CELIAC DISEASE FUN & FORUM

Dominica Gidrewicz, MSc, MD, FRCPC

Pediatric Gastroenterologist

Friday November 8, 2019

• Risk factors for developing celiac

• What do we know?

• Symptoms and follow-up management

• Extra-intestinal features

• Which ones are likely to resolve on a GFD

• Follow-up serology

• Still symptomatic on a GFD

• What is my doctor thinking?

• Associated conditions

Overview

RISK FACTORS FOR

DEVELOPMENT OF CELIAC

DISEASE

WHAT DO WE KNOW?

• Lots of research in this area

• Most around childhood-onset CD

• But CD actually more often diagnosed in adults now

• Triggers for CD in adults may be different than children

• CD may be present for many years in adults before it is

diagnosed

• Triggers may be hard to identify

Risk Factors for Development of CD

1. Gluten ingestion

2. Genetics

3. Infant nutrition

4. Pregnancy and birth-related factors

5. Infections and microbiome

6. Place of living

Risk Factors for Development of CD

Dietary Gluten - α-gliadin peptide

Fasano A et al. Gastro 2015; 148:1195-1204.

• Strong hereditary component

• 80% in monozygotic, 10% in dizygotic twins

• Best characterised genetic susceptibility

• HLA DQ2 and/or DQ8 (+) = 99.6% of CD patients

• These are common HLA types

• 30% of general population also (+) for HLA DQ2

• Genetics necessary but not sufficient

• At least 40 others genes linked to CD

• Gender also important - ~2/3 of patients are female

Ludvigsson JF et Murray JA Epidemiology of celiac disease. Gastroenterol Clin N Am 2019; 48: 1-18.

Genetics

• Swedish “celiac epidemic” (1985-1987) 1

• 4-fold higher rate of celiac in children < 2 yr

• 50/100,000 to 200/100,000

• After 1995, return to previous levels

• 3 factors identified:

1. Amount of gluten given

2. Age at introduction of gluten

3. BF ongoing or not when gluten was introduced

Ivarsson et al. Epidemic of coeliac disease in Swedish children. Acta Paediatr 2000; 89: 165-171.

Infant Nutrition

• Diabetes Autoimmunity Study in the Young

• Prospective study, 1994-2004

• 1560 children, HLA DR3/DR4 or FDR with T1DM

• Looked at CD autoimmunity (CDA)

• 2 (+) blood tests OR 1 (+) blood test & intestinal biopsy

• 51/1560 developed CDA, 25/51 were biopsy positive

• Exposure to gluten < 3 mo (6 vs 3%) or > 7 mo (71 vs 59%)

• Conclusion:

• ↓ risk of CD if first exposed to gluten at 4-6 mo of age versus

< 4 or > 7 months

Norris et al. JAMA 2005; 293:2343-2451

Infant Nutrition – DAISY study

CELIPREV1

▪ 832 newborns & FDR with CD

▪ Introduction of dietary gluten at 6 vs 12 mo

▪ 79% had (+) HLA genotype

▪ Celiac screen at 15, 24, 36 mo, 5, 8, 10 yr

▪ Primary outcome: prevalence of celiac

autoimmunity & bx-confirmed CD at 5 yr of age.

▪ Bx-confirmed CD

▪ 2 yrs of age: 12% vs 5% (P=0.01)

▪ 5 yrs of age: 16% vs 16% (p=0.79)

▪ At 10 yrs: 13.2% overall

▪ 26% vs 16% (high risk HLA vs standard-

risk HLA)

▪ No influence of timing of gluten introduction

▪ HLA status most important factor.

1 Lionetti et al. Introduction of gluten, HLA status, and risk of celiac disease in children. NEJM 2014; 371: 1295-1303.

Multicenter, prospective RCTs

CELIPREV1

▪ 832 newborns & FDR with CD

▪ Introduction of dietary gluten at 6 vs 12 mo

▪ 79% had (+) HLA genotype

▪ Celiac screen at 15, 24, 36 mo, 5, 8, 10 yr

▪ Primary outcome: prevalence of celiac

autoimmunity & bx-confirmed CD at 5 yr of age.

▪ Bx-confirmed CD

▪ 2 yrs of age: 12% vs 5% (P=0.01)

▪ 5 yrs of age: 16% vs 16% (p=0.79)

▪ At 10 yrs: 13.2% overall

▪ 26% vs 16% (high risk HLA vs standard-

risk HLA)

▪ No influence of timing of gluten introduction

▪ HLA status most important factor.

PreventCD2

▪ 944 children, HLA DQ2/8 (+) & FDR with CD.

▪ At 4-6 mo, 100 mg gluten daily vs placebo.

▪ Measured: Anti-TTG2 and anti-gliadin.

▪ Primary outcome: frequency of bx-confirmed

CD at 3 yr of age.

▪ Bx-confirmed CD at 3 yrs of age:

▪ 5.2% vs 5.9% (gluten vs placebo)

▪ Similar rates of ↑ anti-TTG antibodies

▪ 7.0% vs 5.7% (gluten vs placebo)

▪ No influence of breast feeding (exclusive or

whether ongoing) during gluten introduction.

1 Lionetti et al. Introduction of gluten, HLA status, and risk of celiac disease in children. NEJM 2014; 371: 1295-1303.

2 Vriezinga SL et al. Randomised feeding intervention in infants at high risk for celiac disease NEJM 2014; 371: 1304-1315

Multicenter, prospective RCTs

• No protective role of BF at time of gluten introduction 1,2,3

• No long term ↓ risk if gluten delayed > 12mo 1

• Delayed gluten = delayed onset of CD 1

• High risk HLA important predictor of disease 1

• No evidence to support “window of opportunity” of

introducing gluten between 4-6 mo 1,4

• Current research focused on amount of gluten

1 Lionetti et al. NEJM 2014; 371: 1295-1303.2 Vriezinga SL et al. NEJM 2014; 371: 1304-1315.3 Norris et al. JAMA 2005; 293:2343-2451.4 Stordal K et al Pediatrics 2013; 132 e1202-1209.

The Pendulum Swings

Background on TEDDY

• The Environmental Determinants of Diabetes in the Young

• Enrolled children from 2004-2010

• Birth to 15 years

• 4 countries involved:

• Finland, Germany, Sweden, US

• 8676 newborns, HLA (+)

• Swedish subgroup 1

• N = 436

• High intake of gluten during 1st 2 yrs of life, esp 12 mo

of age, associated with risk of CD in childhood 1

• Entire TEDDY grp 2

• Higher gluten intake during the first 5 years associated

with increased risk of CDA and CD

Quantity of gluten intake

1 Aronsson CA et al. Effects of gluten intake on risk of CD: a case control study on a Swedish birth cohort Clin Gastroenterol Hepatol 2016; 14: 403-4092 Aronsson CA et al. Association of gluten intake during the first 5 years of life with incidence of celiac disease autoimmunity and celiac disease among

children at increased risk. JAMA 2019: 322: 514-523.

Aronsson CA et al. Association of gluten intake during the first 5 years of life with incidence of celiac disease autoimmunity and celiac disease

among children at increased risk. JAMA 2019: 322: 514-523

CDA Celiac disease

Reference amount of

gluten (mean 3.7 gm/day)

28% 21%

1 gm/day more 34% 28%

Gluten intake and risk of CD

Risk of developing celiac disease by age 3 yrs

1 gm of gluten = ~ ½ slice of white bread or 75 gm of cooked pasta

Current European recommendations

• Introduce gluten to an infant's diet any time between 4-12

months of age

• In children at high risk for CD, earlier introduction of

gluten (4 vs 6 months or 6 vs 12 months) is associated

with earlier development of CD autoimmunity

• Consumption of large quantities of gluten should be

avoided during the first weeks after gluten introduction

and during infancy

• Optimal amounts of gluten to be introduced at weaning,

however, have not been established

Szajewska H et al. Gluten introduction and risk of celiac disease: a position paper by ESPGHAN J Pediatr Gastroenterol Nutr. 2016; 62: 507

• TEDDY study1

• Multinational prospective screening study > 6000 infants with (+) HLA for celiac

• 25% born by CS

• Once adjusted for confounding variables (eg. HLA risk, maternal education), C-section no longer significant

• CELIPREV study2

• 46% born by CS

• No different in CD at 5, 8 or 10 yrs of age between CS and SVD.

• Environmental factors later in infancy or early childhood more likely responsible for rising incidence…

1. Koletzko S. et al JPGN 2018; 417-424.

2. Lionetti E. et al. J Pediatr 2017; 184: 81-86.

Mode of Delivery

• Likely no effect

• Early-life Abx use (ie CD risk not associated with bacterial

infections) 2

• Protective

• Rotavirus vaccine

• Greatest impact in those exposed to gluten < 6 mo of age 1

• Risk factor for CDA/CD

• Early life infections (> 10 infxns before 18 mo of age) 3

• GI infection: risk of CDA within following 3 mo 4

1. Kemppainen K et al. Clin Gastro Hep 2017; 15:694-702

2. Lionetti et al. J Pediatr 2017; 184: 81-86

3. Marild et al. Am J Gastro 2015; 110: 14775-1484.

4. Kemppainen K et al. JAMA Pediatri 2017; 171: 1217-1225

Infections and Microbiome

• Gradient of CD in Europe

• neighboring Sweden and Denmark

• Finland and Estonia

• Low prevalence in Germany

• People in northern latitudes more likely to have vitamin D

deficiency

• But no association found between neonatal vitamin D

levels and later CD

Place of living

SYMPTOMS AND

FOLLOW-UP MANAGEMENT

Normal bowel Celiac disease

Duodenum

NEJM 2007; 357: 1731.

Dermatitis herpetiformis (1%) ↓ Bone mineral density

Short stature/growth

failure (33%)

Neurologic symptoms

Fatigue

Arthritis

Anemia (20-30%)

Iron (3-12%)

Folate, vit B12 deficiency

Recurrent apthous ulcers

Dental enamel

hypoplasia

Leffler DA et al. Rev. Gastroenterol. Hepatol 2015; 12: 561-571

Jericho H et al. Extraintestinal manifestations of celiac disease: Effectiveness of the gluten-free diet JPGN 2017; 65: 75-79.

Response of EIM to a GFD

Grp C (TTG < 10 x ULN)

P < 0.001

0.3

0.2Cum

ula

tive p

atients

with

positiv

e T

TG

6 12 302418 36

0.1

0

1.0

0.7

0.6

0.5

0.4

0.8

0.9

Grp A (TTG > 10 x ULN & EMA > 1:80)

Grp B (TTG > 10 x ULN & EMA < 1:40)

Gidrewicz et al Normalization Time of Celiac Serology in Children on a Gluten-free Diet JPGN 2017

FOLLOW-UP SEROLOGY ON GFD

• Is there accidental gluten exposure?

• Most common reason

• Check celiac serology

• Concurrent disorder?

• Lactose intolerance – diarrhea and flatulence

• Small bowel bacterial overgrowth – bloating, diarrhea

• Microscopic colitis

• profuse, watery, non-bloody diarrhea

• 4% of patients with celiac

• Is it another autoimmune disorder?

• Is it IBS?

PERSISTENT SYMPTOMS ON A GFD

• Children with IBS have 4-fold higher prevalence of celiac 1

• 30% of pt with CD adherent to GFD have IBS symptoms 2

• 5-fold higher prevalence of IBS, regardless of adherence,

compared to controls 2

1 Cristofori et al. JAMA Pediatr 20142 Sainsbury A et al. Clin Gastro Hepatol 2013; 11: 359

CELIAC AND IBS CROSSOVER

ASSOCIATED

CONDITIONS

Prevalence

FIRST DEGREE RELATIVES

Siblings > Children > Parents

Females > Males

2.3-8.9 %

Singh P et al. Am J Gastro 2015; 110; 1539-1548.

Associated Conditions

Dominica Gidrewicz, MD

Prevalence

FIRST DEGREE RELATIVES

Siblings > Children > Parents

Females > Males

2.3-8.9 %

Singh P et al. Am J Gastro 2015; 110; 1539-1548.

• 85% not likely to develop celiac

• The whole household should not simply go GF

• Screen all first degree relatives > 3 years of age

• Consider rescreening every 2-3 years if asymptomatic

(no guidelines yet for following relatives)

Associated Conditions

Prevalence

Autoimmune thyroid disease 10-20%

Psoriasis 4.3%

Type 1 diabetes 4-6%

Sjogren’s syndrome 2.4%

Hujoel I et al. Celiac Disease Clinical Features & Diagnosis Gastroenterol Clin N Am 2019; 19-27.

Husby et al. ESPGHAN guidelines for the diagnosis of coeliac disease JPGN 2012; 54: 136.

Autoimmune Conditions

Dominica Gidrewicz, MD

• 60% asymptomatic

• T1DM diagnosis precedes CD diagnosis in 75-90% of children

• ~98% have HLA DQ2 and/or DQ8

• Screening HLA not be additionally helpful

• Complications:

• Diabetic retinopathy

• Diabetic nephropathy

• ↑ risk of atherosclerosis

• GFD unlikely improves glycemic control

Cerutti et al. Diabetes Care 2004; 27: 1294-1298.

Greco et al Endocrine 2013; 43: 108-111.

Valerio et al. Diabetologia 2002; 45: 1719-1722.

Lewandowska K et al Autoimmunity 2018; 51: 81-88

Celiac and T1DM

• The Celiac Disease and Diabetes-Dietary Intervention

and Evaluation Trial (CD-DIET) protocol: a randomised

controlled study to evaluate treatment of asymptomatic

celiac disease in type 1 diabetes

• Children and adults, 8-45 yr

• Randomly assigned to treatment with GFD for 1 year or

continue gluten-containing diet

• Primary outcome: change in HBA1c

• Secondary outcome: change in BMT, blood glucose

variability, HRQoL

• Started in 2012

Efficacy of GFD in T1DM and asymptomatic CD

THANK YOUQuestions