Celiac Disease

Marian Rewers, MD, PhD

Professor & Clinical DirectorBarbara Davis Center for Diabetes

University of Colorado School of Medicine

No relevant financial relationships with any commercial interests to disclose

Old paradigm - CD is a disease of small intestine

Celiac disease• villous atrophy • malnutrition

London, year 1938

Diagnosis of celiac diseaseEndoscopic findings suggestive of CD include thinning or loss of duodenal folds, scalloped folds

Normal Celiac

Histology of intestinal biopsy in CD Modified Marsh score

Liu E et al. Clin Gastroenterol Hepatol 2003

Increasing villous atrophy (Marsh Score) 0 1 2 3

0.00.20.40.60.81.01.21.41.6

TG In

dex

TransGlutaminase autoantibody (TG IgA) levels predict severity of villous atrophy

S. Caillat-Zucman, L Mesin, LM Sollid, R Di Niro et al.

Mechanisms leading to the celiac lesion

TG IgA

New paradigm: multi-organ autoimmune disease

Celiac disease• villous athrophy• malnutrition• malignancies

Bone• osteoporosis, fractures• arthritis• dental anomalies

HepatitisCholangitis

Skin & mucosa• dermatitis herpetiformis• aphtous stomatitis• hair loss

Reproductive• miscarriage, infertility• delayed puberty

Central nervous system• ataxia, seizures• depression

Carditis, cardiomyopathy

Anemia

Rewers M. 2008

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

Aphtous Stomatitis

By permission of Dr. C. Mulder

Involve the secondary dentition

Dental Enamel Defects

By permission of Dr. C. Catassi

Osteopenia/Osteoporosis Low bone mineral density by DEXA in a child with untreated CD

By permission of Dr. S. Mora

Ataxia, Occipital Calcification & Epilepsy in CD

By permission of Drs. C. Catassi and G, Holmes

Entheropathy-Associated T-cell Lymphoma

By permission Dr. G. Holmes

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

Prevalence of TG IgA Autoantibodies in 2,949 T1D Patients

Age

Rewers M et al. N Am Clin 2005

0%

2%

4%

6%

8%

10%

12%

14%

0-4 5-9 10-14 15-19 20-24 25-29 30-39 40+

TG IgA+

TG IgA 0.05-0.5 (positive)TG IgA >0.5 (strongly positive)

Patterns of TG IgA levels in asymptomatic patients

0.01

0.1

1

10

5 8 11 14

Positive Biopsy

Normal Biopsy

0.01

0.1

1

10

6 8 10 12 14

Positive Biopsy

TG IgA

Age (years)Liu E et al. Clin Gastroenterol Hepatol. 2003

Patient A Patient B

In asymptomatic cases, biopsy should be recommended at much higher TG levels than the positivity cutoff*

Liu E et al. J Pediatrics 2005

Radioimmunoassay (BDC)

Assay Cutoff0.05* 0.5 0.75 1

Sensitivity 100 82 68 38Specificity -- 65 95 100

PPV 63 80 95 100NPV -- 68 44 49LR -- 2.4 12.4 --

AUC = 0.88ELISA (Inova)

Assay Cutoff20* 60 124 140

Sensitivity 97 82 65 56Specificity 20 70 95 100

PPV 67 82 95 100NPV 80 70 61 57LR 1.2 2.8 12.9 --

AUC = 0.85

Yellow columns show cutoffs that maximize likelihood of a positive biopsy

In asymptomatic cases, biopsy should be recommended at much higher TG levels than the positivity cutoff*

Liu E et al. J Pediatrics 2005

Radioimmunoassay (BDC)

Assay Cutoff0.05* 0.5 0.75 1

Sensitivity 100 82 68 38Specificity -- 65 95 100

PPV 63 80 95 100NPV -- 68 44 49LR -- 2.4 12.4 --

AUC = 0.88ELISA (Inova)

Assay Cutoff20* 60 124 140

Sensitivity 97 82 65 56Specificity 20 70 95 100

PPV 67 82 95 100NPV 80 70 61 57LR 1.2 2.8 12.9 --

AUC = 0.85

Yellow columns show cutoffs that maximize likelihood of a positive biopsy

Red columns show cutoffs that optimize sensitivity and predictive value

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

BDC algorithm for performing biopsy

SymptomaticPatient

TG & total IgA

TG+TG-

&Low total IgA

Biopsy Biopsy

Asymptomatic Patient

TG & total IgA

TG +persistent TG -

Symptoms PeriodicscreeningNo symptoms

Biopsy Biopsy ifTG IgA > 0.5

A girl that refused bread but was neglectedFemale, T1D Dx age 3.9 yr, HLA-DR3/4 DQB1*0201/0302

TG>0.5 (strongly positive)

Height Weight

Pt 38884

BDC 2010

GFD ??

M3b

PROBLEMS:• early child neglect• not GFD compliant• failure to thrive• “stomach tumor” removed at age 10

GFD

M3c

••

Height Weight

PROBLEMS:• early failure to thrive• slow catch-up on GFD• GFD compliant when aged 7-12, but not now• A1c 7.7-9.7 • severe hypoglycemia

A girl that is trying to catch upFemale T1D Dx age 5.3 yr HLA-DR3/4 DQB1*0201/0302 Pt 27188

TG>0.5 (strongly positive) TG 0.05-0.05 (positive)• TG negative

BDC 2010

Obese boy with ‘psychiatric problems’Male, T1D Dx age 4.5, HLA-DR 3/3 DQB1*0201/0201 Pt 7677

BDC 2010

GFD

M3

••

••

•

Height Weight

PROBLEMS:• eating disorder• odd behavior• resolution on GFD

TG>0.5 (strongly positive) TG 0.05-0.05 (positive)• TG negative

A perfect girlFemale, T1D Dx age 2.3 yr, HLA-DR3/4 DQB1*0201/0302

M3c

No GFD

••

Pt 1520

BDC 2010

Height Weight

PROBLEMS:• no GFD • at risk for long- term complications

TG>0.5 (strongly positive) TG 0.05-0.05 (positive)• TG negative

TG+n=65

TG-n=64

p-value

Age 10.6 ±4.4 10.2±7.3 NSDM duration 4.4 ±1 4.4 ±1.9 NS% male 44% 49% NSHbA1c 8.3±1.3% 8.3±1% NSWeight z-score 0.3±1 0.7±0.8 0.04

BMI z-score 0.4±0.9 0.7±0.8 0.02Urinary n-telopeptide 105.7±60.9% 66 ±40.8% 0.0001

PTH 25.1 ±8.5 21.5 ±7 0.02L-spine bone mineral density z-score

-0.18±1.2 0.07±1.3 NS

Vit D 25-OH 29.3 ±7.8 31 ±8 NS

Impact of CD on Growth and Bone in Children with T1DROSE Study, BDC

ROSE Study JH Simmons et al. J Pediatr, 2007

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

Antibodies against deamidated gliadin peptides (DGP) may be a better marker of compliance than TG IgA

Ant

ibod

y le

vel

Age (years)

0 2 4 6 8 10 12

GFD “90%” strict

0.1

10

1

0 2 4 6 8 10 12

DGP

TG

0.1

10

1

GFD strict loose strict

DGP

TG

Patient C

Patient D

Liu E et al. J Pediatr Gastroenterol Nutr. 2007

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??

Take home message: screen, confirm, treat

GFD

1 in 10

TG IgA+

TG IgA++

Biopsy

M1

M2

M3

Normalized DGP, TG IgA

GFDpersistent

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