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Abstract

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 gluten-free diet.
UPDATE IN OFFICE MANAGEMENT
Celiac Disease Diagnosis: Simple Rules Are Better Than
Complicated Algorithms
Carlo Catassi, MD, MPH,
a,b
Alessio Fasano MD
a
a
Mucosal Biology Research and Center for Celiac Research, University of Maryland, School of Medicine, Baltimore;
b
Universita’
Politecnica delle Marche, Ancona, Italy.
ABSTRACT
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
gluten-free diet.
© 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.
1
The clinical
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
poses.
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”).
2,3
However,
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: afasano@mbrc.umaryland.edu
0002-9343/$ -see front matter © 2010 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjmed.2010.02.019
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).
4
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%.
5
In these
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
adults:
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-
plications.
6
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-
ecy).
7
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-
antibodies.
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-
fication).
8
In these cases, the detection of subepithelial
IgA anti-TTG deposits strongly suggests celiac disease.
4
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.
9
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.
10
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
high titer†
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
(HLA-DQB1*02 positive).
§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
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In this paper, we review the histological features of coeliac disease and propose a standardized report scheme based on the Marsh classification. Furthermore, terms used by pathologists are defined. The most important histological differential diagnoses are given, as well as a definition of the different clinical forms of coeliac disease such as symptomatic, silent, latent, potential, treated and refractory coeliac disease, Eur J Gastroenterol Hepatol 11:1185-1194 (C) 1999 Lippincott Williams & Wilkins.
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Genetic susceptibility to celiac disease is strongly associated with HLA-DQA1*05-DQB1*02 (DQ2) and HLA-DQA1*03-DQB1*0302 (DQ8). Study of the HLA associations in patients not carrying these heterodimers has been limited by the rarity of such patients. This European collaboration has provided a unique opportunity to study a large series of such patients. From 1008 European coeliacs, 61 were identified who neither carry the DQ2 nor DQ8 heterodimers. Fifty seven of these encoded half of the DQ2 heterodimer. The remaining 4 patients had a variety of clinical presentations. Three of them carried the DQA1*01-DQB*05 haplotype as did 20/61 of those carrying neither DQ2 nor DQ8. This may implicate a role of the DQA1*01-DQB*05 haplotype. None of these four patients carried the DQB1*06 allele that has previously been reported in this sub-group of patients. Of the 16 DQ2 heterodimer negative patients without DRB1*04 or DRB1*07 haplotypes, it was inferred that none encoded the previously implicated DRB4 gene as none had a DRB1*09 haplotype. These results underline the primary importance of HLA-DQ alleles in susceptibility to celiac disease, and the extreme rarity of celiac patients carrying neither the DQ2 or DQ8 heterodimers nor one half of the DQ2 heterodimer alone.
Article
Celiac disease is an immune-mediated enteropathy caused by a permanent sensitivity to gluten in genetically susceptible individuals. It occurs in children and adolescents with gastrointestinal symptoms, dermatitis herpetiformis, dental enamel defects, osteoporosis, short stature, delayed puberty and persistent iron deficiency anemia and in asymptomatic individuals with type 1 diabetes, Down syndrome, Turner syndrome, Williams syndrome, selective immunoglobulin (Ig)A deficiency and first degree relatives of individuals with celiac disease. The Celiac Disease Guideline Committee of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition has formulated a clinical practice guideline for the diagnosis and treatment of pediatric celiac disease based on an integration of a systematic review of the medical literature combined with expert opinion. The Committee examined the indications for testing, the value of serological tests, human leukocyte antigen (HLA) typing and histopathology and the treatment and monitoring of children with celiac disease. It is recommended that children and adolescents with symptoms of celiac disease or an increased risk for celiac disease have a blood test for antibody to tissue transglutaminase (TTG), that those with an elevated TTG be referred to a pediatric gastroenterologist for an intestinal biopsy and that those with the characteristics of celiac disease on intestinal histopathology be treated with a strict gluten-free diet. This document represents the official recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition on the diagnosis and treatment of celiac disease in children and adolescents.
Article
Reliable markers of early developing coeliac diseases are needed. Coeliac autoantibodies in the serum or Marsh I inflammation may be indicators of subsequent coeliac disease. To investigate whether determination of intestinal transglutaminase 2-targeted autoantibody deposits would detect early developing coeliac disease better than previous methods. The study investigated patients previously excluded for coeliac disease: 25 had positive serum coeliac autoantibodies (endomysial), 25 antibody-negative had Marsh I, and 25 antibody-negative had Marsh 0 finding. Seven (median) years after baseline investigation, new coeliac cases were recorded, and small bowel biopsy was offered to the rest of the patients. Serum and intestinal coeliac autoantibodies and intraepithelial lymphocytes were assessed as indicators of developing coeliac disease. Seventeen patients had developed coeliac disease: 13 in the autoantibody-positive group, three in the Marsh I group and one in the Marsh 0 group. At baseline, intestinal coeliac autoantibody deposits had a sensitivity and specificity of 93% and 93% in detecting subsequent coeliac disease, CD3+ 59% and 57%, gammadelta+ 76% and 60%, and villous tip intraepithelial lymphocytes 88% and 71%, respectively. Endomysial antibodies with normal histology indicates early developing coeliac disease. Transglutaminase 2-targeted intestinal autoantibody deposits proved the best predictor of subsequent coeliac disease.
Article
To explore the natural history of antibodies against tissue transglutaminase (TGA), endomysium (EMA), reticulin (ARA), and gliadin (AGA-IgG and AGA-IgA) in children carrying HLA-conferred risk for celiac disease (CD) and observed frequently from birth. TGA was measured in serum samples obtained between years 2000 and 2003 from 1,320 children carrying genetic CD risk. If a sample was TGA positive, all five antibodies were analyzed in all banked and forthcoming samples from that child, and a duodenal biopsy was recommended. At the end of this observation, in August 2004, the age of the children was from 1 to 9.5 yr (mean 4.1 yr). Forty-nine children (3.7%) were TGA positive. In these children, AGA-IgG had emerged at the mean age (+/- SD, range) of 2.0 +/- 1.5, 0.5-6.6 yr, while TGA, EMA, and ARA all emerged concurrently somewhat later (TGA at 3.2 +/- 1.5, 1.0-7.0 yr, P < 0.001 when compared to AGA-IgG). Despite continuing gluten exposure, positive TGA, EMA, ARA, AGA-IgA, and AGA-IgG values were spontaneously lost in 49%, 45%, 43%, 41%, and 32% of the children, respectively. CD was diagnosed by biopsy in 20 of the 26 TGA-positive children who consented to a biopsy. Potential CD trigger(s) other than only gluten probably function before AGA-IgG emerges, i.e., > or =3 months earlier than the transglutaminase-associated antibodies appear. In a remarkable proportion of the children, antibodies disappear spontaneously suggesting that regulatory immune phenomena under favorable circumstances are able to extinguish incipient CD in genetically at-risk children even without exclusion of gluten from the diet.