Diana Stuber, MA, RD, CDE
Joslin Diabetes Center
Upstate Medical University
Syracuse, NY
[email protected]
Joslin Diabetes Center 2012
Discuss the spectrum of gluten-related
disorders
Define celiac disease (CD)
Identify key indicators of risk of CD
Describe the treatment of CD
Discuss celiac disease and diabetes
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Allergic reactions
Wheat allergy (baker’s asthma, food allergy, wheatdependent exercise-induced anaphylaxis)
Autoimmune reactions
Celiac disease
Dermatitis herpetiformis (DH)
Gluten ataxia
Immune-mediated form
Gluten sensitivity (GS)
Sapone, et al, BMC Medicine. 2012; 10:13
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Defined as a gluten reaction in which both
allergic and autoimmune mechanisms have
been ruled out
Has been estimated that 18 million in U.S. may
have gluten sensitivity*
Individuals with GS often have non-GI
symptoms like headache, “foggy mind,” joint
pain and numbness in the legs, arms or fingers
*BMC Medicine. 2011, 9:23 doi:10.1186/1741-7015-9-2
Diagnosis
Negative immuno-allergy tests to wheat or negative CD
serology where IgA deficiency has been ruled out
Normal duodenal biopsy results
Possible presence of biomarkers of native gluten
immune reaction (anti-gliadin antibody positive)
With clinical symptoms that can overlap with CD or
wheat allergy
Show resolution on a gluten-free diet (ideally
implemented in blinded fashion to avoid placebo
effect)
Celiac disease (CD) is an autoimmune disorder
occurring in genetically susceptible individuals who
develop an immune response to gluten and related
proteins found in wheat, barley and rye
This immune response causes inflammation and
atrophy of the small intestine, resulting in
malabsorption
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It is a unique autoimmune disorder:
Both the environmental trigger (gluten) and the
autoantigen (tissue transglutaminase or tTG) are known
Elimination of the environmental trigger leads to
resolution of symptoms and/or some manifestations of
the disease
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Celiac disease
Villous atrophy
Malnutrition
London, year 1938
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Central Nervous System
Skin and Mucosa
Dermatitis herpetiformis
Aphthous stomatitis
Hair loss
Hepatitis
Cholangitis
Bone
Osteoporosis, fractures
Arthritis
Dental anomalies
Ataxia, seizures
Depression
Carditis, Cardiomyopathy
Anemia
Reproductive
Miscarriage, infertility
Delayed puberty
Hair loss
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Figure 1. World map by WHO Regions, as used as the basis for modeled estimates, showing
underlying assumptions about the population prevalence of childhood coeliac disease.
Byass, et al, PLoS ONE. 2011; 6(7):e22774
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In general population:
1:100 (1%)
With related conditions:
1:56 (1.8%)
In 1st degree relatives:
1:22 (4.5%)
Monozygotic twins:
1:1.4 (70%)
In 2nd degree relatives:
1:39 (2.6%)
In African, Hispanic, AsianAmericans:
1:256 (0.4%)
Fasano, et al, Archives of Internal
Medicine. 2003; 163:286
In 1st degree relatives:*
1:10 (10%)
In sisters
17.6% (29% if DQ2 or DQ8 +)
In brothers
10.8% (15% if DQ2 or DQ8 +)
In parents
3.4% (6% if DQ2 or DQ8 +)
Monozygous twins**
86%
Dizygous twins
20%
*Kneepens, et al, Eur J Pediatr. 2012;
171:1011
**Greco, et al, Gut. 2002; 50:624
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In general population:
1:100 (1%)
With related conditions:
1:56 (1.8%)
In 1st degree relatives:
1:22 (4.5%)
Monozygotic twins:
1:1.4 (70%)
In 2nd degree relatives:
1:39 (2.6%)
In African, Hispanic, AsianAmericans:
1:256 (0.4%)
Fasano, et al, Archives of Internal
Medicine. 2003; 163:286
Autoimmune disorders
Type 1 diabetes
Thyroiditis
Arthritis (RA)
Autoimmune liver disease
Sjögren Syndrome
IgA nephropathy
2-16%
4-8%
1-8%
6-8%
2-15%
3.6%
Genetic disorders
Turners syndrome
Downs syndrome
Williams syndrome
IgA deficiency
4-8%
5-12%
8%
7%
NIH Consensus Development Statement on
Celiac Disease, 2004
Joslin Diabetes Center 2012
The total prevalence of CD nearly doubled in
the last 20 years in Finland1
Prevalence of CD has increased more than 4fold in the U.S. in the last 50 years2
CD prevalence increased 2-fold in the study
group and 5-fold overall in the U.S. since 19743
From 1999 to 2008, cases of celiac disease in
the U.S. increased 5-fold4
1)
2)
3)
4)
Lohi, et al, Ailment Pharmacol Ther. 2007; 26:1217
Rubio-Tapia, et al., Gastroenterology, 2009; 137:88
Catassi, et al, Ann Med, 2010; 42:530
Riddle, et al, Am J Gastroenterol, 2012; 107:1248
~ 30% of the general population has DQ2 or DQ8
Homozygous HLA-DQ2 may increase the risk and
severity of CD, including refractory CD (binds a wider
range of gluten peptides)
At least one in 20 who carry HLA-DQ2 will develop CD
About one in 150 who have HLA-DQ8 will develop CD
Those with other HLA-DQ genes are protected against CD
Over 90% of CD patients have HLA-DQ2 heterodimer
Since 30% of population may carry HLA-DQ2 but only
about 1% of the population has CD, other non-HLA
genes must be involved
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Common disease variants
IL18RAP
Heap, G. A. et al. Hum. Mol. Genet. 2009 18:R101-106R; doi:10.1093/hmg/ddp001
The “hygiene hypothesis”
Humans have adapted to a pathogen-rich environment
that no longer exists in industrialized societies
This change has reduced the exposure of the immune
system to antigens
The immune system overreacts, favoring the
development of chronic inflammatory conditions
(Recent reports suggest that part of susceptibility alleles
for autoimmune disease might be maintained in human
population because they confer increased resistance
against infection)
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What we eat, when we start eating “it” and how
much
Gut is leakier < 4 months, so when babies eat gluten
before 4 months it might increase the risk of CD - cereals
too late (after 6 months) may miss the window for
developing tolerance
Breast feeding through introduction of cereals may be
protective
Change from rice as staple grain to wheat may cause
increase in prevalence in South Asia and West Pacific
regions
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Modern varieties of wheat have greater amounts of
celiac disease epitopes
Germs, viruses, chemicals, surgeries or other
stresses we are exposed to that may cause a
disturbance of the mucosal integrity (leaky gut)
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HLA-DQ2
E
tissue transglutaminase
(tTG)
Digestion
Deamidation
Q
T-cell
E
IFN
“Gluten”
proteins
Resistant
peptides
Injury
Villous atrophy
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Normal small bowel
Celiac disease
Gluten (> 4hr)
Gluten-free diet
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Classic
Near/total malabsorption; usual age at
presentation: 6-24 months
Diarrhea
Abdominal distension
Anorexia
Failure to thrive/wt loss
Abdominal pain
Vomiting
Constipation
Atypical
Some malabsorption; usual age at
presentation: older child to adult
Anemia
Short stature
Osteopenia
Recurrent abortions
Hepatic steatosis
Abdominal pain
60% of newly diagnosed children and 41% of adults in US had no symptoms
Only 35% newly diagnosed had diarrhea
Fasano, et al, Arch Int Med. 2003; 163:286
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Most common age at presentation: older child to adult
Dermatitis herpetiformis
Dental enamel hypoplasia
Ataxia
Alopecia
Primary biliary cirrhosis
Isolated hypertransaminasemia
Recurrent aphthous stomatitis
Fertility problems
Myasthenia gravis
Recurrent pericarditis
Psoriasis
Polyneuropathy
Epilepsy
Vasculitis
Dilative cardiomyopathy
Hypo/hyperthyroidism
Intestinal lymphoma
May be related to autoimmune inflammation or tTG targets:
9 identified human transglutaminase enzymes
TG2 in CD, TG3 in DH, TG6 in gluten ataxia
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Test
Sensitivity %
Specificity %
Comments
IgA-tTg*
98 (86-100)
98 (90-100)
Lower cost, ease of test,
reliability – for initial screening
IgG/IgA-DPG-AGA*
97 (75-99)
95 (87-100)
Very good in children <2 yr; can
identify CD in pts with IgA
deficiency
IgA-EMA
95 (86-100)
99 (97-100)
Operator dependent, prone to
subjective error, expensive
HLA typing
98%
Good negative predictive value
IgA deficiency*
Biopsy
Ig-A antibodies will be negative;
test IgG-tTg and/orDPG
Poor
High
Damage can be pathcy;
depends on grade cut-off point,
biopsy orientation, pathologist
* Celiac Panel at Upstate Medical University
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European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition Guidelines for the
Diagnosis of Coeliac Disease.
Husby, S; Koletzko, S; Korponay-Szabo, IR; Mearin, ML; Phillips, A;
Shamir, R; Troncone, R; Giersiepen, K; Branski, D; Catassi, C; Lelgeman,
M; Maki, M; Ribes-Koninckx, C; Ventura, A; Zimmer, KP; for the
ESPGHAN Working Group on Coeliac Disease Diagnosis, on behalf of
the ESPGHAN Gastroenterology Committee
Journal of Pediatric Gastroenterology & Nutrition. 54(1):136-160,
January 2012.
DOI: 10.1097/MPG.0b013e31821a23d0
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FIGURE 1 . Symptomatic patient. CD = coeliac disease; EMA = endomysial antibodies; F/u = follow-up;
GFD = gluten-free diet; GI = gastroenterologist; HLA = human leukocyte antigen; IgA =
immunoglobulin A; IgG = immunoglobulin G; OEGD = oesophagogastroduodenoscopy; TG2 =
transglutaminase type 2.
7
Copyright 2012 by ESPGHAN and NASPGHAN. Published by Lippincott Williams & Wilkins, Inc.
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FIGURE 2 . Asymptomatic patient. See Fig. 1 for definitions.
8
Copyright 2012 by ESPGHAN and NASPGHAN. Published by Lippincott Williams & Wilkins, Inc.
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AGA recommends ≥4 biopsy samples of the small
intestine (distal duodenum)
Of 132,352 pts with biopsy (2005-2009), only 35% had
at least 4 biopsies (ave. was 2)*
With suspected malabsorption/CD, 39.5% had ≥4
biopsies
Diagnosis of CD was doubled in pts with at least 4
biopsies
2012 ESPGHAN Guidelines for the Diagnosis of Coeliac
Disease recommends at ≥ 1 biopsy from the duodenal
bulb and ≥ 4 from D2 and D3**
*Lewohl, et al, Gastrointestinal Endoscopy. 2011; 74:103
**Husby, et al, J Ped Gastroenterol and Nutr. 2012; 54:136
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Normal 0
Infiltrative 1
Partial atrophy 3a
Subtotal atrophy 3b
Hyperplastic 2
Total atrophy 3c
Horvath K. Recent Advances in Pediatrics. 2002.
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Type 1 diabetes occurs in about one in 300
individuals and is associated with other
autoimmune diseases*
Autoimmune thyroid disease in 15-30%
Celiac disease in 4-9%
Addison disease in 0.5%
Additional autoimmune disease was found in
33% of patients at onset of type 1 diabetes*
*Triolo, et al, Diabetes Care. 2011; 34:1211
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All adult patients with Type 1 diabetes should
be screened at least once, then every 2-3 years,
or with GI symptoms or “brittle diabetes”
Pediatric patients are screened at diagnosis,
then yearly, or with GI symptoms or failure-tothrive
In other endocrine patients consider screening
with non-response to thyroid hormone
replacement, “unexplained” or resistant-totreatment osteoporosis, or “classic” symptoms
of CD
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Diabetes-specific symptoms in CD may include
Unpredictable blood sugars (“brittle diabetes”)
Hypoglycemia within 2 hours of a meal
Hypoglycemia that doesn’t respond to treatment
Treatment of low blood glucose
Use glucose tablets, juice, regular soda, raisins
Milk might not be tolerated
Potato or corn chips may be used, but are slower to
act because of fat content
A1C may not improve with GFD
Nutrient absorption improves
Insulin requirements may increase
Pts may gain weight, even without weight loss prior
to diagnosis of CD, but some overweight/obese
adults lose wt*
Hypoglycemia may be less frequent
*Cheng, et al, J Gastroenterol. 2010; 44:267
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“Starter menus” for CD may be inconsistent in
carbs and carb content is not usually provided*
Carb and fat content of GF substitutes are often
higher than the gluten-containing version
Prior to CD diagnosis, cholesterol levels may be
low, but as the mucosa heals total cholesterol
levels may rise (and HDL may improve**)
*Counting Gluten-Free Carbohydrates can be found at www.csaceliacs.org
**Capristo, et al, J Gastroenterol. 2009; 43:946
People with biopsy-proven celiac disease are at
three-fold increased risk of future end-stage
renal disease
Increased risk of ESRD is seen irrespective of
age at CD diagnosis
Adjusting for diabetes had only a marginal
effect on risk estimate
Welander, et al, Gut. 2012; 61:64
Currently, the only treatment is a life-long
gluten-free diet (GFD)
Eliminate gluten, expand repertoire of GF
foods, optimize nutrient intake
GFD should not be recommended unless
diagnosis is confirmed
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a
b
Wheat flour
Endopeptidase
Celiac-safe flour
Polymeric binder
Gluten
Vaccines and
Biological therapies
c
a
e
Modulation of
the cytokine
network, cell markers
and cell recruitment
d
(i) Modulator of
paracellular permeability
d
b-c
GI LUMEN
Zonulin
LAMINA
PROPRIA
Activated
LTCD4+
Deamidation
by tTG2
(ii) TGinhibitor
APC
HLA-DQ2/8
Pinier, et al, Am J Gastroenterol. 2010; 105:2551
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Wheat:
Bran
Bulgur
Couscous
Cracked Wheat
Durum Flour
Farina
Graham Flour
Matzo
Semolina
Wheat Bran
Wheat Germ
Wheat Starch
Wheat varieties:
Einkorn
Emmer
Kamut
Spelt (Dinkel)
Triticale
Barley:
Malt
Malt Beverages
Malt Extract
Malt Flavoring
Malted Milk
Malt Syrup
Malt Vinegar
Rye
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Applied to labels of FDA regulated foods starting
Jan. 1, 2006
USDA regulated foods do not require identification
of allergens
Labels must state if the food contains:
Milk
Eggs
Fish
Tree nuts
Crustacean shellfish
Peanuts
Wheat
Soynuts
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Define “gluten-free”
Proposed 20 ppm
0.0007 oz gluten per lb of food
50 mg gluten per day probably safe, = 0.0018 oz/day
Develop rules that permit the use of “gluten-free” on the
food label
Labels that state “naturally gluten-free food” may not be glutenfree*
FDA solicited more comments in 2011
Expected to publish rules by the end of fiscal 2012
*Thompson, et al, J Am Diet Assoc. 2010;110:937
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Fresh, frozen or canned fruits
and vegetables
Fresh meats, poultry,
seafood, fish, game, eggs,
some processed meats, dried
peas, beans, lentils, tofu
Milk, yogurt, aged, natural
cheese
Oils, tree nuts, seeds, natural
peanut butter, salad dressing,
spreads
Honey, sugar, pure maple
syrup, corn syrup, jams,
jellies, candy, ice cream
Pure spices and herbs, salt,
soy sauce without wheat,
cider, wine, distilled and nonmalt vinegars
Coffee ground from whole
beans, brewed tea, distilled
alcoholic beverages
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Amaranth
Arrowroot
Whole-bean flour
Buckwheat
Corn*, cornstarch
Flax
Job’s tears
Millet
Nut flours
Oats, oat bran, oat gum**
Pea flour
Potato, sweet potato, yam,
potato flour, potato starch
Quinoa
Rice, wild rice, rice bran, rice
flour
Sago
Sorghum
Soy
Tapioca
Teff
*Some with CD reacted to corn
**Controversial
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Oats:
The immunogenicity of oat varies according to the
cultivar*
After resolution of symptoms up to ½ cup dry rolled
oats or ¼ cup dry steel cut oats per day
Barley lines that lack D and C-hordeins were
found to be 20-fold less immunotoxic than wildtype barley**
*Comino, et. al., Gut. 2011; 60:915
**Tanner, et. al., Ailment Pharmacol Ther. 2010; 32:1184
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Patients with no nutritional deficiencies have the same
nutritional requirements as the general population
Healing takes 6 months to 2 years, although complete
recovery in adults is rare*
Lactose intolerance is common at diagnosis
Studies suggest that osteopenia and vitamin and mineral
deficiencies resolve on the diet
GF foods may be lower in thiamin, riboflavin, niacin, folate,
iron, and fiber (not fortified)
A GF daily multivitamin may be recommended in patients with
CD
*Rubio-Tapia, et al, Am J Gastroenterol. 2010 Medscape posted: 01/23/2011
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Nutrient
Vegetables
Fruits
Protein
Dairy
GF Grains
Calcium
Leafy greens,
sea vegetables
Fortified orange
juice, dried fruit
Ca-rich soy
products, beans,
sardines (with
bones)
Milk, yogurt,
cheese, fortified
soymilk
Quinoa , brown
rice
Iron
Spinach, other
leafy greens
Magnesium
Leafy greens,
peas
Bananas, dried
apricots,
avocados
Vitamin D
Plant oils (eg,
olive)
Avocados
Salmon, nuts,
enriched eggs
Vitamin E
Leafy greens,
vegetable oils
Kiwi, mango
Nuts, seeds
Vitamin K
Leafy greens,
broccoli,
soybean oil
Beef , poultry,
fish, seafood
(heme)
Beans, tofu
(nonheme)
Amaranth, teff,
buckwheat,
quinoa
Fortified milk
GF whole grains
Milk, dairy
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Nutrient
Vegetables
Fruits
Leafy greens
vegetables
Niacin
Vitamin B6
Green and leafy
vegetables
Folate
Leafy green
vegetables
Fruits
GF Grains
Whole grains
Meat
Milk, yogurt,
cottage cheese
Whole-grain or
enriched breads
and cereals
Eggs, meat,
poultry, fish ,
nuts, other
protein-rich
foods
Milk
Whole-grain or
enriched breads
and cereals
Meats, fish,
poultry,
shellfish,
legumes
Whole grains
Legumes, seeds,
liver
Animal products
B-12
Fiber
Dairy
Pork, ham,
bacon, liver,
legumes, nuts
Thiamin
Riboflavin
Protein
Vegetables,
Fresh fruits
Legumes, seeds
Whole grains
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There are many new gluten-free foods available
The compound annual growth rate for gluten-free
products rose 28% in the U.S. over the last 4 years
The U.S. market is predicted to hit $4.2 billion by the
end of this year and $6.6 billion by 2017
More major food manufacturers are labeling their
foods as gluten-free
The IRS allows a tax deduction for the increased cost of
gluten-free foods
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Naturally GF foods cost less than GF substitutes
Potatoes
Rice
Corn, corn tortillas
Homemade foods may cost less than processed GF
foods like bread, pizza, canned or frozen meals
The cost of GF foods replaces the cost of “pills”
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The diagnosis can be “shocking” and depression
or sadness are common
Gluten is found in ~ 90% of processed foods
Hard to tell whether foods contain gluten
Labels can be unreliable and difficult to understand
Gluten is a hidden ingredient in many food and
non-food items (pharmaceuticals, vitamins,
cosmetics, other products)
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Cultivation of grains (leftover wheat seeds in the field)
Harvesting and shipping of grains (bins, rail cars, trucks)
Processing (shared equipment)
Stores (bulk sale bins/scoops)
Home
Shared kitchen items such as toasters, counters, utensils (no wooden
spoons, wooden cutting boards, etc.), storage containers, jars of jam,
peanut butter, and other spreads (no double-dipping), hand towels...
Restaurants
Pans, grills, deep-fat fryers used for multiple foods
Serving utensils used in buffets
Kitchen and wait staff: “Educate, separate, sanitize”
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It is hard to eat out*
There may be limited availability and variety of
GF foods
The price is high and to some the palatability
low
All these factors can lead to problems with the
adoption of and adherence to the diet
*Gluten Intolerance Group Restaurant Dining: Seven Tips for Staying Gluten-Free at www.gluten.net
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Gluten-related disorders include wheat allergy, celiac
disease and gluten sensitivity
The incidence of CD is increasing
The risk of CD is higher in Type 1 DM and other
autoimmune diseases
Ask pts about diarrhea, abdominal pain and “rashes”
Refer your patients with CD to the dietitian
Joslin Diabetes Center 2012
American Celiac Society
59 Crystal Avenue
West Orange, NJ 07052
973-325-8837
Email: [email protected]
Celiac Disease Foundation
13251 Ventura Blvd, Suite 1
Studio City, CA 91604
818-990-2354
www.celiac.org
email: [email protected]
Canadian Celiac Association
90 Britannia Road East, Unit 11
Misissauga, ON L4Z 1W6
Canada
905-507-6208 or 800-363-7296
www.celiac.ca
Gluten Intolerance Group of North America
15110 10th Ave SW, Suite A
Seattle, WA 98166-1820
206-246-6652
www.gluten.net
email: [email protected]
Celiac Sprue Association/ USA Inc
P.O. Box 31700
Omaha, NE 68131-0700
402-558-0600
www.csaceliacs.org
email: [email protected]
Celiac.com
www.celiac.com
Gluten Free Mall
www.glutenfreemall.com
707-509-4528 (Information)
800-986-2705 (Orders only)
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