Marian Rewers, MD, PhD - Denver, Colorado · Marian Rewers, MD, PhD. Professor & Clinical Director....
Transcript of Marian Rewers, MD, PhD - Denver, Colorado · Marian Rewers, MD, PhD. Professor & Clinical Director....
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