Testing for Antireticulin Antibodies in Patients with Celiac Disease Is
Obsolete: a Review of Recommendations for Serologic Screening and
Sarada L. Nandiwada, Anne E. Tebo
Department of Pathology, University of Utah, Salt Lake City, Utah, USA; ARUP Laboratories, Salt Lake City, Utah, USA
of all ages. It is characterized by the presence of diverse clinical
symptoms, CD-specific antibodies, the presence of HLA-DQ2
tutes a genetic risk for CD, several non-HLA genes, especially in-
reported (6, 7). Furthermore, the availability of sensitive and
more-specific serologic tests such as the tissue transglutaminase
(tTG), endomysial antibody (EMA), and more recently the
deamidated gliadin peptide (DGP) antibody assays permits the
efficient screening of symptomatic and nonsymptomatic patients
at risk for CD. The combination of serologic and molecular ge-
netic diagnostic tools has significantly increased our current
knowledge of the clinical spectrum of CD as well as its epidemiol-
ogy. Based on current literature, the estimated ratio of diagnosed
to undiagnosed cases varies between 1:5 to 1:8 with most individ-
uals presenting with atypical clinical manifestations of disease (8,
9). Overall, CD appears to be more common in individuals of
northern European origin; in this population, it is estimated to
affect approximately 1 to 2%. Recent epidemiological studies
show that CD also occurs in other parts of the world. Based on
current trends, the frequency of CD may increase as these devel-
oping countries adopt gluten-rich diets (1, 10, 11).
eliac disease (CD) is an autoimmune disorder elicited by glu-
ten and related proteins in genetically susceptible individuals
PATHOGENESIS OF CELIAC DISEASE
features of its immunopathogenesis and underlying genetics de-
scribed (1, 2, 12, 13). It is thought to be initiated in genetically
teins found in grains such as wheat, rye, and barley. The events
leading to CD are thought to include lumenal and early mucosal
events, activation of the innate and adaptive immune systems, as
well as intestinal tissue damage (12–15). In the early stages of CD,
ingested gluten (gliadin and glutenin are the major protein com-
ponents of gluten) is digested by lumenal and brush-border en-
further degradation. Partially digested ?-gliadin peptides are able
are cross-linked and deamidated by tTG to produce DGP. Induc-
tion of CD4 T-cell-specific responses is thought to be initiated by
DGP bound with high affinity to HLA-DQ2/DQ8 molecules ex-
pressed on the surfaces of antigen-presenting cells (APCs). Acti-
vated CD4 T cells, in addition to providing help to B cells in
eliciting antibody-specific responses produce proinflammatory
cytokines such as gamma interferon (IFN-?), IL-15, and IL-17.
Gliadin is also thought to stimulate the innate immune system
phocytes (IEL) as well as upregulate MIC-A, a stress molecule on
enterocytes and the NKG2D receptor, promoting lymphocyte-
mediated cytotoxicity of enterocytes. Additionally, CD4 T cells
that are activated by IL-15- and IFN-?-secreting dendritic cells
tokines (as described above), apoptotic proteins (granzyme B
and perforin), and cytotoxic proteins (metalloproteinases) are
thought to be responsible for damage to intestinal tissue seen in
patients proven to have CD by biopsy specimens (14–18).
Some models propose that the tTG-gliadin complexes them-
selves are immunogenic, resulting in the production of autoanti-
bodies against tTG (5). Presentation of DGP by APCs requires
HLA-DQ2 or -DQ8 molecules. These HLA types are expressed in
nearly all patients with CD and contribute to the genetic compo-
nent of CD pathophysiology (1, 4, 19).
CLINICAL INDICATIONS AND DIAGNOSTIC
RECOMMENDATIONS FOR CELIAC DISEASE
Timely and accurate diagnosis of CD is important to avoid nega-
tive health outcomes, particularly in children. Untreated CD can
Published ahead of print 30 January 2013
Address correspondence to Anne E. Tebo, firstname.lastname@example.org.
Copyright © 2013, American Society for Microbiology. All Rights Reserved.
April 2013 Volume 20 Number 4 Clinical and Vaccine Immunologyp. 447–451cvi.asm.org
lead to decreased nutrient absorption and malnutrition. Patients
with CD are also at increased risk for other autoimmune diseases
To prevent diagnostic delays, guidelines for the diagnosis of CD
recommend testing based on the presence of symptoms and/or
in children and adolescents include the following: chronic or in-
termittent diarrhea; failure to thrive (FTT); weight loss; stunted
growth; delayed puberty; amenorrhea; iron deficiency; anemia;
nausea; vomiting; chronic abdominal pain, cramping, or disten-
sion; chronic constipation; chronic fatigue; recurrent aphthous
stomatitis (mouth ulcers); dermatitis herpetiformis-like rash;
fracture with inadequate trauma/osteopenia/osteoporosis; and
abnormal liver biochemistry. Individuals with type 1 diabetes
relatives with CD are also considered to be at increased risk for
disease and should be evaluated.
CD, with the most recent recommendations published in 2012 by
and Nutrition (ESPGHAN) (4). Among the most current sources
of recommendations are the 2009 United Kingdom National In-
stitute for Health and Clinical Excellence (NICE) guidelines and
the 2005 North American Society for Pediatric Gastroenterology,
Hepatology and Nutrition (NASPGHAN) (21, 22). The testing
algorithms proposed by different societies endorse the use of a
number of diagnostic tools, albeit in different orders or combina-
tions depending on the presence of symptoms or risk for disease
(4, 21, 22). Diagnostic tools include (i) serologic testing for spe-
cific antibodies, (ii) histological analysis of small bowel biopsy
specimens, and (iii) recommendation for HLA typing (DQ2 and
DQ8) in populations that are at risk as well as an alternative to
biopsy in individuals with elevated CD-specific antibodies. HLA
typing and biopsy specimen evaluations are not the focus of this
minireview and will not be discussed.
CELIAC DISEASE SEROLOGIC TESTS AND
RECOMMENDATIONS FOR SCREENING
CD. The most widely described serologic tests for CD include
EMA, tTG, and DGP antibodies. The ARA test was first intro-
by indirect immunofluorescence assay (IFA) on rat tissue (23).
These antibodies (IgG or IgA) are directed against the reticular
fibers of endomysium, a layer of connective tissue which sheathes
smooth muscle fibers. Five different patterns (R1 to R5) are asso-
acteristic R1 type staining pattern should be seen on three rodent
tissues, namely, the liver, kidney, and stomach. There are several
drawbacks to the ARA test, including multifaceted procedure,
jectivity associated with IFA-based testing (24, 25).
Testing for antigliadin antibodies by enzyme-linked immu-
nosorbent assay (ELISA) was developed in the early 1980s (26).
Although still available for diagnosis, AGA immunoassays dem-
onstrate variable clinical performance, particularly in adults, and
are not recommended in screening patients with symptoms
and/or at risk for CD (4, 21, 22). Subsequent to the development
matitis herpetiformis and CD (27). EMA is detected by IFA using
monkey esophageal or human umbilical cord tissue, and results
are reported in titers. Major limitations of this test include the
inherent subjectivity of IFA, expertise needed for interpretation,
and cost. Despite these challenges, the EMA antibody assay con-
tinues to be a mainstay in the diagnosis of CD due to its excellent
predictive value for disease. Serologic evaluation for AGA, ARA,
and EMA IgA antibodies became a part of the CD diagnostic
scheme for the first time in 1990 (28). Following the 1990
ESPGHAN guidelines, comparison of ARA to AGA and EMA IgA
tests found ARA testing to be a less reliable screening tool, since
only 65% of CD patients were positive (25). Similarly, the clinical
relevance of the AGA test became questionable, as a plethora of
false-positive results occurred in low-risk patients, as well as pa-
tients with non-CD-related gastrointestinal problems (29, 30).
The timely identification of tTG as the target antigen of the
EMA by Dieterich et al. (31) in 1997 with subsequent develop-
ment of anti-tTG immunoassays is believed to have radically
changed how screening for CD is performed. Anti-tTG IgA im-
munoassays are generally more sensitive but less specific than the
EMA immunoassays (32). Furthermore, the diagnostic perfor-
the assay principle, including the source of tTG antigen (human
recombinant or purified tTG of human and nonhuman origin)
(32–36). Despite this, the anti-tTG immunoassays are easier to
perform, less subjective, and more amenable to automation than
EMA immunoassays. Thus, anti-tTG tests are more likely to be
offered as first-line screening assays in the evaluation of CD.
In 1999, Quarsten and colleagues made the seminal observa-
tion that tTG is responsible for the processing events (deamida-
tion of gliadin) leading to the preferential presentation of gliadin
tion of their report by several others, measurement of anti-DGP
antibodies by ELISA was developed and reported in CD patients
for disease compared to its predecessor, the antigliadin antibody
assay. Although the anti-DGP antibody test is not currently rec-
ommended for routine screening, it may be useful for patients in
whom suspicion of CD is high, but anti-tTG and/or EMA is not
detected (39, 40).
In 2005, the North American Society for Pediatric Gastroen-
terology, Hepatology and Nutrition issued guidelines for the di-
agnosis of CD with recommendations for using EMA and/or tTG
dations that did not include ARA and AGA testing in the routine
evaluation for CD (21). Subsequently, other guidelines have been
published in the United Kingdom (31) and by ESPGHAN (4).
None of the three guidelines endorse the use of ARA and/or AGA
subjectivity, anti-tTG IgA is the recommended first-line serologic
recent guidelines (4, 21, 22). The EMA IgA by IFA may also be
used to screen for CD; however, its limited availability, subjectiv-
ity, and cost are usually a deterrent in routine diagnostic evalua-
tion. Of all three guidelines, only the ESPGHAN guideline pro-
vides crucial recommendations regarding the use of anti-tTG IgA
cvi.asm.org Clinical and Vaccine Immunology
levels in the interpretation and prediction of CD. It is also impor-
tant to note that, the use of IgA-specific tests is restricted in the
in patients with CD. Thus, the failure to identify IgA deficiency
to delayed diagnosis of disease. The inclusion of serum IgA deter-
mination as part of CD testing algorithms is a strategy to identify
patients who require IgG-based serologic testing.
TESTING FOR ANTIRETICULIN ANTIBODIES IS OBSOLETE IN
THE EVALUATION OF CELIAC DISEASE
individuals who have CD symptoms or are at risk for CD (4, 21,
specific anti-DGP antibody assays, ARA tests are requested by
quite a number of clinicians in the routine evaluation for CD. To
determine the relevance of ARA in present-day CD diagnostic
practice, we searched PubMed databases from 1990 to 2012 for
sive quantity of published literature on the clinical significance of
discussed how ARA testing fares compared to the more contem-
systemic reviews on the diagnostic performances of CD tests and
selected three to discuss in this minireview. The first, a review by
Maki (25) evaluated ARA, AGA, and EMA assays by pooling spe-
cific diagnostic studies published between 1971 and 1994 (Table
1). Based on these analyses, ARA testing had high specificities
(greater than 96%) in both children and adults; however, a major
setback was its inconsistent sensitivities: 29 to 100% in children
and 41 to 92% in adults. Compared to AGA and ARA tests, the
EMA IgA assay had the best overall clinical performance in both
pediatric and adult populations.
The second, a recent meta-analysis by Leffler and Schuppan in
2010 (41) assessed the diagnostic accuracies of AGA, EMA, and
tTG and DGP antibodies by analyzing results from several publi-
cations between 1999 and 2010. To determine the positive and
disease of 5% for their analysis (Table 2). Their evaluation re-
vealed a wide range in the sensitivities and specificities for AGA
tests compared to EMA, tTG IgA, DGP IgG, and IgA assays. Un-
like the tTG IgA assay, the diagnostic value of the tTG IgG assay
had variable sensitivities with the EMA assay showing the overall
best performance characteristics. In the last review we chose to
tic significances of AGA, EMA, and tTG tests in primary care set-
tings based on populations with a similar prevalence or spectrum
December 2009. The authors emphasized the importance of eval-
uating CD tests in primary care settings which would be reflective
of their actual diagnostic performances. Two reviewers indepen-
Quality Assessment of Diagnostic Accuracy Studies (QUADAS)
tool, recommended by the Cochrane Collaboration. Studies were
eligible for inclusion if they met the following criteria. (i) The
study population consisted of adults, and the prevalence rate of
gastrointestinal symptoms was 50% or greater. (ii) Diagnostic
in which consecutive cases of CD were compared with the appro-
priate controls. Similar to the second review, these analyses also
conveyed that AGA and tTG IgG tests are not dependable due to
the variability in their sensitivities.
All three reviews demonstrated that AGA, EMA, and tTG and
DGP antibody tests are good at predicting the absence of CD;
for AGA (IgA/IgG) and anti-tTG IgG tests (20, 25, 41). The AGA
for IgA and 50 to 94% for IgG isotypes) compared to the DGP
assays (90 to 100% for IgA and 94 to 100% for IgG; Table 2).
test. Early clinical studies suggested that EMA and AGA tests are
useful in very young children (Table 1); however, more-recent
data indicate that anti-tTG or DGP IgA immunoassay is similar
TABLE 1 Diagnostic performance of CD serologic testsa
Test and groupb
aAdapted and modified from Tables 1 and 3 in the review by Maki (25) with
permission from Elsevier. AGA test results are based on studies conducted from 1983 to
1994, ARA test results are based on studies conducted from 1971 to 1994, and EMA test
results are based on studies conducted from 1974 to 1994.
bAbbreviations: AGA, antigliadin antibodies; EMA, endomysial antibodies; IgA,
immunoglobulin A; IgG, immunoglobulin G.
TABLE 2 Diagnostic accuracy of CD-specific serologic testsa
EMA IgA 95 (86–100)99 (97–100)83 996
aAdapted from the review by Leffler and Schuppan (41) with permission from
Macmillan Publishers Ltd., based on the studies conducted from 1999 to 2010.
bAbbreviations: AGA, antigliadin antibodies; DGP, deamidated gliadin peptide; EMA,
endomysial antibodies; IgA, immunoglobulin A; IgG, immunoglobulin G; tTG, tissue
cThe positive predictive value (PPV) and negative predictive value (NPV) both had a
pretest probability of 5%.
April 2013 Volume 20 Number 4cvi.asm.org 449
for CD from birth, AGA IgG appeared ?3 months earlier than
anti-tTG, with anti-tTG, EMA, and ARA emerging concurrently
(44). Unfortunately, anti-DGP antibodies were not evaluated in
this study cohort. Overall, compared to all available serologic
tests for CD, the EMA IgA has the highest positive predictive
value and best positive likelihood ratio for disease irrespective
of age (11, 22).
Celiac disease is a complex, systemic disease affecting the growth,
development, and quality of life of a significant proportion of the
population. Detection of anti-tTG and/or EMA antibodies repre-
sent the cornerstone for identifying patients with CD and/or at
risk for disease. The use of ARA testing deviates from current
recommendations for serologic screening. There are very few re-
cent clinical investigations comparing the diagnostic significance
of ARA to contemporary serologic tests for CD. Based on the
results from these limited studies and their performance in past
investigations, their use in current practice is unwarranted. In
addition, our current knowledge of CD-specific serologic testing
and the immunobiology of disease leads us to conclude that ARA
testing is no longer useful in the routine evaluation of both pa-
tients with CD symptoms and individuals at risk for CD.
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aAdapted and modified from Table 4 in the review by van der Windt et al. (32) with permission of the publisher (Copyright © 2010, American Medical Association. All rights
reserved). Results are based on the search conducted in MEDLINE (beginning in January 1966) and EMBASE (beginning in January 1947) through December 2009.
bAbbreviations: AGA, antigliadin antibodies; me-EMA, monkey esophagus endomysial antibodies; hr-tTG, human recombinant tissue transglutaminase; IgA, immunoglobulin A;
IgG, immunoglobulin G.
cLHR, likelihood ratio.
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