1. Prof. Dr. Giuseppe Magazzu Prof. Dr. Dušanka Mičetić-Turk and all Progress of the Prospective study - Medicel

2. Background  Celiac disease (CD)has increased at an unexpected rate in the last two decades not only in Europe but also in Mediterranean regions.  The consequences of unrecognized CD can be severe particularly with regard to mortality and morbidity among these patients.

3. The aims of study:  To identify the factors that may influence the onset of CD in Mediterranean basin  To identify clinical and laboratory data which can predict the diagnosis of the disease  To determine where the new ESPGHAN diagnostic criteria could be applied and what % of patients can omitt the biopsy

4. Service and survey design:  Prospective cohort observational survey  Duration: April 2013 to March 2014  Setting: 13 CD centers from 12 Mediterranean countries:Albania, Algeria, Croatia, Egypt, Greece, Italy,Malta, Montenegro, Morocco, Slovenia, Tunisia, Turkey  Sample: unselected new cases referred for suspected CD

5. Patients  Data of patients were collected and put into a web-based database of Medicel Mediterranean Network (www.medicel.unina.it/)www.medicel.unina.it/

6. Which data were collected? Pregnancy duration and outcome Birth weight Breastfeeding Age of gluten introduction into the diet Number of previous admissions to hospital Clinical symptoms (main, second and third) Familiarity Associated diseases

7. Which data were collected? Antitransglutaminase antibodies IgA (t-TG) as Nx upper limit of normal (ULN) Endomysial antibodies (EMA) HLA-DQ2/DQ8 Histology (Marsh-Oberhuber classification) DNA, sera and tissue frozen samples were collected for further studies Follow-up to confirm uncertain case

8. Statistics  Crosstabs and stepwise statistics were generated by SPSS and t-Test, Odds Ratio (OR) and Positive Predictive Value (PPV) were estimated for variables.

9. Results of the study

10. CountryTotalCDNCD Albania31283 Algeria312110 Croatia981 Egypt20155 Greece35296 Italy-Me270100170 Italy-Na339196143 Malta1091 Monten.880 Morocco854936 Slovenia613130 Tunisia412021 Turkey1042381 PATIENTS ENROLLED INTO THE STUDY

11. Results  1044 patients enrolled  537 CD  507 NCD 491 NCD 16 potential CD (15 EMA positive)

12. Results  Duration of gestation and breastfeeding were significantly longer in CD  NCD had a heavier birth weight  No difference was found for age of gluten introduction and number of previous hospital admissions

13. Results Symptoms PPV (95% CI) OR (95% CI) Anorexia/lack of appetite 73% (62-81)2.74 (1.64-4.60) Abdominal distention 68% (60-76)2.30 (1.55-3.42) Anemia 63% (53-71)1.71 (1.11-2.63) Vomit 54% (48-62) 1.50 (1.07-2.10) Abdominal pain 63% (53-71)0.66 (0.50-0.87) Contipation 37% (30-44)0.51 (0.35-0.74)

14. Results  PPV of tTGA > 10 x ULN: 0.951 (95% CI:0.922-0.969); LR+ = 21.1 (95%CI: 13.0-34.37).  66.9% tTGA > 10 x ULN might avoid intestinal biopsy (ESPGHAN GL)  4.6% with tTGA > 10 x ULN (EMA positive) had a potential CD.

15. Pre-test probability of a symptom e.g. anorexia 73%(62-81) Decision threshold PPV of tTGA > 10 x ULN: 0.951 (95% CI:0.922- 0.969); LR+ = 21.1 (95%CI: 13.0-34.37).

16. Conclusion  This large prospective study provides for the first time PPV, that is the pre-test probability, of symptoms.  Based on tTGA diagnostic accuracy obtained in own laboratory, single centers can make clinical decision on if and when intestinal biopsy may be omitted, according to the new ESPGHAN guidelines.  There is a chance to meet potential CD even in the presence of a tTGA > 10 x ULN value.

17. Conclusion  The results of the study raises many questions, the most important: Is it ever justifiable to place a child with gastrointestinal symptoms on a gluten-free diet without clearly making a diagnosis of CD?

18. Conclusion  The results of the study raises many questions, the most important: Do we know the natural history of potential CD? We have to determine which factors most influence the onset of CD in Mediterranean basin Are repeat screenings necessary in NCD group, because CD can present at any age, and if so, at what intervals?

19. Conclusion  The results of the study raises many questions, the most important: In further evaluation we have to clearly identify: - which symptoms can be used to identify children for screening and diagnostics? - which laboratory data predict the diagnosis of CD?