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. HLADQ2 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. (JPGN 2012;54: 136–160)

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

/pdf/pathology-and-genetics-of-tumours-of-the-digestive-system-3xy9cwrc3c.pdf

Pathology and genetics of tumours of the digestive system

Gluten, major histocompatibility complex, and the small intestine: A molecular and immunobiologic approach to the spectrum of gluten sensitivity (‘celiac sprue’)

Celiac disease is characterized by small intestinal damage with loss of absorptive villi and hyperplasia of the crypts, typically leading to malabsorption. In addition to nutrient deficiencies, prolonged celiac disease is associated with an increased risk for malignancy, especially intestinal T-cell lymphoma. Celiac disease is precipitated by ingestion of the protein gliadin, a component of wheat gluten, and usually resolves on its withdrawal. Gliadin initiates mucosal damage which involves an immunological process in individuals with a genetic predisposition. However, the mechanism responsible for the small intestinal damage characteristic of celiac disease is still under debate. Small intestinal biopsy with the demonstration of a flat mucosa which is reversed on a gluten-free diet is considered the main approach for diagnosis of classical celiac disease. In addition, IgA antibodies against gliadin and endomysium, a structure of the smooth muscle connective tissue, are valuable tools for the detection of patients with celiac disease and for therapy control. Incidence rates of childhood celiac disease range from 1:300 in Western Ireland to 1:4700 in other European countries, and subclinical cases detected by serological screening revealed prevalences of 3.3 and 4 per 1000 in Italy and the USA, respectively. IgA antibodies to endomysium are particularly specific indicators of celiac disease, suggesting that this structure contains one or more target autoantigens that play a role in the pathogenesis of the disease. However, the identification of the endomysial autoantigen(s) has remained elusive. We identified tissue transglutaminase as the unknown endomysial autoantigen. Interestingly, gliadin is a preferred substrate for this enzyme, giving rise to novel antigenic epitopes.

Identification of tissue transglutaminase as the autoantigen of celiac disease

Background. Adherence is a factor in the outcome of medical treatment, but the strength and moderators of the adherence-outcome association have not been systematically assessed.Objectives. A quantitative review using meta-analysis of three decades of empirical research correlating adherence with ob

Patient Adherence and Medical Treatment Outcomes: A Meta-Analysis

https://www.gastrojournal.org/article/0016-5085(93)90864-9/pdf

Hepatobiliary complications of total parenteral nutrition

Gluten sensitivity is associated with a spectrum of mucosal lesions, arbitrarily termed pre-infiltrative, infiltrative-hyperplastic, flat-destructive and atrophic-hypoplastic Histologically and immunohistologically these lesions are all compatible with T-cell-driven events operative at a local mucosal level They are classifiable either in terms of antibody titres (pre-infiltrative) (see Chapter 10) or by the characteristic disposition of IELs throughout the surface and crypt epithelium From in-vivo challenges, it has been demonstrated: (i) that all these lesions comprise a dynamically interrelated series of events, culminating in the severe flat-destructive lesion; and (ii) that gluten evokes a dose-responsive infiltration of IELs (CD3+ CD8+ and TCR alpha beta + or gamma delta +) into the epithelium Apart from that, little is known of the functions of IELs; it is possible they may have little to do with the evolving mucosal pathology of gluten sensitivity Increasing work seems to support a view, proposed from this laboratory over 10 years ago, that the immune-mediated responses in jejunal tissue in gluten sensitivity arise in the lamina propria, in association with DR+ macrophages and an abundance of CD4(+)-activated lymphocytes Many other inflammatory consequences flow from these interactions, involving activation of mast cells, eosinophils and neutrophils, elaboration of cytokines and other products of inflammation, and increased hyperpermeability of the microvasculature with upregulation of adhesion molecules The result is a doubling of lamina propria volumes in the severe flat lesion Evidence is also given to show that measurable changes in lamina propria inflammation occur with the infiltrative-hyperplastic lesion Symptomatology is not related to the degree of proximal mucosal pathology, but to the extent of the mucosal lesion Data, although scanty, suggests that lesional pathology involves only 30-50% of the entire small bowel mucosa Thus, most patients, irrespective of proximal mucosal damage, have latent (or asymptomatic) gluten sensitivity Symptom development requires additional environmental triggers, of which infection is a major contributor It should also be noted that, while these various environmental triggers may precipitate symptomatology, they do not advance the severity of the mucosal lesion

Morphology of the mucosal lesion in gluten sensitivity.

Susceptibility to coeliac disease is genetically determined by possession of specific HLA-DQ alleles, acting in concert with one or more non-HLA linked genes. The pattern of risk seen in sibs and twins in coeliac disease is most parsimonious with a multiplicative model for the interaction between the two classes of genes. Based on a sib recurrence risk for coeliac disease of 10% and a population prevalence of 0.0033, the sib relative risk is 30. To evaluate the contribution of the MHC region to the familial risk of coeliac disease, we have examined haplotype sharing probabilities across this region in 55 coeliac disease families. Based on these probabilities the sib relative risk of coeliac disease associated with the MHC region is 3.7. Combining these results with published data on allele sharing at HLA, the estimated sib relative risk associated with the MHC region is 3.3. Therefore, the MHC genes contribute no more than 40% of the sib familial risk of coeliac disease and the non-HLA linked gene (or genes) are likely to be the stronger determinant of coeliac disease susceptibility.

https://jmg.bmj.com/content/jmedgenet/36/9/687.full.pdf

Contribution of the MHC region to the familial risk of coeliac disease

A cohort of 123 patients with coeliac disease, diagnosed in the first three years of life and followed up for at least 10 years, was reevaluated during the teenage period in terms of compliance with the diet and clinical state. Mucosal structure and lymphocytes were assessed in small intestinal biopsy specimens obtained from 36 subjects, by computerised image analysis. Of these adolescents with coeliac disease, 65% were adhering to a strict gluten free diet, 11.4% were on a gluten free diet but with occasional gluten intake, and 23.6% were on a gluten containing diet. Clinical symptoms occurred more frequently in patients on a gluten containing diet, but not in patients on a semi-strict diet. Occasional intake of small amounts (0.06-2 g/day) of gluten did not produce increased concentrations of antigliadin antibodies but resulted in an appreciably increased crypt epithelial volume and expanded crypt intraepithelial lymphocyte population.

https://gut.bmj.com/content/gutjnl/32/8/881.full.pdf

Michael N. Marsh

Papers

Gluten, major histocompatibility complex, and the small intestine: A molecular and immunobiologic approach to the spectrum of gluten sensitivity (‘celiac sprue’)

Hepatobiliary complications of total parenteral nutrition

Morphology of the mucosal lesion in gluten sensitivity.

Contribution of the MHC region to the familial risk of coeliac disease

Compliance of adolescents with coeliac disease with a gluten free diet.