1. Celiac Disease and Diabetes Marian Rewers, MD, PhD Professor & Clinical Director University of Colorado, School of Medicine

2. Old paradigm - CD is a disease of small intestine Celiac disease villous atrophy malnutrition London, year 1938

3. New paradigm: multi-organ autoimmune disease Celiac disease villous athrophy malnutrition malignancies Bone osteoporosis, fractures arthritis dental anomalies Hepatitis Cholangitis Skin & mucosa dermatitis herpetiformis aphtous stomatitis hair loss Reproductive miscarriage, infertility delayed puberty Central nervous system ataxia, seizures depression Carditis, cardiomyopathy Anemia

4. Dermatitis Herpetiformis Erythematous macule > urticarial papule > tense vesicles Severe pruritus Symmetric distribution 90% no GI symptoms 75% villous atrophy Gluten sensitive By permission of Dr. A. Fasano

5. Involve the secondary dentition Dental Enamel Defects By permission of Dr. C. Catassi

6. Aphtous Stomatitis By permission of Dr. C. Mulder

7. Osteopenia/Osteoporosis Low bone mineral density by DEXA in a child with untreated CD By permission of Dr. S. Mora

8. Occipital Calcification & Epilepsy By permission of Drs. C. Catassi and G, Holmes

9. Entheropathy-Associated T-cell Lymphoma By permission Dr. G. Holmes

10. Why screening for celiac disease in T1D? Significant health problem, multi-organ morbidity: –Intestinal: diarrhea, distention, vomiting, abdominal pain, weight loss –Extra-intestinal: pubertal/growth delay, anemia, osteopenia, etc. –In type 1 diabetes: unexplained hypoglycemia poor HbA1c

11. T T cell  TCR APC HLA-DQ2 or -DQ8 Pathomechanism of Celiac Disease TG Gluten Transaminated gluten peptides T T T TT T TG

12. Histology of intestinal biopsy in CD Modified Marsh score

13. n 12 2 5 21 TG Index0.050.10.25 0.5 0.75 PPV0.760.800.89 0.96 1 NPV110.75 0.65 0.39 Liu E et al. Clin Gastroenterol Hepatol 2003 1.8 Marsh Score 0123 0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 TG Index

14. Prevalence of TG IgA Autoantibodies in 2,949 T1D Patients Age Rewers M et al. 2004

15. Radioimmunoassay AUC = 0.8765 Inova AUC = 0.8529 Eurospital AUC = 0.8758 IMMCO AUC = 0.8838 Biofons AUC = 0.8676 Binding Site AUC = 0.8644 In asymptomatic cases, biopsy should be recommended at much higher TG levels than the positivity cutoff (*) Highlighted columns show test cutoffs that maximize likelihood of a positive biopsy Liu E et al. J Pediatrics 2005;494-9

16. A girl that refuses pasta and bread Pt 38884, Female T1D Dx age 3.9 yr HLA-DR3/4 DQB1*0201/0302 Height Weight GFD ? M3b TG>0.5 TG 0.05-0.05 TG<0.05

17. A girl that is trying to catch up Pt 27188, Female T1D Dx age 5.3 yr HLA-DR3/4 DQB1*0201/0302 Height Weight GFD M3c TG>0.5 TG 0.05-0.05 TG<0.05

18. A boy that is falling off the curve Pt 38220, Male T1D Dx age 5.3 yr HLA-DR3/4 DQB1*0201/0302 Height Weight TG>0.5 TG 0.05-0.05 TG<0.05 GFD M0

19. Obese boy with ‘psychiatric problems’ Height Weight Pt 7677, Male T1D Dx age 4.5 HLA-DR 3/3 DQB1*0201/0201 GFD M3 TG>0.5 TG 0.05-0.05 TG<0.05

20. A perfect girl Pt 1520, Female T1D Dx age 2.3 yr HLA-DR3/4 DQB1*0201/0302 HeightWeight M3c No GFD TG>0.5 TG<0.05

21. Recommendations All T1D patients should be screened for TG IgA at onset and at least bi- annually until age 10, or if symptomatic In asymptomatic cases, intestinal biopsy should be recommended at TG levels predicting positive biopsy in over 90% of the patients Biopsy should be done after at least 1-2 weeks on a high-wheat diet; samples must be properly oriented and read by a trained pathologist Persistent TG IgA and HLA-DQA1*0501/B1*0201 predict progression to CD even if the initial biopsy is negative GFD should be recommended to all Bx+ patients Insulin dose usually needs to be increased on GFD

22. Rewers et al. EMCNA 2004

23. Thank you GFD 1 in 10 TG IgA +++ Biopsy M1 M2 M3