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without signs or symptoms of CD, but who has small
bowel biopsy evidence of CD; usually these patients
have an associated condition or a family history of
CD, and are identiﬁed on screening as having CD-
■ Latent CD applies to individuals without signs or
symptoms of CD, but who have some risk for future
development of CD, such as expression of CD-
related antibodies or DQ2 or DQ8 permissive genes,
family history of CD, or having an associated condi-
tion. These individuals do not have small bowel
biopsy changes, but may have CD-associated anti-
■ Refractory CD describes an individual with deﬁned
CD who continues to have signs or symptoms of
active CD despite pursuing a GFD. In this situation,
considerations include considered exposure to gluten,
enteropathy-associated T-cell lymphoma (EATL), or
possibly another condition such as allergy or inﬂam-
matory bowel disease.
Incidence and Prevalence
The prevalence in the United States and Europe is
roughly 3–13 cases per 1000 individuals (1:300 to
There is a female predominance with a ratio of
These estimates indicate that there are
approximately 3 million people with CD in the United
States alone, and a roughly equal number in Europe, of
which 90% are undiagnosed (Table 18–1). Recent
screening studies suggest that in developing countries
in Africa, parts of Asia, and South America, the fre-
quency is similar to that of the U.S. and European
To date, there are very little data exploring
DEFINITIONS AND EPIDEMIOLOGY
Celiac disease (CD) is “a permanent sensitivity to gluten
in wheat and related proteins found in barley and rye,
occurring in genetically susceptible individuals, and
manifesting as an immune mediated enteropathy as
deﬁned by characteristic changes seen on intestinal his-
A conservative definition requires the following:
■ typical signs or symptoms;
■ presence of CD-associated antibodies;
■ a small intestinal biopsy showing villous atrophy;
■ resolution of clinical manifestations with a gluten-
free diet (GFD), including complete healing of the
■ reduction or disappearance of the CD-associated
antibodies on a GFD.
In practice, it is questionable whether it is neces-
sary to meet all aspects of this deﬁnition. Controversy
continues about whether a small bowel biopsy is required
to diagnose CD. Because of numerous reports of CD-
associated seropositive individuals with no signs or
symptoms of CD, guidelines continue to require a
biopsy to confirm the diagnosis and need for
Different terms have been applied to common
■ Classic CD refers to a presentation with typical clini-
cal features such as diarrhea, abdominal pain, failure
to thrive, or abdominal distention.
■ Atypical CD describes a non-traditional presentation,
primarily with extraintestinal manifestations, such as
arthritis or iron deﬁciency anemia. In older children
and adults, the atypical presentation may be more
common than the “classic” presentation.
Bishop_Ch18_265-276.indd 265 4/6/10 2:34:30 PM
266 ■ Section 3: Disorders of the Stomach and Intestine
the rates of CD in China, Japan, and Southeast Asian
countries, and these populations are thought to be at
lower genetic risk for CD. A number of conditions are
associated with an increased risk of CD in children and
adults (Table 18–2).
Speciﬁc HLA types are permissive for development of
CD. HLA molecules bind peptide antigens and present
them to CD4
helper T cells. An estimated 95% of CD
patients express the HLA-DQ2 gene and the remain-
der express DQ8.
HLA II molecules are made up of
dimers, expressing one alpha and one beta chain. The
vast majority of CD patients express the HLA II sub-
type DQ2 coded by alleles DQA1*0501 and DQB*0201,
or DQ8 coded by alleles DRB*04-DQA1*03-
DQB1*0302. The DQ2 dimer contains speciﬁc pockets
that bind deamidated gluten peptides and present
them to CD4
lymphocytes. Expressing two copies of
HLA-DQ2 (homozygous state) increases the risk for
developing CD, and an estimated 25% of CD patients
are DQ2 homozygous. The genes coding for HLA II
are located on chromosome 6p21, termed the CELIAC1
However, other genetic factors are important,
and the absolute necessity of DQ2/DQ8 for develop-
ment of CD has been questioned, as apparent cases of
CD occur in individuals who do not express DQ2 or
The DQ2 gene is expressed by approximately
30% of Caucasians, but only 3% of these develop CD.
Having a ﬁrst-degree relative with CD increases the
risk of CD to between 5% and 18%.
There is an esti-
mated 70–86% concordance in monozygotic twins
with CD, but only 30–40% with HLA-matched twins,
and less than 20% concordance in dizygotic twins and
Expression of DQ2 or DQ8 only
accounts for approximately 36–53% of the disease
risk. Therefore, other genetic and environmental fac-
tors are important.
Gene linkage analysis and
genetic-associated studies, including genome-wide
association studies, have identiﬁed a number of other
loci of possible importance in CD
Worldwide Disease Prevalence Based on
1:66 to 1:119
1:99 to 1:67
1:166 to 1:104
Conditions Associated with Increased Risk for CD
in Children and Adults
Condition Prevalence of CD (%)
Type 1 diabetes
First-degree relatives with CD
Short stature/delayed puberty
Dental enamel defects
■ Irritable bowel syndrome
■ Persistent aphthous stomatitis
■ Peripheral neuropathy
■ Unexplained cerebellar ataxia
■ Elevated transaminases
■ Unexplained iron deﬁciency
■ Decreased bone mineral density
Genetic Linkage Studies
Locus Gene Region Function
CELIAC1 6p21 HLA II coding region
CELIAC2 5q31–5q33 Cytokine gene cluster
CELIAC3 2q33 T-cell regulatory genes
CELIAC4 19p13.1 MYO9B—unconventional
Bishop_Ch18_265-276.indd 266 4/6/10 2:34:37 PM
CHAPTER 18 Celiac Disease ■ 267
The exact mechanism by which ingestion of gluten pro-
teins by genetically susceptible individuals leads to
immune-mediated intestinal injury remains unclear
(Figure 18–1). An inciting event such as a viral infec-
tion, plus additional genetic factors, may be important
to development of CD. Both innate and adaptive immu-
nity are thought to be involved.
Gluten proteins are found in wheat and related
grains, and can be divided into gliadin and glutenin
components. Hordeins in barley and secalins in rye are
equivalent proteins that promote the CD process. The
oat avedin protein is more distantly related to Triticeae
Gut lumen Brush border
CD4 + T cell
CD4 αβ TCR
FIGURE 18–1 ■ Cartoon highlighting steps involved in pathogenesis of CD.
Gluten peptides survive digestion and
cross the mucosal epithelium, where deamidation by tissue transglutaminase (TG2) occurs. HLA-DQ2 or -DQ8 molecules
on antigen-presenting cells present these peptides in the intestinal lamina propria where they are recognized by speciﬁc
T cells Adapted by permission from Ref.
(Macmillan Publishers Ltd).
Genetic Association Studies
Gene Region Function/Association
1q31 Contains RGS1, regulator of G protein signaling molecule. Involved in B-cell activation/proliferation; found
in intestinal intraepithelial lymphocytes
2q11–2q12 2 genes coding for receptor for IL-18 that stimulates T-cell synthesis of IFN-gamma
3p21 Large cluster of chemokine receptor genes CCR1, CCR2, CCR3, CCR5, CCRL2, and XCR1
3q25–3q26 Immediately 5′ of IL-12 gene. IL-12 induces Th1 IFN-gamma secretion
3q28 Associated with LPP gene of unclear signiﬁcance
4q27 Strongest current association with CD outside HLA locus. Cluster of 8 associated single nucleotide
polymorphisms; 2 contain genes for IL2 and IL21, involved in T-cell activation. Associated with type 1
diabetes and rheumatoid arthritis
6q25 Contains TAGAP gene (T-cell activation GTPase-activating protein) expressed in activated T cells
12q24 Contains LNK and ATXN2—strongly expressed in monocytes, dendritic cells, and small intestine
Bishop_Ch18_265-276.indd 267 4/6/10 2:34:37 PM
268 ■ Section 3: Disorders of the Stomach and Intestine
glutens, and seems to be non-immunogenic for most
Several properties of gluten may be important in
stimulating the immune response of CD:
■ Gliadin stimulation of IL-15 secretion through a non-
■ Gliadin induction of zonulin expression in small
intestinal epithelium, with subsequent increase in
intestinal permeability, CD4
T-cell antigen exposure,
and alteration in cell morphology.
■ The high proline (15%) and glutamine (35%) content
confers important chemical properties to gluten. First,
gluten peptides resist human acid and peptic diges-
tion, and reach the intestinal mucosa in antigenic seg-
ments. Second, constitutively expressed tissue trans-
glutaminase (TTG) in the small intestine alters gliadin
peptides by deamidating speciﬁc glutamine residues
to the negatively charged glutamate. Individuals with
CD express antibodies to both TTG and deamidated
gliadin peptides; these antibodies are speciﬁc sero-
logic markers for CD. Deamidated gliadin peptides
show enhanced binding to speciﬁc pockets in the DQ2
molecule, resulting in enhanced presentation to
T cells by local antigen-presenting cells
Both activated APCs and CD4
T cells secrete
increased amounts of inﬂammatory cytokines such as
IFN-gamma and IL-15, causing local recruitment of
ﬁbroblasts and clonal expansion of cytotoxic intraepi-
thelial lymphocytes (IELs). The increased numbers of
IELs and the subsequent mucosal damage are the
classic changes seen on intestinal biopsy of CD
Well-recognized clinical presentations of pediatric CD
include: failure to thrive, chronic diarrhea, distended
abdomen, irritability, constipation, and growth or puber-
tal delay (Table 18–5).
such as arthritis, iron deﬁciency anemia, dental enamel
defects, and dermatitis herpetiformis (DH) are also com-
mon. Asymptomatic children may be identiﬁed on
screening because of increased risk due to having an
associated condition or a family history of CD or diabe-
tes (Table 18–2). Recently, a variety of presentations have
been imputed to be related to undiagnosed CD in adults
(Table 18–2). These include neuropsychiatric presenta-
tions such as ataxia and epilepsy, as well as infertility.
Because the signs and symptoms may be mild, vague,
and non-speciﬁc, delays in diagnosis are common.
“Celiac crisis” is a rare medical emergency charac-
terized by explosive, watery diarrhea and dehydration/
electrolyte imbalances, marked abdominal distension,
hypotension, and lethargy. It is typically seen in toddlers
and responds to corticosteroids within a few days.
Clinical Course/Progression of Disease
With institution of a GFD, symptoms often improve by
the second week, but may take months to completely
resolve. Normalization of the intestinal histology may
take 6–12 months. Lactose intolerance tends to resolve
within a few weeks. Treatment of nutritional deﬁcien-
cies, such as iron deﬁciency, is generally not needed over
long term. Adults tend to improve more slowly.
For those with silent or latent CD, continued expo-
sure to gluten leads to eventual clinical manifestations in
Manifestations of CD
Classic CD Extraintestinal Neuropsychiatric Symptoms
Failure to thrive
Dental enamel defects
Epilepsy ϩ/Ϫ cerebral calciﬁcations
Abnormal liver function tests
Pubertal delay/short stature
Recurrent fetal loss
Strong evidence for association.
Bishop_Ch18_265-276.indd 268 4/6/10 2:34:38 PM
CHAPTER 18 Celiac Disease ■ 269
at least some individuals.
Data from the adult literature
also show a mortality risk signiﬁcantly above the stan-
dard mortality rate (SMR) by a factor of two- to three-
fold for patients not adhering to a GFD, not responding
to the GFD, or with lengthy delay in diagnosis.
reasonable evidence that early compliance with a GFD
reduces the risk of mortality to close to baseline.
The two- to three-fold increase in all-cause mortality in
CD adult patients, as compared to controls, is mostly
due to gastrointestinal malignancies such as EATL, non-
Hodgkin lymphoma (NHL), and small bowel adenocar-
cinoma. CD is associated with an increased relative risk
2.1–6.6 times above baseline for NHL and a 30-fold
increased risk for small bowel adenocarcinoma.
DH is the most common skin lesion associated with CD,
occurring in up to 24% of adult patients with CD, but is
rare in children. Classic DH is a chronic, pruritic, papu-
lar/vesicular rash symmetrically located on the extensor
surfaces of the elbows, knees, buttocks, back, and sacrum,
and occasionally is seen on the face, neck, and trunk.
Biopsy of skin lesions shows microabscesses with neu-
trophils and eosinophils in the dermal papillae. Immu-
noﬂuorescence of adjacent skin shows IgA deposits in
the papillary dermis directed toward an unknown anti-
gen, but theorized to possibly be epidermal transglu-
taminase. Markers of CD are often elevated in DH, with
positive TTG IgA, endomyseal antibody assay (EMA),
and anti-gliadin antibody assays (AGA). The vast major-
ity of DH patients will have villous ﬂattening or increased
IELs, even in the absence of overt gastrointestinal symp-
toms. Most, 85–90%, are HLA B8 positive, and there is a
strong association with HLA DW3, and DRW3. A glu-
ten-containing diet is necessary to manifest the lesions of
DH, and symptoms often resolve with GFD. Dapsone is
often used as a suppressive medication.
There is strong evidence supporting the increased risk
for osteopenia and osteoporosis in untreated CD. Bone
mineral density, area, and content may be reduced but
assessment should adjust for growth and pubertal delay.
In children, bone density normalizes within 1–2 years of
treatment with GFD.
Association with Other
The most commonly seen concurrent autoimmune dis-
eases are type 1 diabetes and Hashimoto thyroiditis.
Less common are associations with juvenile arthritis,
alopecia areata, vitiligo, hepatitis and cholangitis,
Sjogren’s syndrome, Addison’s disease, peripheral neu-
ropathy, psoriasis, and autoimmune cardiomyopathy.
Because of its many and varied clinical features, CD can
be a great imitator of other disorders, and it can also be
silent. The differential diagnosis depends on the way it
manifests as well as the age of the patient (Table 18–6).
The presentation of diarrhea, abdominal distention,
irritability, and vomiting may mimic gastroesophageal
reﬂux, milk or soy protein allergy, Giardia infection,
malrotation, lymphangiectasia, and iron deﬁciency ane-
mia in toddlers. The same presentation in school age
children and adolescents should lead to considerations
Toddler School Age and Adolescent Flattened Mucosa (Villous Atrophy)
Gastroesophageal reﬂux Irritable bowel syndrome Malnutrition
Milk or soy protein allergy Functional abdominal pain Infectious enteropathy: Giardia
Giardia Post-infectious chronic diarrhea Tropical sprue
Lymphangiectasia Small bowel bacterial overgrowth IgA/immunodeﬁciency
Malrotation Immunodeﬁciency (IgA deﬁciency, HIV, other) Allergic enteropathy: cow/soy milk
Iron deﬁciency anemia IBD (Crohn’s disease) Autoimmune enteropathy
Growth hormone deﬁciency Zollinger–Ellison syndrome
Acid peptic disease, ulcer
Bishop_Ch18_265-276.indd 269 4/6/10 2:34:38 PM
270 ■ Section 3: Disorders of the Stomach and Intestine
of irritable bowel syndrome, inﬂammatory bowel dis-
ease, lactose intolerance, ulcer, post-infectious diarrhea/
bacterial overgrowth, as well as parasite infection, and
immunodeﬁciency such as IgA deﬁciency or HIV. Of
note, lactose intolerance may be a consequence of the
intestinal injury of CD and often resolves with therapy.
The histological hallmark of CD is the small bowel
biopsy showing increased numbers of IELs and villous
atrophy. The differential diagnosis for this histological
ﬁnding includes HIV and immunodeﬁciency, allergy,
Giardia infection, viral gastroenteritis, autoimmune
enteropathy, Zollinger–Ellison syndrome, tropical sprue,
and malnutrition (Table 18–6).
The criteria for diagnosis of CD have been recently
updated separately by the North American Society for
Pediatric Gastroenterology, Hepatology and Nutrition
the Federation of International Societ-
ies of Pediatric Gastroenterology Hepatology and Nutri-
the National Institutes of Health (NIH),
the American Gastroenterological Society (AGA).
Unfortunately, these guidelines are not uniform. In gen-
eral, the diagnostic algorithm depends on whether the
presentation includes clinical signs or symptoms (Fig-
ure 18–2), or whether identiﬁed because of associated
conditions or risks (Figure 18–3).
The current NASPGHAN and FISPGHAN rec-
ommendations are to use TTG antibody assays or EMA
as the single screening test. These tests have sensitivity
and speciﬁcity above 0.95. The role of new serologic
tests such as the deamidated gliadin peptide antibody
test is not yet clear. There is no beneﬁt to a celiac “panel”
of multiple antibody tests. Because of the rare case of
CD in a patient with IgA deﬁciency, and to increase the
conﬁdence in a negative result, quantitative IgA levels
may be obtained, or IgA plus IgG-based TTG tests
ordered. AGA are no longer recommended for any
patient suspected to be at risk for CD as it has a low
speciﬁcity and high false-positive rate.
A positive serologic screening test should be fol-
lowed by a small bowel biopsy showing villous atrophy
in order to conﬁrm the diagnosis of CD, and to exclude
other causes for the symptoms. The presence of increased
IELs alone, the Marsh 1 lesion, is commonly seen in
other conditions and experts do not consider it enough
for diagnosis of CD. Multiple biopsies (four to six)
should be taken from the second portion and distal
duodenum. Villous atrophy with increase in IELs is the
characteristic ﬁnding (Figure 18–4), but is not speciﬁc
for CD (see Table 18–6). Finally, a complete resolution
of symptoms within weeks of following a GFD clinches
the diagnosis in the child with a clinical presentation
Value of DQ2/DQ8 Testing
Virtually all patients with CD will test positive for DQ2
or DQ 8. However, 30–40% of Caucasians will express
DQ2 or DQ8, and fewer than 5% will ever develop CD.
Therefore, the value of HLA haplotype testing is in its
Clinical signs or symptoms
TTG and quantitative IgA
with celiac disease
Gluten free diet
Consider repeat biopsy, trial
of gluten free diet, other
If normal, celiac disease
unlikely, evaluate further
If abnormal, refer to
pediatric GI for small
FIGURE 18–2 ■ Diagnostic algorithm for evaluation of the symptomatic child.
Bishop_Ch18_265-276.indd 270 4/6/10 2:34:38 PM
CHAPTER 18 Celiac Disease ■ 271
high negative predictive value. Situations to consider
DQ2/8 testing include those individuals with an unclear
diagnosis and those with a risk factor but negative initial
screening. In this situation, if testing is negative for DQ2
or DQ8, CD is unlikely.
Current recommendations for biopsy-positive indi-
viduals are to recheck TTG 6 months after initiating GFD
to measure compliance and response, as serology should
normalize during this time with good compliance. For the
asymptomatic patient, TTG should be rechecked at inter-
vals of 1 year or longer. Gluten challenge and repeat biopsy
are no longer recommended if patient improves on GFD.
If the patient has been on a GFD after serologic testing but
prior to biopsy, or if the patient is receiving corticoster-
oids or immunosuppressants, biopsy results may not
reﬂect true level of disease. In this situation, a gluten
“load” of 2–4 weeks of a gluten-containing diet usually is
sufﬁcient to produce typical CD changes on biopsy.
Fecal tests for CD-associated antibodies are commer-
cially available but have not been well validated in adults
and have not been studied in children.
Rapid In-ofﬁce Assays
Rapid whole blood assays for TTG are also being com-
mercialized, with as yet limited data on use in clinical
Asymptomatic, at-risk child
with celiac disease
Consider gluten-free diet
Consider repeat biopsy,
trial of gluten-free diet
If normal, consider re-
screening every 2-3 years,
sooner if clinical concerns
If abnormal, either re-test
to confirm, or refer to
pediatric GI for small
FIGURE 18–3 ■ Diagnostic algorithm for evaluation of the asymptomatic child with
FIGURE 18–4 ■ Small bowel biopsy features of CD, hematoxylin and eosin stain. Panel A shows normal small bowel biopsy with tall slender
villi, 10x magniﬁcation (Marsh score 0) Panel B shows tall villi with increased numbers of intra-epithelial lymphocytes, 40x magniﬁcation (Marsh
score 1) Panel C shows total villous atrophy typical of celiac disease, 10x magniﬁcation (Marsh score 3).
A B C
Bishop_Ch18_265-276.indd 271 4/6/10 2:34:39 PM
272 ■ Section 3: Disorders of the Stomach and Intestine
Non-celiac Gluten Sensitivity
“Gluten sensitivity,” “gluten intolerance,” and “gluten syn-
drome” are terms used by a growing number of alterna-
tive and complementary care practitioners to describe a
condition in which patients report myriad intestinal or
extraintestinal manifestations that are attributed to inges-
tion of gluten proteins but do not meet diagnostic criteria
for CD. These patients generally report neuropsychiatric,
dermatologic, rheumatologic, and non-celiac gastrointes-
tinal complaints such as headache, sinusitis or rhinor-
rhea, concentration and learning problems, fatigue, ﬁbro-
myalgia, and malaise. This entity is becoming more
popular with the lay public, with estimates that 10% of
the population may be affected. The theory is that ingested
gluten induces immunologic response affecting the body
without intestinal involvement, and without develop-
ment of TTG or deamidated gliadin peptide antibodies.
The presence of higher titer anti-gliadin antibodies is
viewed as consistent with this entity.
The only known treatment for CD currently is strict
lifelong adherence to a GFD. With the seeming omni-
presence of gluten-containing foods in the food
supply, this requires considerable education, effort,
and discipline. There exist both overt and occult
sources of gluten in the diet, and failure of the CD
patient to improve clinically is often the result of these
hidden sources. A list of common gluten-free ingredi-
ents, foods to question, and common sources of glu-
ten exposure is shown in Table 18–7. More compre-
hensive and updated information is provided by the
multiple CD or gluten intolerance organizations,
listed in Table 18–8.
Consideration should be given to identifying and
treating speciﬁc nutritional deﬁciencies associated with
CD. In most pediatric patients, these deﬁciencies resolve
with GFD and supplementation is usually only short
term. Testing should be considered for: iron deﬁciency
anemia (iron studies including TIBC, ferritin, and trans-
, folate, and zinc as well as vitamin D and
calcium. Deﬁciency of vitamins A, E, and K and phos-
phorus is rare.
How Much Gluten is Safe?
Based on a double-blind, placebo-controlled study,
patients with CD should ingest less than 50 mg of glu-
ten per day in order to remain symptom-free.
Food Allergen Labeling and Consumer Protection Act
Food and Ingredient List for the Gluten-free Diet
Food Item Foods/Ingredients Allowed Foods/Ingredients to Question Foods/Ingredients Not Allowed
Amaranth, arrowroot, bean ﬂour (lentil,
romano, garbanzo, etc.), buckwheat, carob
ﬂour, chickpea ﬂour, corn ﬂour, corn meal,
cornstarch, job’s tears, kasha (roasted
buckwheat), kudzu root starch, maize,
maize waxy, masa ﬂour, harina, millet,
Montina Flour (Indian ricegrass), nut ﬂour
(almond, chestnut, etc.), pea ﬂour
(chickpea, besan, cowpea, etc.), potato
ﬂour, potato starch, quinoa, ragi, rape, rice
ﬂour (white, brown, sweet, bran), sago
ﬂour, soba ﬂour, sorghum, soy ﬂour,
tapioca ﬂour, taro root, teff ﬂour, yam ﬂour
Safe ﬂours in bulk bins in stores Barley (malt, pearl, grass, etc.),
bleached ﬂour, bran, bread
ﬂour, brown ﬂour, farina,
graham, fu (dried wheat
gluten), gluten ﬂour, graham
ﬂour, granary ﬂour
Groats can be from either safe
or unsafe grains
Groats (arley, heat), alt, matzo
semolina, ats, ye, emolina, pelt,
heat (emolina, prouted, urum,
tarch, bulgar, Kamut, rass, etc.),
Cereals Hot and cold cereals made from the
allowed grains, cream of rice, cream of
buckwheat, grits corn, hominy grits
Commercial cereals made in a
Hot and cold cereals containing
a grain not allowed
Cereals made with malt
or malt extract
Bishop_Ch18_265-276.indd 272 4/6/10 2:34:53 PM
CHAPTER 18 Celiac Disease ■ 273
(FALCPA), which took effect on January 1, 2006,
requires food labels to clearly identify eight common
food allergens: wheat, eggs, ﬁsh, milk, peanuts, shell-
ﬁsh, soybeans, and tree nuts. This law does not, how-
ever, address the use of barley (malt), rye, or oats. FAL-
CPA also requires the U.S. Food and Drug
Administration to develop rules for the use of the term
“gluten-free” on product labels. The ﬁnal ruling is still
pending, although the FDA proposal is available from
the federal register at http://www.cfsan.fda.gov/%7Elrd/
fr070123.html. The parameter for a naturally gluten-
free product is 20 ppm per serving, and for a food ren-
dered gluten-free is 200 ppm.
NEW THERAPIES UNDER
While the only current treatment for CD is lifelong adher-
ence to a GFD, several alternative treatments are currently
being investigated as possible adjunctive therapies.
One of the properties of gluten that makes it immuno-
genic is the ability to reach the lamina propria in large,
antigenically intact peptide fragments. This is due to
lack of native peptidases capable of cleavage of peptide
Food and Ingredient List for the Gluten-free Diet
Food Item Foods/Ingredients Allowed Foods/Ingredients to Question Foods/Ingredients Not Allowed
Pastas made from allowed grains, rice
including white brown and wild, corn
tacos and corn tortillas, potatoes,
saifun (bean threads), rice noodles
Commercial rice and pasta mixes,
French fries, fried restaurant
All pastas made from grains not
allowed, couscous, tabbouleh,
Fruits and fruit
Fresh fruit, pure fruit juices Thickened or prepared fruits and
pie ﬁllings, dried fruit mixes, jelly
Beverages Tea (black, green, and white), coffee
(plain), pure fruit juices, cider
Soy and rice beverages, instant
tea and coffee, ﬂavored tea and
coffee, hot cocoa, hot chocolate,
soda, sports drinks, nutritional
Malted beverages, ground
coffee with added grains
Vinegar Vinegars (apple cider, rice, wine,
Flavored vinegars Malt vinegar
Condiments Salt, pepper (black, white, and red), pure
herbs, pure spices, pure ﬂavoring
extracts, wheat-free soy sauce, cream
of tartar, pickles, honey
Ground spices, seasoning and
spice mixes, gravy cubes and
mixes, bouillon cubes and
powder, ketchup, mustard,
mustard powder, Worcestershire
sauce, salad dressings, soy
sauce, teriyaki sauce, relish
Most soy sauces contain wheat
Miscellaneous Seaweed (algin, algae, alginate),
Yeast, yeast ﬂakes, bicarbonate of
soda, baking soda, baking
powder, powdered sugar,
molasses, rice paper,
Non-food Lotions, creams, cosmetics, lip
gloss, lip balm, sunscreen,
products used in dental ofﬁces,
and over the counter (many
contain gluten), laxatives,
vitamins, stamps, envelopes,
and gummed labels, Play Doh,
Table 18–7. (Continued)
Bishop_Ch18_265-276.indd 273 4/6/10 2:34:53 PM
274 ■ Section 3: Disorders of the Stomach and Intestine
bonds of proline residues. Currently being investigated
is the use of exogenous bacterial derived prolyl-
endopeptidases to cleave these peptides into smaller,
less immunogenic fragments prior to reaching the
lamina propria. There are published data on in vitro
and in vivo animal models, and ex vivo human T cells,
with promising results. Controlled studies in CD
patients using these enzymes are yet to be
Inhibition of Intestinal tTG
Early work is underway at developing a site-speciﬁc
inhibitor of intestinal tTG, to prevent the local deami-
dation and binding enhancement of gluten peptides.
There are potential side effects with such an inhibitor,
such as impaired wound healing and perturbation of
the extracellular matrix.
Theoretically, a compound can be formulated that will
occupy the binding groove on HLA-DQ2 or -DQ8 and
prevent gluten peptide antigen presentation. This would
effectively block the immunogenic reaction. To our
knowledge, no such compound has yet been formu-
Another theoretic therapy would be to stimulate
apoptosis in gluten-speciﬁc T cells, or induce toler-
ance in these T cells by targeting tolerogenic dendritic
cells. These therapies again are still in theoretic
Several trials of anti-inﬂammatory cytokine therapy are
underway for other chronic diseases such as RA and
IBD. IL-15 antagonists have been developed by several
pharmaceutical companies for treatment of RA, but
have therapeutic potential for CD as well. IFN-γ antago-
nists have been developed and are in phase II testing for
reduction of inﬂammation in IBD, but are being recog-
nized for potential in CD treatment as well. IL-10 has
been tested in both refractory CD and IBD for its poten-
tial ability to shift away from TH1 immune reaction.
Unfortunately, neither trial has so far showed any
Genetically Modiﬁed Wheat
Work is currently underway to evaluate the feasibility of
engineering and cultivating a modiﬁed, gluten-free
strain of wheat that would lack immunogenic peptides.
Barriers to this would include cost, palatability, and
industrial quality of the ﬂour derived from such a strain.
This project is in its early stages, and would not be avail-
able to the mass market for many years, if ever.
Monoclonal antibodies to the adhesion molecule integ-
rin a4 are currently being used for multiple sclerosis and
are also in phase II trials for IBD. These compounds
may have potential for CD by prevention of T-cell
migration into the lamina propria. Zonulin antagonists
are being looked at for prevention of gluten-induced
intestinal hyper-permeability. The concept of using
NGK2D antagonists to prevent the phenotypic conver-
sion of CD4 T cells to cytotoxic T cells in the intestinal
epithelium has also been raised.
With a more thorough understanding of the pathogen-
esis of CD, more emphasis may start being placed on the
prevention of development rather than treatment.
In a recent meta-analysis of breastfeeding prac-
tices and effect on CD, the authors concluded that dura-
tion of breastfeeding and breastfeeding during introduc-
tion of grains reduced future risk of CD development.
This is not uniformly accepted, however, and some inves-
tigators feel that breastfeeding may delay or mask, but
not prevent the development of CD.
The mechanism is
speculative, but involvement of probiotic bacteria is
thought to be important for development of tolerance to
food proteins and maintenance of intact intestinal
epithelial barrier in infancy. It is also speculated that
Celiac Disease and Gluten Sensitivity Resources
www.celiac.com: celiac and gluten-free information
www.celiac.org: Celiac Disease Foundation
www.gluten.net: Gluten Intolerance Group of North America
www.celiac.nih.gov: Celiac Disease Awareness Campaign
www.celiaccentral.org: National Foundation for Celiac
www.celiachealth.org: Children’s Digestive Health and
www.americanceliac.org: American Celiac Disease Alliance
www.eatright.org: American Dietetic Association
www.csaceliacs.org: Celiac Sprue Association
www.cdhnf.org: Children’s Digestive Health and Nutrition
Bishop_Ch18_265-276.indd 274 4/6/10 2:34:54 PM
CHAPTER 18 Celiac Disease ■ 275
probiotic therapy in at-risk individuals may help to pro-
mote tolerance and prevent CD.
Timing of introduction of gluten and quantity of
gluten in the diet are other controversial topics in pre-
vention of CD. Early (prior to 3 months of age) and late
(after 7 months) introduction of gluten were associated
with increased risk of CD in one prospective study.
Several recent papers documented a four-fold rise in
incidence of CD in Sweden in children less than 2 years
old, after a signiﬁcant increase in gluten intake in this
population. A later decrease in gluten consumption cor-
responded to a drop in CD.
Prevention of infectious triggers such as rotavirus
and the subsequent effect on CD risk is another area
currently being researched. If the increased permeabil-
ity and inﬂammation corresponding with infection can
be avoided in at-risk individuals, perhaps breakdown of
tolerance will not occur.
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