Carlo Catassi

European Society for Pediatric Gastroenterology, Hepatology, and Nutrition Guidelines for the Diagnosis of Coeliac Disease

Objective: Diagnostic criteria for coeliac disease (CD) from the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) were published in 1990. Since then, the autoantigen in CD, tissue transglutaminase, has been identified; the perception of CD has changed from that of a rather uncommon enteropathy to a common multiorgan disease strongly dependent on the haplotypes human leukocyte antigen (HLA)-DQ2 and HLA-DQ8; and CD-specific antibody tests have improved. Methods: A panel of 17 experts defined CD and developed new diagnostic criteria based on the Delphi process. Two groups of patients were defined with different diagnostic approaches to diagnose CD: children with symptoms suggestive of CD (group 1) and asymptomatic children at increased risk for CD (group 2). The 2004 National Institutes of Health/Agency for Healthcare Research and Quality report and a systematic literature search on antibody tests for CD in paediatric patients covering the years 2004 to 2009 was the basis for the evidence-based recommendations on CD-specific antibody testing. Results: In group 1, the diagnosis of CD is based on symptoms, positive serology, and histology that is consistent with CD. If immunoglobulin A anti-tissue transglutaminase type 2 antibody titers are high (>10 times the upper limit of normal), then the option is to diagnose CD without duodenal biopsies by applying a strict protocol with further laboratory tests. In group 2, the diagnosis of CD is based on positive serology and histology. HLA-DQ2 and HLA-DQ8 testing is valuable because CD is unlikely if both haplotypes are negative. Conclusions: The aim of the new guidelines was to achieve a high diagnostic accuracy and to reduce the burden for patients and their families. The performance of these guidelines in clinical practice should be evaluated prospectively.

Coeliac disease in the year 2000: exploring the iceberg

It is now generally believed that subclinical coeliac disease is common in the general population. We have undertaken screening for this disorder in a school district in central Italy. Screening was divided into three levels: first, IgG and IgA antigliadin antibody (AGA) assay on capillary blood obtained by finger prick; second, AGA plus IgA anti-endomysium antibody (AEA) test and measurement of serum immunoglobulins in venous blood; and third, intestinal biopsy. 3351 students (66% of the eligible population) aged 11-15 years attended first-level screening. 71 (2%) were recalled because of AGA positivity; 18 of these satisfied second-level criteria and underwent intestinal biopsy. Coeliac disease was diagnosed in 11 subjects, most of whom had no serious symptoms. Selective IgA deficiency was found in 4 subjects, 1 of whom also had coeliac disease. The prevalence of subclinical coeliac disease in the study group was 3.28 per 1000. Coeliac disease screening is feasible and involves only slight discomfort to the general population. Such screening can detect large numbers of cases of coeliac disease, which can be treated with a gluten-free diet. Many subclinical cases of coeliac disease would not be detected by screening only a selected group of at-risk patients.

Spectrum of gluten-related disorders: consensus on new nomenclature and classification

A decade ago celiac disease was considered extremely rare outside Europe and, therefore, was almost completely ignored by health care professionals. In only 10 years, key milestones have moved celiac disease from obscurity into the popular spotlight worldwide. Now we are observing another interesting phenomenon that is generating great confusion among health care professionals. The number of individuals embracing a gluten-free diet (GFD) appears much higher than the projected number of celiac disease patients, fueling a global market of gluten-free products approaching

The prevalence of celiac disease in Europe: Results of a centralized, international mass screening project

2.5 billion (US) in global sales in 2010. This trend is supported by the notion that, along with celiac disease, other conditions related to the ingestion of gluten have emerged as health care concerns. This review will summarize our current knowledge about the three main forms of gluten reactions: allergic (wheat allergy), autoimmune (celiac disease, dermatitis herpetiformis and gluten ataxia) and possibly immune-mediated (gluten sensitivity), and also outline pathogenic, clinical and epidemiological differences and propose new nomenclature and classifications.

The coeliac iceberg in Italy. A multicentre antigliadin antibodies screening for coeliac disease in school-age subjects

Abstract Introduction. Although the prevalence of celiac disease (CD) has been extensively investigated in recent years, an accurate estimate of CD frequency in the European population is still lacking. The aims of this study were: 1) to establish accurately the prevalence of CD in a large sample of the European population (Finland, Germany, Italy, and UK), including both children and adults; and 2) to investigate whether the prevalence of CD significantly varies between different areas of the European continent. Materials and methods. Samples were drawn from the four populations. All 29,212 participants were tested for CD by tissue transglutaminase (tTG) antibody test. Positive and border-line findings were further tested for serum endomysial antibodies (EMA). All serological determinations were centrally performed. Small-bowel biopsies were recommended to autoantibody-positive individuals. Previously diagnosed cases were identified. Results. The overall CD prevalence (previously diagnosed plus anti-tTG and EMA positives) was 1.0% (95% CI 0.9–1.1). In subjects aged 30–64 years CD prevalence was 2.4% in Finland (2.0–2.8), 0.3% in Germany (0.1–0.4), and 0.7% in Italy (0.4–1.0). Sixty-eight percent of antibody-positive individuals showed small-bowel mucosal changes typical for CD (Marsh II/III lesion). Conclusions. CD is common in Europe. CD prevalence shows large unexplained differences in adult age across different European countries.

Clinical practice. Celiac disease.

Background: Recent studies suggest that coeliac disease (CD) is one of the commonest, life‐long disorders in Italy. The aims of this multicentre work were: (a) to establish the prevalence of CD on a nationwide basis; and (b) to characterize the CD clinical spectrum in Italy. Patients and methods: Fifteen centres screened 17201 students aged 6–15 years (68.6% of the eligible population) by the combined determination of serum IgG‐ and IgA‐antigliadin antibody (AGA) test; 1289 (7.5%) were IgG and/or IgA‐AGA positive and were recalled for the second‐level investigation; 111 of them met the criteria for the intestinal biopsy: IgA‐AGA positivity and/or AEA positivity or IgG‐AGA positivity plus serum IgA deficiency. Results: Intestinal biopsy was performed on 98 of the 111 subjects. CD was diagnosed in 82 subjects (75 biopsy proven, 7 not biopsied but with associated AGA and AEA positivity). Most of the screening‐detected coeliac patients showed low‐grade intensity illness often associated with decreased psychophysical well‐being. There were two AEA negative cases with associated CD and IgA deficiency. The prevalence of undiagnosed CD was 4.77 × 1000 (95% CI 3.79–5.91), 1 in 210 subjects. The overall prevalence of CD, including known CD cases, was 5.44 × 1000 (95% CI 4.57–6.44), 1 in 184 subjects. The ratio of known to undiagnosed CD cases was 1 in 7. Conclusions: These findings confirm that, in Italy, CD is one of the most common chronic disorders showing a wide and heterogeneous clinical spectrum. Most CD cases remain undiagnosed unless actively searched.

Non-Celiac Gluten Sensitivity: The New Frontier of Gluten Related Disorders

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Gliadin, zonulin and gut permeability: Effects on celiac and non-celiac intestinal mucosa and intestinal cell lines

Non Celiac Gluten sensitivity (NCGS) was originally described in the 1980s and recently a “re-discovered” disorder characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected with either celiac disease (CD) or wheat allergy (WA). Although NCGS frequency is still unclear, epidemiological data have been generated that can help establishing the magnitude of the problem. Clinical studies further defined the identity of NCGS and its implications in human disease. An overlap between the irritable bowel syndrome (IBS) and NCGS has been detected, requiring even more stringent diagnostic criteria. Several studies suggested a relationship between NCGS and neuropsychiatric disorders, particularly autism and schizophrenia. The first case reports of NCGS in children have been described. Lack of biomarkers is still a major limitation of clinical studies, making it difficult to differentiate NCGS from other gluten related disorders. Recent studies raised the possibility that, beside gluten, wheat amylase-trypsin inhibitors and low-fermentable, poorly-absorbed, short-chain carbohydrates can contribute to symptoms (at least those related to IBS) experienced by NCGS patients. In this paper we report the major advances and current trends on NCGS.

Detection of Celiac Disease in Primary Care: A Multicenter Case-Finding Study in North America

Objective. Little is known about the interaction of gliadin with intestinal epithelial cells and the mechanism(s) through which gliadin crosses the intestinal epithelial barrier. We investigated whether gliadin has any immediate effect on zonulin release and signaling. Material and methods. Both ex vivo human small intestines and intestinal cell monolayers were exposed to gliadin, and zonulin release and changes in paracellular permeability were monitored in the presence and absence of zonulin antagonism. Zonulin binding, cytoskeletal rearrangement, and zonula occludens-1 (ZO-1) redistribution were evaluated by immunofluorescence microscopy. Tight junction occludin and ZO-1 gene expression was evaluated by real-time polymerase chain reaction (PCR). Results. When exposed to gliadin, zonulin receptor-positive IEC6 and Caco2 cells released zonulin in the cell medium with subsequent zonulin binding to the cell surface, rearrangement of the cell cytoskeleton, loss of occludin-ZO1 protein–protein interaction, and increased monolayer permeability. Pretreatment with the zonulin antagonist FZI/0 blocked these changes without affecting zonulin release. When exposed to luminal gliadin, intestinal biopsies from celiac patients in remission expressed a sustained luminal zonulin release and increase in intestinal permeability that was blocked by FZI/0 pretreatment. Conversely, biopsies from non-celiac patients demonstrated a limited, transient zonulin release which was paralleled by an increase in intestinal permeability that never reached the level of permeability seen in celiac disease (CD) tissues. Chronic gliadin exposure caused down-regulation of both ZO-1 and occludin gene expression. Conclusions. Based on our results, we concluded that gliadin activates zonulin signaling irrespective of the genetic expression of autoimmunity, leading to increased intestinal permeability to macromolecules.

Introduction of Gluten, HLA Status, and the Risk of Celiac Disease in Children

BACKGROUND:Celiac disease (CD) is one of the most common lifelong disorders in western countries. However, most cases remain currently undiagnosed in North America, mostly due to poor awareness of CD by primary care physicians.OBJECTIVES:The aims of this study were (a) to determine whether an active case-finding strategy in primary care could increase the frequency of CD diagnosis and (b) to determine the most common clinical presentations of the condition.METHODS:This was a multicenter, prospective study involving adult subjects during the years 2002–2004, attending one of the participating practices. All individuals with symptoms or conditions known to be associated with CD were tested for immunoglobulin A anti-transglutaminase (tTG) antibodies, and those with elevated anti-tTG were subsequently tested for IgA antiendomysial antibodies (EMA). All subjects who were positive for EMA were advised to undergo an intestinal biopsy and HLA typing.RESULTS:The study group included 737 women and 239 men, with a median age of 54.3 yr. A positive anti-tTG test was found in 30 out of 976 investigated subjects (3.07%, 95% CI 1.98–4.16). CD was diagnosed in 22 patients (18 women, 4 men). The most frequent reasons for CD screening in these 22 cases were bloating (12/22), thyroid disease (11/22), irritable bowel syndrome (7/22), unexplained chronic diarrhea (6/22), chronic fatigue (5/22), and constipation (4/22). The prevalence of CD in the serologically screened sample was 2.25% (95% CI 1.32–3.18). The diagnostic rate was low at baseline (0.27 cases per thousand visits, 95% CI 0.13–0.41) and significantly increased to 11.6 per thousand visits (95% CI 6.8–16.4, P < 0.001) following active screening implementation.CONCLUSIONS:This study demonstrates that an active case-finding strategy in the primary care setting is an effective means to improve the diagnostic rate of CD in North America.