Gutjnl-2011-301346 1.10

Gut Online First, published on February 16, 2012 as 10.1136/gutjnl-2011-301346
The Oslo definitions for coeliac disease andrelated terms Jonas F Ludvigsson,1,2 Daniel A Leffler,3 Julio C Bai,4 Federico Biagi,5 Alessio Fasano,6Peter H R Green,7 Marios Hadjivassiliou,8 Katri Kaukinen,9 Ciaran P Kelly,3Jonathan N Leonard,10 Knut Erik Aslaksen Lundin,11 Joseph A Murray,12David S Sanders,13,14 Marjorie M Walker,14 Fabiana Zingone,15 Carolina Ciacci16 Objective The literature suggests a lack of consensus on the use of terms related to coeliac disease (CD) and gluten.
Design A multidisciplinary task force of 16 physicians from seven countries used the electronic database < There is a lack of consensus on the use of terms PubMed to review the literature for CD-related terms up related to coeliac disease (CD) and gluten.
to January 2011. Teams of physicians then suggested < Variability in the use of terminology has led to a definition for each term, followed by feedback of these difficulty when comparing and evaluating clinical definitions through a web survey on definitions, discussions during a meeting in Oslo and phone conferences. In addition to ‘CD’, the following descriptors of CD were evaluated (in alphabetical order): < The panel reached agreement on the definition asymptomatic, atypical, classical, latent, non-classical, of terms related to CD and/or gluten currently in overt, paediatric classical, potential, refractory, silent, use in clinical practice and research.
subclinical, symptomatic, typical, CD serology, CD < Some terms in current use should be abandoned autoimmunity, genetically at risk of CD, dermatitis because they are outdated or misleading.
herpetiformis, gluten, gluten ataxia, gluten intolerance,gluten sensitivity and gliadin-specific antibodies.
How might it impact on clinical practice in the Results CD was defined as ‘a chronic small intestinal immune-mediated enteropathy precipitated by exposure < Uniform definitions for common terms relating to dietary gluten in genetically predisposed individuals’.
Classical CD was defined as ‘CD presenting with signs researchers, clinicians and the general public, and symptoms of malabsorption. Diarrhoea, and will ensure that research is conducted and steatorrhoea, weight loss or growth failure is required.’ ‘Gluten-related disorders’ is the suggested umbrella termfor all diseases triggered by gluten and the term glutenintolerance should not to be used. Other definitions are The first consensus definition of CD was published in Acta Paediatrica in 1970.2 This publi- Conclusion This paper presents the Oslo definitions for cation defined CD as a permanent condition of gluten intolerance with mucosal flattening thatreversed on a gluten-free diet (GFD) and thenrelapsed on re-introduction of gluten. Although thedefinition of CD has undergone minor changes since 1970,3 4 consensus definitions have been Coeliac disease (CD) is a chronic small intestinal restricted to CD. However, the scientific commu- immune-mediated enteropathy precipitated by nity has come to recognise that there is a spectrum exposure to dietary gluten in genetically predis- of disorders related to gluten ingestion.
posed people. Although symptoms and signs of CD Due to a lack of common definitions for the have been recognised for more than 100 years, it spectrum of terms and disorders related to CD, was in the 1940s that the Dutch paediatrician a multidisciplinary task force of 16 physicians from Dicke established a link between the protein seven countries with particular expertise in diag- component of wheat (gluten) exposure and CD.1 nosis and treatment of CD proposes the following CD and related diseases are now common chronic definitions for the variety of vague and often diseases in children and adults, and increased diag- confusing terms currently in use in the literature.
nosis has led to a proliferation of research activities.
These definitions are based on thorough literature As with many other chronic conditions, the reviews (table 1), a discussion in Oslo at the 14th boundaries of CD are not always clear, with the International Coeliac Disease Symposium in June consequence that there is considerable confusion 2011, and agreement on consensus statements by and a lack of consensus regarding diagnostic criteria a web survey and phone conferences. We refer to our definitions as the ‘Oslo definitions’.
Ludvigsson JF, Leffler DA, Bai JC, et al. Gut (2012). doi:10.1136/gutjnl-2011-301346 Copyright Article author (or their employer) 2012. Produced by BMJ Publishing Group Ltd (& BSG) under licence.
included CD and the following descriptors of CD: asymptom- atic, 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.
The literature review was mostly restricted to original papers and reviews. Most papers had been published after 1990. The teams then suggested definitions for each term.
A web survey was then conducted and all suggested definitions were listed and subjected to peer review (online appendix).
Comments and feedback from the web survey were taken into account when creating a second set of definitions.
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 confer- ences in which the remaining definitions were discussed until consensus was achieved. We did not grade the evidence under- lying each definition because that was not the purpose of the task force and this review did not deal with clinical manage- ment. For the convenience of readers, each definition given in the Results section below 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’, which were discussed through email.
*We searched PubMed for the period 1 January 1900 to 31 January 2011. Individualauthors then examined papers deemed most relevant. When the phrase ‘coeliac disease’ ispart of the definition, we searched PubMed for the relevant term and coeliac disease (British and American spelling). For example, ‘silent coeliac disease’ [All Fields] OR ‘silent coeliac disease’ [All Fields] AND (‘1900/01/01’ [PDAT]: ‘2011/01/31’ [PDAT]).
yFor these terms, our literature review was entirely based on expert consensus of the Coeliac disease is a chronic small intestinal immune-mediated literature because it was beyond the scope of this paper to review all papers identified enteropathy precipitated by exposure to dietary gluten in through PubMed (or as in the case of ‘paediatric classical CD’ there were no hits).
zWe searched for ‘coeliac disease autoimmunity’ and ‘coeliac autoimmunity’ (British and genetically predisposed individuals.
CD is triggered by the ingestion of gluten (definition below), xA search for ‘gluten and antibodies’ yielded 2529 hits.
the protein component of wheat, rye, barley, but not oats.5 6 {Although we discourage the use of the term ‘CD serology’, we have provided a definitionfor this term.
Such exposure results in a variable degree of intestinal damage.7In most patients with CD, the enteropathy will reverse ona GFD.2e4 According to the suggested definition, CD is a chronic The purpose of our recommended definitions is to create disease, but as the discussion of the terms potential CD and a foundation for clinical management and research. Clear defi- latent CD will show, there are reports of transient CD.8 nitions will allow more efficient and generalisable advances in Although CD is the most common cause of enteropathy in CD research relating to aetiology, incidence, prevalence, the western world and enteropathy is a prerequisite for CD, it complications and treatment of patients with CD and other should be noted that other diseases may cause small intestinal inflammation but do not qualify as CD.9 Typically, the inflam-mation in CD includes an increased intraepithelial lymphocyte (IEL) count, most often >25/100 cells.9 10 Another feature of CD is that it incorporates an adaptive T-cell-mediated response (to Members of this collaborative effort were invited to participate gluten) and that it occurs in people who are DQ2eDQ8 posi- by two of the authors (DAL and CC). The constitution of the tive.11 12 Increasingly, the presence of specific endomysial anti- group reflects the wide variety of disciplines to which CD may bodies (EMA, also called AEA), anti-tissue transglutaminase present in practice: gastroenterology, histopathology, paediat- antibodies (TTG, a-tTG, TTA), and/or deamidated antigliadin rics, neurology and dermatology. Members of the task force were antibodies (DGP) plays an important role in the serological from Sweden, the USA, Argentina, Italy, the UK, Finland and work-up for CD. These antibodies strongly support the diag- Norway. Four of the five physicians from the USA had trained nosis of CD, but by themselves are not confirmatory.
elsewhere (two in Ireland, one in Australia and one in Italy).
To confirm a diagnosis of CD, biopsies of the duodenum must be taken when patients are on a gluten-containing diet.
Consensus states four to six biopsies are necessary for diag- Teams of three or four physicians were assigned between one nosis,13 including from the duodenal bulb.14 15 and four CD-related terms. Each team carried out a literature Three histological classifications of CD are used: Marsh,7 search (table 1) of the entire electronic database PubMed up to MarsheOberhuber16 and Corazza.10 A comparison of these January 2011 using the terms as key words. These terms classifications is shown in table 2.
Ludvigsson JF, Leffler DA, Bai JC, et al. Gut (2012). doi:10.1136/gutjnl-2011-301346 Comparison of histopathological classifications Normal architecture and increased intraepithelial lymphocytes $25/100 enterocytesNormal architecture and increased intraepithelial lymphocytes $40/100 enterocytesNormal architecture and increased intraepithelial lymphocytes $40/100 enterocytes with crypt hyperplasiaPartial villous atrophy and increased intraepithelial crypt height and influx ofinflammatory cells Type 3a partial villous atrophy;villi blunt and shortened witha villous:crypt ratio, 1:1 Type 3b subtotal villous atrophy;villi atrophic but still separateand recognisable Total villous atrophy intraepithelial lymphocytes Atrophic hypoplastic lesion: flat mucosa, normal crypt height, no inflammation with normal intraepitheliallymphocyte counts *Marsh initially explored the association of mucosal damage with a progressively increased gluten intake in treated patients with celiac disease. This staging has since been used asa classification.
Historically, CD has been equivalent to sprue, coeliac sprue, gluten-sensitive enteropathy and gluten intolerance. In the past Asymptomatic CD is not accompanied by symptoms even in the terms non-tropical sprue and idiopathic steatorrhoea were response to direct questioning at initial diagnosis.
used.17 18 None of these terms are currently recommended.
Individuals with asymptomatic CD do not manifest any symptoms commonly associated with CD and have no symp- toms that respond to gluten withdrawal, even in response to Gluten is the commonly used term for the complex of water direct questioning. These patients are often diagnosed through insoluble proteins from wheat, rye and barley that are harmful testing of populations enrolled in screening programmes or in case-finding strategies for detecting CD in patients with disor- The major seed proteins in cereals are the alcohol-soluble ders that are associated with a high risk for CD.21e33 Many of prolamins, a complex group of alcohol-soluble polypeptides these patients suffer from decreased quality of life. Sometimes that make up about half of the protein in the mature grain.
minor symptoms (eg, fatigue) are only recognised after the The term gluten indicates a broad group of prolamins (gliadins introduction of a GFD;34 such patients do not suffer from and glutenins) found in wheat. Other prolamins showing true asymptomatic CD and should be reclassified as having similar immunogenic properties are also found in rye (secalins), barley (hordeins) and other closely related grains.13 19 Themajor prolamins of the more distantly related maize (zeins) seem to have evolved independently and show no harmful Historically, typical CD has denoted a gluten-induced enterop- effects in patients with CD. Oats have also been shown to be athy presenting with signs or symptoms of malabsorption/ non-immunogenic in most patients with CD.20 A GFD usually global malabsorption (such as diarrhoea or malnutrition) or indicates a diet free from wheat, rye, barley, triticale, kamut a malabsorption syndrome (indicated by weight loss, steator- rhoea and oedema secondary to hypoalbuminemia). The above Gluten is poorly digested in the human intestine with or use is questionable in that the clinical presentation of CD has without CD. Gluten peptides cross intact into the submucosa of changed over time,35e37 and the word ‘typical’ implies that the small intestine. In the submucosa of the small intestine the this form is the most frequently encountered form of CD. In human enzyme transglutaminase 2 also referred to as tissue contrast, many current patients have symptoms such as transglutaminase (tTG) deamidates gluten peptides, which anaemia,38e40 fatigue41 42 and abdominal pain.43 allows for high-affinity binding to human leucocyte antigen We therefore discourage the use of the term typical CD.
(HLA) DQ2 and HLA DQ8 molecules, subsequently triggeringan inflammatory reaction in patients with CD.12 Gluten content in food is regulated by the Codex Alimentarius Atypical CD can only be used in reference to typical CD.
Historically, atypical CD has been used to describe patients with STAN 118e1979 revised in 2008) states that gluten-free foods gluten-induced enteropathy who have no weight loss but are foods or ingredients naturally free of gluten, in which the present with any of the following symptoms or signs: gastro- measured gluten level is #20 mg/kg in total, or processed to intestinal symptoms,44 including symptoms suggestive of irri- <100 mg/kg. According to the current Codex, foods meeting table bowel syndrome45 46 and liver dysfunction47 48; these criteria may be labelled as a ‘gluten-free food’.
extraintestinal manifestations, such as metabolic disease/ Ludvigsson JF, Leffler DA, Bai JC, et al. Gut (2012). doi:10.1136/gutjnl-2011-301346 symptoms (failure to thrive, thyroid dysfunction (hypo/ hyper))49 50; neurologic findings,51e53 including depression54 Symptomatic CD is characterised by clinically evident gastro- and gluten ataxia55; reproductive disease,56e58 including abnor- intestinal and/or extraintestinal symptoms attributable to malities in menarche and menopause58 59; oral/cutaneous disease,60e64 including dermatitis herpetiformis (DH);65 and The clinical manifestations of CD vary from none (asymp- skeletal findings.66 Atypical CD has also been used to denote tomatic CD) to a wide spectrum of symptoms. The vast patients with a gluten-induced enteropathy and significant majority of authors describing symptomatic CD do not distin- nutritional deficiencies (such as iron deficiency). We argue guish between CD with gastrointestinal symptoms and CD that the term atypical CD should not be used. Some patients previously described as having atypical CD may fulfil the What was previously called overt CD should be considered requirements for non-classical CD (see below).
Classical CD presents with signs and symptoms of malabsorp- Overt CD has most often been characterised by clinically tion. Diarrhoea, steatorrhoea, weight loss or growth failure is (dyspepsia, diarrhoea and bloating) or extraintestinal (neuro- Classical and typical CD have traditionally been similar logical symptoms and fatigue).99 100 We recommend that the concepts defining the presence of a gluten-induced enteropathy term overt CD should not be used; symptomatic CD is the presenting with diarrhoea, malnutrition or a malabsorption syndrome (indicated by weight loss, steatorrhoea and oedemasecondary to hypoalbuminemia).7 67 these symptoms are not specific to CD, we encourage the use of Refractory CD (RCD) consists of persistent or recurrent classical CD, as defined above, because the term ‘classical’ does malabsorptive symptoms and signs with villous atrophy (VA) not imply that this type of CD is more common than CD despite a strict GFD for more than 12 months.
without clinical malabsorption. Examples of classical CD are Although definitions of RCD differ slightly,101e118 most patients with diarrhoea and weight loss but also patients with expert-opinion-based definitions include persistence or recur- rence of malabsorptive symptoms and signs (eg, diarrhoea, Paediatric classical CD is the paediatric equivalent of classical abdominal pain, involuntary loss of weight, low haemoglobin CD. These children are often characterised by failure to thrive, and hypoalbuminemia) associated with persistent or recurrent diarrhoea, muscle wasting, poor appetite and abdominal VA despite a strict GFD for more than 12 months (or severe distension.75e79 Many children with classical CD and malab- persistent symptoms independently of the duration of GFD) in sorption also show signs of emotional distress (‘change of the absence of other causes of VA or malignant complications119 and after the confirmation of the initial diagnosis of CD.
Generally, most patients are negative for EMA and TTG at the time of RCD diagnosis, but the presence of persisting elevated titres of circulating EMA and/or TTG does not neces- Non-classical CD presents without signs and symptoms of sarily rule out RCD, though this should lead to questions about dietary adherence. In all cases, a careful dietary interview In non-classical CD the patient does not suffer from malab- should be performed to exclude gluten exposure before sorption (eg, a patient with constipation and abdominal diagnosing RCD.120 Not all dietary non-responsive CD is pain but no malabsorption). Patients with monosymptomatic disease (other than diarrhoea or steatorrhoea) usually have RCD is divided into two categories111 115: type I, in which a normal IEL phenotype is found; and type II, in which there isa clonal expansion of an aberrant IEL population. The abnormal phenotype is supported by loss of normal surface markers CD3, Silent CD is equivalent to asymptomatic CD. We discourage the CD4 and CD8 with preserved expression of intracytoplasmic CD3 (CD3e) in >50% of IELs as evaluated by immunohisto-chemistry or >20% as determined by flow cytometry, and by Subclinical CDSubclinical CD is below the threshold of clinical detection.
The term subclinical has often been used to denote silent CD80e82 or patients with CD and extraintestinal symptoms(and no gastrointestinal symptoms).83 The term has also beenused for patients with CD who have 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 associa- tions have been regularly found and populations tested for CDhave changed in response. For this reason, what is ‘subclinical’has changed over time. To provide a stable definition, we spec-ified subclinical CD to be disease that is below the threshold ofclinical detection without signs or symptoms sufficient totrigger CD testing in routine practice.
often been used interchangeably, resulting in confusion, we test positive for HLA-DQ2 or HLA-DQ8, with the under- discourage the use of the term latent CD.
standing that the risk varies between 2% and 20%, depending onthe degree of the relative with CD and the number of copies of HLA-DQ2 genes. However, people who harbour these genes are Potential CD relates to people with a normal small intestinal mucosa who are at increased risk of developing CD as indicatedby positive CD serology.
Potential CD is also often used with different meanings. For The term gluten intolerance has been used as a synonym of some, potential CD means that the patient has an increased CD and to indicate that a patient experiences a clinical number of IELs in the villi138 or increased expression of g or improvement after starting a GFD, even when they do not have d cells.139 To others, potential CD describes people with normal CD.8 76 122 155e166 However, we believe the term gluten intol- mucosa but positive CD serology.140 141 Adding to this is the erance is non-specific and carries inherent weaknesses and suggestion by Ferguson et al that all first-degree relatives to contradictions. Although gluten intolerance could be a conse- quence of poor digestion, it could also be the effect of some We recommend that the term potential CD be used for people lectin-like properties of gluten or foods generated from gluten with normal small intestinal mucosa who are at increased risk of that cause gastrointestinal upset. Another problem is that gluten developing CD as indicated by positive CD serology. A difficulty intolerance may not truly reflect intolerance to gluten but to in the definition of this group is variability in the adequacy of other wheat components.156 Because of these contradictions, we the biopsies that were taken to exclude the diagnosis of active recommend that the term gluten intolerance should not be used CD, especially with the current knowledge that at least four and that gluten-related disorders be used instead.
biopsies need to be taken143 and the bulb may be the onlylocation of VA.15 Gluten-related disordersGluten-related disorders is a term used to describe all conditions CD autoimmunity relates to increased TTG or EMA on at least We recommend that this term is used to describe all condi- two occasions when status of the biopsy is not known. If the tions related to gluten. This may include disorders such as biopsy is positive, then this is CD, if the biopsy is negative than gluten ataxia, DH, non-coeliac gluten sensitivity (NCGS) and The term ‘coeliac disease autoimmunity’ or ‘coeliac autoim- munity’ has been used to describe: individuals with positive TTG,144e147 positive EMA,148 positive EMA with positive/ In some papers the term gluten sensitivity is used synony- borderline TTG,149 positive TTG on at least two occasions,150 mously with CD.7 Other papers used the concept of gluten and positive TTG on two occasions or a positive small bowel sensitivity as an umbrella term to include CD and other condi- biopsy after only a single positive TTG.151 tions related to gluten ingestion, such as DH,169 gluten ataxia170 We defined CD autoimmunity as positive TTG or EMA on at and NCGS.156 Most recently,157 171e174 several authors least two occasions. In a clinical setting this will lead to a small employed the term gluten sensitivity to describe a condition in intestinal biopsy, and patients can then be classified as either CD which symptoms are triggered by gluten ingestion, in the (positive biopsy) or potential CD (negative biopsy), but in absence of TTG or EMA antibodies and enteropathy, with a research setting there are circumstances when small intestinal variable HLA status and variable anti-gliadin (AGA) presence. It biopsy has not been performed. The term CD autoimmunity is important to distinguish CD from less well characterised should then be used. When TTG or EMA has only been tested diseases related to gluten ingestion. We therefore recommend on one occasion, it is preferable to refer to patients as TTG that the term gluten sensitivity should not be used and that Family members of patients with CD that test positive for HLA The term NCGS relates to one or more of a variety of immu- DQ2 and/or DQ8 are genetically at risk of CD.
nological, morphological or symptomatic manifestations that CD is a multifactorial condition with unparallelled evidence of are precipitated by the ingestion of gluten in people in whom the pivotal role of HLA-DQA1*05-DQB1*02 (DQ2) and DQA1*03-DQB1*0302 (DQ8) in disease predisposition.152 153 NCGS is a condition in which gluten ingestion leads to DQ2 and DQ8 are major risk factors carried by almost all morphological or symptomatic manifestations despite the patients with CD. Interestingly, when carried in trans on DR5/ absence of CD.172e176 As opposed to CD, NCGS may show signs DR7 (ie, DQA1*05-DQB1*0301/DQA1*0201-DQB1*02) or DR3/ of an activated innate immune response but without the DR7 (ie, DQA1*05-DQB1*02/DQA1*0201-DQB1*02) genotypes, enteropathy, elevations in tTG, EMA or DGP antibodies, and the risk of CD in southern Europeans is higher than when the alleles are carried in cis on DR3 (ie, DQA1*05-DQB1*02) alone, Recently, in a double-blind randomised trial, Biesiekierski et al suggesting that additional factors in the region may be influ- showed that patients with NCGS truly develop symptoms when eating gluten.156 It is unclear at this time what compo- Non-HLA genes together contribute more to genetic suscep- nents of grains trigger symptoms in people with NCGS and tibility (approximately 65%) than the HLA genes (the remaining whether some populations of patients with NCGS have subtle 35%), but the contribution from each single, predisposing non- small intestinal morphological changes. While there is currently no standard diagnostic approach to NCGS, systematic evalua- At the moment, the concept of genetically at risk for CD tion should be conducted, including exclusion of CD and other should be limited to family members (of patients with CD) who Ludvigsson JF, Leffler DA, Bai JC, et al. Gut (2012). doi:10.1136/gutjnl-2011-301346 Gliadin-specific antibodiesThese are AGAs of IgA and IgG subclass recognising the gliadinmoiety of wheat. Antibodies recognising native gluten are nowrarely used for diagnostic purposes because they lack generalspecificity. Antibodies recognising DGP demonstrate high spec-ificity and sensitivity. They can also be used for measurement ofgluten in foodstuffs.
Use of the term gliadin-specific antibodies generally refers to antibodies directed against the gliadin moiety of wheat prola-mins. The following four aspects of these antibodies are relevantto the spectrum of gluten-induced disease.
Diagnostic valueAfter introduction in the 1980s, IgA antibodies against wheatgliadin (AGAs) served as the best serological test for CD for someyears.177 178 However, the low positive predictive value179 meantthat this test has since been abandoned for the investigationof CD,13 179 except for in children younger than 18 months, inwhom IgA AGA seems to have high sensitivity.180 Recently,assays for IgA and IgG antibodies against DGP have been definitions. We tried to avoid cumbersome definitions and have Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A mostly avoided the inclusion of specific techniques, antibodies molecular and immunobiologic approach to the spectrum of gluten sensitivity(‘celiac sprue’). Gastroenterology 1992;102:330 and measurements or units in these definitions. Cumbersome Walker-Smith JA. Transient gluten intolerance. Arch Dis Child 1996;74:183e4.
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