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Celiac Dz - Peds

Celiac Dz - Peds

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Celiac diseases
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■ Silent CD describes the situation of an individual

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-
associated antibodies.
■ 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
roughly 2:1.
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
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
intestinal mucosa;
■ 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
clinical situations:
■ 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.
Celiac Disease
Edward Hoffenberg
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).
Genetic Considerations
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
first-degree relatives.
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
(Tables 18–3
and 18–4).
Worldwide Disease Prevalence Based on
Screening Data
United Kingdom
United States
1:66 to 1:119
1:99 to 1:67
1:166 to 1:104
Table 18–1.
Conditions Associated with Increased Risk for CD
in Children and Adults
Condition Prevalence of CD (%)
Type 1 diabetes
Down syndrome
Turner syndrome
Williams syndrome
IgA deficiency
Autoimmune thyroiditis
First-degree relatives with CD
Second-degree relatives
Dermatitis herpetiformis
Short stature/delayed puberty
Dental enamel defects
Adults specifically:
■ Irritable bowel syndrome
■ Persistent aphthous stomatitis
■ Peripheral neuropathy
■ Unexplained cerebellar ataxia
■ Elevated transaminases
■ Unexplained iron deficiency
■ Decreased bone mineral density
■ Infertility
Table 18–2.
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
myosin molecule
Table 18–3.
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
T cell
CD4 + T cell
CD4 αβ TCR
or -DQ8
Lamina propria
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
Table 18–4.
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
CD patients.
Several properties of gluten may be important in
stimulating the immune response of CD:
■ Gliadin stimulation of IL-15 secretion through a non-
HLA-binding mechanism.
■ 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).
Extraintestinal manifestations
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
Dermatitis herpetiformis

Dental enamel defects
Epilepsy ϩ/Ϫ cerebral calcifications

Abdominal distension

Aphthous stomatitis

Abdominal pain


Abnormal liver function tests

Pubertal delay/short stature
Peripheral neuropathy


Recurrent fetal loss

Strong evidence for association.

Less strong.
Table 18–5.
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.
There is
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.
Dermatitis Herpetiformis
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.
Skeletal Manifestations
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
Autoimmune Diseases
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
Differential Diagnosis
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
Chronic constipation/
Growth hormone deficiency Zollinger–Ellison syndrome
Acid peptic disease, ulcer
Table 18–6.
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
of CD.
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
Biopsy consistent
with celiac disease
Gluten free diet
Biopsy uncertain
Consider repeat biopsy, trial
of gluten free diet, other
If normal, celiac disease
unlikely, evaluate further
If abnormal, refer to
pediatric GI for small
bowel biopsy
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.
Stool Testing
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
Biopsy consistent
with celiac disease
Consider gluten-free diet
Biopsy uncertain
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
bowel biopsy
FIGURE 18–3 ■ Diagnostic algorithm for evaluation of the asymptomatic child with
a risk.
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).
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-
ferrin), B
, 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
Grains and
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.),
hole-eal lour
Wheat germ
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
non-dedicated facility
Hot and cold cereals containing
a grain not allowed
Cereals made with malt
or malt extract
Table 18–7.
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.
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.
Bacterial Prolyl-endopeptidases
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, potatoes,
and other
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
foods (gluten-contaminated
grease), polenta
All pastas made from grains not
allowed, couscous, tabbouleh,
soba noodles
Fruits and fruit
Fresh fruit, pure fruit juices Thickened or prepared fruits and
pie fillings, dried fruit mixes, jelly
and jam
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,
and balsamic)
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),
alfalfa, aspic
Yeast, yeast flakes, bicarbonate of
soda, baking soda, baking
powder, powdered sugar,
molasses, rice paper,
confectioner sugar
Communion wafers,
brewer’s yeast
Non-food Lotions, creams, cosmetics, lip
gloss, lip balm, sunscreen,
toothpaste, mouthwash,
products used in dental offices,
medications: prescription
and over the counter (many
contain gluten), laxatives,
vitamins, stamps, envelopes,
and gummed labels, Play Doh,
paper mache
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.
DQ2/DQ8-binding Peptides
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-
T-cell Silencing
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
Cytokine Therapy
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.
Other Possibilities
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
Nutrition Foundation
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
Table 18–8.
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.
1. Hill ID, Dirks MH, Liptak GS, et al. Guideline for the diag-
nosis and treatment of celiac disease in children: recom-
mendations of the North American Society for Pediatric
Gastroenterology, Hepatology and Nutrition. J Pediatr
Gastroenterol Nutr. 2005;40:1–19.
2. Megiorni F, Mora B, Bonamico M, et al. HLA-DQ and
susceptibility to celiac disease: evidence for gender differ-
ences and parent-of-origin effects. Am J Gastroenterol.
3. Cataldo F, Montalto G. Celiac disease in the developing
countries: a new and challenging public health problem.
World J Gastroenterol. 2007;13:2153–2159.
4. Bonamico M, Ferri M, Mariani P, et al. Serologic and
genetic markers of celiac disease: a sequential study in the
screening of first degree relatives. J Pediatr Gastroenterol
Nutr. 2006;42:150–154.
5. Wolters VM, Wijmenga C. Genetic background of celiac
disease and its clinical implications. Am J Gastroenterol.
6. Nistico L, Fagnani C, Coto I, et al. Concordance, disease
progression, and heritability of coeliac disease in Italian
twins. Gut. 2006;55:803–808.
7. Kagnoff MF. Celiac disease: pathogenesis of a model
immunogenetic disease. J Clin Invest. 2007;117:41–49.
8. Sollid LM. Hunting for celiac disease genes. Gastroenterol-
ogy. 2008;134:869–871.
9. Catassi C, Fasano A. Celiac disease. Curr Opin Gastroen-
terol. 2008;24:687–691.
10. Kemppainen T, Janatuinen E, Holm K, et al. No observed
local immunological response at cell level after five years
of oats in adult coeliac disease. Scand J Gastroenterol.
11. National Institutes of Health Consensus Development
Conference Statement on Celiac Disease, June 28–30,
2004. Gastroenterology. 2005;128:S1–S9.
12. NIH Consensus Development Conference on Celiac Dis-
ease. NIH Consens State Sci Statements. 2004;21:1–23.
13. Fasano A. Clinical presentation of celiac disease in the
pediatric population. Gastroenterology. 2005;128:
14. Troncone R, Auricchio R, Granata V. Issues related to
gluten-free diet in coeliac disease. Curr Opin Clin Nutr
Metab Care. 2008;11:329–333.
15. Rostom A, Murray JA, Kagnoff MF. American Gastroen-
terological Association (AGA) Institute technical review
on the diagnosis and management of celiac disease. Gas-
troenterology. 2006;131:1981–2002.
16. Halfdanarson TR, Litzow MR, Murray JA. Hematologic
manifestations of celiac disease. Blood. 2007;109:412–421.
17. Collin P, Reunala T. Recognition and management of the
cutaneous manifestations of celiac disease: a guide for
dermatologists. Am J Clin Dermatol. 2003;4:13–20.
18. Zone JJ. Skin manifestations of celiac disease. Gastroenter-
ology. 2005;128:S87–S91.
19. Zanchi C, Di Leo G, Ronfani L, Martelossi S, Not T, Ven-
tura A. Bone metabolism in celiac disease. J Pediatr.
20. Fasano A, Araya M, Bhatnagar S, et al. Federation of Inter-
national Societies of Pediatric Gastroenterology, Hepatol-
ogy, and Nutrition consensus report on celiac disease.
J Pediatr Gastroenterol Nutr. 2008;47:214–219.
21. AGA Institute medical position statement on the diagno-
sis and management of celiac disease. Gastroenterology.
22. Catassi C, Fabiani E, Iacono G, et al. A prospective, dou-
ble-blind, placebo-controlled trial to establish a safe glu-
ten threshold for patients with celiac disease. Am J Clin
Nutr. 2007;85:160–166.
23. Cerf-Bensussan N, Matysiak-Budnik T, Cellier C, Heyman
M. Oral proteases: a new approach to managing coeliac
disease. Gut. 2007;56:157–160.
24. Matysiak-Budnik T, Candalh C, Cellier C, et al. Limited
efficiency of prolyl-endopeptidase in the detoxification of
gliadin peptides in celiac disease. Gastroenterology.
25. Gass J, Bethune MT, Siegel M, Spencer A, Khosla C. Com-
bination enzyme therapy for gastric digestion of dietary
gluten in patients with celiac sprue. Gastroenterology.
26. Mitea C, Havenaar R, Drijfhout JW, Edens L, Dekking L,
Koning F. Efficient degradation of gluten by a prolyl endo-
protease in a gastrointestinal model: implications for coe-
liac disease. Gut. 2008;57:25–32.
27. Stepniak D, Spaenij-Dekking L, Mitea C, et al. Highly effi-
cient gluten degradation with a newly identified prolyl
endoprotease: implications for celiac disease. Am J Physiol
Gastrointest Liver Physiol. 2006;291:G621–G629.
28. Marti T, Molberg O, Li Q, Gray GM, Khosla C, Sollid LM.
Prolyl endopeptidase-mediated destruction of T cell
epitopes in whole gluten: chemical and immunological
characterization. J Pharmacol Exp Ther. 2005;312:19–26.
29. Shan L, Marti T, Sollid LM, Gray GM, Khosla C. Com-
parative biochemical analysis of three bacterial prolyl
endopeptidases: implications for coeliac sprue. Biochem J.
30. Sollid LM, Khosla C. Future therapeutic options for celiac
disease. Nat Clin Pract Gastroenterol Hepatol. 2005;2:
Bishop_Ch18_265-276.indd 275 4/6/10 2:34:54 PM
276 ■ Section 3: Disorders of the Stomach and Intestine
31. Schuppan D, Dieterich W. A molecular warhead and its
target: tissue transglutaminase and celiac sprue. Chem
Biol. 2003;10:199–201.
32. Gianfrani C, Auricchio S, Troncone R. Possible drug tar-
gets for celiac disease. Expert Opin Ther Targets.
33. Di Sabatino A, Ciccocioppo R, Cupelli F, et al. Epithelium
derived interleukin 15 regulates intraepithelial lymphocyte
Th1 cytokine production, cytotoxicity, and survival in
coeliac disease. Gut. 2006;55:469–477.
34. Salvati VM, Mazzarella G, Gianfrani C, et al. Recombinant
human interleukin 10 suppresses gliadin dependent T cell
activation in ex vivo cultured coeliac intestinal mucosa.
Gut. 2005;54:46–53.
35. Akobeng AK, Heller RF. Assessing the population impact
of low rates of breast feeding on asthma, coeliac disease
and obesity: the use of a new statistical method. Arch Dis
Child. 2007;92:483–485.
36. Troncone R, Auricchio S. Rotavirus and celiac disease:
clues to the pathogenesis and perspectives on prevention.
J Pediatr Gastroenterol Nutr. 2007;44:527–528.
37. Norris JM, Barriga K, Hoffenberg EJ, et al. Risk of celiac
disease autoimmunity and timing of gluten introduction
in the diet of infants at increased risk of disease. JAMA.
38. Ivarsson A. The Swedish epidemic of coeliac disease
explored using an epidemiological approach—some les-
sons to be learnt. Best Pract Res Clin Gastroenterol.
39. Pavone P, Nicolini E, Taibi R, Ruggieri M. Rotavirus and
celiac disease. Am J Gastroenterol. 2007;102:1831.
40. Stene LC, Honeyman MC, Hoffenberg EJ, et al. Rotavirus
infection frequency and risk of celiac disease autoimmu-
nity in early childhood: a longitudinal study. Am J Gastro-
enterol. 2006;101:2333–2340.
41. Sollid LM. Coeliac disease: dissecting a complex inflam-
matory disorder. Nat Rev Immunol. 2002;2:647–655.
42. Hoffenberg EJ, Bao F, Eisenbarth GS, et al. Transglutami-
nase antibodies in children with a genetic risk for celiac
disease. J Pediatr. 2000;137:356–360.
43. Dubois PC, van Heel DA. Translational mini-review series
on the immunogenetics of gut disease: immunogenetics
of coeliac disease. Clin Exp Immunol. 2008;153:162–173.
44. Hunt KA, Zhernakova A, Turner G, et al. Newly identified
genetic risk variants for celiac disease related to the
immune response. Nat Genet. 2008;40:395–402.
45. Smyth DJ, Plagnol V, Walker NM, et al. Shared and dis-
tinct genetic variants in type 1 diabetes and celiac disease.
N Engl J Med. 2008;359:2767–2777.
Bishop_Ch18_265-276.indd 276 4/6/10 2:34:54 PM

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