UPDATE IN OFFICE MANAGEMENT
Celiac Disease Diagnosis: Simple Rules Are Better Than
Carlo Catassi, MD, MPH,
Alessio Fasano MD
Mucosal Biology Research and Center for Celiac Research, University of Maryland, School of Medicine, Baltimore;
Politecnica delle Marche, Ancona, Italy.
Celiac disease is the only treatable autoimmune disease, provided that a correct diagnosis is achieved and
a strict, lifelong gluten-free diet is implemented. The current diagnostic algorithm for celiac disease
includes initial screening serological tests, followed by a conﬁrmatory small intestinal biopsy showing the
autoimmune insult typical of celiac disease. The biopsy, considered the diagnostic gold standard, has been
recently questioned as a reliable and conclusive test for every case. Indeed, the wide variability of celiac
disease-related ﬁndings suggests that it is difﬁcult to conceptualize the diagnostic process into rigid
algorithms that do not always cover the clinical complexity of this disease. Instead we ﬁnd clinically useful
the shifting to a quantitative approach that can be deﬁned as the “4 out of 5” rule: the diagnosis of celiac
disease is conﬁrmed if at least 4 of the following 5 criteria are satisﬁed: typical symptoms of celiac disease;
positivity of serum celiac disease immunoglobulin, A class autoantibodies at high titer; human leukocyte
antigen (HLA)-DQ2 or DQ8 genotypes; celiac enteropathy at the small bowel biopsy; and response to the
© 2010 Elsevier Inc. All rights reserved. •The American Journal of Medicine (2010) 123, 691-693
KEYWORDS: Algorithm; Celiac disease; Diagnosis; Intestinal biopsy
Celiac disease is the immune-mediated intolerance to di-
etary gluten, a protein contained in wheat, rye, and barley,
affecting genetically predisposed individuals.
spectrum of celiac disease is wide, including cases with
either typical intestinal (eg, chronic diarrhea, weight loss) or
“atypical” extraintestinal (eg, anemia, osteoporosis, neuro-
logical disturbances) features, and silent forms that are oc-
casionally discovered because of serological screening.
Given the protean clinical presentation of celiac disease
potentially involving any organ or tissue of our body, in-
ternists and general pediatricians are the ﬁrst line of scrim-
mage facing the diagnostic challenges that this disease
The typical jejunal damage associated with active celiac
disease, showing villous atrophy, crypt hypertrophy, and
increased intraepithelial lymphocyte count, was ﬁrst de-
scribed in 1957 by John Paulley in the UK. Since then, the
histological analysis of small bowel biopsy specimens, ini-
tially taken by capsule and then by standard upper endos-
copy, has become the gold standard for celiac disease diag-
nosis. The small intestinal biopsy is still considered a
necessary investigation in the current guidelines of North
American and European gastroenterological societies (“no
small intestinal biopsy, no celiac disease”).
during these last decades, accurate tests have been added to
the diagnostic tool kit, for example, the determination of
serum immunoglobulin A (IgA) class anti-tissue transglu-
taminase (TTG) and endomysial (EMA) antibodies, IgG
class anti-deamidated gliadin peptide antibodies, and human
leukocyte antigen (HLA)-DQ2 and -DQ8 predisposing ge-
notypes. As far as the small bowel biopsy is concerned,
recently developed immunohistochemical techniques, par-
ticularly the detection of subepithelial IgA deposits, have
Funding: This manuscript was partially funded by the Center for
Celiac Research, University of Maryland School of Medicine.
Conﬂict of Interest: Both authors disclose no conﬂict of interests
related to the content of this manuscript.
Authorship: Both authors had access to the data and had equal role in
writing the manuscript.
Requests for reprints should be addressed to Alessio Fasano, MD,
Mucosal Biology Research Center and Center for Celiac Research, Uni-
versity of Maryland School of Medicine, Health Science Facility II, Room
S345, 20 Penn Street, Baltimore, MD 21201.
E-mail address: firstname.lastname@example.org
0002-9343/$ -see front matter © 2010 Elsevier Inc. All rights reserved.
improved the diagnostic accuracy of this procedure. How-
ever, major limitations of conventional histology also have
become clear, such as the frequent tangential artifact (a
normal mucosa may appear atrophic when the specimen is
not cut longitudinally), the poor speciﬁcity (particularly of
minor lesions such as duodenal lymphocytosis), and patch-
iness of the mucosal damage (some sections appearing nor-
mal and others showing variable degree of damage).
In many cases the clinical, serological, and histological
ﬁndings are consistent and the diagnosis of celiac disease is
straightforward. When celiac autoantibodies IgA-TTG and
-EMA are found at high titers in a patient with typical
symptoms, the probability of identifying a celiac enteropa-
thy at the small intestinal biopsy is almost 100%.
cases, the small intestinal biopsy does not add any relevant
information for celiac disease diagnosis and treatment.
However, the following “borderline” situations are in-
creasingly detected in clinical practice in both children and
●Patients with so called “potential” celiac disease show
positivity of serum celiac autoantibodies despite a (nearly)
normal histological picture at the small intestinal biopsy.
In many of these cases, the deterioration of jejunal archi-
tecture takes place over time. Implementation of the glu-
ten-free diet is indicated in potential celiac disease, both
for treating symptoms and for preventing late-onset com-
●Conversely, so-called seronegative celiac disease is char-
acterized by clinical, genetic, and histological data indi-
cating celiac disease in a patient lacking serum TTG and
EMA antibodies. Seronegative celiac disease is likely to
be underestimated due to the tendency to perform small
intestinal biopsy only in patients with positive celiac
disease serum markers (so called self-fulﬁlling proph-
A peculiar type of seronegative celiac disease is
found in patients that also have IgA deﬁciency, who
usually lack IgA but often show IgG class celiac auto-
●Diagnosis may be difﬁcult in celiac disease patients
showing modestly increased levels of serum celiac dis-
ease autoantibodies, as many of these subjects also have
only slight enteropathy at the small intestinal biopsy
(graded as 1 or 2 lesion by the Marsh-Oberhuber classi-
In these cases, the detection of subepithelial
IgA anti-TTG deposits strongly suggests celiac disease.
●The clinician is sometimes faced with the puzzling situ-
ation of “clear-cut” celiac disease in patients lacking the
HLA-DQ2 or DQ8 haplotypes. Large multicenter studies
have indeed shown that 0.4 % of celiac disease patients
are both DQ2 and DQ8 negative.
●Finally, prospective data on at-risk children suggest that
serum celiac disease antibodies may disappear early in
life, particularly when the titer is not very high. In symp-
tom-free children it is, therefore, advisable to perform 2
or more antibody determinations on samples taken at least
3 months apart.
The above-mentioned wide variability of celiac disease-
related ﬁndings suggests that it is difﬁcult to conceptualize
the diagnostic process into rigid algorithms that do not
always cover all the facets of this chameleonic disease.
Instead, we ﬁnd operationally useful the shifting to a quan-
titative approach to celiac disease diagnosis that can be
deﬁned as the “4 out of 5” rule: the diagnosis of celiac
disease is conﬁrmed when at least 4 of these criteria are
satisﬁed (Table). If the HLA genotype is not routinely
performed, 3 of 4 criteria will sufﬁce. This proposal appar-
ently encompasses almost all of the typical and borderline
situations that we have brieﬂy listed above.
An important corollary of this rule is that the small intestinal
biopsy may be avoided in selected cases, for example, very
young children with typical symptoms of celiac disease (eg,
parabola-shaped weight growth curve) and high-titer IgA class
anti-TTG and EMA antibodies. This is good news for both
patients and patients’ parents (who dislike this invasive inves-
tigation) and the health care system that pays for it. The small
intestinal biopsy is still required in other less clear situations,
for example, patients with minimal/absent complaints, or with
modest/discordant elevation of celiac antibodies, or lacking the
typical predisposing genotypes. In these situations, an accurate
evaluation of small intestinal biopsy specimens taken at dif-
ferent levels, including quantitative morphometry and detec-
tion of IgA deposits, should ﬁnd wider application (fewer
biopsies, better biopsies). Finally, in questionable cases, a glu-
ten provocation test (challenge) after at least 2 years of gluten-
free diet should be considered.
In conclusion, we propose simple diagnostic criteria that
could facilitate the ascertainment of celiac disease in clinical
Table Diagnostic Criteria for Celiac Disease (At Least 4 of 5
or 3 of 4 if the HLA Genotype Is Not Performed)
Typical symptoms of celiac disease*
Positivity of serum celiac disease IgA class autoantibodies at
HLA-DQ2 or DQ8 genotypes‡
Celiac enteropathy at the small intestinal biopsy§
Response to the GFD¶
IgA ⫽immunoglobulin A; GFD ⫽gluten-free diet.
Notes: A family history of celiac disease adds evidence to the diag-
nosis; in symptom-free patients, particularly young children, it is advis-
able to conﬁrm antibody positivity on 2 or more samples taken at least
3 months apart; in selected cases, a gluten challenge after at least 2
years of GFD might be required for diagnosis conﬁrmation.
*Examples of typical symptoms are chronic diarrhea, growth faltering
(children) or weight loss (adults), and iron deﬁcient anemia.
†Both IgA class TTG and EMA in IgA-sufﬁcient or IgG class TTG and
EMA in IgA-deﬁcient subjects. The ﬁnding of IgG class anti-deamidated
gliadin peptide adds evidence to the diagnosis.
‡HLA-DQ2 positivity includes subjects with only half the heterodimer
§Including Marsh-Oberhuber 3 lesions, Marsh-Oberhuber 1-2 lesions
associated with positive celiac antibodies positive at low/high titer, or
Marsh-Oberhuber 1-3 lesion associated with IgA subepithelial deposits.
¶Histological in patients with sero-negative celiac disease or asso-
ciated IgA deﬁciency.
692 The American Journal of Medicine, Vol 123, No 8, August 2010
practice. These rules should periodically be revised to take into
account the continuous evolution of both advances in patho-
physiological knowledge of the disease and diagnostic tools
development. Given the permanent nature of the celiac condi-
tion, diagnostic accuracy remains a must. This requirement
depends more on the level of expertise provided by the diag-
nostic center, in terms of clinical experience and diagnostic
procedures, than on the rigid application of a protocol that
always includes the small intestinal biopsy.
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693Catassi and Fasano New Celiac Disease Diagnosis Criteria