15/09/2023, 10:03 Diagnosis of celiac disease in adults - UpToDate

Official reprint from UpToDate®

www.uptodate.com © 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Diagnosis of celiac disease in adults

AUTHOR: Ciarán P Kelly, MD
SECTION EDITOR: J Thomas Lamont, MD
DEPUTY EDITOR: Shilpa Grover, MD, MPH, AGAF

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Aug 2023.

This topic last updated: Feb 14, 2023.

INTRODUCTION

Celiac disease is a small bowel disorder characterized by mucosal inflammation, villous

atrophy, and crypt hyperplasia, which occur upon exposure to dietary gluten and
demonstrate improvement after withdrawal of gluten from the diet. Celiac disease should be
differentiated from nonceliac gluten sensitivity in order to identify the risk for nutritional
deficiency and complications of celiac disease and to determine the necessary degree and
duration of adherence to a gluten-free diet. The diagnosis of celiac disease also has
important implications for family members who may be at risk for celiac disease and
associated disorders.

This topic will review the diagnosis of celiac disease. Our recommendations are largely
consistent with a consensus statement from the National Institutes of Health, the American
College of Gastroenterology and American Gastroenterological Association guidelines [1-3].
The clinical manifestations and management of celiac disease in children and adults is
discussed in detail separately. (See "Epidemiology, pathogenesis, and clinical manifestations
of celiac disease in adults" and "Management of celiac disease in adults" and "Diagnosis of
celiac disease in children" and "Epidemiology, pathogenesis, and clinical manifestations of
celiac disease in children" and "Management of celiac disease in children".)

WHO SHOULD BE TESTED

The benefit of population screening for asymptomatic celiac disease has not been
demonstrated [4-9]. However, guidelines suggest screening for celiac disease be considered
in asymptomatic first-degree relatives of patients with a confirmed diagnosis of celiac

https://www.uptodate.com/contents/diagnosis-of-celiac-disease-in-adults/print?search=celiac diseae&topicRef=4774&source=see_link 1/14

15/09/2023, 10:03 Diagnosis of celiac disease in adults - UpToDate

disease [3,9]. Serologic testing for celiac disease is recommended in adults with any of the
following:

Suggestive gastrointestinal symptoms — Gastrointestinal symptoms include chronic or

recurrent diarrhea or constipation, malabsorption, unexpected weight loss, abdominal pain,
distension, or bloating. Testing should therefore be performed in patients with symptoms
suggestive of irritable bowel syndrome or refractory lactose intolerance. (See "Clinical
manifestations and diagnosis of irritable bowel syndrome in adults", section on 'Laboratory
testing' and "Lactose intolerance and malabsorption: Clinical manifestations, diagnosis, and
management".)

Extraintestinal signs/symptoms suggestive of celiac disease — Patients with

extraintestinal symptoms, signs, or laboratory evidence for which celiac disease is a treatable
cause. This includes patients without other explanations for iron deficiency anemia, folate or
vitamin B12 deficiency, persistent elevation in serum aminotransferases, dermatitis
herpetiformis, fatigue, recurrent headaches, recurrent fetal loss, low birthweight offspring,
reduced fertility, persistent aphthous stomatitis, dental enamel hypoplasia, metabolic bone
disease and premature osteoporosis, idiopathic peripheral neuropathy, or nonhereditary
cerebellar ataxia.

DIAGNOSTIC APPROACH

Overview — The diagnostic approach is based on the risk for celiac disease and whether the
patient is on a gluten-containing diet. All testing for celiac disease should ideally be
performed while patients are on a gluten-containing diet. An approach to diagnosis of celiac
disease is summarized in the following algorithm ( algorithm 1). (See 'Patients on a gluten-
free diet' below.)

Individuals with low celiac disease probability — The probability of celiac disease is low
in individuals with one or more of the following clinical scenarios:

● Absence of suggestive signs or symptoms of malabsorption such as significant chronic

diarrhea/steatorrhea or weight loss
● Absence of family history of celiac disease
● Chinese, Japanese, or Sub-Saharan African descent

Individuals at low risk for celiac disease should undergo serologic testing. Patients with
positive serologic testing, should undergo an upper endoscopy with small bowel biopsy to
diagnose celiac disease. The serum tissue transglutaminase (tTG)-immunoglobulin A (IgA)
and endomysial (EMA)-IgA antibody tests have similar sensitivities. A negative result for
either test in individuals at low risk for celiac disease has a high negative predictive value and

https://www.uptodate.com/contents/diagnosis-of-celiac-disease-in-adults/print?search=celiac diseae&topicRef=4774&source=see_link 2/14

15/09/2023, 10:03 Diagnosis of celiac disease in adults - UpToDate

obviates the need for small bowel biopsy. The specificities of the EMA IgA and tTG-IgA are
high. Thus, their positive predictive values are high even in low-risk populations [4,5,10]. The
EMA-IgA test has the highest diagnostic accuracy but is more costly and less widely available
than the tTG-IgA test ( algorithm 1) [10,11]. Combining several tests for celiac disease is
not recommended in low-risk populations in lieu of performing tTG-IgA alone as this may
marginally increase the sensitivity but substantially reduces specificity. (See 'Serologic
evaluation' below.)

Individuals with high celiac disease probability — Both serologic testing and small bowel
biopsy (regardless of celiac specific serology results) should be performed in individuals with
a high probability of celiac disease ( algorithm 1). (See 'Serologic evaluation' below and
'Endoscopy with small bowel biopsy' below.)

Individuals with a high celiac disease probability include:

● Individuals whose clinical presentation is highly suggestive for celiac disease such as
chronic diarrhea/steatorrhea with weight loss.

● Individuals with both risk factors that place them at moderate to high risk of celiac
disease and consistent gastrointestinal or extraintestinal symptoms/signs of celiac
disease. (See 'Suggestive gastrointestinal symptoms' above and 'Extraintestinal
signs/symptoms suggestive of celiac disease' above.)

Risk factors that place an individual at moderate to high risk for celiac disease include:

• First- and second-degree relative with confirmed celiac disease

• Type 1 diabetes
• Autoimmune thyroiditis
• Down and Turner syndromes
• Pulmonary hemosiderosis (moderate risk)

Serologic evaluation — Tissue transglutaminase (tTG)-IgA antibody is the single preferred

test for detection of celiac disease in adults. In addition, we concurrently measure total IgA
levels. In patients with IgA deficiency, we perform IgG-based testing with deamidated gliadin
peptide (DGP)-IgG. An alternative approach is to perform both IgA- and IgG-based testing, in
particular, tTG-IgA and DGP-IgG, in patients with a high probability of celiac disease. (See 'IgA
deficiency' below.)

Serum antibody assays — Serologic studies for celiac disease can be divided into two
groups based upon their target antigens [11]:

● Autoantibodies:

• Anti-endomysial antibody (EMA-IgA)

https://www.uptodate.com/contents/diagnosis-of-celiac-disease-in-adults/print?search=celiac diseae&topicRef=4774&source=see_link 3/14
15/09/2023, 10:03 Diagnosis of celiac disease in adults - UpToDate

• Anti-tissue transglutaminase antibodies (tTG) (tTG-IgA, tTG-IgG)

● Antibodies targeting gliadin:

• Antibody to native gliadin: Antigliadin antibody (AGA-IgA, AGA-IgG)

• Antibodies against synthetic deamidated gliadin peptides: Deamidated gliadin
peptide (DGP)-IgA, DGP-IgG

● Anti-endomysial antibody – Endomysial antibodies bind to connective tissue

surrounding smooth muscle cells and produce a characteristic staining pattern, which is
visualized by indirect immunofluorescence [4,5,10-17]. The target antigen has been
identified as a tissue transglutaminase. EMA-IgA is moderately sensitive and highly
specific for untreated celiac disease (sensitivity 85 to 98 percent; specificity 97 to 100
percent, respectively) [18-22]

The test result is often reported simply as positive or negative since even low titers of
EMA-IgA are specific for celiac disease. Serum levels of EMA-IgA fall on a gluten-free
diet [14]. Limitations of this test include its cost, complexity, and operator dependency
that may result in interobserver variation.

● Anti-tissue transglutaminase antibodies – The antigen against which antiendomysial

antibodies are directed is tTG-2 [23]. Anti-tTG antibodies are highly sensitive and
specific for the diagnosis of celiac disease (sensitivity 90 to 98 percent; specificity 95 to
97 percent) [24-28]. The positive predictive value of a strongly positive TG2-IgA (>10
upper normal limit) combined with a positive endomysial antibody is approximately 100
percent [2].

Enzyme-linked immunosorbent assay tests for tTG-IgA antibodies are now widely
available and are easier to perform and less costly than the immunofluorescence assay
used to detect IgA endomysial antibodies. The diagnostic accuracy of anti-tTG
immunoassays has been improved further by the use of human tTG in place of the
nonhuman tTG preparations used in earlier immunoassay kits [29].

● Antigliadin antibody assays – Gliadin is a component of the wheat storage protein,

gluten.

• Anti-deamidated gliadin peptide – The DGP uses synthetic gliadin peptides that
mimic tTG-modified gliadin sequences to capture serum IgA or IgG against DGP
[19,20]. DGP-IgA has a sensitivity and specificity of 94 percent and 99 percent,
respectively. The DGP-IgG has a sensitivity and specificity of 92 percent and 100
percent, respectively [18-22]. (See "Epidemiology, pathogenesis, and clinical
manifestations of celiac disease in adults".)

https://www.uptodate.com/contents/diagnosis-of-celiac-disease-in-adults/print?search=celiac diseae&topicRef=4774&source=see_link 4/14

15/09/2023, 10:03 Diagnosis of celiac disease in adults - UpToDate

• Antigliadin antibody – The traditional antigliadin antibody tests (AGA-IgA and AGA-
IgG) have lower diagnostic accuracy as compared with other serologic tests for celiac
disease and are no longer recommended because they yield false-positive results in
15 to 20 percent of subjects tested [11,12].

The diagnostic performance of serologic tests for celiac disease are influenced by the
following factors:

● Variation among testing methods – Technical and methodologic factors might affect
the reported accuracies of diagnostic tests. However, the literature reports wide
variations in test sensitivity and specificity among different laboratories [11,30]. It is
therefore important to know the sensitivity and specificity of the assay as performed by
the testing laboratory before determining the clinical significance of a particular test
result [31].

● Severity of celiac disease – In addition to laboratory variation, the sensitivity of these

tests may depend upon the severity of celiac disease. In one report, as an example,
serum antibodies were determined in 101 patients with biopsy-proven celiac disease
[32]. The sensitivity of EMA-IgA varied from 100 percent in patients with total villous
atrophy to only 31 percent in those with partial villous atrophy.

● Dietary factors – A weakly positive serologic test for celiac disease may become
negative within weeks of adherence to a gluten-free diet. (See 'Patients on a gluten-free
diet' below.)

● Patient age – tTG-IgA and EMA-IgA may be falsely negative in children under two years.
(See "Diagnosis of celiac disease in children", section on 'Children younger than two
years'.)

● IgA deficiency – Undetectable IgA levels but not partial immunoglobulin A deficiency
(low but detectable serum IgA) decreases the sensitivity of TTG-IgA [33]. (See 'IgA
deficiency' below.).

Test interpretation

Positive serology — Individuals with positive serology require a small bowel biopsy to
confirm the diagnosis. Exceptions are patients with positive serology and biopsy-proven
dermatitis herpetiformis in whom the diagnosis can be established without a small bowel
biopsy. (See 'Endoscopy with small bowel biopsy' below and 'Dermatitis herpetiformis'
below.)

Negative serology — Serologic studies are useful in excluding the diagnosis of celiac
disease but cannot exclude celiac disease with 100 percent accuracy. Negative celiac

https://www.uptodate.com/contents/diagnosis-of-celiac-disease-in-adults/print?search=celiac diseae&topicRef=4774&source=see_link 5/14

15/09/2023, 10:03 Diagnosis of celiac disease in adults - UpToDate

serologies in patients with celiac disease may be due to any one of the following:

● IgA deficiency – tTG-IgA serology will be falsely negative in untreated celiac disease in
patients with IgA deficiency, common variable immunodeficiency, or the use of an
immunosuppressant. (See 'IgA deficiency' below.)

● Low gluten/gluten-free diet – The individual may already be on a low gluten diet. An
approach to diagnosis of celiac disease in patients on a gluten-free diet is summarized
in the following algorithm ( algorithm 2). (See 'Patients on a gluten-free diet' below.)

● False negative – The serologic test (tTG-IgA) could be falsely negative. tTG-IgA
antibodies have a very high sensitivity (90 to 98 percent), but a false-negative serologic
test is possible. False-negative serology is more common in patients with mild disease
on histology. In such cases, DGP (IgA or IgG) antibody testing may be useful. However, a
small bowel biopsy is needed to make a diagnosis. (See 'Endoscopy with small bowel
biopsy' below.)

Endoscopy with small bowel biopsy — Upper endoscopy with small bowel biopsy serves to
establish the diagnosis in patients with suspected celiac disease ( algorithm 1).

Endoscopic features and biopsy technique — Endoscopic features of celiac disease

include atrophic appearing mucosa with loss of folds, visible fissures, nodularity, scalloping,
and prominent submucosal vascularity ( picture 1). However, endoscopic features
suggestive of celiac disease have low sensitivity (59 to 94 percent). The reported specificity
ranges from 92 to 100 percent and these findings may be seen with other disorders such as
giardiasis, autoimmune enteropathy, and HIV infection [34]. Histology remains important in
making a diagnosis of celiac disease, regardless of the endoscopic appearance.

Multiple biopsies of the duodenum (one or two from bulb and four from distal duodenum)
are necessary for diagnosis of celiac disease [3]. Bulb biopsies, if taken, should be clearly
labeled as such to help ensure that the pathologist takes into account the different mucosal
architecture of the bulb to avoid false-positive reports of villous atrophy. The accuracy of
biopsies can be improved with staining techniques and magnification endoscopy; however,
these approaches are not routinely used [35-37]. (See "Magnification endoscopy" and
"Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults", section
on 'Gastrointestinal manifestations'.)

Histologic features — Histologic features of celiac disease in the small intestine range from
a mild alteration characterized only by increased intraepithelial lymphocytes, to a severely
atrophic mucosa with complete loss of villi, enhanced epithelial apoptosis, and crypt
hyperplasia [38-43]. The histologic severity of intestinal lesions in celiac disease is graded
using the Marsh-Oberhuber classification ( figure 1) or the Corazza classification [3,44].
Marsh type 2 and 3 lesions (Corazza B1 or B2), while not pathognomonic for celiac disease,
https://www.uptodate.com/contents/diagnosis-of-celiac-disease-in-adults/print?search=celiac diseae&topicRef=4774&source=see_link 6/14
15/09/2023, 10:03 Diagnosis of celiac disease in adults - UpToDate

are supportive of the diagnosis ( figure 1 and table 1). Causes of small intestinal villous
atrophy other than celiac disease are shown in a table ( table 2 and algorithm 3). (See
'Positive serology and diagnostic small bowel biopsy' below.)

Intestinal biopsies should be interpreted by an expert pathologist. A gradient of decreasing

histologic severity from the proximal to the distal small intestine is often observed,
correlating with the higher proximal concentration of dietary gluten. The degree of the
villous atrophy does not necessarily correlate with the severity of clinical symptoms, and
sampling error can occur due to some inhomogeneity of mucosal inflammation and injury.

Interpretation and additional evaluation

Positive serology and diagnostic small bowel biopsy — The diagnosis of celiac
disease is established when duodenal biopsy samples showing increased intraepithelial
lymphocytes with crypt hyperplasia (Marsh type 2), or, more commonly, also with villous
atrophy (Marsh type 3) in a patient with positive celiac serology ( algorithm 1).

Discordant serology and small bowel biopsy

● Positive serology and nondiagnostic small bowel biopsies – tTG-IgA serology may
occasionally be positive but the small intestinal biopsy may be normal or equivocal
(Marsh 0 or 1, respectively) ( figure 1). Discordant serology and biopsy results may be
due to the following:

• False-positive tTG – False-positive tTG results are rare but do occur and are usually
low titer (typically less than twice the upper limit of normal). Case reports suggest
that tTG-IgA antibodies may be falsely elevated during or after a febrile illness [45].
There are also concerns about the quantitative variability and lack of standardization
between commercially available serologic tests for celiac disease. (See 'Serum
antibody assays' above.)

• False-negative biopsy results – Celiac disease may have a patchy distribution or

initially be confined to the duodenal bulb. (See 'Endoscopic features and biopsy
technique' above.)

The intestinal biopsy should be reviewed by a pathologist familiar with celiac disease to
look for subtle abnormalities of celiac disease. In addition, we perform an alternate
antibody test (EMA-IgA or DGP-IgA). If serology and histology remain discordant, we
perform HLA-DQ2/DQ8 typing ( algorithm 1).

• If HLADQ2/DQ8 is negative, celiac disease is excluded. Lymphocytic infiltration of the

intestinal epithelium in the absence of villous atrophy is not specific for celiac
disease and other causes should be considered. Other conditions associated with

https://www.uptodate.com/contents/diagnosis-of-celiac-disease-in-adults/print?search=celiac diseae&topicRef=4774&source=see_link 7/14

15/09/2023, 10:03 Diagnosis of celiac disease in adults - UpToDate

lymphocytic duodenosis, including Helicobacter pylori infection, medications (eg,

nonsteroidal anti-inflammatory drugs), small intestinal bacterial overgrowth, and
systemic autoimmune disorders [46]. (See 'HLA testing in selected patients' below.)

• If HLADQ2/DQ8 is positive, the patient can be placed on a high-gluten diet (>10

grams per day, equivalent of at least four slices of gluten containing bread per day)
and, after 6 to 12 weeks, additional biopsies obtained from multiple sites in the mid
and distal duodenum since celiac disease enteropathy can be patchy and missed
due to sampling error. Staining techniques and high resolution magnification
endoscopy can help identify areas of villous atrophy for biopsy. (See 'Serum antibody
assays' above.)

The finding of Marsh type 2 or 3 lesions on histology in a patient with positive celiac
serology is diagnostic of celiac disease ( figure 1). (See 'Positive serology and
diagnostic small bowel biopsy' above.)

Patients with positive celiac-specific serologies in the absence of crypt hyperplasia or

villous atrophy (Marsh 0 or Marsh 1) are considered to have potential celiac disease
( figure 1) [3,47]. This is most frequently encountered in patients screened for
celiac disease due to a positive family history or a diagnosis of type 1 diabetes
mellitus. Symptomatic patients with potential celiac disease are likely to benefit from
treatment with a gluten-free diet. Asymptomatic patients can remain on a normal
diet unless clinical features of celiac disease develop [48]. (See 'Suggestive
gastrointestinal symptoms' above and 'Extraintestinal signs/symptoms suggestive of
celiac disease' above and "Epidemiology, pathogenesis, and clinical manifestations
of celiac disease in adults", section on 'Clinical manifestations'.)

● Negative serology and abnormal small bowel biopsy – For patients with histologic
findings suggestive of celiac disease (eg, villous atrophy) but negative serologies, we
perform HLA-DQ2/DQ8 genotyping. If haplotypes HLA-DQ2 or DQ8 are present, we
recommend a gluten-free diet for 12 to 24 months and monitor the clinical response.
We also perform a repeat upper endoscopy with biopsies after 12 to 24 months of a
gluten-free diet to confirm mucosal healing. Patients with a histologic response are
likely to have sero-negative celiac disease. Individuals without a histologic response
likely have non-celiac villous atrophy ( table 2 and algorithm 3).

HLA testing in selected patients — The haplotypes HLA-DQ2 or DQ8 are present in almost
all patients with celiac disease. Testing for these haplotypes has a negative predictive value
of greater than 99 percent, but positive predictive value is only around 12 percent because
these haplotypes are common in the general population [49]. Hence, HLA testing is useful
only in ruling out celiac disease:

https://www.uptodate.com/contents/diagnosis-of-celiac-disease-in-adults/print?search=celiac diseae&topicRef=4774&source=see_link 8/14

15/09/2023, 10:03 Diagnosis of celiac disease in adults - UpToDate

● Patients with discordant celiac-specific serology and histology (see 'Discordant serology
and small bowel biopsy' above).

● Patients who refuse upper endoscopy (see 'Patients unable/unwilling to undergo upper
endoscopy' below).

● Evaluation of patients on a gluten-free diet with negative baseline serologies (see

'Patients on a gluten-free diet' below).

● Patients with suspicion of refractory celiac disease where the original diagnosis of celiac
disease remains in question (see "Management of celiac disease in adults", section on
'Non-responders').

● HLA typing is sometimes performed in patients at high risk for celiac disease (eg, family
history of celiac disease). A negative result will exclude celiac disease risk. This approach
is most commonly used in at-risk children to obviate the need for periodic serology
testing. (See "Diagnosis of celiac disease in children", section on 'Members of high-risk
groups'.)

Diagnosis — The diagnosis of celiac disease is established by the presence of increased

intraepithelial lymphocytes with crypt hyperplasia (Marsh type 2) alone, or in conjunction
with villous atrophy (Marsh type 3) on small bowel biopsy in a patient with positive celiac
serology ( figure 1 and algorithm 1). Demonstration of histologic normalization on a
gluten-free diet is not required to establish the diagnosis of celiac disease in adults.

In patients with biopsy-proven dermatitis herpetiformis, the diagnosis can be established by

serology without a small bowel biopsy. (See 'Dermatitis herpetiformis' below.)

Symptomatic adults who are unwilling or unable to undergo upper GI endoscopy but have a
high-level tTG IgA (>10-fold elevation above the upper limit of normal) with a positive
endomysial antibody (EMA) in a second blood sample can be diagnosed as likely celiac
disease [3]. (See 'Patients unable/unwilling to undergo upper endoscopy' below.)

EVALUATION IN SPECIAL SITUATIONS

Patients on a gluten-free diet — While there are limited data with regard to the decrease in
antibody titers in individuals on a gluten-free diet, a weakly positive test may become
negative within weeks of strict adherence to a gluten-free diet [50]. After 6 to 12 months on a
gluten-free diet, approximately 80 percent of individuals with celiac disease will test negative
by serology. By five years, more than 90 percent of patients on a gluten-free diet will have
negative serologies [51,52]. An approach to diagnosis of celiac disease in patients on a
gluten-free diet is summarized in the following algorithm ( algorithm 2) [3,53].

https://www.uptodate.com/contents/diagnosis-of-celiac-disease-in-adults/print?search=celiac diseae&topicRef=4774&source=see_link 9/14

15/09/2023, 10:03 Diagnosis of celiac disease in adults - UpToDate

● Baseline evaluation and gluten challenge – Baseline antibody testing should be

performed. Patients with positive serology should undergo a small bowel biopsy
( algorithm 2). (See 'Endoscopy with small bowel biopsy' above.)

Patients with negative serologies should undergo HLA-DQ2/DQ8 testing to determine if

the patient is genetically susceptible to celiac disease.

• If HLA-DQ2/DQ8 testing is negative, celiac disease is excluded.

• If HLA-DQ2/DQ8 testing is positive, patients should undergo a gluten challenge with

3 g gluten per day (equivalent to 1 slice of gluten-containing bread) for two weeks. If
tolerated, the gluten challenge should be extended for an additional six weeks).
Duodenal biopsies are performed at the end of the gluten challenge (ie, after two
weeks or, ideally, eight weeks of challenge). Serology should be checked at the end
of the gluten challenge and, if negative, serology should be repeated two to four
weeks later.

Patients who opt to continue on a strictly gluten-free diet without undergoing formal
gluten challenge may be managed in a similar fashion to those with known celiac
disease ( algorithm 2). (See "Management of celiac disease in adults".)

● HLA-DQ-gluten tetramer – A novel HLA-DQ-gluten tetramer-based assay that detects

gluten-specific T cells in blood may be able to identify patients with celiac disease,
regardless of whether testing is performed on a gluten-free diet [54]. While the assay
has demonstrated a high degree of accuracy in an early study, the results require
validation before it can be used clinically.

IgA deficiency — IgA deficiency is more common in celiac disease (2 to 5 percent) than in
the general population (<0.5 percent). IgA EMA and IgA tTG are falsely negative in patients
with IgA deficiency. In patients in whom very low IgA or selective IgA deficiency is identified,
IgG-based testing should be performed. We perform IgG DGP due to its higher sensitivity
and specificity as compared with IgG anti-tissue transglutaminase antibodies. IgG antigliadin
is also usually positive in the 1 to 2 percent of celiac patients who have IgA deficiency [55,56].

Dermatitis herpetiformis — The diagnosis of celiac disease in patients with biopsy-proven

dermatitis herpetiformis can be established by serology alone without a small bowel biopsy.
(See 'Serologic evaluation' above and "Dermatitis herpetiformis".)

Patients unable/unwilling to undergo upper endoscopy — Symptomatic adults who are

unwilling or unable to undergo upper GI endoscopy but have a high-level TTG IgA (>10-fold
elevation above the upper limit of normal) with a positive endomysial antibody (EMA) in a
second blood sample can be diagnosed as likely celiac disease [3].

https://www.uptodate.com/contents/diagnosis-of-celiac-disease-in-adults/print?search=celiac diseae&topicRef=4774&source=see_link 10/14

15/09/2023, 10:03 Diagnosis of celiac disease in adults - UpToDate

In patients without a high-level tTG IgA, we perform HLA testing. Absence of alleles encoding
DQ2 or DQ8 excludes celiac disease. In patients who are DQ2- or DQ8-positive and have
positive celiac serologies, a video capsule endoscopy (VCE) may reveal visible features of
celiac disease in the small intestine. However, as endoscopic features are not specific for
celiac disease, VCE should not be used for initial diagnosis except for patients with positive
celiac-specific serology who are unwilling or unable to undergo upper endoscopy with biopsy
[57]. (See "Wireless video capsule endoscopy", section on 'Small bowel tumors, polyps, and
other pathology'.)

DIFFERENTIAL DIAGNOSIS

The most common disorders in the differential diagnosis of celiac disease include irritable
bowel syndrome, small intestinal bacterial overgrowth, lactose intolerance, chronic
pancreatitis, microscopic colitis, and inflammatory bowel disease. Celiac disease can be
differentiated from these by serologic evaluation and small bowel biopsy. Approach to the
evaluation of patients with diarrhea is discussed in detail separately. (See "Clinical
manifestations and diagnosis of irritable bowel syndrome in adults", section on 'Diagnosis'
and "Small intestinal bacterial overgrowth: Clinical manifestations and diagnosis", section on
'Diagnosis' and "Microscopic (lymphocytic and collagenous) colitis: Clinical manifestations,
diagnosis, and management" and "Lactose intolerance and malabsorption: Clinical
manifestations, diagnosis, and management", section on 'Diagnostic evaluation' and
"Approach to the adult with chronic diarrhea in resource-abundant settings", section on
'Initial evaluation'.)

Non-celiac gluten sensitivity (NCGS) describes a syndrome of symptomatic response to

gluten ingestion in patients with no serologic or histologic evidence of celiac disease. The
clinical response to a gluten-free diet may be caused by a variety of mechanisms, including
placebo effect and fermentable oligo-, di-, and monosaccharides and polyols reduction, as
well as by true gluten sensitivity in some of patients. For individuals with symptoms that they
attribute to gluten, it is important to test for both celiac disease and IgE-mediated wheat
allergy. NCGS is discussed in detail separately. (See "Epidemiology, pathogenesis, and clinical
manifestations of celiac disease in children", section on 'Nonceliac gluten sensitivity'.)

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".)

https://www.uptodate.com/contents/diagnosis-of-celiac-disease-in-adults/print?search=celiac diseae&topicRef=4774&source=see_link 11/14

15/09/2023, 10:03 Diagnosis of celiac disease in adults - UpToDate

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 topics (see "Patient education: Celiac disease (The Basics)")

● Beyond the Basics topics (see "Patient education: Celiac disease in children (Beyond the
Basics)" and "Patient education: Celiac disease in adults (Beyond the Basics)")

PATIENT PERSPECTIVE TOPIC

Patient perspectives are provided for selected disorders to help clinicians better understand
the patient experience and patient concerns. These narratives may offer insights into patient
values and preferences not included in other UpToDate topics. (See "Patient perspective:
Celiac disease".)

SUMMARY AND RECOMMENDATIONS

● When to suspect celiac disease – Testing for celiac disease should be performed in
adults with suggestive gastrointestinal or extraintestinal signs/symptoms of celiac
disease. Extraintestinal signs/symptoms of celiac disease include unexplained iron
deficiency anemia, folate or vitamin B12 deficiency, persistent elevation in serum
aminotransferases, dermatitis herpetiformis, fatigue, recurrent headaches, recurrent
fetal loss, low birthweight offspring, reduced fertility, persistent aphthous stomatitis,
dental enamel hypoplasia, metabolic bone disease and premature osteoporosis,
idiopathic peripheral neuropathy, or nonhereditary cerebellar ataxia. (See 'Who should
be tested' above.)

https://www.uptodate.com/contents/diagnosis-of-celiac-disease-in-adults/print?search=celiac diseae&topicRef=4774&source=see_link 12/14

15/09/2023, 10:03 Diagnosis of celiac disease in adults - UpToDate

● Diagnostic approach – Testing for celiac disease should ideally be performed while
patients are on a gluten-containing diet. The testing approach varies based on the
probability of celiac disease.

• Individuals with a low probability of celiac disease – Evaluation begins with

serologic testing. Patients with positive serologic testing should undergo an upper
endoscopy with small bowel biopsy to diagnose celiac disease. (See 'Individuals with
low celiac disease probability' above.)

• Individuals with a high probability of celiac disease – Both serologic testing and
small bowel biopsy (regardless of celiac-specific serology results) should be
performed ( algorithm 1). (See 'Individuals with high celiac disease probability'
above.)

• Patients on a gluten-free diet – For patients who are already on a gluten-free diet,
an approach to diagnosis of celiac disease is summarized in the following algorithm
( algorithm 2). (See 'Patients on a gluten-free diet' above.)

● Serologic evaluation – Immunoglobulin A (IgA) anti-tissue transglutaminase (tTG)

antibody is the single preferred test for detection of celiac disease in adults. In addition,
we concurrently measure total IgA levels. In patients with IgA deficiency we perform
IgG-based testing with deamidated gliadin peptide (DGP) IgG. (See 'Serologic
evaluation' above and 'Evaluation in special situations' above.)

● Diagnostic histologic features on small bowel biopsy – The diagnosis of celiac

disease is established by the presence of increased intraepithelial lymphocytes with
crypt hyperplasia (Marsh type 2) alone, or in conjunction with villous atrophy (Marsh
type 3) on small bowel biopsy in a patient with positive celiac serology ( figure 1).
However, villous atrophy can be patchy and may also be present in a variety of other
disorders that should be considered in appropriate clinical settings ( table 2). (See
'Dermatitis herpetiformis' above.)

● Additional evaluation in patients with equivocal or discordant results

• Positive serology and nondiagnostic small bowel biopsies – Discordant serology

and biopsy results may be due to a false-positive tTG serology or a false-negative
biopsy result as celiac disease may have a patchy distribution. The intestinal biopsy
should be reviewed by a pathologist familiar with celiac disease to look for subtle
abnormalities of celiac disease. In addition, we perform an alternate antibody test
(EMA-IgA or DGP-IgA). If serology and histology remain discordant, we perform HLA-
DQ2/DQ8 typing ( algorithm 1).

https://www.uptodate.com/contents/diagnosis-of-celiac-disease-in-adults/print?search=celiac diseae&topicRef=4774&source=see_link 13/14

15/09/2023, 10:03 Diagnosis of celiac disease in adults - UpToDate

• Negative serology and abnormal small bowel biopsy – For patients with
histologic findings suggestive of celiac disease (eg, villous atrophy) but negative
serologies, we perform HLA-DQ2/DQ8 genotyping. If haplotypes HLA-DQ2 or DQ8
are present, we recommend a gluten-free diet for 12 to 24 months and monitor the
clinical response. We also perform a repeat upper endoscopy with biopsies after 12
to 24 months of a gluten-free diet to confirm mucosal healing. Patients with a
histologic response are likely to have celiac disease. Individuals without a histologic
response likely have non-celiac villous atrophy ( table 2 and algorithm 3).

Use of UpToDate is subject to the Terms of Use.

Topic 4771 Version 38.0

https://www.uptodate.com/contents/diagnosis-of-celiac-disease-in-adults/print?search=celiac diseae&topicRef=4774&source=see_link 14/14