Celiac Disease. Marian Rewers, MD, PhD. Professor & Clinical Director Barbara Davis Center for Diabetes University of Colorado School of Medicine

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1 Celiac Disease Marian Rewers, MD, PhD Professor & Clinical Director Barbara Davis Center for Diabetes University of Colorado School of Medicine No relevant financial relationships with any commercial interests to disclose

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

3 Diagnosis of celiac disease Endoscopic findings suggestive of CD include thinning or loss of duodenal folds, scalloped folds Normal Celiac

4 Histology of intestinal biopsy in CD Modified Marsh score

5 TransGlutaminase autoantibody (TG IgA) levels predict severity of villous atrophy TG Index Increasing villous atrophy (Marsh Score) Liu E et al. Clin Gastroenterol Hepatol 2003

6 Mechanisms leading to the celiac lesion TG IgA S. Caillat-Zucman, L Mesin, LM Sollid, R Di Niro et al.

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

8 Dermatitis Herpetiformis Erythematous macule > urticarial papule > tense vesicles Severe pruritus Symmetric distribution 90% no GI symptoms 75% villous atrophy Responds to Gluten-free Diet By permission of Dr. A. Fasano

9 Aphtous Stomatitis By permission of Dr. C. Mulder

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

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

12 Ataxia, Occipital Calcification & Epilepsy in CD By permission of Drs. C. Catassi and G, Holmes

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

14 Rationale for celiac disease screening in T1D Significant multi-organ morbidity: Intestinal: diarrhea, vomiting, abdominal pain, weight loss, micronutrient deficiencies Extra-intestinal: pubertal/growth delay, anemia, osteopenia, fetal loss, neurological, lymphoma, etc. In type 1 diabetes: unexplained hypoglycemia poor HbA1c

15 Prevalence of TG IgA Autoantibodies in 2,949 T1D Patients 14% 12% 10% 8% 6% 4% 2% TG IgA+ TG IgA (positive) TG IgA >0.5 (strongly positive) 0% Age Rewers M et al. N Am Clin 2005

16 Patterns of TG IgA levels in asymptomatic patients 10 Patient A 10 Patient B TG IgA 1 Positive Biopsy 1 Positive Biopsy Liu E et al. Clin Gastroenterol Hepatol Age (years) Normal Biopsy

17 In asymptomatic cases, biopsy should be recommended at much higher TG levels than the positivity cutoff* Yellow columns show cutoffs that maximize likelihood of a positive biopsy Radioimmunoassay (BDC) AUC = 0.88 Assay Cutoff 0.05* Sensitivity Specificity PPV NPV LR ELISA (Inova) AUC = 0.85 Assay Cutoff 20* Sensitivity Specificity PPV NPV LR Liu E et al. J Pediatrics 2005

18 In asymptomatic cases, biopsy should be recommended at much higher TG levels than the positivity cutoff* Yellow columns show cutoffs that maximize likelihood of a positive biopsy Radioimmunoassay (BDC) AUC = 0.88 Assay Cutoff 0.05* Sensitivity Specificity PPV NPV LR ELISA (Inova) AUC = 0.85 Assay Cutoff 20* Sensitivity Specificity PPV NPV LR Red columns show cutoffs that optimize sensitivity and predictive value Liu E et al. J Pediatrics 2005

19 Summary When following an individual at risk for CD TG IgA precedes the development of intestinal injury Higher TG IgA predicts more severe villous atrophy TG IgA levels may fluctuate A single measurement may not be sufficient TG IgA levels are important when deciding to biopsy

20 BDC algorithm for performing biopsy TG+ Symptomatic Patient TG & total IgA TG- & Low total IgA Symptoms TG + persistent Asymptomatic Patient TG & total IgA No symptoms TG - Periodic screening Biopsy Biopsy Biopsy Biopsy if TG IgA > 0.5

A girl that refused bread but was neglected Female, T1D Dx age 3.9 yr, HLA-DR3/4 DQB1*0201/0302 Pt 38884 Height Weight TG>0.

21 A girl that refused bread but was neglected Female, T1D Dx age 3.9 yr, HLA-DR3/4 DQB1*0201/0302 Pt Height Weight TG>0.5 (strongly positive) M3b PROBLEMS: early child neglect not GFD compliant failure to thrive stomach tumor removed at age 10 GFD?? BDC 2010

22 A girl that is trying to catch up Female T1D Dx age 5.3 yr HLA-DR3/4 DQB1*0201/0302 Pt Height TG>0.5 (strongly positive) TG (positive) TG negative Weight M3c PROBLEMS: early failure to thrive slow catch-up on GFD GFD compliant when aged 7-12, but not now A1c severe hypoglycemia GFD BDC 2010

23 Obese boy with psychiatric problems Male, T1D Dx age 4.5, HLA-DR 3/3 DQB1*0201/0201 Pt 7677 Height Weight TG>0.5 (strongly positive) TG (positive) TG negative M3 GFD PROBLEMS: eating disorder odd behavior resolution on GFD BDC 2010

24 A perfect girl Female, T1D Dx age 2.3 yr, HLA-DR3/4 DQB1*0201/0302 Pt 1520 Height Weight M3c PROBLEMS: no GFD at risk for longterm complications TG>0.5 (strongly positive) TG (positive) TG negative No GFD BDC 2010

25 Impact of CD on Growth and Bone in Children with T1D ROSE Study, BDC TG+ n=65 TGn=64 p-value Age 10.6 ± ±7.3 NS DM duration 4.4 ±1 4.4 ±1.9 NS % male 44% 49% NS HbA1c 8.3±1.3% 8.3±1% NS Weight z-score 0.3±1 0.7± BMI z-score 0.4± ± Urinary n-telopeptide 105.7±60.9% 66 ±40.8% PTH 25.1 ± ± L-spine bone mineral density z-score -0.18± ±1.3 NS Vit D 25-OH 29.3 ± ±8 NS ROSE Study JH Simmons et al. J Pediatr, 2007

26 2-year follow-up of the ROSE cohort TG levels decreased but did not normalize in many children on GFD Children persistently TG+ continued to have: lower weight and BMI higher bone turnover Those persistently highly TG ++ had lower: bone mineral density vit. D 25OH ferritin levels, compared to TG- patients 27% of children switched to GFD and 8% of those on GFD switched to regular diet HbA1c levels and frequency of severe hypoglycemia did not differ between the groups ROSE Study JH Simmons et al. J Pediatr, 2011

27 Antibodies against deamidated gliadin peptides (DGP) may be a better marker of compliance than TG IgA GFD 90% strict Antibody level TG DGP GFD strict loose strict TG Patient C Patient D 0.1 DGP Age (years) Liu E et al. J Pediatr Gastroenterol Nutr. 2007

28 Recommendations All T1D patients should be screened for TG IgA at onset of diabetes and bi-annually (until age 10?), or if symptomatic In asymptomatic cases, biopsy recommended if TG IgA high Biopsy should be done after at least 1-2 weeks on a regular diet with wheat; samples must be properly oriented and read by a trained pathologist Persistent TG IgA and HLA-DQ2 or DQ8 are diagnostic for CD even if biopsy is negative GFD should be recommended to all biopsy+ or high TG+ patients Insulin dose usually needs to be increased on GFD DGP antibody HbA1c for GFD compliance??

29 Take home message: screen, confirm, treat M1 Biopsy M2 GFD 1 in 10 TG IgA+ M3 TG IgA++ persistent GFD Normalized DGP, TG IgA

Proposed Gluten Free Designation on Labels FDA Definition:

any ingredient derived from those grains Product

started the Gluten Free Certification Organization <10 ppm

30 Proposed Gluten Free Designation on Labels FDA Definition: prohibited grains - any species of wheat, rye, barley or any ingredient derived from those grains Product containing <20 ppm of gluten Gluten Intolerance Group started the Gluten Free Certification Organization <10 ppm gluten Celiac Sprue Association Recognition Seal <5ppm gluten Owen D, 2010

Definition. Celiac disease is an immune-mediated enteropathy caused by a permanent sensitivity to gluten in genetically susceptible individuals.

Definition. Celiac disease is an immune-mediated enteropathy caused by a permanent sensitivity to gluten in genetically susceptible individuals. Definition 1 Definition Celiac disease is an immune-mediated enteropathy caused by a permanent sensitivity to gluten in genetically susceptible individuals. It occurs in symptomatic subjects with gastrointestinal