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lördag 20 januari 2018

Kromosomi 18.n eräs geeni SMAD7

Immunology. 2017 Mar;150(3):356-363. doi: 10.1111/imm.12690. Epub 2016 Dec 12.

High Smad7 sustains inflammatory cytokine response in refractory coeliac disease.

Abstract

Refractory coeliac disease (RCD) is a form of coeliac disease (CD) resistant to gluten-free diet and associated with elevated risk of complications. Many effector cytokines over-produced in the gut of patients with RCD are supposed to amplify the tissue-destructive immune response, but it remains unclear if the RCD-associated mucosal inflammation is sustained by defects in counter-regulatory mechanisms. The aim of the present study was to determine whether RCD-related inflammation is marked by high Smad7, an intracellular inhibitor of transforming growth factor-β1 (TGF-β1 ) activity. Smad7 was evaluated in duodenal biopsy samples of patients with RCD, patients with active CD, patients with inactive CD and healthy controls by Western blotting, immunohistochemistry and real-time PCR. In the same samples, TGF-β1 and phosphorylated (p)-Smad2/3 were evaluated by ELISA and immunohistochemistry, respectively. Pro-inflammatory cytokine expression was evaluated in RCD samples cultured with Smad7 sense or antisense oligonucleotide. Smad7 protein, but not RNA, expression was increased in RCD compared with active and inactive CD patients and healthy controls and this was associated with defective TGF-β1 signalling, as marked by diminished p-Smad2/3 expression. TGF-β1 protein content did not differ among groups. Knockdown of Smad7 in RCD biopsy samples reduced interleukin-6 and tumour necrosis factor-α expression. In conclusion, in RCD, high Smad7 associates with defective TGF-β1 signalling and sustains inflammatory cytokine production. These results indicate a novel mechanism by which the mucosal cytokine response is amplified in RCD and suggest that targeting Smad7 can be therapeutically useful in RCD.
KEYWORDS:
gluten; inflammation; mucosal immune response; transforming growth factor-β
PMID:
27861825
PMCID:
PMC5290231
[Available on 2018-03-01]
DOI:
10.1111/imm.12690
[Indexed for MEDLINE]

söndag 7 januari 2018

Kaurapellon, kaurapellon pellon kaurapellon pientarella

kasvoi pieni kukka!
https://youtu.be/VrmFQn_tZdU

 https://www.ncbi.nlm.nih.gov/pubmed/22825364
Despite excellent villous recovery in this study, persistent intraepithelial lymphocytosis was still common among celiac disease patients on a long-term strict gluten-free diet. Consumption of oats was associated with persistent duodenal lymphocytosis and this calls for further investigations. The prognosis of patients with persistent intraepithelial lymphocytosis seems to be good while adhering to a gluten-free diet for a mean of 11 years.

Vehnäpöly ja keuhkot

https://www.ncbi.nlm.nih.gov/pubmed/12822139
Am J Ind Med. 2003 Jul;44(1):75-82.

Wheat flour exposure results in recruitment of inflammatory cells in the lungs of healthy individuals.

Abstract
BACKGROUND:
Flour dust in bakeries is known to cause allergic as well as nonallergic respiratory symptoms. Fungal alpha-amylase is a commonly used baking additive that has been shown to have allergenic properties. The aim of this study was to investigate any effects on bronchoalveolar lavage (BAL) cells and peripheral blood lymphocytes (PBL) of healthy individuals exposed to airborne wheat flour dust with or without fungal alpha-amylase added.
METHODS:
Fifteen subjects were exposed during 1 hr in an exposure chamber, ten individuals to wheat flour alone and five with alpha-amylase added. BAL was performed 2-6 weeks before and 1 day after the exposure. BAL cells were differentially counted and flowcytometric analysis of the expression of activation, adhesion, and subset markers on alveolar macrophages (AM) and T cells in BAL fluid and peripheral blood were carried out.
RESULTS:
Exposure to wheat flour dust increased the total number of cells in BAL fluid from 75.4 (i.q. range 70.4-104.1) to 127.4 (92.1-187.4) cells x 10(6)/L, P < 0.01. There was a significant difference in the change of total BAL cell concentration between the study group exposed to wheat flour only (n = 10; increase with 91.9 x 10(6)/L) and the group exposed to wheat flour with the baking additive fungal alpha-amylase (n = 5; decrease with 5.4 x 10(6)/L). The exposure level of respirable dust was lower in the group that received alpha-amylase and the increase in BAL cell concentration showed a positive correlation with the concentration of respirable dust in the exposure chamber (r = 0.80, P < 0.001). The phenotypic analysis of AM indicated an influx of monocytic cells.
CONCLUSIONS:
The results indicate that the concentration of respirable dust, but not alpha-amylase, is of importance for the recruitment of inflammatory cells to the peripheral airways in healthy individuals exposed to wheat flour dust.

Alveolioireinen keliakia?

https://www.ncbi.nlm.nih.gov/pubmed/?term=alveolar+coeliacia

ICDS 2011. 14. konferenssi Oslossa (vehnä, ruis, ohra ag käsitelty)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3440559/
SITAATTI  netistä

Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Gut. Author manuscript; available in PMC 2014 Jan 1.
Published in final edited form as:
Published online 2012 Feb 16. doi:  10.1136/gutjnl-2011-301346
PMCID: PMC3440559
NIHMSID: NIHMS382798

The Oslo definitions for coeliac disease and related terms

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 (Table 1), 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”.
Table 1
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 (Table 1). 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.24 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 –Oberhuber16 and Corazza10. A comparison of these classifications is shown in Table 2.
Table 2
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 CD2133 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,3537 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,3840 fatigue,41, 42 and abdominal pain43.
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) symptoms44 including symptoms suggestive of irritable bowel syndrome,45, 46 and liver dysfunction47, 48; (b) extraintestinal manifestations, such as metabolic disease/symptoms (failure to thrive, thyroid dysfunction (hypo/hyper)49, 50; (c) neurologic findings,5153 including depression54 and gluten ataxia55; (d) reproductive disease5658 including abnormalities in menarche and menopause58, 59; (e) oral/cutaneous disease6064 including dermatitis herpetiformis (DH)65; and (f) skeletal findings66. 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, 6774 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.7579 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 CD8082 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.8598
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,101118 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 complications119 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.121123
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 VA124129 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.130134 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 villi138 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 taken143 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 TTG144147, positive EMA148, positive EMA with positive/borderline TTG149, positive TTG on at least two occasions150, and positive TTG on 2 occasions or a positive small bowel biopsy after only a single positive TTG151.
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, 155166 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, 171174 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.172176 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 value179 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 introduced181 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.185187 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 ataxia170, 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, 191199
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 skin200202 DH is strongly linked to an immune mediated enteropathy precipitated by gluten, 65, 203205 and responds to a GFD.206209 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.24 As opposed to previous studies,24 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

  1. There is a lack of consensus on the use of terms related to coeliac disease and gluten.
  2. Variability in the use of terminology has led to difficulty when comparing and evaluating clinical studies and research findings.

What are the new findings

  1. The panel reached agreement regarding the definition of terms related to coeliac disease and/or gluten currently in use in clinical practice and research.
  2. 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?

  1. 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

AGAanti-gliadin antibodies
CDCoeliac disease
EMAEndomysial antibodies
DHDermatitis herpetiformis
GFDGluten-free diet
IELIntraepithelial lymphocytes
TTGTissue 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

  1. 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.
  2. Daniel A Leffler, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
  3. Julio Bai, Department of Medicine, Dr C. Bonorino Udaondo Gastroenterology Hospital. Del Salvador University, Buenos Aires, (1264) Argentina.
  4. Federico Biagi, Coeliac Centre/1st Dept. of Internal Medicine, University of Pavia, Fondazione IRCCS Policlinico San Matteo, P.le Golgi, 19, Pavia, 27100 Italy.
  5. Alessio Fasano, Center for Coeliac Research University of Maryland School of Medicine, Baltimore, Maryland, USA.
  6. Peter HR Green, MD Coeliac Disease center at Columbia University, New York, NY, 10032, USA.
  7. Marios Hadjivassiliou, Department of Neurology, Royal Hallamshire Hospital, Sheffield, 2JF UK.
  8. Katri Kaukinen, School of Medicine, FIN-33014 University of Tampere, Finland.
  9. Ciaran Kelly, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
  10. Jonathan N Leonard, Department of Dermatology, Imperial College NHS Healthcare Trust, St Mary’s Hospital, London W2 1NY, UK.
  11. Knut E Lundin, Dept of Gastroenterology and Centre for Immune Regulation, Oslo University Hospital, 0027 Oslo, Norway.
  12. Joseph A Murray, Mayo Clinic, Rochester, MN, USA.
  13. David S Sanders, Gastroenterology and Liver Unit, Royal Hallamshire Hospital & University of Sheffield, Sheffield, 2JF UK.
  14. Marjorie M Walker, Centre for Pathology, Faculty of Medicine, Imperial College, St Mary’s Hospital, London W2 1NY, UK.
  15. Fabiana Zingone, Department of Clinical and Experimental Medicine, Federico II University of Naples, Naples, 80131, Italy.
  16. Carolina Ciacci, Chair of Gastroenterology, University of Salerno, Salerno, 84084 Italy.

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