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

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

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

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

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

Aphtous Stomatitis By permission of Dr. C. Mulder

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

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

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

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

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

Histology of intestinal biopsy in CD Modified Marsh score

n TG Index PPV NPV Liu E et al. Clin Gastroenterol Hepatol Marsh Score TG Index

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

Radioimmunoassay AUC = Inova AUC = Eurospital AUC = IMMCO AUC = Biofons AUC = Binding Site AUC = 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

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 TG<0.05

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 TG<0.05

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 TG<0.05 GFD M0

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 TG<0.05

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

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

Rewers et al. EMCNA 2004

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