Transcript Slides - CT-AAP

To Eat Gluten or Not To Eat Gluten:
Answers to Questions on Celiac and
Gluten-Related Disorders:
Anthony F. Porto, M.D. M.P.H.
Assistant Professor of Pediatrics
Associate Clinical Chief, Pediatric Gastroenterology
Yale University
Goals
• Understand how to evaluate children for
gluten-related disorders
• Describe when a gluten free diet is medically
indicated
• Discuss potential nutritional risks associated
with a gluten free diet
Increased awareness of
gluten-related disorders
Reilly et al. Journal of Pediatrics 2016
Trends in following a GFD
• Whose following a GFD?
–
–
–
–
1/5 in the US follow a gluten free diet
1/3 of millennials
Females = male
Nonwhite > White
• No difference based on socioeconomic status
– 20% of households with income <$30,000
• Why follow a gluten-free diet?
– 35% - no reason
– 26% - healthier
– 13% - weight loss
When is a Gluten Free Diet Medically
Needed?
Gluten Related Disorders
Medically
Necessary
Immune Mediated
Celiac Disease
(~1%)
Wheat Allergy
(0.1%)
Biomarkers available
Not Medically
Necessary
Non- Immune Mediated
Non-celiac gluten sensitivity
(Wheat Intolerance)
(0.3%-5-6%)
No biomarkers available yet
Symptoms of Celiac Disease
TYPICAL
GI MANIFESTATIONS
(6 -24 mo)
ATYPICAL
NON-GASTROINTESTINAL
MANIFESTATIONS
(OLDER CHIDREN)
Weight loss
Dermatitis Herpetiformis
Abdominal Pain
Hepatitis
Anorexia
Iron deficient anemia
Intussusception
Osteopenia/Osteoporosis
Arthritis/Joint/Bone Pain
Constipation/Diarrhea
Failure to thrive
Vomiting
~1/3 may be overweight at
diagnosis
Headaches
Dental enamel defects
Pubertal Delay/ Short stature
Fatigue/Foggy Mind/Psych
Symptoms of Celiac Disease
TYPICAL
GI MANIFESTATIONS
(6 -24 mo)
Weight loss
Abdominal Pain
Anorexia
Intussusception
Constipation/Diarrhea
Failure to thrive
Vomiting
~1/3 may be overweight at
diagnosis
Symptoms of Celiac Disease
ATYPICAL
NON-GASTROINTESTINAL
MANIFESTATIONS
(OLDER CHIDREN)
Dermatitis Herpetiformis
Hepatitis
Iron deficient anemia
Osteopenia/Osteoporosis
•
Erythematous macule > urticarial papule
> tense vesicles
•
Severe pruritus
•
Symmetric distribution
•
90% no GI symptoms
Pubertal Delay/ Short stature
•
75% villous atrophy
Fatigue/Foggy Mind/Psych
•
Gluten sensitive
Arthritis/Joint/Bone Pain
Headaches
Dental enamel defects
Symptoms of Celiac Disease
ATYPICAL
NON-GASTROINTESTINAL
MANIFESTATIONS
(OLDER CHIDREN)
Dermatitis Herpetiformis
Hepatitis
Iron deficient anemia
Osteopenia/Osteoporosis
Arthritis/Joint/Bone Pain
Headaches
Dental enamel defects
Pubertal Delay/ Short stature
Fatigue/Foggy Mind/Psych
Symptoms of Celiac Disease
ATYPICAL
NON-GASTROINTESTINAL
MANIFESTATIONS
(OLDER CHIDREN)
Dermatitis Herpetiformis
Hepatitis
• Pitting, and grooving with
occasional complete loss of
enamel
• Involves the secondary
dentition
• May be the ONLY presenting
sign of celiac disease
• Improves on GFD
Iron deficient anemia
Osteopenia/Osteoporosis
Arthritis/Joint/Bone Pain
Headaches
Dental enamel defects
Pubertal Delay/ Short stature
Fatigue/Foggy Mind/Psych
Symptoms of Celiac Disease
ATYPICAL
NON-GASTROINTESTINAL
MANIFESTATIONS
(OLDER CHIDREN)
Dermatitis Herpetiformis
Hepatitis
Iron deficient anemia
Osteopenia/Osteoporosis
Arthritis/Joint/Bone Pain
Headaches
Dental enamel defects
Pubertal Delay/ Short stature
Fatigue/Foggy Mind/Psych
Symptoms of Celiac Disease
TYPICAL
GI MANIFESTATIONS
(6 -24 mo)
ATYPICAL
NON-GASTROINTESTINAL
MANIFESTATIONS
(OLDER CHIDREN)
Weight loss
Dermatitis Herpetiformis
Abdominal Pain
Hepatitis
Anorexia
Iron deficient anemia
Intussusception
Osteopenia/Osteoporosis
Arthritis/Joint/Bone Pain
Constipation/Diarrhea
Failure to thrive
Vomiting
~1/3 may be overweight at
diagnosis
Headaches
Dental enamel defects
Pubertal Delay/ Short stature
Fatigue/Foggy Mind/Psych
Case #1
• 12 year old girl comes into the office for
evaluation of slow weight gain and delayed
puberty
• She also has notable behavior changes
(tantrums like a 2 year old)
• Mom states that her symptoms have
improved on a gluten free diet
• Mom would like her evaluated for celiac
disease
Improvement of Celiac Serology
AGA
EMA
1980
Celiac Markers
• Total IgA
• Anti-gliadin IgA/G (AGA)
• Deaminated anti-gliadin IgA/G (DGP)
• Tissue transglutaminase IgA (TTG)
• Anti-endomysial Antibody (EMA)
1990
TTG
2000
Celiac genetics
HLA-DQ2 and HLA-DQ8
Community Pediatrician’s Approach to
a Child with Celiac Disease
• Pilot study
• Cross sectional survey among community
pediatricians in Connecticut
• 58 responders
• 83% in practice >10 years
Community Pediatrician’s Approach to
a Child with Celiac Disease
• Screening
– Majority of pediatricians correctly screen using tissue
transglutaminase IgA
– Other serology are often checked as well
• Management
– 25% recommend GFD at least most of the time prior to GI
referral
– Approximately 2/3 make diagnosis of celiac disease based on
serology at least some of the time
• Referral
– Majority refer to pediatric GI
Continue on a gluten containing diet until after
evaluation by pediatric gastroenterology
Use of Celiac Panels May Lead to
Unnecessary Testing
• Survey to assess serologic tests available at
laboratories throughout Connecticut
• 25 hospitals and laboratories identified
– Information collected from 23 laboratories
• Majority of laboratories offer a total of 16 unique
celiac panels
– More than half of panels include anti-gliadin IgA or
IgG or endomysial antibodies
– More than 1/3 of panels include deaminated gliadin
IgA or IgG
Avoid use of celiac panels!
Screening Guidelines
• Screening with Serum IgA and tissue transglutaminase IgA
• For children under 2 years of age:
– Screen with serum IgA and tissue transglutaminase IgA – FALSE NEGATIVES
– Role of deaminated anti-gliadin IgG
– ?Utility of Celiac genetics (HLA-DQ2/DQ8)
• For children who are IgA deficient
– May use tissue transglutaminase ,endomysial, deaminated gliadin IgG
– ?Utility of Celiac genetics (HLA-DQ2/DQ8)
• Gold Standard of Diagnosis
– Biopsy of the duodenum and duodenal bulb
What if a patient is already on a
gluten-free diet?
• Check genetic markers
• Resume gluten in diet – 3g daily for 2 weeks
– Minimum of ½-1 slice of gluten-containing bread/day
• If not able to tolerate longer than 2 weeks 
endoscopy
• If able to tolerate  continue for up to 6 weeks
check serology
– If positive  endoscopy
– If negative  repeat serology 2-6 weeks after end of
challenge
Intestinal changes detected as soon as two weeks
while serology may increase in up to 12 weeks
How to interpret Celiac Genetics?
(+)
G
E
N
E
T
I
C
S
Homozygous DQ2
95%
Heterozygous DQ2
Homozygous DQ8
5%
Heterozygous DQ8
Hetero-half dimer β-chain
Hetero-half dimer α-chain
DQ2 and DQ8 negative
D
E
C
R
E
A
S
E
D
15% w/ celiac by 3 years
20-40% w/ celiac by 5 years
4% with celiac by 3 years
1% with celiac by 3 years
R
I
S
K
Found in approximately 40% of the general population
Helpful if negative – essentially eliminates celiac disease as a diagnosis.
Case # 2
• 12 year old F here with abnormal celiac
markers
• TTG IgA >100
• Screened secondary to eczema rash
• Mom hesitant to do an endoscopy
To Biopsy OR Not To Biopsy
• ESPGHAN guidelines
– Biopsy may NOT be needed in a ‘classic’ symptomatic
patient with:
• tissue transglutaminase IgA >10x upper limit of normal
• Anti-endomysial antibody POSITIVE
• HLA-DQ2 and/or HLA-DQ8 POSITIVE
– Biopsy indicated in an asymptomatic patient
At least 5 biopsies of duodenum with at least 1
duodenal bulb is recommended
Still controversial in the United States
Use of ESPGHAN guidelines
Celiac plus
additional
diagnosis – 12%
Other diagnoses
include:
Peptic ulcer disease
H. pylori infection
Eosinophilic
esophagitis
Celiac disease only – 88%
Newland C, Guandalini D – JPGN 2013
Case # 2 continued
• Does not meet ESPGHAN guidelines
• Endoscopy would be ideal
• If hesitant, check genetic markers to help
determine next steps
Case #3
• 14 year old girl presents for evaluation of
celiac disease
• She was well until 2 weeks ago when she had
a viral gastro.
• Diarrhea improved but she continues to vomit
and complains of abdominal pain
• Blood work
– Total IgA 80
– TTG IgA 8 (nl <3)
An Elevated TTG = Celiac
•
•
•
•
•
Liver disease
Any Autoimmune Condition (esp T1DM)
Crohn disease
Tumors
Viral Infections
Case #3 continued
• If no other symptoms, may recheck celiac
serology in 3-6 months
• If symptomatic  may need further serologic
testing or endoscopy
• No diet changes at this time
Case #4
• 8 year old M with celiac disease
• He eats Cheerios and oatmeal daily
• Mom wants to know if this is ok?
Use of Oats
• Introduction once stabilized on the glutenfree diet and their celiac antibody levels
should have normalized
• If symptoms develop  check for cross
contamination with gluten
• Eat oats and oat products labeled glutenfree!
– 50 grams of gluten-free dry oats:
• 1⁄2 cup dry rolled oats, 1⁄4 cup steel cut oat
• 1 packet instant oatmeal; 1⁄2 cup granola
• Due to fiber/increased GI symptoms, start
slow in children with 10-25 grams(1/8-1/4
cup)/d and gradually increase as tolerated
Canadian Celiac Association
North American Society for the Study of Celiac Disease
Case #5
• An 8-week-old male infant is seen for 2month well visit. He is exclusively breastfed.
• She informs you that the infant’s father has
biopsy-confirmed celiac disease
• She wants to know if she can prevent the
development of celiac disease in the child.
Risk Factors for Celiac
• Infant feeding not preventative
– Breast feeding
– Delayed introduction
• Seasonal
– <2 year old with celiac  boys born in spring/summer
• Infections
– Rotavirus – direct
– H. pylori – indirect
• Increased Bacteroides> Bifid
– Does not correct with GFD
– Increased incidence in Celiac
Introduction of wheat at ~6 months
High Risk Groups
– Relatives (especially parents and siblings)
• Healthy population:
1:133
• 1st degree relatives:
1:18 to 1:22 (up to 1:10)
• 2nd degree relatives:
1:24 to 1:39
– Diabetes Type I
– Autoimmune thyroiditis
– Other high-risk groups:
• Down, William, Turner,
• Selective IgA deficiency (1:500 incidence) – 2-3% of celiacs
Routine and regular screening may be needed
Fasano, et al, Arch of Intern Med, Volume 163: 286-292, 2003
Case #6
• 14 year old M diagnosed with celiac disease 3
years ago presents for follow-up
• TTG IgA 45
Potential Cross Contamination
–
–
–
–
–
–
–
–
Candy
Communion wafers
Matzo
Drink mixes
Soy sauce
Lipstick, Shampoo, mouthwash
Play Dough
Restaurants
– Fast food
– Sushi – imitation crab
– Mexican – chips, fried
– Pizza
– Sandwich shops
Health Care Maintenance and
Celiac Disease
• At diagnosis: iron studies, CBC, hepatic function, thyroid studies,
Ca, vitamin D
• Annually: CBC, TSH, free T4, vitamin D
• May need to check vitamin AEK levels; vitamin Bs (1,2,6 and 12),
zinc, folate levels as well in select patients
• Check for response to Hepatitis B vaccine at time of diagnosis 
revaccinate once on a gluten free diet
• ACG/NASPGHAN recommends checking celiac markers
(specifically TTG IgA +/- DGP IgG) in 3-6 months and every 6
months until normalized to monitor for improvement and
adherence to diet
– Once normalized, check annually or if symptoms develop
Case #7
• EP is a 1 year old girl with poor weight gain
– 37% at 6 months – 5% at 1 year
•
•
•
•
•
Develops diarrhea
TTG IgA normal; anti-gliadin 28
EGD/Colon: normal
Celiac genetics: NEGATIVE
Improves on GFD
Wheat Allergy
• IgE-mediated food allergy depends on an
underlying immune-mediated process
• Most common in the first year of life and
decreases in adolescence and adulthood
– 20% by 4 yrs, 52% by 8 yrs, 66% by 12 yrs and 76%
by 18 yrs
– Discrepancy between parent’s report and
objective tests
Clinical Manifestations of Wheat
Allergy
• Symptoms: Abdominal pain, nausea, vomiting, diarrhea, skin
rashes, rhinitis, conjunctivitis
• Baker’s Asthma: most common asthma associated with a specific
occupation
– Inhalation of cereal proteins (rye and wheat)
– Symptoms: cough, wheezing, rhinitis, congestion and conjunctivitis
• Wheat-dependent, Exercise-Induced Anaphylaxis
– Exercise within two hours of ingesting wheat  avoid exercise for 4-5
hours
– Mild – intense exercise
– Severe reaction – dose of wheat, intensity of exercise, timing of
exercise , aggravated by aspirin
Diagnostic tests for wheat allergy
• Skin prick tests
• RAST serum IgE antibody
• Oral wheat challenge – DBPC
• Endoscopy for eosinophilic esophagitis
Use the results as a guide
What is Non-Celiac Gluten Sensitivity?
• Occurrence of GI and non-GI symptoms after
the ingestion of gluten and improvement after
gluten withdrawal (Vanga R, Leffler D. Gastro 2013)
• Symptoms overlap with allergy or celiac
Allergic and celiac mechanisms have been
ruled out
• Celiac serology – NEGATIVE
• Allergy test to wheat – NEGATIVE
• Duodenum normal
Wheat or all gluten containing grains?
Diagnostic Tests for NCGS
• Clinical diagnosis of exclusion
IgG testing
Case # 7 continued
• Seen by allergist
• PATCH testing positive for wheat
• Added rye and barley back  symptoms
developed
• Still on GFD
• Attempt reintroduction ANNUALLY
Is the GFD healthy?
• Diet may be low in
– Fiber, Iron, B vitamins
– Calcium, Phosphorus
– Zinc
• Risk of Fe deficiency anemia, reduced bone
mineral density, constipation
• Reliance on rice  increased arsenic exposure
• Processed GF foods – not fortified or enriched
• Weight gain is a risk factor
Gluten-Free vs Gluten Containing
Foods
Flour
Calories
Salt
HIGHER
HIGHER
Fiber
Cereal
Bars
HIGHER
LOWER
Pasta
HIGHER
LOWER
Cookies
LOWER
LOWER
Bakery
LOWER
HIGHER
Protein
Total
Carbs
Saturated
Fat
LOWER
HIGHER
HIGHER
LOWER
LOWER
HIGHER
1/3 less protein and 2x more fat (primarily saturated)
in gluten free products
Simon et al.
Plant Foods 2014
GFD can be well balanced
• Careful planning to ensure a variety of grains
• Amaranth, millet, buckwheat, teff
– High in B vitamins, Fe and fiber
• MVI in the beginning
– www.glutenfreedrugs.com
• Eat naturally gluten free products vs.
processed
– Fasano Diet: veggies, fruits, meats and fish
Working with a dietitian experienced in gluten free diet is important
Quality of Life on GFD
•
•
•
•
•
•
Cost - $$$
Availability
Taste
Social Isolation
School lunches
Eating Out
FDA gluten-free guidelines
• In August 2014, FDA issued a final rule defining the term
“gluten-free” for voluntary use in the labeling of foods.
• Definition: < 20 parts per million (ppm) of gluten in the
food = 20 mg of gluten per 1 kg of food
• Applies to all FDA-regulated packaged foods, including
dietary supplements and shell eggs
• Does not include foods regulated by the USDA or
Alcohol and Tobacco Tax and Trade Bureau.
– USDA: Poultry, meats, and egg products
– TTB: most alcoholic beverages, including all distilled spirits,
wines > 7 percent alcohol by volume, and malted beverages
Case #8
• Mom comes in with her child for their annual follow-up
for celiac disease. Overall he is doing well but it is hard
for him to follow a gluten free diet with friends. Mom
has bought him glutenase over the counter and states
he does not have any symptoms when eating gluten.
• Mom would like to know about the availability of
medications that can be used with celiac disease when
her child is eating out.
•
What information will you give mom about these
medications?
Potential Non-Dietary Treatments
Intraluminal Therapies
– ALV003 (Abbvie) –
PHASE II
• Modify gluten
– BL-7010
• Binds to gliadin
Gluten
Fragments
– Lazarotide (Alba) –
PHASE II
• Increases Tight Junctions
Potential Non-Dietary Treatments
Immunotherapies
Increased IEL
and villous
atrophy
• Nexvax 2: vaccine
CD8 Cell
Activation
• COUR-NP-GL1
CD4 CELL
ACTIVATION
IL-21
IL-15
DENTRITIC
CELL
NK
cell
glutamine
– nanoparticle
Gluten
Fragments
GOAL to restore gluten
tolerance
TG2
Glutamic
acid
Potential Non-Dietary Treatments
Immunosuppressants
Increased IEL
and villous
atrophy
CD8 Cell
Activation
• Hu-MiK-Beta1/AMG714 (IL-15
antibody)
CD4 CELL
ACTIVATION
IL-21
IL-15
DENTRITIC
CELL
NK
cell
glutamine
Gluten
Fragments
TG2
Glutamic
acid
• CCX282-B agent
(CCR9 blocker)
• Montelukast (LTRantagonist)
Conclusions
• Gluten-related disorders are increasing in
prevalence
• Gluten free diet can be healthy but has the
potential to be associated with vitamin
deficiencies
• Children should be continued on a gluten
containing diet until they are fully evaluated
• Currently the GFD is the only treatment option
though adjunctive therapies may soon be
available.
Any Questions?