Mandile, Roberta Potential celiac disease: natural history and predictive biomarkers. [Tesi di dottorato]

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Abstract

Potential celiac disease (PCD) is a clinical condition characterised by the presence of a positive CD associated serology without intestinal damage. Its clinical management is extremely heterogeneous among different centres and Countries due to the lack of sufficient knowledge about its natural history. Indeed, the aim of this thesis is the better characterization of long term natural history of potential celiac disease in children, the identification of biomarkers able to predict future evolution to villous atrophy and the immunological aspects that sustain this condition. Chapter 3 describes the whole cohort of PCD children we prospectively follow-up since diagnosis on, analysing clinical, immunological and histological aspects. We describe the clinical strategies for monitoring them with a scheduled follow-up and the long-term outcome of PCD patients maintained on a gluten containing diet. Only around one third of them will develop symptoms or villous atrophy, while the vast majority will remain asymptomatic without developing intestinal damage. In chapter 4 we thus investigated whether, in those PCD children that persistently remain clinically asymptomatic and histologically healthy, growth, nutritional and autoimmune parameters can be somehow altered, even in a subclinical way, by chronic gluten consumption. We performed a case control study where we compared different parameters in the same patient at diagnosis and on the occasion of last follow up. We will demonstrate that these patients do not tend to develop complications and gluten consumption seems to be safe for PCD children that do not present clinical symptoms or intestinal damage. Of course, it would be very interesting from a pathological point of view and useful from a clinical point of view to identify since diagnosis those patients committed to develop the classical form of the disease. In this context, in chapter 5 we study how to possibly identify since diagnosis, PCD patients committed to develop villous atrophy in future. Our group had already demonstrated in a previously published work that the combining of clinical, histological and genetical features was able to predict future evolution with an accuracy of prediction of around 80%, somewhat uncertain to take such a life-long clinical decision. Moreover, the traditional multivariate model we proposed required stringent assumptions that may not be answered in the clinical setting. Starting from the dataset available for PCD, we propose the application of Machine Learning (ML) methodologies to extend the analysis on available clinical data and to detect most influent features predicting the outcome. The best model, optimized Boosted Trees, is able to classify PCD starting from the selected 19 features with an accuracy of 0.80, sensitivity of 0.58 and specificity of 0.84. (Chapter 5.1). In the same chapter (chapter 5.2) we also analyse how the different concentration of 92 serum inflammatory proteins is able to correctly differentiate since diagnosis PCD children destined to develop villous atrophy with an even higher precision (around 95%). This study also highlights how specific changes in abundance inflammatory proteins in circulation are associated with small intestinal damage. The correct study of the intestinal mucosa is fundamental for CD diagnosis, and even more for PCD diagnosis, where, in presence of a positive CD associated serology, villous atrophy must be excluded. In chapter 7 we analyse other aspects of the deep relation between celiac disease and the intestinal mucosa. In the first study we aimed at investigating histological and immunohistochemical features in CD patients on a long-term gluten free diet (GFD) and to correlate them to the GFD duration. We will demonstrate that villi to crypt ratio as well as the level of inflammation in lamina propria (expressed by the number of CD25 positive cells) normalise after GFD while other parameters, such as  positive cells, decreases but never normalise, representing a hallmark of the condition regardless of the stage of disease. In the second work we aimed at reporting distribution, clinical, and immunohistochemical features of patients with a biopsy proved intestinal atrophy in absence of a positive CD associated serology. We will show that this condition is not rare representing up to 5% of the cases of VA but the entity of seronegative celiac disease is virtually absent in the paediatric age. Immunohistochemical analysis may be helpful in excluding CD, whereas the finding of mucosal anti-TG2, particularly with a weak staining, shows no absolute specificity for CD.

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