https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3440559/
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The Oslo definitions for coeliac disease and related terms
Jonas F Ludvigsson,
Daniel A Leffler,
* Julio Bai,
Federico Biagi,
Alessio Fasano,
Peter HR Green,
Marios Hadjivassiliou, MD,
Katri Kaukinen,
Ciaran Kelly,
Jonathan N Leonard,
Knut E Lundin,
Joseph A Murray,
David S Sanders,
Marjorie M Walker,
Fabiana Zingone, and
Carolina Ciacci
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Abstract
Background
The literature suggests a lack of consensus on the use of terms related to coeliac disease (CD) and gluten.
Methods
A
multi-disciplinary task force of 16 physicians from 7 countries used
the electronic database PubMed to review the literature with regards to
CD-related terms up to January 2011. Teams of physicians then suggested a
definition for each term, followed by feedback of these definitions
through a web survey on definitions, discussions during a meeting in
Oslo, and phone conferences. We evaluated the following terms (in
alphabetical order): Coeliac disease and the following descriptors of
CD: asymptomatic, atypical, classical, latent, non-classical, overt,
paediatric classical, potential, refractory, silent, subclinical,
symptomatic, typical, CD serology, CD autoimmunity, genetically at risk
of CD, dermatitis herpetiformis, gluten, gluten ataxia, gluten
intolerance, gluten sensitivity, and gliadin-specific antibodies.
Results
CD was defined as “a
chronic small intestinal immune-mediated enteropathy precipitated by
exposure to dietary gluten in genetically predisposed individuals”. Classical CD was defined as “CD presenting with signs and symptoms of malabsorption. Diarrhoea, steatorrhoea, weight loss or growth failure is required.”
We suggest that “gluten-related disorders” is the umbrella term for all
diseases triggered by gluten and that the term gluten intolerance is
not to be used. Other definitions are presented in the paper.
Conclusion
This paper presents the Oslo definitions for CD-related terms.
Keywords: adult, autoimmunity, child, coeliac, gluten, sensitivity, intolerance
BACKGROUND
Coeliac
disease (CD) is a chronic small intestinal immune-mediated enteropathy
precipitated by exposure to dietary gluten in genetically predisposed
individuals. Although symptoms and signs of CD have been recognised for
more than 100 years, it was in the 1940s that the Dutch paediatrician
Dicke established a link between the protein component of wheat (gluten)
exposure and CD.
1
CD and related diseases are now common chronic diseases in children and
adults, and increased diagnosis has lead to proliferation of research
activities. As with many other chronic conditions, the boundaries of CD
are not always clear, with the consequence that there is considerable
confusion and a lack of consensus regarding diagnostic criteria of CD
and related conditions.
The first consensus definition of CD was published in
Acta Paediatrica in 1970.
2
This publication defined CD as a permanent condition of gluten
intolerance with mucosal flattening that (a) reversed on a gluten-free
diet (GFD) and (b) then relapsed on re-introduction of gluten. Although
the definition of CD has undergone minor changes since 1970,
3, 4
consensus definitions have been restricted to CD. However, the
scientific community has come to recognise that there is a spectrum of
disorders related to gluten ingestion.
Due to a lack of
common definitions for the spectrum of terms and disorders related to
CD, a multi-disciplinary task force of 16 physicians from 7 countries
with particular expertise in diagnosis and treatment of CD proposes the
following definitions for the variety of vague and often confusing terms
currently in use in the literature. These definitions are based on
thorough literature reviews (), a discussion in Oslo at the 14th
International Coeliac Disease Symposium in June 2011, and agreement on
consensus statements by web survey and phone conferences. We refer to
our definitions as the “Oslo Definitions”.
Terms evaluated for this review.
The
purpose of our recommended definitions is to create a foundation for
both clinical management and research. Clear definitions will allow for
more efficient and generalizable advances in CD research concerning
aetiology, incidence, prevalence, complications, and treatment of
patients with CD and other gluten-related disorders.
METHODS
Task force constitution
Members
of this collaborative effort were invited by DAL and CC. The
constitution of the group reflects the wide variety of disciplines to
which CD may present in practice: gastroenterology, histopathology,
paediatrics, neurology, and dermatology. Members of the task force
originated from Sweden, US, Argentina, Italy, UK, Finland and Norway.
Four of the five physicians from the US had trained elsewhere (two in
Ireland, one in Australia and one in Italy).
Literature review
Teams of 3–4 physicians were assigned 1–4 CD-related terms. Each team first carried out a literature search ().
We searched the entire electronic database PubMed up to January 2011
using the terms of this review as key words. These included: Coeliac disease and these descriptors of CD:
asymptomatic, atypical, classical, latent, non-classical, overt,
paediatric classical, potential, refractory, silent, subclinical,
symptomatic, typical, CD serology, CD autoimmunity, genetically at risk
of CD, dermatitis herpetiformis, gluten, gluten ataxia, gluten
intolerance, gluten sensitivity, and gliadin-specific antibodies.
We
restricted most of our review to original papers and reviews. Most
papers had been published after 1990. The teams then suggested
definitions for each term.
Web survey
We then constructed a web survey from which all suggested definitions were listed and subjected to peer review (Appendix).
Comments and feedback from the web survey were taken into account when constructing a second set of definitions.
Discussions and phone meetings
The revised definitions and appending comments were then discussed in Oslo at the 14th
international CD symposium in June 2011. This discussion was followed
by two phone conferences in which the remaining definitions were
discussed until consensus was achieved. We did not grade the evidence
underlying each definition because that was not the purpose of our task
force and this review did not deal with clinical management. For the
convenience of the readers, each definition is followed by a short
literature review of each term. Two terms were added after the initial
web survey and the meeting in Oslo: Dermatitis herpetiformis and CD autoimmunity were discussed through email.
RESULTS
Coeliac disease
A
chronic small intestinal immune-mediated enteropathy precipitated by
exposure to dietary gluten in genetically predisposed individuals
CD is triggered by the ingestion of gluten (definition below), the protein component of wheat, rye, barley, but not oats.
5, 6 Such exposure results in a variable degree of intestinal damage.
7 In most patients with CD, the enteropathy will reverse on a GFD.
2–4
According to the suggested definition, CD is a chronic disease, but as
the discussion of the terms potential CD and latent CD will show, there
are reports of transient CD.
8
Although
CD is the most common cause of enteropathy in the western world and
enteropathy is a prerequisite for CD, it should be noted that other
diseases may cause small intestinal inflammation but do not qualify as
CD.
9 Typically, the inflammation in CD includes an increased intraepithelial lymphocyte count, most often >25/100 cells.
9, 10
Another feature of CD is that it incorporates an adaptive
T-cell-mediated response (to gluten) and that it occurs in
DQ2-DQ8-positive individuals.
11, 12
Increasingly, the presence of specific endomysial antibodies (EMA, also
called AEA), anti-tissue transglutaminase antibodies (TTG, a-tTG, TTA),
and/or deamidated antigliadin antibodies (DGP) plays an important role
in the serological work-up for CD. These antibodies strongly support the
diagnosis of CD, but by themselves are not confirmatory.
To
confirm a diagnosis of CD biopsies of the duodenum must be taken when
patients are on a gluten-containing diet. Consensus states 4–6 biopsies
are necessary for diagnosis,
13 including from the duodenal bulb.
14, 15
Three histological classifications of CD are used: Marsh,
7 Marsh –Oberhuber
16 and Corazza
10. A comparison of these classifications is shown in .
Comparison of histopathological classifications.
Historically, CD has been equivalent to
sprue,
coeliac sprue,
gluten-sensitive enteropathy, and
gluten intolerance. In the past the terms
non-tropical sprue and
idiopathic steatorrhoea were used.
17, 18 None of these terms are currently recommended.
Gluten
Gluten
is the commonly used term for the complex of water insoluble proteins
from wheat, rye and barley that are harmful to coeliac disease patients
The
major seed proteins in cereals are the alcohol soluble prolamins, a
complex group of alcohol-soluble polypeptides that make up about half of
the protein in the mature grain. The term gluten indicates a broad
group of prolamins (gliadins and glutenins) found in wheat. Other
prolamins showing similar immunogenic properties are found also in rye
(secalins), barley (hordeins), and other closely related grains.
13, 19
The major prolamins of the more distantly related maize (zeins) seem to
have evolved independently and show no harmful effects in coeliac
patients. Oats also have been shown to be non-immunogenic in most
individuals with CD.
20 A gluten-free diet usually indicates a diet free from wheat, rye, barley, triticale, kamut and spelt.
Gluten
is poorly digested in the human intestine with or
without CD. Gluten
peptides cross intact into the submucosa of the small intestine. In the
submucosa of the small intestine the human enzyme transglutaminase 2
(TG2) also referred to as tissue transglutaminase (tTG) deamidates
gluten peptides, which allows for high-affinity binding to HLA DQ2 and
HLA DQ8 molecules, subsequently triggering an inflammatory reaction in
patients with CD.
12
Gluten-content in food is regulated by the Codex Alimentarius (
http://www.codexalimentarius.net).
This codex (CODEX STAN 118 – 1979 revised in 2008) states that
gluten-free foods are those foods or ingredients naturally free of
gluten, in which the measured gluten level is ≤20 mg/kg in total, or
processed to <100 a="" as="" be="" by="" codex="" criteria="" current="" food="" foods="" gluten-free="" kg.="" labelled="" may="" meeting="" mg="" p="" the="" this="">
Asymptomatic CD
CD not accompanied by symptoms even in response to direct questioning at initial diagnosis
Individuals
with asymptomatic CD do not manifest any symptoms commonly associated
with CD and have no symptoms that respond to gluten withdrawal, even in
response to direct questioning. These patients are often diagnosed
through testing of populations enrolled in screening programs or in
case-finding strategies for detecting CD in patients with disorders that
are associated with a high risk for CD
21–33
Many of these patients suffer from decreased quality of life. Sometimes
minor symptoms (e.g., fatigue) are only recognized after the
introduction of a GFD,
34 such patients do not suffer from true asymptomatic CD and should be re-classified as having
subclinical CD.
Typical CD
Historically,
typical CD has denoted a gluten-induced enteropathy presenting with
signs or symptoms of malabsorption/global malabsorption (such as
diarrhoea or malnutrition) or a malabsorption syndrome (indicated by
weight loss, steatorrhoea, and oedema secondary to hypoalbuminemia). The
above use is questionable in that the clinical presentation of CD has
changed over time,
35–37
and the word “typical” implies that this form is the most frequently
encountered form of CD. In contrast, many current patients have symptoms
such as anaemia,
38–40 fatigue,
41, 42 and abdominal pain
43.
We therefore discourage the use of the term Typical CD.
Atypical CD
Atypical
CD can only be used in reference to typical CD. Historically, atypical
CD has been used to describe patients with gluten-induced enteropathy
that have no weight loss but present with any of the following
symptoms/signs: (a) gastrointestinal (GI) symptoms
44 including symptoms suggestive of irritable bowel syndrome,
45, 46 and liver dysfunction
47, 48; (b) extraintestinal manifestations, such as metabolic disease/symptoms (failure to thrive, thyroid dysfunction (hypo/hyper)
49, 50; (c) neurologic findings,
51–53 including depression
54 and gluten ataxia
55; (d) reproductive disease
56–58 including abnormalities in menarche and menopause
58, 59; (e) oral/cutaneous disease
60–64 including dermatitis herpetiformis (DH)
65; and (f) skeletal findings
66.
Atypical CD has also been used to denote patients with a gluten-induced
enteropathy and significant nutritional deficiencies (such as iron
deficiency).
We argue that the term atypical CD should not be used. Some patients previously described as having atypical CD may fulfil the requirements for
non-classical CD (below).
Classical CD
CD presenting with signs and symptoms of malabsorption. Diarrhoea, steatorrhoea, weight loss or growth failure is required
Classical
and typical CD have traditionally been similar concepts defining the
presence of a gluten-induced enteropathy presenting with diarrhoea,
malnutrition, or a malabsorption syndrome (indicated by weight loss,
steatorrhoea, and oedema secondary to hypoalbuminemia).
7, 67–74
While recognizing that these symptoms are not specific to CD, we
encourage the use of
classical CD, as defined above, because the term
“classical” does not imply that this type of CD is more common than CD
without clinical malabsorption. Examples of classical CD are patients
with diarrhoea and weight loss but also patients with weight loss and
anaemia.
Paediatric classical CD is the
paediatric equivalent of classical CD. These children are often
characterised by failure to thrive, diarrhoea, muscle wasting, poor
appetite, and abdominal distension.
75–79 Many children with classical CD and malabsorption also show signs of emotional distress (“change of mood”) and lethargy.
72
Non-classical CD
CD presenting without signs and symptoms of malabsorption
In
non-classical CD the patient does not suffer from malabsorption (e.g., a
patient with constipation and abdominal pain but no malabsorption).
Patients with monosymptomatic disease (other than
diarrhoea/steatorrhoea) usually suffer from non-classical CD.
Silent CD
Silent CD is equivalent to asymptomatic CD. We discourage the use of the term silent CD.
Subclinical CD
CD that is below the threshold of clinical detection
The term subclinical has often been used to denote silent CD
80–82 or CD patients with extraintestinal symptoms (and no GI symptoms)
83. The term has also been used for CD patients having
clinical or laboratory signs
(iron deficiency anaemia, abnormalities in liver function tests, enamel
defects, incidental endoscopic features, osteoporosis, etc.) but
no symptoms.
84
As
understanding of CD has advanced, new disease associations have been
regularly found and populations tested for CD have changed in response.
For this reason what is ‘subclinical’ has changed over time. In order to
provide a stable definition, we specified subclinical CD to be disease
that is below the threshold of clinical detection without signs or
symptoms sufficient to trigger CD testing in routine practice.
Symptomatic CD
CD characterized by clinically evident gastrointestinal and/or extraintestinal symptoms attributable to gluten intake
The
clinical manifestations of CD vary from none (asymptomatic CD) to a
wide spectrum of symptoms. The vast majority of authors describing
symptomatic CD do not distinguish between CD with GI and CD with
extraintestinal symptoms.
85–98
What was previously called overt CD should be considered part of symptomatic CD.
Overt CD
Overt
CD has most often been characterised by clinically evident
gluten-related symptoms, either GI (dyspepsia, diarrhoea, and bloating)
or extraintestinal (neurological symptoms and fatigue).
99, 100
We recommend that the term overt CD should not be used, and that
symptomatic CD is preferred.
Refractory CD
Persistent
or recurrent malabsorptive symptoms and signs with villous atrophy
despite a strict gluten free diet for more than 12 months
Although definitions of refractory CD (RCD) differ slightly,
101–118
most expert opinion based definitions include persistence or recurrence
of malabsorptive symptoms and signs (e.g., diarrhoea, abdominal pain,
involuntary loss of weight, low haemoglobin, and hypoalbuminemia)
associated with persistent or recurrent villous atrophy (VA) despite a
strict GFD for more than 12 months (or severe persistent symptoms
independently of the duration of GFD) in the absence of other causes of
VA or malignant complications
119 and after the confirmation of the initial diagnosis of CD.
Generally,
most patients have negative EMA and TTG antibodies at the time of RCD
diagnosis, but the presence of persisting elevated titres of circulating
EMA and/or TTG antibodies does not necessarily rule out RCD, though
this should lead to questions about dietary adherence. In all cases, a
careful dietary interview should be performed to exclude gluten exposure
before diagnosing RCD.
120 Not all dietary non-responsive CD is refractory CD.
121–123
RCD is divided into two categories:
111, 115
type I, in which a normal intraepithelial lymphocyte (IEL) phenotype is found, and
type II,
in which there is a clonal expansion of an aberrant IEL population. The
abnormal phenotype is supported by: loss of normal surface markers CD3,
CD4, and CD8 with preserved expression of intracytoplasmic CD3 (CD3ε)
in >50% of intraepithelial lymphocytes as evaluated by
immunohistochemistry or >20% as determined by flow cytometry, and by
detection of clonal rearrangement of T-cell receptor chains (γ or δ) by
polymerase chain reaction.
104, 107, 108, 115, 116
Latent CD
The
literature reveals at least five definitions of latent CD: (1) Positive
CD serology in patients with normal mucosa or absence of VA
124–129 and (2) normal mucosa in patients who are on a gluten-containing diet, but have had an
earlier or will have a
later flat mucosa when they eat gluten.
130–134 To some physicians latent CD is (3) simply equivalent to undiagnosed CD,
135, 136
(4) whereas others refer to latent CD as CD preceded by another
autoimmune disease (e.g., type 1 diabetes or thyroid disease). Finally,
(5) latent CD is sometimes used to denote normal mucosa with
non-serological abnormalities, such as an increased number of
gamma-delta cells or increased mucosal permeability.
137 Considering that the terms potential CD and latent CD have often been used interchangeably, resulting in confusion,
we discourage the use of latent CD.
Potential CD
Individuals
with a normal small intestinal mucosa who are at increased risk of
developing CD as indicated by positive CD serology
Potential
CD is also often used with different meanings. For some, potential CD
means that the patient has an increased number of IELs in the villi
138 or increased expression of gamma-delta cells.
139 To others potential CD describes individuals with normal mucosa but positive CD serology.
140, 141 Adding to this is the suggestion by Ferguson
et al that
all first-degree relatives to patients with CD have potential CD.142
We
recommend that the term potential CD be used for individuals with
normal small intestinal mucosa who are at increased risk of developing
CD as indicated by positive CD serology. A difficulty in the definition
of this group is variability in the adequacy of the biopsies that were
taken to exclude the diagnosis of active CD, especially with the current
knowledge that at least four biopsies need to be taken
143 and the bulb may be the only location of VA.
15
Coeliac disease autoimmunity
Increased
TTG or EMA on at least two occasions when status of the biopsy is not
known. If the biopsy is positive, then this is CD, if the biopsy is
negative than this is potential CD
The term “coeliac disease autoimmunity” or “coeliac autoimmunity” has been used to describe: individuals with positive TTG
144–147, positive EMA
148, positive EMA
with positive/borderline TTG
149, positive TTG on at least
two occasions150, and positive TTG on 2 occasions or a positive small bowel biopsy after only a single positive TTG
151.
We
defined coeliac disease autoimmunity as positive TTG or EMA on at least
two occasions. In a clinical setting this will lead to a small
intestinal biopsy, and patients can then be classified as either CD
(positive biopsy) or potential CD (negative biopsy), but in a research
setting there are circumstances where small intestinal biopsy has not
been performed. The term coeliac disease autoimmunity should then be
used. When TTG or EMA has only been tested on one occasion, it is
preferable to refer to patients as TTG+ or EMA+.
Genetically at risk of CD
Family members of CD patients that test positive for HLA DQ2 and/or DQ8
CD
is a multi-factorial condition with unparalleled evidence of the
pivotal role of human leukocyte antigen (HLA)-DQA1*05-DQB1*02 (DQ2) and
DQA1*03-DQB1*0302 (DQ8) in disease predisposition.
152, 153 Both DQ2 and DQ8 are major risk factors carried by almost all CD patients. Interestingly, when carried in
trans on DR5/DR7 (i.e.
DQA1*05-DQB1*0301/DQA1*0201-DQB1*02) or DR3/DR7 (i.e.
DQA1*05-DQB1*02/DQA1*0201-DQB1*02) genotypes, the risk of CD in Southern Europeans is higher than when the alleles are carried in cis on DR3 (i.e.
DQA1*05-DQB1*02) alone, suggesting that additional factors in the region may be influencing disease propensity.
Non-HLA
genes together contribute more to genetic susceptibility (approximately
65%) than do the HLA genes (the remaining 35%), but the contribution
from each single, predisposing non-HLA gene appears to be modest.
154
At
the moment, the concept of genetically at risk for CD should be limited
to family members (of CD patients) who test positive for HLA-DQ2 or
HLA-DQ8, with the understanding that the risk varies between 2% and 20%,
depending on the degree of the relative with CD and the number of
copies of HLA-DQ2 genes. However, any individual who harbours these
genes are at risk of developing CD.
Gluten intolerance
The
term gluten intolerance has been used both as a synonym of CD and to
indicate that a patient experiences a clinical improvement after
starting a GFD, even when he/she does not have CD.
8, 76, 122, 155–166
However, we believe the term gluten intolerance is non specific and
carries inherent weaknesses and contradictions. Although gluten
intolerance could be a consequence of poor digestion, it could also be
the effect of some
lectin-like properties of gluten or foods generated
from gluten that cause GI upset. Another problem is that gluten
intolerance may not truly reflect intolerance to gluten but to
other
wheat components.156 Because of these contradictions,
we recommend that the term gluten intolerance should not be used and that
gluten-related disorders be used instead.
Gluten-related disorders
Gluten-related disorders is a term used to describe all conditions related to gluten
We
recommend that the term gluten-related disorders be used to describe
all conditions related to gluten. This may include such disorders as
gluten ataxia, dermatitis herpetiformis (DH), non-coeliac gluten
sensitivity, and CD.
115, 167, 168
Gluten sensitivity
In some papers the term gluten sensitivity is used synonymously with CD.
7
Other papers used the concept of gluten sensitivity as an umbrella term
to include CD and other conditions related to gluten ingestion, such as
DH,
169 gluten ataxia,
170 and non-coeliac gluten sensitivity.
156 Most recently,
157, 171–174
several authors employed the term gluten sensitivity to describe a
condition in which symptoms are triggered by gluten ingestion, in the
absence of TTG or EMA antibodies and enteropathy, with variable HLA
status as well as variable AGA presence. It is important to distinguish
CD from less well characterized diseases related to gluten ingestion. We
therefore recommend that the term gluten sensitivity should not be used and that
non-coeliac gluten sensitivity be used instead.
Non-coeliac gluten sensitivity
One
or more of a variety of immunological, morphological, or symptomatic
manifestations that are precipitated by the ingestion of gluten in
individuals in whom CD has been excluded
Non-coeliac
gluten sensitivity (NCGS) is a condition in which gluten ingestion
leads to morphological or symptomatic manifestations despite the absence
of CD.
172–176
As opposed to CD, NCGS may show signs of an activated innate immune
response but without the enteropathy, elevations in tTG, EMA or DGP
antibodies, and increased mucosal permeability characteristic of CD.
173 Recently, Biesiekierski
et al in a double-blind randomized trial showed that patients with NCGS truly develop symptoms when eating gluten.
156
It is unclear at this time what components of grains trigger symptoms
in individuals with NCGS and whether some populations of NCGS patients
have subtle small intestinal morphological changes. While there
currently is no standard diagnostic approach to NCGS, systematic
evaluation should be conducted including exclusion of CD and other
inflammatory disorders.
Gliadin-specific antibodies
Anti-gliadin
(AGA) antibodies of both IgA and IgG subclass recognizing the gliadin
moiety of wheat. Antibodies recognizing native gluten are now rarely
used for diagnostic purposes because they lack general specificity.
Antibodies recognizing deamidated gliadin peptides demonstrate high
specificity and sensitivity. They can also be used for measurement of
gluten in food-stuffs
Use of the term
gliadin specific antibodies generally refers to antibodies directed
against the gliadin moiety of wheat prolamins. Four aspects of these
antibodies are relevant to the spectrum of gluten-induced disease
(I–IV).
(I)
Diagnostic value.
After introduction in the 1980s IgA antibodies against wheat gliadin
(AGA, anti-gliadin antibodies) served as the best serological test for
CD for some years.
177, 178 However, its low positive predictive value
179 meant that it has since been abandoned for the investigation of CD,
13, 179 outside of children below the age of 18 months, where IgA AGA seems to have high sensitivity.
180 Recently assays for IgA and IgG antibodies against deamidated gliadin peptides (DGP) have been introduced
181 and perform similarly to TTG-based tests.
179 (II) Elevated levels of AGA have also been used for the investigation of possible
increased gut permeability
but this use in clinical practice lacks a strong scientific background.
(III) AGAs are also relevant to gluten-induced disorders
beyond the classical enteropathy.
The most well-known example is that for gluten ataxia. Patients with
this disorder may have CD or only elevated levels of IgA or IgG AGAs.
55 (See Gluten Ataxia) (IV) Gluten-specific antibodies have a clear role in the food industry in that they are indispensable for
measurement of gluten in foods. More recently, an assay using a monoclonal antibody recognising a major coeliac toxic epitope has been developed.
182 This assay is now the preferred method for gluten analysis in food.
183
Coeliac disease serology
“Coeliac
disease serology” is a term that includes endomysium, transglutaminase,
deamidated gliadin antibodies, and in small children also gliadin
antibodies for the assessment of CD
Since
the introduction of AGA, antibodies have become an important means to
diagnose CD. Serological testing has been used routinely in the
investigation of CD since the 1980s. Whereas AGA tests were common in
the 1980s and 1990s,
184 laboratories have since gradually shifted to EMA and TTG tests.
185–187 In most patient groups with suspected CD, EMA, and TTG tests have a higher sensitivity and specificity than the AGA test.
188
We defined CD serology as an all encompassing term that includes all
available tests which have been shown in clinical studies to be
sensitive for assessment of CD. Accordingly, we
discourage the use of the term CD serology
in that it is preferable to specify the antibody tests used because
sensitivity and specificity differ substantially. We have nevertheless
suggested a definition of this term, since it is extensively used.
Gluten ataxia
Idiopathic sporadic ataxia and positive serum antigliadin antibodies even in the absence of duodenal enteropathy
Gluten ataxia is one of a number of neurological manifestations attributed to CD. Defining criteria for gluten ataxia
170, 189, 190
include otherwise idiopathic sporadic ataxia in association with
positive AGA with or without enteropathy on duodenal biopsy. Most
reports (22/35 reports) after 1998 have used the same definition, i.e.
idiopathic sporadic ataxia with positive AGA (IgG or IgA, or both).
However, a number of reports refer to patients with established CD
(13/35 reports) without always providing serological information on
these patients other than stating that the patient had CD (taken to
imply the presence of enteropathy).
170, 191–199
One
report examined the presence of IgA deposits on duodenal biopsies and
found that all 10 patients with gluten ataxia (without enteropathy) had
such deposits.
195 One study has identified a novel transglutaminase (TTG6) as a potential
new serological marker for gluten ataxia,
192 but currently the most appropriate definition for gluten ataxia remains that of idiopathic sporadic ataxia with positive AGA.
Dermatitis herpetiformis (DH)
DH
is a cutaneous manifestation of small intestinal immune-mediated
enteropathy precipitated by exposure to dietary gluten. It is
characterized by herpetiform clusters of pruritic urticated papules and
vesicles on the skin, especially on the elbows, buttocks, and knees, and
IgA deposits in the dermal papillae. DH responds to a GFD
DH is characterized by the presence of IgA deposits in the skin
200–202 DH is strongly linked to an immune mediated enteropathy precipitated by gluten,
65, 203–205 and responds to a GFD.
206–209
A study from the USA in 1992 documented a prevalence of 11.2 per
100,000 people and an incidence of 0.98 per 100,000 people per year,
210 these rates are comparable to earlier studies of prevalence of DH in Northern Europe.
205
Villous
atrophy will be revealed by a single intestinal biopsy in two thirds of
patients, and by multiple biopsies in 95%. The enteropathy is variable
in severity, but even in the presence of normal villous architecture,
elevated levels of γδ T lymphocytes in the intestinal mucosa, elevated
intraepithelial lymphocyte counts and induction of villous atrophy are
noted on gluten challenge, and these patients are very likely to reflect
the entire spectrum of histological and clinical CD in adults.
65, 211 The association with HLA is the same as in CD, 90% of patients have HLA DQ2 and, almost all the remainder, HLA DQ8.
212 The skin lesions clear with gluten withdrawal but may also require treatment by the neutrophil inhibitor Dapsone.
207, 208, 213
In the long term, adherence to a strict GFD shows 47% of patients can
stop drug treatment completely; however 15% will not be able to reduce
the dose of Dapsone.
214
DISCUSSION
This
review was done on the basis of PubMed literature searches and expert
meetings. We aimed to define key concepts relevant to CD and related
disorders. The character of the current paper implies that we did not
pool any data or use any statistical tools. Instead, we assembled an
international team of recognized experts in CD research, discussed
definitions and tried to reach a consensus. This approach is similar to
that of previous papers on definitions in CD.
2–4 As opposed to previous studies,
2–4
however, we did not limit ourselves to “CD only” but defined a large
number of concepts. In addition, we give guidance to the scientific and
clinical community as to which terms should be used and which are to be
abandoned.
Overall, we evaluated more than 300 papers in
detail and all authors participated in the discussion leading to
consensus definitions. We tried to avoid cumbersome definitions and have
mostly avoided the inclusion of specific techniques, antibodies, and
measurements/units in these definitions. Cumbersome definitions are
rarely used in practice and because of the progress in the CD research
field, statements on specific tests may rapidly become obsolete.
Our
research team was multi-disciplinary and was composed of specialists
from gastroenterology, pathology, paediatrics, neurology, and
dermatology. We hope that our definitions will be acceptable to all
specialties dealing with CD and gluten-related disorders and anticipate
that they will facilitate both research and clinical management of
patients with these disorders.
SUMMARY BOX
What is already known about this subject
There is a lack of consensus on the use of terms related to coeliac disease and gluten.
Variability
in the use of terminology has led to difficulty when comparing and
evaluating clinical studies and research findings.
What are the new findings
The
panel reached agreement regarding the definition of terms related to
coeliac disease and/or gluten currently in use in clinical practice and
research.
Some terms in current use should be abandoned because they are outdated or misleading.
How might it impact on clinical practice in the foreseeable future?
Uniform
definitions for common terms relating to coeliac disease will improve
communication between researchers, clinicians, and the general public,
and will ensure that research is conducted and reported in a consistent
manner.
Acknowledgments
Grant Support (Funding)
JFL
was supported by the Swedish Research Council (522-2A09-195) and the
Swedish Society of Medicine while writing the draft of this paper.
DAL is supported by the National Institute of Health (NIH DK1042103881).
Independence (role of the sponsors):
None of the funders had any role in the design and conduct of the
study; collection, management, analysis, and interpretation of the data;
and preparation, review, or approval of the manuscript.
Abbreviations used in this article
| AGA | anti-gliadin antibodies |
| CD | Coeliac disease |
| EMA | Endomysial antibodies |
| DH | Dermatitis herpetiformis |
| GFD | Gluten-free diet |
| IEL | Intraepithelial lymphocytes |
| TTG | Tissue transglutaminase antibodies |
Footnotes
Conflicts of interest/Disclosure requirement
All authors declare that they have no conflicts of interest and therefore nothing to declare.
Copyright statement
The
Corresponding Author has the right to grant on behalf of all authors
and does grant on behalf of all authors, an exclusive licence (or
non-exclusive for government employees) on a worldwide basis to the BMJ
Group and co-owners or contracting owning societies (where published by
the BMJ Group on their behalf), and its Licensees to permit this article
(if accepted) to be published in Gut and any other BMJ Group products and to exploit all subsidiary rights, as set out in our licence.
Contributors
CC
and DAL initiated the study. JFL coordinated the project, conducted the
web survey on coeliac disease definitions, and wrote the first draft of
the paper. All authors contributed to the literature searches,
contributed to the writing of the manuscript, and approved the final
version of the manuscript.
Contributor Information
- Jonas F Ludvigsson, Department of Paediatrics, Örebro University Hospital, 701 85 Örebro, Sweden and Clinical Epidemiology Unit, Department of Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden.
- Daniel A Leffler, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
- Julio Bai,
Department of Medicine, Dr C. Bonorino Udaondo Gastroenterology
Hospital. Del Salvador University, Buenos Aires, (1264) Argentina.
- Federico Biagi,
Coeliac Centre/1st Dept. of Internal Medicine, University of Pavia,
Fondazione IRCCS Policlinico San Matteo, P.le Golgi, 19, Pavia, 27100
Italy.
- Alessio Fasano, Center for Coeliac Research University of Maryland School of Medicine, Baltimore, Maryland, USA.
- Peter HR Green, MD Coeliac Disease center at Columbia University, New York, NY, 10032, USA.
- Marios Hadjivassiliou, Department of Neurology, Royal Hallamshire Hospital, Sheffield, 2JF UK.
- Katri Kaukinen, School of Medicine, FIN-33014 University of Tampere, Finland.
- Ciaran Kelly, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
- Jonathan N Leonard, Department of Dermatology, Imperial College NHS Healthcare Trust, St Mary’s Hospital, London W2 1NY, UK.
- Knut E Lundin, Dept of Gastroenterology and Centre for Immune Regulation, Oslo University Hospital, 0027 Oslo, Norway.
- Joseph A Murray, Mayo Clinic, Rochester, MN, USA.
- David S Sanders, Gastroenterology and Liver Unit, Royal Hallamshire Hospital & University of Sheffield, Sheffield, 2JF UK.
- Marjorie M Walker, Centre for Pathology, Faculty of Medicine, Imperial College, St Mary’s Hospital, London W2 1NY, UK.
- Fabiana Zingone, Department of Clinical and Experimental Medicine, Federico II University of Naples, Naples, 80131, Italy.
- Carolina Ciacci, Chair of Gastroenterology, University of Salerno, Salerno, 84084 Italy.
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