Epidemiology, Pathogenesis, and Clinical Manifestations of Celiac Disease in Children - UpToDate

18.10.
2023, 11:33 Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children - UpToDate
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Epidemiology, pathogenesis, and clinical manifestations of

celiac disease in children
AUTHORS: Marisa Stahl, MD, MSCS, Edwin Liu, MD
SECTION EDITOR: B UK Li, MD
DEPUTY EDITOR: Alison G Hoppin, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2023.

This topic last updated: Jan 25, 2023.
INTRODUCTION
Celiac disease, also known as gluten-sensitive enteropathy, is a common immune-mediated inflammatory

disease of the small intestine caused by sensitivity to dietary gluten and related proteins in genetically
predisposed individuals. It differs from food allergies (including wheat allergy), which are mediated by
immunoglobulin (Ig) E or IgG. The appropriate treatment is a lifelong gluten-free diet to mitigate the
associated mucosal inflammation and prevent future adverse complications, which may include intestinal
lymphoma.
The epidemiology, pathogenesis, and clinical manifestations of celiac disease are reviewed here. Other
aspects of celiac disease in children are discussed in the following topic reviews:
● (See "Diagnosis of celiac disease in children".)
● (See "Management of celiac disease in children".)
EPIDEMIOLOGY
General population — Celiac disease is a common chronic condition, with a pooled global prevalence of
1.4 percent [1] but can be much higher in certain regions. In a prospective birth cohort study of infants at
risk for celiac disease in Europe and the United States, the estimated incidence was as high as 3 percent in
Sweden and 2.4 percent in Colorado [1,2]. Besides region of birth, a family history of celiac disease, female
sex, and amount of gluten consumed in early life are important factors in disease risk. Females are
affected approximately twice as often as males, although the ratio varies depending on the strategy used
to find cases [3-5].
Celiac disease is also common in some non-European populations, including northern Africa, the Middle
East, and South Asia [1,4]. The prevalence in South America varies considerably by country [6-10]. Celiac
disease was previously thought to be uncommon in Asia, but a meta-analysis found pooled
seroprevalence of 1.2 in the general population in the Asia-Pacific region [11], and a report based on
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18.10.2023, 11:33 Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children - UpToDate
serologic testing among adolescents and young adults in China specifically suggests that the prevalence
may be as high as 0.76 percent in regions where wheat is a prominent part of the diet [12]. The prevalence
in some resource-limited countries is probably underestimated due to limited access to diagnostic testing
and confounding by other diarrheal diseases that cause small intestinal injury. Overall, the global
distribution of the disease seems to parallel the distribution of human leukocyte antigen (HLA) genotypes
that predispose to celiac disease, provided that the population is also exposed to gluten [2,13].
Access to medical care and case-finding bias likely play a role in some of the observed differences
between populations [14]. Decisions about diagnostic testing should be based on symptoms, signs, and
risk factors, without regard to the individual's ancestry or race/ethnicity. (See "Diagnosis of celiac disease
in children".)
High-risk groups — The prevalence of celiac disease, as detected by screening programs using specific
antibodies, is substantially increased in the following groups compared with the general population
( table 1). Because of the increased risk, we suggest routine screening for celiac disease in
asymptomatic children with these conditions [15], although this approach is somewhat controversial (see
"Diagnosis of celiac disease in children", section on 'Members of high-risk groups'):
● First- and second-degree relatives of individuals with celiac disease
● Autoimmune disorders/immunodeficiency:
• Type 1 diabetes
• Autoimmune thyroiditis
• Juvenile idiopathic arthritis
• Autoimmune liver disease
• Selective IgA deficiency
● Genetic syndromes:
• Down syndrome
• Turner syndrome
• Williams syndrome
For these groups, th e risk of celiac disease is approximately 3- to 10-fold higher than in the general
population. Evidence for these associations is discussed below.
● Relatives of individuals with celiac disease – The prevalence of celiac disease is approximately 7.5
percent (1:13) for first-degree relatives of people with celiac disease and approximately 2.3 percent
(1:43) for second-degree relatives [16]. The risk is higher in female relatives of the proband
compared with male relatives.
● Autoimmune disorders/immunodeficiency
• Type 1 diabetes – Celiac disease is associated closely with type 1 diabetes mellitus [17-19].
Publications report a wide range of prevalence depending on the region and method of
screening. In one systematic review, up to 16 percent of children with type 1 diabetes had celiac
disease diagnosed by intestinal biopsy [20]. Children with type 1 diabetes are commonly
asymptomatic at the time of celiac disease diagnosis [21]. Of note, celiac disease and type 1
diabetes share HLA susceptibility alleles [22], but the co-occurrence of the disorders is not fully
explained by shared high-risk HLA and non-HLA genetic loci [19]. Interestingly, there is also
regional variation in the prevalence of celiac disease in children with type 1 diabetes, suggesting
the importance of environmental factors [23]. (See "Associated autoimmune diseases in children
and adolescents with type 1 diabetes mellitus", section on 'Celiac disease'.)
• Autoimmune thyroiditis – Approximately 2 to 7 percent of individuals with autoimmune

thyroiditis develop celiac disease [24-26]. The association is weak during childhood and appears
to increase with age [27]. Conversely, individuals with celiac disease have up to a fourfold risk of
autoimmune thyroiditis. The clinical course of the thyroiditis does not appear to be affected by a
gluten-free diet, although data are mixed [28-33]. Antithyroid antibodies at diagnosis have a low
predictive value for the development of thyroid hypofunction [31]. (See "Acquired hypothyroidism
in childhood and adolescence", section on 'Autoimmune thyroiditis'.)
• Rheumatic diseases – Celiac disease is reported in 2 to 3 percent of children presenting with

juvenile idiopathic arthritis, many of whom have no gastrointestinal symptoms [34,35].
Conversely, a Swedish population-based study of children with known celiac disease found a
nearly threefold increased risk of developing juvenile idiopathic arthritis [36].
The association between celiac disease and other pediatric rheumatic diseases such as systemic
lupus erythematosus is less clear [35].
• Autoimmune liver disease – Children with autoimmune hepatitis also have a higher risk of celiac
disease, with a systematic review and meta-analysis finding a pooled prevalence for celiac disease
of 3.6 percent [37]. Weaker associations with primary biliary cirrhosis and primary sclerosing
cholangitis have also been described [38]. Evidence for these associations is described separately.
(See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section
on 'Associated conditions'.)
More commonly, a cryptogenic hypertransaminasemia (also referred to as a celiac hepatitis) is

seen in children with untreated celiac disease (pooled proportion 36 percent) [37]. This condition
typically resolves during treatment with a gluten-free diet.
• Selective IgA deficiency – Approximately 0.63 to 9.9 percent of individuals with selective IgA
deficiency have celiac disease. Conversely, 0.5 to 16.7 percent of individuals with celiac disease
may have IgA deficiency [39].
Patients with known IgA deficiency require special strategies when screening for celiac disease
because most serologic tests for celiac disease are IgA antibodies. In addition, the possibility of
undiagnosed IgA deficiency should be explored when performing serologic screens by measuring
a total IgA level, if not already done. (See "Diagnosis of celiac disease in children", section on
'Special populations'.)
● Genetic syndromes – Other disorders possibly associated with celiac disease include:
• Down syndrome – Celiac disease develops in 5 to 12 percent of individuals with Down syndrome
[40-43]. Pooled prevalence estimates for celiac disease are 1:13 (7.6 percent), approximately a
sixfold increase in risk over the general population, and some studies even point to an 18-fold
higher incidence [40,44]. The mechanism for this association is unclear, although it is consistent
with the propensity for other autoimmune diseases among individuals with Down syndrome. One

theory is that trisomy 21 leads to an activated interferon response, resulting in an increased risk
of autoimmunity [45]. (See "Down syndrome: Clinical features and diagnosis", section on
'Immunodeficiency' and "Down syndrome: Clinical features and diagnosis", section on
'Gastrointestinal abnormalities'.)
• Turner syndrome – In a systematic review, the pooled prevalence estimate for celiac disease in
Turner syndrome was 4.5 percent [46]. As in Down syndrome, the mechanism of this increased
risk is unknown [47].
• Williams syndrome – Up to 10.8 percent of individuals with Williams syndrome have celiac
disease, based on limited data [48,49]. (See "Clinical manifestations and diagnosis of Turner
syndrome", section on 'Autoimmune disorders' and "Williams syndrome".)
PATHOGENESIS AND RISK FACTORS
Celiac disease is caused by an inappropriate immune reaction to dietary gluten and related proteins in
genetically predisposed individuals. The common grains that contain the triggering proteins are wheat,
barley, and rye. Ingestion of these proteins by a susceptible individual causes immune-mediated mucosal
inflammation of the proximal small intestine, with villous atrophy and crypt hyperplasia ( figure 1),
which often leads to malabsorption and gastrointestinal symptoms. The immune response is mediated by
gliadin-reactive T cells, in contrast with wheat allergy, which is mediated by IgE or IgG. The intestinal
lesions and symptoms resolve when gluten is eliminated from the diet. (See "Epidemiology, pathogenesis,
and clinical manifestations of celiac disease in adults", section on 'Pathogenesis' and "Management of
celiac disease in children", section on 'Principles of a gluten-free diet'.)
Genetic factors — The genetic basis of the disease is shown by the frequent intrafamilial occurrence and
the remarkably close association with the human leukocyte antigen (HLA) DR3-DQ2 and/or DR4-DQ8 gene
locus. More than 99 percent of individuals with celiac disease have HLA DR3-DQ2 and/or DR4-DQ8,
compared with approximately 40 percent of the general population [50]. Among individuals with celiac
disease, approximately 90 percent will have DQ2 and the remainder will have DQ8. Homozygotes for DR3-
DQ2 are at the highest risk for celiac disease, which develops in approximately 11 percent of individuals
with this genotype by five years of age [51]. While the presence of either the HLA-DQ2 or DQ8 genotype is
essential to confer disease, it is not alone sufficient and other genetic, epigenetic, and environmental
factors have also been implicated [6]. In rare instances, individuals without these genotypes develop celiac
disease [52].
Because of common genetic contributors, several groups are at increased risk for celiac disease (see
'High-risk groups' above). The genetic contributors to celiac disease are discussed in detail separately. (See
"Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section on 'Genetic
factors'.)
Feeding practices in infancy and early childhood — The pathogenesis of celiac disease at any age
requires exposure to gluten. Efforts to reduce the risk of celiac disease have focused on the initial timing
and amount of gluten exposure and whether breastfeeding or the use of hydrolyzed formula (avoidance
of cow's milk protein) reduce the risk of developing celiac disease.

● Breastfeeding and gluten exposure – A preponderance of evidence suggests that the timing of
initial gluten introduction during infancy and breastfeeding does not appear to affect celiac disease
risk [53]. However, studies indicate that the quantity of gluten in the infant's diet plays a role, such
that greater amounts of gluten consumption are associated with higher disease risk in genetically
predisposed children. Overall, these studies cannot be translated into clinical practice yet and further
research is needed to understand how the amount of gluten may interact with other environmental
triggers such as upper respiratory or gastrointestinal infections. Therefore, feeding
recommendations should continue to follow standard pediatric guidelines set by each governing
body.
Evidence supporting this guidance includes:
• Timing of gluten introduction – Observational studies initially suggested that the timing of
gluten introduction (particularly either early introduction before four months of age or late
introduction after seven months of age) increased the risk of celiac disease in genetically
predisposed individuals [54-59]. However, a subsequent multicenter prospective observational
study and two randomized trials failed to confirm this hypothesis and reported no association
between the timing of gluten introduction or breastfeeding and celiac disease risk [60]. The role
of gluten introduction in celiac disease prevention remains controversial, with another open-label
randomized clinical trial finding decreased celiac disease risk in infants who were introduced to
gluten (in fairly high quantities) between four to six months of age [61]. Celiac disease was not a
primary endpoint of this study, and the results were limited by a small sample size and available
parameters for the definition of celiac disease cases. Overall, timing of gluten introduction may
play a role in disease risk, but study results are conflicting.
• Quantity of gluten exposure – The quantity of gluten in the infant's diet may affect celiac
disease risk or the age of presentation. In a prospective observational multinational study of 6605
children with genetic predisposition for celiac disease due to their HLA antigen genotype, the
quantity of gluten exposure during the first five years of life was associated with development of
celiac autoimmunity and confirmed celiac disease [62]. A Norwegian prospective cohort study
similarly found that higher gluten intake at 18 months of age increased the risk of later
development of celiac disease [63].
A separate study found that the amount of gluten consumed between 11 and 36 months of age
did not influence the risk of developing celiac disease [64]. Long-term follow-up of these children
is needed to determine whether the amount of gluten consumed at an early age ultimately has
any effect on the subsequent development of celiac disease.
● Cow's milk protein – Avoidance of cow's milk protein during the weaning period does not appear to
reduce the risk for celiac disease autoimmunity or celiac disease. This was shown in a randomized
trial of 230 infants who were considered at risk for celiac disease because of their HLA type and at
least one family member having type 1 diabetes [65]. Infants weaned to an extensively hydrolyzed
formula did not have decreased risk for tissue transglutaminase (tTG) positivity or celiac disease
compared with those weaned to a cow's milk-based formula, with up to 10 years follow-up.
Observational data from the TEDDY study parallel this finding of no association between milk
powder in early childhood and celiac disease risk [66].

Additional trigger factors — In some cases, celiac disease in genetically predisposed individuals may be
precipitated by a separate risk or trigger factor in addition to gluten exposure. Prior intestinal infections,
and, in particular, infection with rotavirus or enterovirus, are more common in children with celiac disease
than in those without [67-69]. If true, the precise mechanisms by which these events affect the onset of
disease remain unclear. Exposure to antibiotics is probably not a risk factor, although more research is
needed on the effect of the microbiome in disease pathogenesis [70,71].
CLINICAL MANIFESTATIONS
In the past, celiac disease classically presented in infants and young children with malabsorption and
failure to thrive. Now, with the increasing recognition of subclinical and nonclassical presentations and
widely available serologic testing, celiac disease is often diagnosed in older children with milder
gastrointestinal or non-gastrointestinal manifestations [72]. Despite the advancing age at diagnosis and
fewer classical presentations, data indicate that celiac disease develops early in childhood (before 10
years) [73], even among those who are not diagnosed until later in life.
"Classical" gastrointestinal symptoms — Classically, celiac disease presented between 6 and 24 months
of age, after the introduction of gluten into the diet [27]. The children have chronic diarrhea, anorexia,
abdominal distension and pain, and failure to thrive or weight loss; some may also have vomiting. If the
diagnosis is delayed, children may present with signs of severe malnutrition. Although rare, a few severely
affected infants may present with the hemodynamic and metabolic consequences of dehydration, known
as a celiac crisis.
Gastrointestinal symptoms in older children and adults are similar but usually less pronounced. In a
European collaborative study, symptoms of malabsorption were the most common gastrointestinal
manifestation in children under age three, while abdominal pain was the most common gastrointestinal
symptom in older children [74].
Paradoxically, the disease may cause either diarrhea (64 percent) or constipation (8 percent) [75]. When
diarrhea is present, the stools are often bulky and foul-smelling and may float.
Non-gastrointestinal manifestations — Numerous non-gastrointestinal manifestations of celiac disease

have been described ( table 2). In some patients, non-gastrointestinal symptoms are the primary
presenting complaint and should prompt the consideration of serologic testing. Conditions associated
with celiac disease in adults are described in detail separately [76]. (See 'Phenotypes' below and
"Diagnosis of celiac disease in children" and "Epidemiology, pathogenesis, and clinical manifestations of
celiac disease in adults".)
● Growth and development – Children who develop symptomatic celiac disease often have delayed
linear growth. Indeed, between 8 and 10 percent of children with apparent "idiopathic" short stature
have serologic evidence of celiac disease [27]. The growth delay may occur even when weight-for-
height is relatively normal and in the absence of significant gastrointestinal symptoms [77-79]. Thus,
the growth attenuation is probably not entirely attributable to undernutrition. On the other hand,
young children with persistently positive celiac-specific antibodies but without symptoms generally
have normal growth, suggesting that the effects of celiac disease on growth probably depend on
disease severity and/or duration [80]. In children with growth delay, catch-up growth is typically rapid

during the first year after starting a gluten-free diet and continues for up to three years, although, in
some children, catch-up growth may be incomplete [81].
Studies from the United States, Europe, and Australia report that a substantial number of children
(up to 12 percent) have overweight or obesity at the time that celiac disease is diagnosed, although
the prevalence of obesity tends to be somewhat lower than in the local population [82-85].
Adolescent girls may have an increased frequency of menstrual abnormalities such as delayed
menarche and, later, may have problems with infertility and experience an early menopause [86-90].
Boys with untreated celiac disease have reduced levels of serum dihydrotestosterone in a pattern
suggesting androgen resistance [27,86]. Treatment with a gluten-free diet appears to prevent these
problems. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults",
section on 'Menstrual and reproductive issues'.)
● Behavioral and neurologic symptoms
• Short-term – Subclinical or subtle behavioral or neurologic abnormalities appear to be common

and tend to resolve on a gluten-free diet, as shown in these studies:
- Subtle behavioral abnormalities were demonstrated in a study of 3.5-year-old children, in

which those with persistently positive tissue transglutaminase (tTG) antibodies on a gluten-
containing diet were more likely to manifest behavioral symptoms (anxiety, depression,
aggressive behavior, or sleep problems) compared with those with negative antibody tests
[91]. Unlike previous studies, the parents were unaware of the child's elevated tTG at the time
that they reported the symptoms, avoiding that potential bias. This finding was no longer
observed at 4.5 years of age. A similar screening study in school-aged children also reported
a modest association between tTG antibody positivity and anxiety symptoms [92]. Finally, in a
cross-sectional study of children with celiac disease (from the pre-coronavirus disease 2019
[COVID-19] era), clinically significant concerns for anxiety and depression were present in
over one-third of patients, with the majority unrecognized by parents and caregivers [93].
- Subclinical neurologic abnormalities were suggested by a study of children with newly

diagnosed celiac disease, in which almost 20 percent had subclinical neurologic
abnormalities [94]. Among 27 children, two had peripheral polyneuropathy documented with
electromyography, one had prolonged latencies in somatosensory evoked potential, and two
had central magnetic resonance imaging abnormalities consisting of pontine demyelination
or cortical atrophy. Similarly, there is some evidence of regional brain hypoperfusion in adults
with untreated celiac disease [95]. In most, but not all, such conditions, improvement was
observed after treatment with a gluten-free diet [96-99].
• Long-term – Celiac disease may be associated with a modestly increased risk of neurobehavioral
disorders in long-term follow-up. The best evidence comes from a large case-control study in
Sweden, which found that individuals with childhood-onset celiac disease had a 1.4-fold increased
risk of developing a neurobehavioral or psychiatric disorder in long-term follow-up (median
follow-up 9.6 years), including mood, anxiety, eating, and behavioral disorders; attention deficit
hyperactivity disorder (ADHD); autism spectrum disorder; and intellectual disability [100]. This
higher risk was not observed in siblings of the patients with celiac disease, arguing against a
genetic component. Other less robust studies also suggest an association between celiac disease

and mood disorders, behavioral disorders, developmental delay, ADHD, headache, and cerebellar
ataxia [97,101-103].
Epileptic disorders are only slightly more common among children with celiac disease, and there
is no increase in frequency of tic disorders. Conversely, celiac disease does not appear to be
overrepresented in groups of children with neurologic or psychiatric disorders [102,104].
Reports of neurologic and neuropsychiatric symptoms in adults with celiac disease are discussed
separately. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults",
section on 'Neuropsychiatric'.)
The pathogenesis of the neurologic symptoms is unclear. Some of the disorders, such as infantile
hypotonia and developmental delay, may be caused by malnutrition, including specific micronutrient
deficiencies; these problems tend to resolve on a gluten-free diet. However, there is increasing
evidence that some or all of these neurologic abnormalities are caused by autoimmune mechanisms.
As an example, widespread tTG-IgA deposition around blood vessels in the cerebellum has been
described [105]. In particular, antiganglioside antibodies may be involved in the pathogenesis of
neurologic symptoms [106], although relevant studies have yielded somewhat conflicting results.
These findings suggest that an immune-mediated process may lead to gluten ataxia and/or
peripheral neuropathy [105,107].
● Liver disease – Studies of children with celiac disease suggest that aminotransferase elevations are
also common at diagnosis (15 to 35 percent), particularly in patients presenting with the classical
symptoms of the disease [37,108,109]. In most patients, the aminotransferases normalize with a
gluten-free diet. In adults, similar mild elevations in serum alanine aminotransferase or aspartate
aminotransferase were seen in 42 percent of adult patients with celiac disease [110]. Conversely,
celiac disease is found in 5 to 10 percent of adults with chronic elevations of aminotransferases
[111].
Patients with celiac disease also appear to have increased risks for a broad spectrum of liver
diseases, including acute hepatitis, primary biliary cholangitis (previously known as primary biliary
cirrhosis), and chronic hepatitis including autoimmune hepatitis [112-115]. Several cases of severe
liver disease with cirrhosis in children with celiac disease have been reported [116], but celiac disease
was not established as a causative factor. (See "Epidemiology, pathogenesis, and clinical
manifestations of celiac disease in adults", section on 'Liver disease'.)
● Iron deficiency – The prevalence of iron deficiency is increased among children with celiac disease
and appears to be correlated with severity of mucosal injury. In one prospective study, the
prevalence of low ferritin (defined in this case as <10 micrograms/mL) was 21 percent in patients
with "potential" celiac disease, 35 percent in those with partial villous atrophy, and 87 percent among
those with total villous atrophy, compared with 0 percent in healthy controls [117]. Conversely, a
systematic review and meta-analysis found that celiac disease was found in approximately 3 percent
of individuals with iron deficiency anemia [118]. For this reason, testing for celiac disease is indicated
in children with iron deficiency anemia who have no other clear reason for the deficiency.
● Dermatitis herpetiformis – Dermatitis herpetiformis is a common skin manifestation of celiac

disease, occurring in up to 24 percent of adult patients with celiac disease [119,120]. It is rare in
children, but cases have been reported [121,122]. Similar to celiac disease, antibodies to tTG are

elevated in patients with dermatitis herpetiformis, confirming the pathogenic similarities between
these diseases [123].
Approximately 85 percent of adult patients with dermatitis herpetiformis have the characteristic
changes of celiac disease on intestinal biopsy, although most have no gastrointestinal symptoms.
Dermatitis herpetiformis is less common prior to puberty but has been reported in patients as young
as eight months old [124,125].
Dermatitis herpetiformis is characterized by an itchy papular vesicular eruption, usually located

symmetrically on the extensor surfaces of the elbows, knees, buttocks, sacrum, face, neck, trunk,
and, occasionally, within the mouth ( picture 1A-B). It is commonly misdiagnosed as atopic
dermatitis, scabies, or linear IgA dermatosis [126]. The clinical manifestations and diagnosis of
dermatitis herpetiformis are discussed separately. (See "Dermatitis herpetiformis", section on
'Clinical findings'.)
Many experts recommend a lifelong gluten-free diet based on the results of the skin biopsy alone,
and an intestinal biopsy is not required. Although patients with dermatitis herpetiformis may have a
symptomatic response to medications such as dapsone, the skin lesions usually will not resolve
without gluten withdrawal [127]. (See "Dermatitis herpetiformis", section on 'Treatment'.)
● Dental enamel defects – Dental enamel defects involving the secondary dentition are more
common among children and adults with celiac disease compared with the general population and
may occur in the absence of gastrointestinal symptoms [128-130]. The enamel defects considered to
be specific to celiac disease are symmetrically distributed and detectable in all four quadrants of the
dentition [129]. Defects may consist of cream, yellow, or brown opacities; loss of enamel glaze;
horizontal grooves; or shallow pits ( picture 2). The incisors are most commonly affected. There is
some evidence that these defects are mediated by immunologic mechanisms (associated with the
human leukocyte antigen [HLA] allele DR3) and not by malabsorption of nutrients such as calcium
[131]. Early identification and treatment of celiac disease may prevent the development of the
enamel defects [132].
● Metabolic bone disease – Bone loss (usually osteomalacia) occurs commonly in untreated celiac
disease and can occur in patients without gastrointestinal symptoms [78,133-137]. These patients
have secondary hyperparathyroidism that is probably caused by vitamin D deficiency [138,139].
Children with a lower body mass index at diagnosis may be at higher risk of metabolic bone disease
[140].
In children, metabolic bone disease generally resolves with a gluten-free diet [137,139,141,142]. In a
study of 30 children and adolescents maintained on a long-term gluten-free diet (average 10.7
years), bone mineral density and serum markers of bone metabolism completely normalized [142].
● Arthritis – Arthralgias or arthritis are reported by approximately 10 percent of children at diagnosis

of celiac disease [143], sometimes with few or no gastrointestinal symptoms [34]. In some cases, the
symptoms are attributable to co-occurring juvenile idiopathic arthritis, which is associated with celiac
disease. (See 'High-risk groups' above.)
It is uncertain whether treatment with a gluten-free diet improves arthritic symptoms. Most reports
of children with celiac disease and arthritis experience improvement in joint effusions and arthritic

symptoms after initiating a gluten-free diet [34,144,145], but one study of children with confirmed
juvenile idiopathic arthritis reported a more severe disease course among those with celiac disease
[146].
Subclinical disease — Many individuals with celiac disease have mild and nonspecific symptoms, such as
fatigue, anemia (usually due to iron deficiency), attenuated growth, or otherwise unexplained elevations in
serum aminotransferases [78,147,148], or no symptoms at all [136].
The range of symptoms in children with subclinical disease is illustrated by a study of children whose
celiac disease was diagnosed through a screening program [149]. Most of these children had minimal
gastrointestinal symptoms. However, there were numerous important clinical and laboratory findings,
such as recurrent abdominal pain, mood changes, and iron deficiency. In another study, 31 percent of
patients with subclinical disease (versus 67 percent with classic symptoms) were malnourished (defined as
body weight less than 90 percent of ideal) [150]. Once on a gluten-free diet, all reported objective and
subjective improvement of well-being as they recognized symptoms they had not previously considered to
be abnormal, especially fatigue and abdominal pain.
Even in individuals with minimal symptoms, establishing and treating subclinical celiac disease may help
to identify and treat unsuspected nutritional deficiencies and to reduce adverse birth and pregnancy
outcomes. It is less clear whether these individuals have increased risk for autoimmune diseases or
malignancies that might be reduced by treatment with a gluten-free diet.
Risk of malignancy — Several reports have suggested increased risk for some malignancies, particularly
non-Hodgkin lymphoma and gastrointestinal cancers, in adults with celiac disease compared with the
general population. The incidence of cancer does not appear to be increased during childhood or
adolescence.
A few studies suggest that the risk for malignancy is reduced by long-term treatment with a gluten-free
diet. Although this has not been fully established, it is one of the rationales for recommending lifelong
treatment for all patients with celiac disease, even for those with minimal gastrointestinal symptoms. (See
"Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section on
'Prognosis'.)
PHENOTYPES
Historically, celiac disease was defined by its classic clinical manifestations. However, the combination of
serologic, genetic, and histologic data has led to an appreciation of the highly variable clinical
manifestations of the condition and the description of other subcategories of celiac disease. According to
the Oslo criteria, celiac disease can be categorized as classic, nonclassic, subclinical, symptomatic,
asymptomatic, or potential, depending on the clinical phenotype ( table 3) [151]. This classification
scheme helps to identify patients who present with different clinical features and to monitor those who do
not meet full diagnostic criteria for celiac disease.
NONCELIAC GLUTEN SENSITIVITY
Nonceliac gluten sensitivity (NCGS) describes a syndrome of symptomatic response to gluten ingestion in
patients with no serologic or histologic evidence of celiac disease. The most common complaints are
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abdominal pain, bloating, and/or change in bowel patterns, but some patients complain of extraintestinal
symptoms. The onset is typically within hours or a few days of ingesting gluten. This time course
distinguishes NCGS from the rapid onset of symptoms in wheat allergy (minutes to hours) but can overlap
with the delayed onset of symptoms in celiac disease (days to weeks) ( table 4) [15].
● Pathophysiology – In many patients with symptoms that they attribute to gluten, gluten is probably
not the specific trigger. The symptoms are not replicated on double-blind gluten challenge,
suggesting a placebo or non-gluten-related physiologic effect. An example of the latter are adults
whose gastrointestinal symptoms appear to be induced by the fermentable, poorly absorbed short-
chain carbohydrates (fermentable oligo-, di-, and monosaccharides and polyols [FODMAP]). Since
these sugars are also reduced in a gluten-free diet, the clinical response may result from reduction in
the oligosaccharides rather than from elimination of the gluten itself [152]. These patients are
probably more accurately categorized as having irritable bowel syndrome triggered by
oligosaccharides rather than NCGS. (See "Treatment of irritable bowel syndrome in adults", section
on 'Gluten avoidance'.)
In a smaller number of patients with these symptoms, it appears that gluten itself is the specific
trigger for symptoms, in which case, they are appropriately categorized as NCGS. The most
compelling evidence comes from a double-blind, placebo-controlled crossover food challenge in
Italian children with suspected NCGS, based on reported symptomatic response to dietary gluten
and lack of serologic evidence of celiac disease or IgE-mediated allergy to wheat or gluten. NCGS was
confirmed in 39 percent of subjects, based on the development of symptoms in response to the
gluten challenge (with no change in FODMAP content) [153]. NCGS was disproven in the remaining
61 percent. The estimated prevalence of NCGS in children with functional gastrointestinal symptoms
was between 0.3 and 1 percent.
For a subset of individuals who appear to react to gluten-containing grains, another possible trigger
of symptoms is the presence of amylase trypsin inhibitors (ATIs), which are found in grains including
wheat, rye, and barley. ATIs are a group of proteins that contribute to the natural defense against
pests and pathogens and have been proposed to activate the innate immune system [154]. (See
"Grain allergy: Allergens and grain classification".)
Together, these studies suggest that a clinical response to a gluten-free diet may be caused by a
variety of mechanisms, including placebo effect and FODMAP reduction, as well as by true NCGS in
fewer than one-half of patients.
● Diagnosis – For children with symptoms that they attribute to gluten, it is important to rule out both
celiac disease and IgE-mediated wheat allergy. Serologic testing (and further evaluation for celiac
disease, if indicated) should be performed before eliminating gluten from the diet because these
tests may be falsely negative if performed while on a gluten-free diet. Individuals with positive
testing should be referred to a pediatric gastroenterologist for further workup because positive
serology alone does not confirm the diagnosis. The diagnostic evaluation for celiac disease is
discussed separately (see "Diagnosis of celiac disease in children", section on 'Initial serologic
testing'), including strategies for evaluating patients who are already on a gluten-free diet. (See
"Diagnosis of celiac disease in children", section on 'Special populations'.)
The possibility of NCGS may be entertained if celiac disease and wheat allergy have been excluded.
However, no tests can reliably distinguish those with true NCGS from those with irritable bowel
syndrome or other symptoms that are not specifically related to gluten. Therefore, the diagnosis of
NCGS should be approached with caution and should not be based solely on a short-term
improvement in symptoms on a gluten-free diet. Neither antigliadin antibodies nor other serologic
biomarkers can reliably identify patients with NCGS [155], nor is there a genetic test for this
condition. The diagnosis of NCGS relies on patient-reported symptoms but can be made more
objectively by use of a standardized questionnaire before and six weeks after instituting a gluten-
free diet, or by use of a double-blind gluten challenge and crossover in patients already on a gluten-
free diet [156]. However, a rigorous double-blind gluten challenge is difficult to implement in a
clinical setting and is rarely performed except in research studies.
Before a patient with suspected NCGS embarks on a gluten elimination diet, the patient and family
should be educated on the possible reasons for a clinical response to this diet and counseled on the
potential nutritional deficiencies associated with a gluten-free diet. Involving a knowledgeable
dietitian in the care of children who are beginning a gluten-free diet is highly recommended. There
are no known long-term complications of NCGS. Therefore, the gluten-free diet may not need be as
strict as that for celiac disease and treatment may be based solely on symptom control.
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions around the
world are provided separately. (See "Society guideline links: Celiac disease" and "Society guideline links:
Dermatitis herpetiformis".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The
Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and
they answer the four or five key questions a patient might have about a given condition. These articles are
best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the
Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are
written at the 10th to 12th grade reading level and are best for patients who want in-depth information
and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail
these topics to your patients. (You can also locate patient education articles on a variety of subjects by
searching on "patient info" and the keyword(s) of interest.)
● Basics topic (see "Patient education: Celiac disease (The Basics)")
● Beyond the Basics topic (see "Patient education: Celiac disease in children (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
● Pathogenesis – Celiac disease is an immune-mediated inflammatory disease of the small intestine

caused by sensitivity to dietary gluten and related proteins in genetically sensitive individuals. The
grains that contain the triggering proteins are wheat, barley, and rye. The small intestinal mucosa

improves morphologically when treated with a gluten-free diet and relapses when gluten is
reintroduced. (See 'Pathogenesis and risk factors' above.)
● Epidemiology and risk factors – Celiac disease is common, occurring in 0.5 to 1 percent of the
general population in most countries, but is as high as 2 to 3 percent of the population in certain
regions. The prevalence of celiac disease is substantially increased in first- and second-degree
relatives of patients with celiac disease and in individuals with certain genetic syndromes, type 1
diabetes mellitus, selective IgA deficiency, and several autoimmune conditions ( table 1).
We suggest routine surveillance for celiac disease in pediatric patients in high-risk groups, although
this approach is somewhat controversial. This is discussed separately. (See 'High-risk groups' above
and "Diagnosis of celiac disease in children", section on 'Indications for testing'.)
● Clinical manifestations
• Gastrointestinal – Classic gastrointestinal symptoms of patients with celiac disease include

symptoms of malabsorption such as diarrhea, steatorrhea, weight loss, or other signs of nutrient
or vitamin deficiency. (See '"Classical" gastrointestinal symptoms' above.)
• Extraintestinal – Some patients with celiac disease have non-gastrointestinal manifestations, in

addition to or instead of gastrointestinal symptoms. The most specific extraintestinal
manifestation is dermatitis herpetiformis, which is uncommon prior to puberty ( picture 1A-B).
Other extraintestinal manifestations include delayed growth and pubertal development,
neurologic disease and behavioral symptoms, arthritis, dental enamel defects, liver disease, and
iron deficiency ( table 2). (See 'Non-gastrointestinal manifestations' above.)
● Phenotypes of celiac disease
• Classic celiac disease is characterized by gastrointestinal and/or other symptoms outlined above,
with associated villous atrophy on small intestinal biopsy ( picture 3A-B), and resolution of the
clinical symptoms and mucosal lesions upon withdrawal of gluten-containing foods. (See
'Phenotypes' above.)
• Other phenotypes of celiac disease including nonclassic, subclinical, asymptomatic, and potential
are summarized in the table ( table 3). (See 'Phenotypes' above.)
● Nonceliac gluten sensitivity (NCGS) – This describes a syndrome of symptomatic response to

gluten ingestion in patients with no serologic or histologic evidence of celiac disease or wheat
allergy. In many patients with symptoms that they attribute to gluten, gluten is probably not a
specific trigger. In a smaller number of patients with these symptoms, it appears that gluten itself is
the specific trigger for symptoms, in which case, they are appropriately categorized as NCGS. (See
'Nonceliac gluten sensitivity' above.)
ACKNOWLEDGMENT
The UpToDate editorial staff acknowledges Ivor D Hill, MD, who contributed to earlier versions of this topic
review.

Use of UpToDate is subject to the Terms of Use.
Topic 5899 Version 73.0

GRAPHICS
Prevalence of celiac disease in special populations
Fold increase in risk

Percent of group
compared with
affected
general population
General population (United States and Europe) [1] 0.7 to 1.0 –
Relatives of patient with celiac disease* [1,2]
First-degree relatives 5 to 7.5 5 to 11
Second-degree relatives 2 to 3 2 to 4
Down syndrome [3,4] 5 to 12 7 to 18
Type 1 diabetes [3,9] 5 to 10 7 to 13
Autoimmune liver disease [5] 3.6 6.6
Juvenile idiopathic arthritis [6-8] 2 to 3 3
IgA deficiency [10] 8 11
Autoimmune thyroid disease [3,11] 2 to 7 6 (less in children)
Turner syndrome [3] 4 to 8 5 to 11
Williams syndrome [12] 8 11
IgA: immunoglobulin A.
* The risk also varies with the relationship to the proband (eg, higher for siblings than for parents of the
proband) [2] .
Data from:
1. Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: A large
multicenter study. Arch Intern Med 2003; 163:286.
2. Singh P, Arora S, Lal S, et al. Risk of celiac disease in the first- and second-degree relatives of patients with celiac disease: A
Systematic Review and Meta-Analysis. Am J Gastroenterol 2015; 110:1539.
3. Hill ID, Dirks MH, Liptak GS, et al. Guideline for the diagnosis and treatment of celiac disease in children: recommendations of the
North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2005; 40:1.
4. Rostom A, Murray JA, Kagnoff MF. American Gastroenterological Association (AGA) Institute technical review on the diagnosis and
management of celiac disease. Gastroenterology 2006; 131:1981.
5. Vajro P, Paolella G, Maggiore G, Giordano G. Pediatric celiac disease, cryptogenic hypertransaminasemia, and autoimmune
hepatitis. J Pediatr Gastroenterol Nutr 2013; 56:663.
6. Sherman Y, Karanicolas R, DiMarco B, et al. Unrecognized celiac disease in children presenting for rheumatology evaluation.
Pediatrics 2015; 136:e68.
7. Poddighe D, Romano M, Dossybayeva K, et al. Celiac disease in juvenile idiopathic arthritis and other pediatric rheumatic disorders.
J Clin Med 2022; 11:1089.
8. Doyle JB, Lebwohl B, Askling J, et al. Risk of juvenile idiopathic arthritis and rheumatoid arthritis in patients with celiac disease: A
population-based cohort study. Am J Gastroenterol 2022; 117:1971.
9. Crone J, Rami B, Huber WD, et al. Prevalence of celiac disease and follow-up of EMA in children and adolescents with type 1 diabetes
mellitus. J Pediatr Gastroenterol Nutr 2003; 37:67.
10. Meini A, Pillan NM, Villanacci V, et al. Prevalence and diagnosis of celiac disease in IgA-deficient children. Ann Allergy Asthma
Immunol 1996; 77:333.
11. Ch'ng CL, Biswas M, Benton A, et al. Prospective screening for coeliac disease in patients with Graves' hyperthyroidism using anti-
gliadin and tissue transglutaminase antibodies. Clin Endocrinol (Oxf) 2005; 62:303.
12. Giannotti A, Tiberio G, Castro M, et al. Coeliac disease in Williams syndrome. J Med Genet 2001; 38:767.
Graphic 50751 Version 5.0

Intestinal lesions in celiac disease
Schematic drawing of the characteristic histologic changes seen in celiac disease as

described by Marsh. The lesions range in severity from only increased numbers of
intraepithelial lymphocytes in the early stages (Type I) to elongation of the crypts (Type
II) and progressive villus atrophy (Type 3a to 3c).
IEL: intraepithelial lymphocytes; EC: epithelial cells (in villus).
Modified from: Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A molecular
and immunobiologic approach to the spectrum of gluten sensitivity ('celiac sprue'). Gastroenterology 1992;
102:330.

Nongastrointestinal manifestations of celiac disease in children
Growth and development
Short stature
Delayed puberty
Neurologic and behavioral symptoms
Hypotonia
Developmental delay
Learning disorders
Headache
Cerebellar ataxia
Epilepsy
Liver disease
Iron deficiency
Skin
Dermatitis herpetiformis
Others (weak association with psoriasis, vitiligo, alopecia areata, eczema, and urticaria)
Dental enamel defects
Metabolic bone disease
Arthritis
Cardiomyopathy

Dermatitis herpetiformis in a child with celiac disease
(A) Erythematous, papular, and vesicular lesions in a 14-year-old child with atopic dermatitis and diagnosis of
celiac disease.
(B, C) A magnification of the dermatitis herpetiformis shows a typical polymorphism consisting of erythema,
urticarial plaques, papules, grouped vesicles, and blisters associated with intense itch and, therefore,
followed by erosions, excoriations, and hyperpigmentation.
From: Persechino F, Galli G, Persechino S, et al. Skin Manifestations and Coeliac Disease in Paediatric Population. Nutrients 2021;
13:3611. Copyright © 2021 The Authors. Available at: https://www.mdpi.com/2072-6643/13/10/3611 (Accessed on July 26, 2022).
Reproduced under the terms of the CreativeCommons Attribution License 4.0.

Dermatitis herpetiformis
Herpetiform clusters of vesicles on an erythematous, edematous base

with crusts and postinflammatory pigmentation on the upper back and
shoulder.
Reproduced with permission from: Skin signs of immune, autoimmune, and rheumatic
diseases. In: Color Atlas and Synopsis of Clinical Dermatology, 3rd ed, Fitzpatrick TB,
Johnson RA, Wolff K (Eds), McGraw-Hill, New York 1997. p.327. Copyright © 1997
McGraw Hill.

Dental enamel defects in a child with celiac disease
Dental enamel defects associated with celiac disease may consist of

cream-, yellow-, or brown-colored opacities, loss of enamel glaze,
horizontal grooves, or shallow pits.
Courtesy of Lisa Papagiannoulis, DDS, MS, School of Dental Medicine, University of

Athens, Greece.

Phenotypes of celiac disease in children
Celiac disease Definition Comments

phenotype
Classic Individual meets standard criteria for celiac More common in children diagnosed in
disease* and has signs of malabsorption early childhood. Children in this category
such as diarrhea, steatorrhea, weight loss, may or may not have extraintestinal
or growth failure. manifestations.
Nonclassic Individual meets standard criteria for celiac Symptoms are often extraintestinal and
disease* but without signs and symptoms may be monosymptomatic. This phenotype
of malabsorption. is more common in older children.
Subclinical Individual meets standard criteria for celiac In the past, the term "silent" was used.
disease* but has symptoms that are below After beginning a gluten-free diet, many of
the threshold of clinical detection and these individuals experience improvement
would not otherwise trigger testing in and thus retrospectively recognize that they
routine practice. had been experiencing subclinical
symptoms.
Symptomatic A general term describing celiac disease In the past, the term "overt" celiac disease
with gastrointestinal or extraintestinal was used, but this term is now discouraged.
symptoms (in contrast with asymptomatic
celiac disease, described below).
Asymptomatic Individual meets standard criteria for celiac These individuals are often diagnosed
disease* but experiences no related through screening of high-risk groups ¶ or
symptoms and does not notice any from the general population. If symptoms
changes upon gluten withdrawal. are recognized to resolve upon gluten
withdrawal, the patient should be
reclassified as having subclinical celiac
disease.
Potential Individual has positive celiac-specific These celiac autoantibody-positive

antibodies (eg, anti-tTG) but normal small individuals are identified based on testing
intestinal biopsies. for clinical indications or because they are
members of a group at increased risk for
celiac disease ¶ .
Some of these children (eg, 40% over 12

years of age [1] ) will develop celiac disease,
some will eventually become seronegative,
and some will remain persistently
seropositive and not progress to celiac
disease [1-3] .
These descriptions are from a multinational consensus conference, known as the "Oslo definitions" [4] .
tTG: tissue transglutaminase immunoglobulin A antibody; IgA: immunoglobulin A.
* Standard criteria for diagnosis of celiac disease consist of a positive celiac specific antibody (usually tTG-IgA)
and characteristic histologic abnormalities on intestinal biopsy (villous atrophy and elongated crypts). Refer to
UpToDate content on diagnosis of celiac disease.
¶ High-risk groups include first- or second-degree relatives of probands with celiac disease, children with
certain genetic syndromes (Down, Turner, or Williams syndromes), autoimmune diseases (type 1 diabetes,
autoimmune thyroiditis, juvenile idiopathic arthritis, or autoimmune liver disease), or selective IgA deficiency.

References:
1. Auricchio R, Mandile R, Del Vecchio MR, et al. Progression of Celiac Disease in Children With Antibodies Against Tissue
Transglutaminase and Normal Duodenal Architecture. Gastroenterology 2019; 157:413.
2. Auricchio R, Tosco A, Piccolo E, et al. Potential celiac children: 9-year follow-up on a gluten-containing diet. Am J Gastroenterol 2014;
109:913.
3. Lionetti E, Castellaneta S, Pulvirenti A, et al. Prevalence and natural history of potential celiac disease in at-family-risk infants
prospectively investigated from birth. J Pediatr 2012; 161:908.
4. Ludvigsson JF, Leffler DA, Bai JC, et al. The Oslo definitions for coeliac disease and related terms. Gut 2013; 62:43.

Common clinical manifestations of gluten-related disorders
Non-celiac
Celiac disease gluten Wheat allergy
sensitivity
Time from exposure to symptoms Hours to months Hours to days Minutes to hours
Gastrointestinal
Diarrhea X X X
Abdominal pain X X X
Constipation X X X
Gas/bloat/distention X X X
Poor weight gain X X X
Malodorous, fatty stools X
Vomiting X X X
Extraintestinal
Pubertal delay X
Unexplained weight loss X X X
Poor height gain X
Bone/joint pain X X X
Rash of dermatitis herpetiformis X
Eczema X X
Hives/atopic dermatitis X
Fatigue X X X
Headache/migraine X X X
Foggy mind X X
Angioedema X
Anaphylaxis X
Respiratory
Asthma X
Cough X
Postnasal drip, throat clearing, rhinitis X
From: Hill ID, Fasano A, Guandalini S, et al. NASPGHAN clinical report on the diagnosis and treatment of gluten-related disorders. J Pediatr
Gastroenterol Nutr 2016; 63(1):156-65. DOI: 10.1097/MPG.0000000000001216. Copyright © 2016 ESPGHAN and NASPGHAN. Reproduced
with permission from Lippincott Williams & Wilkins. Unauthorized reproduction of this material is prohibited.

Celiac disease histology
High-power view of the duodenal biopsy reveals a marked increase in intraepithelial lymphocytes. The
expanded lamina propria contains an increase in lymphocytes, plasma cells, and eosinophils.
Courtesy of Edward Uhlemann, MD.

Celiac disease
Low-power view of a small bowel biopsy from a patient with celiac

disease. The mucosa is flat with complete loss of the normal villous
architecture.
Courtesy of Robert Odze, MD.
Normal small intestine
Low-power (left) and high-power (right) views of the normal villous

architecture of the small intestine. The high-power view shows the
enterocytes and interspersed goblet cells (arrows).
Courtesy of Robert Odze, MD.

Contributor Disclosures
Marisa Stahl, MD, MSCS Consultant/Advisory Boards: Pfizer [Celiac disease]; Takeda [Celiac disease]. All of the
relevant financial relationships listed have been mitigated. Edwin Liu, MD Consultant/Advisory Boards: Takeda [Celiac
disease]. All of the relevant financial relationships listed have been mitigated. B UK Li, MD Consultant/Advisory
Boards: GLG Consulting [Antiemetics]; Takeda [Antiemetics]. All of the relevant financial relationships listed have been
mitigated. Alison G Hoppin, MD No relevant financial relationship(s) with ineligible companies to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed
by vetting through a multi-level review process, and through requirements for references to be provided to support
the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of
evidence.
Conflict of interest policy

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Official reprint from UpToDate®

Epidemiology, pathogenesis, and clinical manifestations of

Literature review current through: Sep 2023.

Celiac disease, also known as gluten-sensitive enteropathy, is a common immune-mediated inflammatory

● (See "Diagnosis of celiac disease in children".)

● (See "Management of celiac disease in children".)

https://www.uptodate.com/contents/epidemiology-pathogenesis-and-clinical-manifestations-of-celiac-disease-in-children/print?search=celiac dis… 1/26

● First- and second-degree relatives of individuals with celiac disease

• Autoimmune thyroiditis – Approximately 2 to 7 percent of individuals with autoimmune

• Rheumatic diseases – Celiac disease is reported in 2 to 3 percent of children presenting with

More commonly, a cryptogenic hypertransaminasemia (also referred to as a celiac hepatitis) is

https://www.uptodate.com/contents/epidemiology-pathogenesis-and-clinical-manifestations-of-celiac-disease-in-children/print?search=celiac dis… 3/26

PATHOGENESIS AND RISK FACTORS

https://www.uptodate.com/contents/epidemiology-pathogenesis-and-clinical-manifestations-of-celiac-disease-in-children/print?search=celiac dis… 4/26

Evidence supporting this guidance includes:

https://www.uptodate.com/contents/epidemiology-pathogenesis-and-clinical-manifestations-of-celiac-disease-in-children/print?search=celiac dis… 5/26

Non-gastrointestinal manifestations — Numerous non-gastrointestinal manifestations of celiac disease

https://www.uptodate.com/contents/epidemiology-pathogenesis-and-clinical-manifestations-of-celiac-disease-in-children/print?search=celiac dis… 6/26

● Behavioral and neurologic symptoms

• Short-term – Subclinical or subtle behavioral or neurologic abnormalities appear to be common

- Subtle behavioral abnormalities were demonstrated in a study of 3.5-year-old children, in

- Subclinical neurologic abnormalities were suggested by a study of children with newly

https://www.uptodate.com/contents/epidemiology-pathogenesis-and-clinical-manifestations-of-celiac-disease-in-children/print?search=celiac dis… 7/26

● Dermatitis herpetiformis – Dermatitis herpetiformis is a common skin manifestation of celiac

https://www.uptodate.com/contents/epidemiology-pathogenesis-and-clinical-manifestations-of-celiac-disease-in-children/print?search=celiac dis… 8/26

Dermatitis herpetiformis is characterized by an itchy papular vesicular eruption, usually located

● Arthritis – Arthralgias or arthritis are reported by approximately 10 percent of children at diagnosis

https://www.uptodate.com/contents/epidemiology-pathogenesis-and-clinical-manifestations-of-celiac-disease-in-children/print?search=celiac dis… 9/26

NONCELIAC GLUTEN SENSITIVITY

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

● Basics topic (see "Patient education: Celiac disease (The Basics)")

SUMMARY AND RECOMMENDATIONS

● Pathogenesis – Celiac disease is an immune-mediated inflammatory disease of the small intestine

https://www.uptodate.com/contents/epidemiology-pathogenesis-and-clinical-manifestations-of-celiac-disease-in-children/print?search=celiac di… 12/26

• Gastrointestinal – Classic gastrointestinal symptoms of patients with celiac disease include

• Extraintestinal – Some patients with celiac disease have non-gastrointestinal manifestations, in

● Phenotypes of celiac disease

● Nonceliac gluten sensitivity (NCGS) – This describes a syndrome of symptomatic response to

https://www.uptodate.com/contents/epidemiology-pathogenesis-and-clinical-manifestations-of-celiac-disease-in-children/print?search=celiac di… 13/26

Use of UpToDate is subject to the Terms of Use.

Topic 5899 Version 73.0

https://www.uptodate.com/contents/epidemiology-pathogenesis-and-clinical-manifestations-of-celiac-disease-in-children/print?search=celiac di… 14/26

Prevalence of celiac disease in special populations

Fold increase in risk

General population (United States and Europe) [1] 0.7 to 1.0 –

Relatives of patient with celiac disease* [1,2]

First-degree relatives 5 to 7.5 5 to 11

Down syndrome [3,4] 5 to 12 7 to 18

Type 1 diabetes [3,9] 5 to 10 7 to 13

Autoimmune liver disease [5] 3.6 6.6

Juvenile idiopathic arthritis [6-8] 2 to 3 3

IgA deficiency [10] 8 11

Autoimmune thyroid disease [3,11] 2 to 7 6 (less in children)

Turner syndrome [3] 4 to 8 5 to 11

Williams syndrome [12] 8 11

Graphic 50751 Version 5.0

https://www.uptodate.com/contents/epidemiology-pathogenesis-and-clinical-manifestations-of-celiac-disease-in-children/print?search=celiac di… 15/26

Intestinal lesions in celiac disease

Schematic drawing of the characteristic histologic changes seen in celiac disease as

IEL: intraepithelial lymphocytes; EC: epithelial cells (in villus).

Graphic 60343 Version 6.0