Celiac Disease in Children:The Calgary Clinic Data

Calgary Celiac Disease Conference

25 October 2008

J. Decker Butzner, MD, FRCPCHead , Division of Pediatric Gastroenterology

Alberta Children’s Hospital,

Professor, University of Calgary

1

Disclosures

• Member Professional Advisory Board – Canadian Celiac Association

• Member Professional Advisory Board – Canadian Celiac Association –Calgary Chapter

• Financial Disclosures - Nil

2

Objectives

• Provide an update on the genetics and pathophysiology of celiac disease

• Southern Alberta data on celiac disease in children – Diagnosis– Follow up

• Compare to Canadian Pediatric Celiac Survey from 2002

3

Definition

• Celiac disease is an autoimmune condition• Occurs in genetically susceptible individuals

– DQ2 and/or DQ8 positive HLA haplotype is necessary but not sufficient

• A unique autoimmune disorder because:– both the environmental trigger (gluten) and the autoantigen

(tissue Transglutaminase) are known– elimination of the environmental trigger leads to a complete

resolution of the disease

4

Risk Factors

The Grains

The Genes

Celiac disease is not just a disease of Caucasians 5

Dietary Factors

FestucoideaeSubfamily

Tribe

Zizaneae Oryzeae Hordeae Aveneae Festuceaea Chlorideae

wild rice rice wheat oat finger millet teff

(ragi)

rye

barley

The Grass Family - (GRAMINEAE)

6

• Multiple genes involved

• The most consistent genetic component depends on the presence of HLA-DQ (DQ2 and / or DQ8) genes

• DQ2 or DQ8 found in 99% of celiac patients

• DQ2 or DQ8 found in 40% of the general population

• HLA-DQ2 and / or DQ8 genes are necessary (No DQ2/8, no Celiac Disease!) but not sufficient for the development of the disease

• Other genes (not yet identified) account for 60 % of the inherited component of the disease

HLA

?? ?

?

Gluten

Celiac Disease

+

Genes

Genetics

7

Pathogenesis

Celiac disease

Gluten NecessaryCauses

GenderInfant feedingInfectionsOthers

Risk Factors

Pathogenesis?

Genetics

8

9

Normal small bowelNormal small bowel Celiac diseaseCeliac disease

Gluten

Gluten-free diet

APC

Submucosa

TTG

T

Intestinal lumen

10

Intestinal Lumen

Submucosa

TTG

TAPC

11

Intestinal lumen

Submucosa

T

BAGA, EMA,

TTG

Cytokines (IL-15)Tk

P APC

12

“Classic” Celiac Disease

13

Gastrointestinal Manifestations(“Nonclassic”)

• Irritable bowel syndrome – C & D types• Chronic diarrhea without weight loss• Abdominal pain• Vomiting• Constipation

14

Non Gastrointestinal Manifestations

• Dermatitis Herpetiformis• Iron-deficiency anemia resistant to oral Fe

• Dental enamel hypoplasia

of permanent teeth• Osteopenia/Osteoporosis• Short Stature• Delayed Puberty

• Elevated transaminases• Arthritis• Neurological

- Epilepsy with occipital calcifications - Ataxia - Peripheral neuropathy• Infertility

Most common age of presentation: older child to adult

15

Associated Conditions

Relatives IDDM Thyroiditis Downsyndrome

0

4

8

12

16

20

per

cen

tag

e

GeneralPopulation

16

ACH Celiac Disease Database• Create a database to examine incidence, primary

symptoms, mode of presentation, associated diseases and family history in children diagnosed at ACH since 1990

• Compare the prescreening era (1990 – 1996) to the screening era (2000 – 2006)

• Collect prospective data on adherence to a gluten-

free diet, ongoing health issues, quality of life in children with long standing celiac disease

17

Children Diagnosed with Celiac Disease at Alberta Childrens’ Hospital

_______Pre-screening_____ _________Screening________

266 children61% female

Median age at Dx 8 yrs

18

Comparison of Pre – Screening Era to the Screening Era in Calgary Clinic

Pre-screening (1990-96)

Screening (2000-06)

Patients, n 36 199

Female:male 1.6:1 1.6:1Median age at diagnosis (yrs)

2 9

p<0.001Incidence (/100,000/yr) 2.0 7.3

p<0.03Incidence classic celiac disease (/100,000/yr)

0.8 1.6

p=0.154

19

Clinical Presentations 1990 - 2006

Symptom or

Condition

Pre-screening n=36 (1990-96)

n (%)

Screening n=199 (2000-06)

n (%)

Family History 0 35 (17.6)

Abdominal Pain +Other * 5 (13.9) 34 (17.1)

Abdominal Pain Only 0 18 (9.0)

Type 1 Diabetes 2 (5.6) 14 (7.0)Failure to Thrive ** 1 (2.8) 13 (6.5)

Endoscopy for Other † 0 8 (4.0)Chronic Diarrhea ‡ 1 (2.8) 7 (3.5)

Short Stature 0 6 (3.0)

Fe Deficiency ±Anemia 1 (2.8) 6 (3.0)

Trisomy 21 0 5 (2.5)

Constipation 0 5 (2.5)

Vomiting 1 (2.8) 2 (1.0)

Dermatitis Herpetiformis 0 2 (1.0)

Food Allergy 0 1 (0.5)

Abdominal Distention 0 1 (0.5)

Elevated Transaminases 0 1 (0.5)

Hypothyroidism 0 1 (0.5)

Dental Enamel Defects 0 1 (0.5)

Hypoalbuminemia 1 (2.8) 0

Classic celiac 24 (67) 39 (20)

* Symptoms or conditions** No GI symptoms

† Blood in stool, reflux‡ No weight loss or FTT

20

Distribution of Patients by Presentation and Gender after Introduction of Screening

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

< 3 3 - 9 10 - 17 . Female Male

Age (years)

Pa

tie

nts

(%

)

Classic Celiac GI Symptoms Extra-intestinal Silent

n = 30 n = 82 n = 87 n = 123 n = 86 21

2000 - 2006

Conclusions: Impact of screening on the Calgary Clinic

• Screening tripled the incidence and quadrupled the median age at diagnosis of celiac disease in children

• The classic celiac presentation remains common (67%) in younger children (<3 yr old), while “atypical” presentations are frequently observed in older children

• 12 new clinical presentations observed in 42% of children in the screening group

• Gastrointestinal symptoms still predominate the clinical presentation, but they are increasingly diverse

• Currently, one quarter of children are diagnosed due to family history or a celiac-associated condition

22

Childhood Celiac Health Surveys: Calgary Clinic & Canada

• Follow up of individuals with celiac disease

diagnosed in childhood

• Calgary Clinic includes children from Southern Alberta and SE British Columbia Children

• Canadian data includes follow up children who are members of the CCA across the country

• Calgary data (n = 146); Canada data (n = 168)23

• Questionnaire sent to 267 children who were diagnosed with celiac disease from 1990 – 2006

– 45 were undeliverable

• 146/222 respondents (66%)

• Time since diagnosis 2.5 yr (range .5 – 17 years) 62 on diet < 2 years

41 on diet 2 – 5 years 43 on diet > 5 years

Methods Calgary Clinic Children’s Survey

24

Calgary Clinic Pediatric Survey Data

Calgary

N = 146

Median age of participants

11 yrs

Age range participants 1 – 31 yrs

% Female 61%

Median age at Dx 8 yrs

Age range at Dx 1 – 17 yrs

Member of CCA 58%

25

Are Asymptomatic Children Really Asymptomatic?

• 125 symptomatic and 21 asymptomatic– Family hx (15), Type-1-diabetes (4), thyroid (2)

• 14 / 21 “asymptomatic” reported improvement in 1 or more symptoms after starting GFD – Fatigue – 57%, abdo pain – 43%, nausea – 36%, bloating – 36%

• Health improved: “a lot” – 22%, “somewhat” – 64%,

“not at all/ worse” – 14%• React to gluten: “always” – 29%, “sometimes” – 24%,

“rarely / never” – 47%

• Many “asymptomatic” children retrospectively report symptoms that improve on a GFD and react to gluten

26

Follow up of family members after diagnosis – Calgary study

• First degree relatives screened– All – 37%, Some – 41%, None – 22%

• Second degree relatives screened– Yes – 38%, No – 62%

• Family members diagnosed with celiac disease– Yes, before my Dx – 25%– Yes, after my Dx – 17%– No – 58%

27

Follow up of family members after diagnosis – Calgary study

• Family members starting GFD without biopsy– Yes – 17%, No – 81%

• My family eats gluten and I eat GFD– All/Most of time – 57%, Some of time – 37%, Never – 5%

• My family reads labels to determine GF foods– All/Most of time – 94%, Some of time – 3%, Never – 2%

• I participate in determining if my food is GF– Always – 38%, daily – 34%, weekly – 15%, monthly – 8%, never – 15%

28

Canadian Pediatric Celiac Health Survey

Mohsin Rashid, Anne Cranney, Marion Zarkadas, Connie Switzer, Ian D. Graham, Shelly Case, Mavis Molloy, Ralph Warren, Vern Burrows, J Decker Butzner

Pediatrics Dec 2005;116:e754-759

29

• Questionnaire sent to all members of the Canadian Celiac Association (n=5,240) in 2002• 3,048 respondents (65%)

• 194 children (<16 years)• 168 children had biopsy-confirmed celiac disease

Methods Canadian Survey Data on presentation of celiac disease

30

Comparison of Calgary Clinic & Canadian Pediatric Survey Data

Calgary Canada

N = 146 168

Median age of participants

11 yrs 9 yrs

Age range participants 1 – 31 yrs 2 – 15 yrs

% Female 61% 58%

Median age at Dx 8 yrs 3 yrs

Age range at Dx 1 – 17 yrs 1 – 15 yrs

Member of CCA 58% 100% by def.

31

Comparison of Calgary Clinic & Canadian Pediatric Survey Data

Reaction after accidental ingestion of gluten

Calgary Canada

% with reaction 61% 54%

Abdominal pain 87% 87%

Diarrhea 67% 64%

Bloating 71% 57%

Fatigue 51% 37%

Headache 29% 24%

Median time to Sx 2hrs 2 hrs

Time range to Sx 15 min – 48 hr 20 min – 60 hr

Most displayed more than one symptom during a reaction32

All or Most Some of Never of the time the time

(%) (%) (%) (%) (%) (%)

• Avoided restaurants 39 54 41 41 20 5

• Avoided traveling 3 15 23 31 75 54

• Found it difficult to find 12 28 63 62 24 10 gluten-free foods at stores

• Found it difficult to determine if 3 27 63 65 34 8

the food was gluten-free

• Felt that they were not invited out 3 10 25 35 72 53 for meals due to celiac disease

Celiac Health Surveys: Calgary & CanadaCalgary data (n = 146); Canada data (n = 168)

33

All or Most Some of Never of the time the time

(%) (%) (%) (%) (%) (%)

• Felt left out of activities at 8 13 38 48 54 37 school or friends’ homes

• Felt different from other kids 20 18 48 51 30 29 because of celiac disease

• Felt embarrassed to bring 9 23 34 30 56 45 gluten-free foods to parties

• Felt angry about having to follow 15 23 41 49 41 26 a special diet

• Felt they can be healthy without 4 4 21 22 74 71 following a special diet

Celiac Health Surveys: Calgary & CanadaCalgary data (n = 146); Canada data (n = 168)

34

Gluten Ingestion in Children in Calgary Clinic

N = 146 < 1 time /year

1-3 times /year

1-3 times

/month

1-3 times /week

Daily Missing

Accidental 20% 50% 23% 3% 2% 2%

Intentional 64% 13% 13% 4% 4% 2%

Reasons

No reaction to gluten – 10%, No effect on health – 8%Difficult to determine if Gluten Free – 26%, Hidden gluten – 41%Difficult to order GF meal – 32%, Do not like taste of GF – 10%Feel different – 14%, Angry about CD – 11%, No GF prep in home – 3%

35

Gluten ingestion: Risk factors in Calgary Clinic

• Children with poor compliance displayed: – Increasing age

– 40% >18yo, 29% 13-17 yo,

21% 9-12yo, 7% 5-8yo

– Time since diagnosis– 40% >5yrs, 15% 2-5 yrs,

13% <2yrs since diagnosis

– Reaction to gluten– 23% no/rare reaction – 33% sometimes reaction– 12% always reaction

– No medical follow up for celiac disease – 38%

– Medical follow up – 15%

• No effect on compliance:– Age at diagnosis– Sex of child– Asymptomatic at diagnosis– Membership in Canadian

Celiac Assoc

36

Conclusions

Celiac Health Surveys: Pediatric Data

• Calgary and Canadian data generally similar• Children with celiac disease can present with a

variety of symptoms• Many have had other diagnoses prior to that of celiac

disease and delays in diagnosis are common• While most adjust well, 10 to 20% continue to have

significant difficulties in modifying their lifestyles • Many “asymptomatic” children retrospectively report

symptoms that improve on a GFD and react to gluten

37

AcknowledgementsSummer students Calgary Celiac AssocDerek Castiglione Karen RenaudKelly E. McGowan

SecretariesTanya Fillion

Supported by grants from the Calgary Chapter of the Canadian Celiac Assoc, the University of Calgary and the Canadian Association of Gastroenterology.

38

Other diagnoses prior to the diagnosis of celiac disease

Canadian Celiac Health Survey:Pediatric data (n=168)

%Anemia 15 Irritable bowel syndrome 11 Gastroesophageal reflux 8 Stress 8 Stomach ulcer 4

39

Physician consulted before the diagnosis of celiac disease confirmed

Canadian Celiac Health Survey:Pediatric data (n=168)

24% consulted ≥ 2 family physicians

30% consulted ≥ 2 pediatricians

6% consulted ≥ 2 gastroenterologistsAverage time from development of symptoms

to diagnosis = 1 year40

%Abdominal pain 90Weight loss 71Poor growth 70Diarrhea 65Extreme weakness64Nausea, vomiting 53Anemia 40

%Mood swings/depression37

Constipation 30Eczema 24Bone/joint pain 21

Mouth ulcers 16Muscle cramps 14Easy bruising 11

Clinical symptoms prior to diagnosis of celiac disease

Canadian Celiac Health Survey:Pediatric data (n=168)

41

ACH Celiac Disease Database

Number of Cases Diagnosed

020406080

100120140160180200

1990-1995 1996-2000 2001-2006

Year

# o

f ca

ses

0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

70.0%

Per

cen

tag

e o

f ye

ars

tota

l #

of

case

s

Number Per cent with Classic CD

42

Short Stature/Delayed Puberty

• Short stature in children / teens:10% of short children and teens have

evidence of celiac disease

• Delayed menarche: Higher prevalence in teens with untreated celiac disease

43