Neuropathies Dementia Ischemic stroke Tic disorders Learning disabilities / ADHD CVS?

41. Celiac Disease and CNS Findings Celiac patients on a gluten diet demonstrate cerebral hypoperfusion (via PET scan measurement). Increased thrombotic potential (mainly described in case reports; etiology unclear). CNS disease is seen in other AUTOIMMUNE GI diseases (Crohn’s, UC). Antibodies in celiac disease may affect voltage- gated calcium and potassium channels as well as glutamate receptors in the CNS.

42. Celiac Disease and CNS Findings What benefit exists with gluten-free diet? Improvement only seen in those patients with transient infantile hypotonia and migraine headaches Pediatrics. 2004 Jun;113(6):1672-6. Range of neurologic disorders in patients with celiac disease. Zelnik N, Pacht A, Obeid R, Lerner A. Case in Point: Our patient improved considerably over time as he was placed on a gluten-free diet. Did the patient have CVS due to migraine disease?

43. Bottom Line… Celiac disease is more common than we realize. Any child with FTT, chronic diarrhea, or IBS (esp. diarrhea predominant) should be screened. The phenotypic presentation is changing. Ab tests have excellent sensitivity and specificity (esp. EMA and tTG). Gluten free diet is mandatory and curative. Keep in mind high risk of other autoimmune disorders with celiac disease. Screen 1 st degree relatives.

44. The End Proceed to the post test Down load the post test Complete the post test Return the post test to Dr. Sandra Oliver 407 I TAMUII

45. Post test question 1 1. Individuals with celiac disease may experience which of the following: A.Constipation B. Weakness C. Weight gain Hyperactivity

46. Post test question 2 2. Pathology of Celiac disease includes: A. Villous atrophy B. Hypoplasia of the crypts of Lieberkuhn C. Decreased plasma cell infiltration of the lamina propria D. Increased b rush border hydrolases

47. Post test question 3 3. Treatment of celiac disease includes removal of which of the following? A. Wheat and buckwheat B. Rye and corn C. Rice and potatoe D. Oats and barley

48. Post test question 4 4. Prognosis for celiac disease includes all of the following except: A. Increased risk for adenocarcinoma of the small bowel B. Increased risk for cardiovascular disease. C. Increased risk for lymphoma D. Increased risk for osteoporosis

49. Scott & White Memorial Hospital and Clinic Texas A&M University Health Science Center Scott & White Memorial Hospital and Clinic Texas A&M University Health Science Center Thank you!