Review
Diagnosis and classification of celiac disease and gluten sensitivity
Introduction
Celiac disease (CD) is a chronic, immune-mediated, gluten-induced gut disorder that manifests itself with a range of clinical symptoms in genetically susceptible subjects. Immune reaction to wheat, barley and rye gliadin fractions and glutenins [1] triggers an inflammatory state of the duodenal mucosa: the result is reduced intestinal villus height and hyperplastic cryptae that may lead to complete villus atrophy. The critical role played by gluten is demonstrated by the fact that in CD patients on a gluten free diet (GFD) clinical symptoms disappear, anti-transglutaminase 2 antibodies (anti-tTG2, the serological markers of the disorder) normalize, and villus atrophy recedes. As to the role of genetic factors, CD development has been demonstrated to be closely associated with MHC class II HLA-DQ2 and HLA-DQ8 molecules; in fact, virtually all CD patients express at least one of these HLA molecules compared to the general population in which about 30–35% have either DQ2 or DQ8 [2], [3].
A new gluten-associated clinical condition, named ‘non-celiac gluten sensitivity’ (NCGS) [4], also described in literature as gluten hypersensitivity or gluten intolerance, has been recently identified. NCGS is characterized by gastrointestinal or extraintestinal symptoms comparable, in many cases, to those of CD patients; however, to date no specific immunological mechanisms or serological markers have been identified for this disorder. The diagnosis is made by exclusion of CD or IgE-mediated allergy to wheat, and is based on the direct association between gluten ingestion and symptom onset.
Section snippets
Pathogenesis
CD is initiated by the ingestion of gliadin which is present in foods containing wheat, barley and rye. It is well established that the pathogenic mechanism is related to an alteration in the integrity of the tight junction system of intestinal epithelium cells, enabling the passage of macromolecules such as gluten in the submucosa. Gluten is an excellent substrate for transglutaminase 2 (TG2, also known as tissue transglutaminase). This enzyme converts glutamine residues into negatively
Epidemiology
The development of highly sensitive immunological methods for identifying diagnostic antibodies (e.g. anti-tTG autoantibodies and anti-DGP antibodies) has enabled an increasing number of CD patients with vague or asymptomatic clinical presentations to be identified. Population-based studies now indicate that approximately 0.5–1% of the Western European and Northern American populations suffer from CD. In a recent paper, Abadie and coworkers [8] correlate gluten consumption with HLA DQ2 and DQ8
Clinical manifestations
CD is characterized by multiple clinical expressions. An ESPGHAN (European Society for Paediatric Gastroenterology, Hepatology and Nutrition) working group has recently developed new guidelines for the diagnosis of CD based on scientific and technical developments using an evidence-based approach [10]. The ESPGHAN working group decided to revise the classification, also taking into consideration signs and symptoms that had not been considered in the previous classification. In particular, it
Antibodies
The serological diagnosis of CD is based on the detection of class IgA anti-tTG and EMA antibodies. In patients with IgA deficiency, IgG anti-DGP or anti-tTG is used [11]. Anti-tTG measurement can be performed on serum or plasma samples through different immunometric methods (ELISA, radioimmunoassay, fluorimetric assays, etc.) using human or recombinant purified TG2. Anti-tTG tests currently in use provide quantitative results expressed in arbitrary units and calculated on the basis of
Intestinal biopsy
CD is characterized by varying degrees of atrophy of the intestinal mucosa, with reduced height or disappearance of the villi. The degree of the intestinal lesion is defined on the basis of the widely used Marsh–Oberhuber classification [19] which describes the degree of architectural changes in the mucosa and outlines three categories of CD-associated lesion:
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Type 1: infiltrative
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Type 2: infiltrative–hyperplastic
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Type 3: atrophic: 3a) mild villous atrophy, 3b) moderate villous atrophy, 3c) total
Diagnostic criteria
The diagnostic criteria proposed by ESPGHAN in 1990 [20] envisaged the performance of gastroduodenoscopy and histological confirmation of mucosal damage as the conclusive phase of the diagnostic process. These criteria did not indicate which serological tests should be positive, were not applicable to children aged below 2 years, and in any case required other clinical conditions to be ruled out. Therefore, in 2010, the ESPGHAN working group deemed appropriate to set out new criteria based on
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