Celiac Disease in Children: The Calgary Clinic Data

Calgary Celiac Disease Conference 25 October 2008

J. Decker Butzner, MD, FRCPC
Head , Division of Pediatric Gastroenterology Alberta Childrens Hospital, Professor, University of Calgary
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Disclosures
Member Professional Advisory Board Canadian Celiac Association Member Professional Advisory Board Canadian Celiac Association Calgary Chapter Financial Disclosures - Nil

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

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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

Risk Factors
The Grains

The Genes
Celiac disease is not just a disease of Caucasians
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Dietary Factors
The Grass Family - (GRAMINEAE)
Subfamily Festucoideae

Tribe
Zizaneae Oryzeae Hordeae Aveneae Festuceaea Chlorideae

wild rice

rice

wheat

oat

finger millet (ragi)

teff

rye

barley
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Genetics
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
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Genes

? ?

?
HLA

+
Gluten

Celiac Disease

Pathogenesis
Genetics Gluten

Necessary Causes
Gender Infant feeding Infections Others

Pathogenesis ?

Risk Factors

Celiac disease
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Normal small bowel

Celiac disease

Gluten

Gluten-free diet

Intestinal lumen

TTG T APC

Submucosa

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Intestinal Lumen

TTG APC T

Submucosa

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Intestinal lumen

Tk P T AGA, EMA, ETTG B

Cytokines (IL-15) APC

Submucosa
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Classic Celiac Disease

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Gastrointestinal Manifestations (Nonclassic)

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

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Non Gastrointestinal Manifestations

Most common age of presentation: older child to adult 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
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Associated Conditions
20 16

percentage

12 8 4 0 Relatives IDDM Thyroiditis Down syndrome

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General Population

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

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Children Diagnosed with Celiac Disease at Alberta Childrens Hospital

266 children 61% female Median age at Dx 8 yrs

_______Pre-screening_____

_________Screening________ 18

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

Pre-screening Screening (1990-96) (2000-06) 36 199 1.6:1 2 2.0 0.8 1.6:1 9 p<0.001 7.3 p<0.03 1.6 p=0.154

Patients, n Female:male Median age at diagnosis (yrs) Incidence (/100,000/yr) Incidence classic celiac disease (/100,000/yr)

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Clinical Presentations 1990 - 2006

Symptom or Condition Family History * Symptoms or conditions ** No GI symptoms Blood in stool, reflux No weight loss or FTT Abdominal Pain +Other * Abdominal Pain Only Type 1 Diabetes Failure to Thrive ** Endoscopy for Other Chronic Diarrhea Short Stature Fe Deficiency sAnemia Trisomy 21 Constipation Vomiting Dermatitis Herpetiformis Food Allergy Abdominal Distention Elevated Transaminases Hypothyroidism Dental Enamel Defects Hypoalbuminemia Classic celiac Pre-screening n=36 Screening n=199 (2000-06) (1990-96) n (%) n (%) 0 5 (13.9) 0 2 (5.6) 1 (2.8) 0 1 (2.8) 0 1 (2.8) 0 0 1 (2.8) 0 0 0 0 0 0 1 (2.8) 24 (67) 35 (17.6) 34 (17.1) 18 (9.0) 14 (7.0) 13 (6.5) 8 (4.0) 7 (3.5) 6 (3.0) 6 (3.0) 5 (2.5) 5 (2.5) 2 (1.0) 2 (1.0) 1 (0.5) 1 (0.5) 1 (0.5) 1 (0.5) 1 (0.5) 0 39 (20)

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Distribution of Patients by Presentation and Gender after Introduction of Screening

Classic Celiac GI Symptoms Extra-intestinal Silent

2000 - 2006
100% 90% 80% 70%

P tie ts(% a n )

60% 50% 40% 30% 20% 10% 0%

< 3 3 - 9 10 - 17 . Female Male

Age (years)

n = 30

n = 82

n = 87

n = 123

n = 86

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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
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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)
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Methods Calgary Clinic Childrens Survey 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
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Calgary Clinic Pediatric Survey Data

N= Median age of participants Age range participants % Female Median age at Dx Age range at Dx Member of CCA Calgary 146 11 yrs 1 31 yrs 61% 8 yrs 1 17 yrs 58%

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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
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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%
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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%

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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

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Methods Canadian Survey

Data on presentation of celiac disease
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

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Comparison of Calgary Clinic & Canadian Pediatric Survey Data

N= Median age of participants Age range participants % Female Median age at Dx Age range at Dx Member of CCA Calgary 146 11 yrs 1 31 yrs 61% 8 yrs 1 17 yrs 58% Canada 168 9 yrs 2 15 yrs 58% 3 yrs 1 15 yrs 100% by def.
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Comparison of Calgary Clinic & Canadian Pediatric Survey Data

Reaction after accidental ingestion of gluten
Calgary % with reaction Abdominal pain Diarrhea Bloating Fatigue Headache Median time to Sx Time range to Sx 61% 87% 67% 71% 51% 29% 2hrs Canada 54% 87% 64% 57% 37% 24% 2 hrs

15 min 48 hr 20 min 60 hr

Most displayed more than one symptom during a reaction

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Celiac Health Surveys: Calgary & Canada

Calgary data (n = 146); Canada data (n = 168)
All or Most of the time (%) (%) Avoided restaurants Avoided traveling 39 54 3 15 Some of the time (%) (%) 41 23 63 63 25 41 31 62 65 35 Never (%) (%) 20 5

75 54 24 10 34 8

Found it difficult to find 12 28 gluten-free foods at stores Found it difficult to determine if 3 27 the food was gluten-free Felt that they were not invited out 3 10 for meals due to celiac disease

72 53

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Celiac Health Surveys: Calgary & Canada

Calgary data (n = 146); Canada data (n = 168)
All or Most of the time (%) (%) Felt left out of activities at school or friends homes Felt different from other kids because of celiac disease Felt embarrassed to bring gluten-free foods to parties 8 13 20 18 9 23 Some of the time (%) (%) 38 48 34 41 21 48 51 30 49 22 Never (%) (%) 54 30 56 41 74
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37 29 45 26 71

Felt angry about having to follow 15 23 a special diet Felt they can be healthy without following a special diet 4 4

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 Intentional

20% 64%

50% 13%

23% 13%

3% 4%

2% 4%

2% 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%
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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

No effect on compliance:
Age at diagnosis Sex of child Asymptomatic at diagnosis Membership in Canadian Celiac Assoc

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%

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Celiac Health Surveys: Pediatric Data Conclusions

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
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Acknowledgements
Summer students Derek Castiglione Kelly E. McGowan Calgary Celiac Assoc Karen Renaud

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

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Canadian Celiac Health Survey:

Pediatric data (n=168) Other diagnoses prior to the diagnosis of celiac disease
Anemia Irritable bowel syndrome Gastroesophageal reflux Stress Stomach ulcer % 15 11 8 8 4
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Canadian Celiac Health Survey:

Pediatric data (n=168) Physician consulted before the diagnosis of celiac disease confirmed
24% consulted 2 family physicians 30% consulted 2 pediatricians 6% consulted 2 gastroenterologists
Average time from development of symptoms to diagnosis = 1 year
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Canadian Celiac Health Survey:

Pediatric data (n=168) Clinical symptoms prior to diagnosis of celiac disease
% Abdominal pain 90 Weight loss 71 Poor growth 70 Diarrhea 65 Extreme weakness64 Nausea, vomiting 53 Anemia 40 % Mood swings/depression37 Constipation 30 Eczema 24 Bone/joint pain 21 Mouth ulcers 16 Muscle cramps 14 Easy bruising 11
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ACH Celiac Disease Database

Number of Cases Diagnosed
Number 200 180 160 140 120 100 80 60 40 20 0 1990-1995 1996-2000 Year 2001-2006 Per cent with Classic CD 70.0% Percentage of years total # of cases 60.0% 50.0% 40.0% 30.0% 20.0% 10.0% 0.0%

# of cases

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Short Stature/Delayed Puberty

Short stature in children / teens:
y

b10% of short children and teens have evidence of celiac disease Higher prevalence in teens with untreated celiac disease

Delayed menarche:
y

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Why talk about celiac disease?

Celiac disease affects between 1 in 100 and 1 in 300 North Americans Only 1 in 5 present with classic symptoms It takes an average of 11 years from the onset of symptoms to make the diagnosis Canadian data 2,681 patients 37 % of patients saw 2 or more physicians prior to diagnosis Celiac disease has many atypical presentations
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WHO criteria for disease screening

Disease causes serious health problems Screening test should be reliable (few false negatives and false positives) for the target disease A treatment for the disease must be available If not recognized in time, the disease could result in difficult to manage complications

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