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Celiac Disease: Exploring the Iceberg. Stefano Guandalini, M.D. Professor of Pediatrics Chief, Section of Gastroenterology, Hepatology and Nutrition University of Chicago . We’ll talk about. How we define celiac disease Who gets it and how? How common it is

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celiac disease exploring the iceberg

Celiac Disease:Exploring the Iceberg

Stefano Guandalini, M.D.

Professor of Pediatrics

Chief, Section of Gastroenterology, Hepatology and Nutrition

University of Chicago

we ll talk about
We’ll talk about...
  • How we define celiac disease
  • Who gets it and how?
  • How common it is
  • What are its clinical manifestations
  • What conditions can accompany it
  • Complications
  • How it is diagnosed and treated
definition
Definition

Celiac disease is a permanent condition affecting

primarily the intestine and caused by an abnormal reaction to gluten occurring in the immune (defense) system of the gut of individuals who possess

certain genes.

It leads to gastrointestinal and non-gastrointestinal symptoms, but it my as well be asymptomatic.

Indeed, celiac disease occurs more often in people who have few or no symptoms!

slide4

Flattened villi

Malabsorption

Normal villi

Absorption

Gluten

where is gluten found1

I’m Innocent!!

Where is gluten found?

The Grass Family - (GRAMINEAE)

Subfamily

Tribe

Festucoideae

Zizaneae Oryzeae Hordeae Aveneae Festuceaea Chlorideae

wild rice ricewheat oat finger millet teff

(ragi)

rye

barley

slide7

And what exactly is it?

Gluten is made up by Gliadin and Glutenin

A (huge!) grain of wheat

Some well-identified pieces (called “peptides”)of gliadin are resistant to digestion in the gut and are toxic for celiac patients

we ll talk about1
We’ll talk about...
  • How we define celiac disease
  • Who gets it and how?
  • How common it is
  • What are its clinical manifestations
  • What conditions can accompany it
  • Complications
  • How it is diagnosed and treated
who gets celiac disease

Gluten

HLA is not

DQ2, DQ8

Who gets celiac disease?

Nothing....

slide10

Other necessary

Risk Factors

Gluten

Infant feeding

Infections...

HLA is either

DQ2 or DQ8

Who gets Celiac Disease?

Celiac Disease

slide11

Breast feeding and celiac disease Odds ratios (95% CI) of effect of breast feeding at the time of gluten introduction on development of CD.

Akobeng AK et al., Arch Dis Child 2006

slide12
Timing of gluten introduction and risk of celiac disease autoimmunity- A prospective study on 1560 children at risk

1307 children followed from birth:

996 for cord blood HLA-DR3

311 for FH of IDDM

253 children enrolled at age 2-3

for FH of IDDM

Interviews with telephone questionnaire

At age 3, 6, 9, 12, 15 months

Same dietary information

collected retrospectively

Blood drawn for celiac serology (TG2)

at 9, 15, 24 m and then annually

Blood drawn for celiac serology (TG2)

at enrollment and then annually

Norris JM et al., JAMA 2005

slide13
Timing of gluten introduction and risk of celiac disease autoimmunity- A prospective study on 1560 children at risk

Norris JM et al., JAMA 2005

amount of gluten at weaning and celiac disease the swedish experience
Amount of gluten at weaning and celiac diseaseThe Swedish experience

Ivarsson A et al., Eur J Epidemiol 2003

slide16
“The rise in incidence was preceded by a twofold increase in the average daily consumption of gluten, and later the decline in incidence coincided with a consumption decrease by one third.”

Hernell O et al., Celiac Disease: Effect of Weaning on Disease Risk, 2005

slide18
Does the timing of gluten introduction influence the timing of appearance and/or the presenting symptoms of celiac disease?
breast feeding at time of gluten introduction influences the presenting symptoms of celiac disease
Breast feeding at time of gluten introduction influences the presenting symptoms of celiac disease

P<0.01

%

Symptoms at diagnosis

Guandalini S., UCCDP – n=92 pts., in press

changing pattern of celiac disease according to age at presentation
Changing pattern of celiac disease according to age at presentation

%

Guandalini S., UCCDP – n=92 pts., in press

in summary the role of environmental factors in celiac disease
In summary, the role of environmental factors in celiac disease
  • Breast feeding reduces the risk of celiac disease and/or at least delays its onset.
  • Introducing gluten at 4-6 months seems to be associated with the lowest risk of celiac disease.
  • Infants non breast-fed at the time of gluten introduction seem to be more likely to develop typical (GI) celiac disease.
  • To reduce risk of celiac disease, gluten should be introduced in small amounts.
  • Intestinal infections – especially by Rotavirus – increase the risk of developing celiac disease
we ll talk about2
We’ll talk about...
  • How we define celiac disease
  • Who gets it and how?
  • How common it is
  • What are its clinical manifestations
  • What conditions can accompany it
  • Complications
  • How it is diagnosed and treated
how common is celiac disease
How common is celiac disease?

Currently accepted worldwide

Prevalence (in Caucasians):

1%

Projected number of celiacs in North America: about 3,000,000

Actual number of known celiacs: about 50,000

For each known celiac there are 53 undiagnosed patients.

the celiac iceberg
The Celiac Iceberg

Symptomatic

Celiac Disease

Intestine

is damaged

Silent Celiac

Disease

Intestine

appears normal

Latent Celiac Disease

Genetic susceptibility: - DQ2, DQ8

Positive serology

we ll talk about3
We’ll talk about...
  • How we define celiac disease
  • Who gets it and how?
  • How common it is
  • What are its clinical manifestations
  • What conditions can accompany it
  • Complications
  • How it is diagnosed and treated
clinical manifestations
Clinical Manifestations
  • Gastrointestinal symptoms/signs (“typical”)
  • Non-gastrointestinal symptoms/signs (“atypical”)

Symptomatic

Celiac disease

  • Celiac Disease may also be associated with other conditions,
  • and mostly with:
  • Autoimmune disorders
  • Some syndromes
gastrointestinal symptoms
Gastrointestinal symptoms

Most common age of presentation: 6-24 months

  • Chronic or recurrent diarrhea
  • Constipation
  • Anorexia
  • Failure to thrive or weight loss
  • Abdominal pain, bloating
  • Vomiting
non gastrointestinal symptoms
Non Gastrointestinal symptoms

Most common age of presentation: older child to adult

  • Dermatitis Herpetiformis
  • Dental enamel hypoplasia

of permanent teeth

  • Osteopenia/Osteoporosis
  • Short Stature
  • Delayed Puberty
  • Iron-deficient anemia resistant to oral Fe
  • Liver disease
  • Arthritis
  • Neurological problems
  • Psychiatric Disorders
  • Women Sub-In-fertility and/or miscarriages and/or low birth babies
the list keeps growing
The list keeps growing
  • Idiopathic dilated cardiomyopathy
  • Pancreatitis (ESPGHAN 2007)
  • Cardiac valves involvement (ESPGHAN 2007)
dermatitis herpetiformis
Erythematous macules > urticarial papules > tense vesicles

Severe itching

Most have no GI symptoms

75% Gluten dependent villous atrophy

Serology positive in only 30-40%

Dermatitis Herpetiformis
it s not just dh other skin disorders possibly associated with celiac disease
It’s not just DH!Other skin disorders possibly associated with celiac disease
  • Urticaria
  • Hereditary angioneurotic edema
  • Cutaneous vasculitis
  • Erythema nodosum
  • Psoriasis
  • Vitiligo
  • Dermatomyositis
  • Alopecia aerata…

Abenavoli L et al., World J Gastroenterol 2006

dental enamel defects
Dental Enamel Defects

Involve the permanent teeth and

can be the only presenting sign of Celiac Disease

low bone density osteoporosis
Low bone density (Osteoporosis)

Normal Peak Bone Mass can be achieved at puberty by celiac children on a GFD, but only if the diet is strict!

short stature delayed puberty
Short Stature/Delayed Puberty

Can anyone guess how many children who are short

have celiac disease as cause of their reduced height?

  • Short stature in children / teens:

~10% of short children and teens are celiacs

  • Delayed onset of menstrual periods:

 Not uncommon in teen girls with untreated Celiac Disease

anemia
Anemia
  • Considered the most common non-GI manifestation in older teenagers and adults
  • 5-8% of adults with unexplained iron deficiency anemia have Celiac Disease
  • In children with newly diagnosed Celiac Disease:

 Anemia is very common

 However, in children presenting with anemia only, celiac disease is not very frequent

liver disease a study on 14 000 cd patients and 67 000 controls
Liver disease: A study on 14,000 CD patients and 67,000 controls

Highly statistically (p<0.001) increased risk for the following conditions in celiac disease (occurring before and after diagnosis) is shown for:

  • Acute and chronic hepatitis
  • Primary sclerosing cholangitis
  • Fatty liver
  • Liver failure
  • Liver cirrhosis or fibrosis
  • Primary biliary cirrhosis

Ludvigsson JF et al. Clin Gastroenterol Hepatol 2007

arthritis and neurological problems
Arthritis and Neurological Problems
  • Arthritis in adults
    • Fairly common, including those on gluten-free diets
  • Juvenile chronic arthritis
    • Up to 3% have Celiac Disease
  • Neurological problems in teenagers and adults
    • Cerebellar ataxia (abnormal gait)
    • Peripheral neuropathies
    • Epilepsy with cranial calcifications
asymptomatic
Asymptomatic
  • Silent:No symptoms Damaged mucosa

Positive serology(=elevated celiac antibodies in the blood)

Silent Latent

  • Latent: No symptomsNormal mucosaPositive Serology (=elevated celiac antibodies in the blood)
we ll talk about4
We’ll talk about...
  • How we define celiac disease
  • Who gets it and how?
  • How common it is
  • What are its clinical manifestations
  • What conditions can accompany it
  • Complications
  • How it is diagnosed and treated
other conditions can be associated with celiac disease
Other conditions can be associated with celiac disease

The prevalence of Celiac Disease is higher in patients who have the following:

  • Relative of a celiac person
  • Certain genetic disorders or syndromes
  • Other autoimmune conditions
associated conditions
Associated Conditions

20

16

12

percentage

8

4

General

Population

0

Relatives

Down

syndrome

Thyroiditis

IDDM

celiac disease and autoimmunity
Celiac Disease and Autoimmunity

The Prevalence Of Autoimmune Disorders Increases As Diagnosis Is Delayed

p = 0.000001

Age at diagnosis (years)

Ventura A et al., Gastroenterology 1999

we ll talk about5
We’ll talk about...
  • How we define celiac disease
  • Who gets it and how?
  • How common it is
  • What are its clinical manifestations
  • What conditions can accompany it
  • Complications
  • How it is diagnosed and treated
major complications of celiac disease
Refractory celiac disease and related disorders

Intestinal lymphoma

Reduced life expectancy

(if not on the diet!)

Major Complications of Celiac Disease
effects of diagnostic delay and adherence to gfd on mortality in celiac patients
Effects of Diagnostic Delay and Adherence to GFD on Mortality in Celiac Patients

Corrao et al., Lancet Aug 2001

slide49
‘‘The most important diagnostic test in CD is the suspicion of the disease.’’

NIH consensus 2004

slide51
Gliadin antibodies
    • Gliadin is the alcohol soluble fraction of gluten
    • Elicits a strong humoral response in CD
    • Anti-food protein antibodies, IgG and IgA
    • Known to be also often positive in:
      • Milk protein allergy
      • Crohn’s disease
      • Post-gastroenteritis
      • GERD
      • Etc……………
  • Anti-Reticulin, Anti-Endomysium, Anti-tissue Transglutaminase Antibodies
    • IgA and IgG auto-antibodies
slide52

Anti-gliadin IgG

Sensitivity 83-100% Average 93%

Specificity47-94% Average 71%

Anti-gliadin IgA

Sensitivity 51-100% Average 79%

Specificity 71-100% Average 89%

slide53

Anti-Endomysium Antibodies (EMA)

Sensitivity 88-100% Average 95%

Specificity 98-100% Average 99%

Anti-Tissue Transglutaminase Antibodies (TTG)

Sensitivity 78-100% Average 94%

Specificity96-100% Average 98%

iga deficiency a common problem in celiac patients

Corollary: always test for total serum IgA when looking for celiac disease

IgA Deficiency: a common problem in celiac patients
  • 5-7% of celiac patients are IgA-deficient, thus unable to produce any IgA autoantibodies (either EMA or TTG).
  • In this subset of patients, research shows that IgG-EMA and IgG-TTG can be detected and are as sensitive and as specific for the diagnosis of celiac disease.

Cataldo F et al., Gut 2000

Korponay-Szabo, Gut 2003

Dahlbom I, Clin Diagn Lab Immunol. 2005

cd antibodies in other biological fluids

Stools

AGA

TTG

CD Antibodies in other biological fluids?

Kappler M et al., BMJ 2006

slide56

Celiac

Normal

Celiac

histological features
Histological Features

Normal 0

Infiltrative 1

Hyperplastic 2

Partial atrophy 3a

Subtotal atrophy 3b

Total atrophy 3c

suggested diagnostic strategy i
Suggested Diagnostic Strategy: I

Strong suspicion of CD?

(“Typical” GI presentation)

Do NOT initiate a gluten-free diet!

Refer to Pediatric GI for EGD with biopsies

slide59

Suggested Diagnostic Strategy: II

  • Signs of possible extra-intestinal CD and/or associated conditions
  • Dental enamel hypoplasia
  • Recurrent aphtous stomatitis
  • Any autoimmune disorder (Diabetes, Hashimoto, SLE, etc.)
  • Short Stature/Delayed Puberty
  • Persistently Elevated AST/ALT
  • Epilepsy or Ataxia
  • Fe-resistant anemia
  • Weakness, fatigue, lethargy
  • Syndromes: Down, Turner, Williams
  • Total IgA Deficiency
  • First-degree relative of a celiac or of a type 1 diabetic
  • History of recurrent miscarriages

Patient in a group at risk?

Check tTG, total serum IgA

Negative

Positive

No CD

Refer to Pediatric GI for EGD with biopsies

slide64

“By applying simple and well-established criteria for CD case finding

on a sample of adults, we achieved a 32- to 43-fold increase

in the diagnosis rate of this condition.”

after diagnosis use serology to monitor the dietetic compliance of celiac patients
After diagnosis, use serology to monitor the dietetic compliance of celiac patients
  • In adults, TTG and EMA are poor predictors of dietary transgressions
  • In children, TTG and AGA can both be used to monitor compliance: AGA disappear before TTG
  • Periodic monitoring of serology is an integral component of proper follow-up in children with celiac disease

Vahedi Y et al., Am J Gastroenterol 2003

Cataldo F et al., Acta Pediatr 1995

NASPGHAN guideline, JPGN 2005