Computers in Biology and Medicine 104 (2019) 335–338 Contents lists available at ScienceDirect Computers in Biology and Medicine journal homepage: www.elsevier.com/locate/compbiomed Coeliac disease under a microscope: Histological diagnostic features and confounding factors T ∗ Giulia Gibiinoa, , Loris Lopetusoa, Riccardo Riccib, Antonio Gasbarrinia, Giovanni Cammarotaa a Internal Medicine and, Gastroenterology and Hepatic Diseases Unit, IRCCS Fondazione Policlinico Universitario A. Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy b Institute of Pathology, IRCCS Fondazione Policlinico Universitario A. Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy ARTICLE INFO ABSTRACT Keywords: Coeliac disease (CD) and gluten-related disorders represent an important cornerstone of the daily practice of Gluten gastroenterologists, endoscopists and dedicated histopathologists. Despite the knowledge of clinical, serological Intraepithelial lymphocyte (IEL) and histological typical lesions, there are some conditions to consider for differential diagnosis. From the first Microscopic enteritis description of histology of CD, several studies were conducted to define similar findings suggestive for micro- Non-coeliac gluten-sensitivity scopic enteritis. Considering the establishment of early precursor lesions, the imbalance of gut microbiota is Gut microbiota another point still requiring a detailed definition. This review assesses the importance of a right overview in case of suspected gluten-related disorders and the several conditions mimicking a similar histology. 1. Introduction Sometimes, people begin gluten-free diet before of a definite diagnosis or before initiating a correct gastroenterological assessment. Another Coeliac disease is a chronic small intestinal immune-mediated dis- confusing point regards the need of histology in paediatric population, order, triggered by gluten exposition in genetically susceptible subjects. since European guidelines recommend only serological tests in oppo- The term “gluten” is used to define the variety of proteins of the grain, sition to American recommendations [4,5]. Coeliac disease is a typical rye and barley that can induce the damage usually observed in coeliac example of expression of a continuous dialogue between gastro- subjects. enterologist, endoscopist and pathologist since it is a complex alteration An early diagnosis, preferably in childhood, and a lifelong gluten- requiring a specific evaluation from the clinical presentation to the free diet are the most important contributions to prevent subsequent histopathological architecture, involving dedicated experts. complications. The first step in the diagnosis of coeliac disease, across We performed a review to assess the role of histopathology in the all ages, is a reliable screening of selected populations with symptoms correct diagnosis and follow-up of the adult population affected by or risk factors. Yet, the diagnosis of coeliac disease is often considerably coeliac disease. delayed, exposing patients to needless suffering and morbidity. The diagnosis of coeliac disease is currently based on symptoms, clinical 2. Histological diagnostic features: from Marsh-Oberhuber evaluation, serologic tests in combination with histopathological as- classification to the advanced molecular biology sessment of small intestinal biopsy specimens. In some cases, there are no clear diagnostic criteria and a critical and challenging evaluation of Histologic evaluation of the small intestinal mucosa using endo- laboratory and histopathology results is required. scopic biopsy samples is the mainstay of the diagnosis of coeliac dis- The Oslo Consensus provided a benchmark for the definition of ease. The unique serological diagnosis in adults should be reserved only classical, non-classical, asymptomatic, refractory and other categories for those patients at elevated risk for an endoscopic procedure [3]. In included in the wide variety of coeliac disease [1,2]. this setting it is usually observed a specific damage to the superficial Despite the popular knowledge of this disease, there are still many mucosa while submucosal, muscolaris propria and serosal layers are controversial aspects in the management of these patients [3]. only rarely implicated. Histological specimens should be multiple and Abbreviations: (CD), Coeliac Disease; (GFD), Gluten-free Diet; (IEL), Intraepithelial Lymphocyte; (Vh), Villus height; (Cd), Crypt depth; (SIBO), Small intestinal bacterial overgrowth ∗ Corresponding author. Internal Medicine and, Gastroenterology and Hepatic Diseases Unit, IRCCS Fondazione Policlinico Universitario A. Gemelli, Università Cattolica del Sacro Cuore, Rome, Italy. E-mail addresses: [email protected], [email protected] (G. Gibiino). https://doi.org/10.1016/j.compbiomed.2018.10.020 Received 15 July 2018; Received in revised form 16 October 2018; Accepted 17 October 2018 0010-4825/ © 2018 Elsevier Ltd. All rights reserved. G. Gibiino et al. Computers in Biology and Medicine 104 (2019) 335–338 taken when patients are on a gluten-containing diet [5,6]. Since his- treatment with a GFD both to confirm the diagnosis of a gluten-sensitive tologic alterations in CD are patchy, multiple biopsies, one to two enteropathy and to evaluate the degree of response to therapy [5,6] biopsies from the duodenal bulb and no less than four from the distal Second, the examination of biopsy histopathology and its comparison to duodenum should be performed. Proper tissue orientation of the biopsy prior biopsies is a pivotal point in the differential diagnosis and man- sections, perpendicular to the luminal surface, is required for accurate agement of non-responsive coeliac disease. Current guidelines use this quantitative and also qualitative classifications [7]. assessment of histopathologic response to determine the course of fur- Macroscopic features can include the typical flat mucosa corre- ther investigation and treatment [5,6]. This important evaluation is sponding to a completely modified structure of deformed villi [8]. best achieved by quantitative measurement of the relevant biopsy Advanced studies in the epithelial turnover showed that there is also an specimens in order to provide clinicians with the best possible in- effective increase in the enteropoiesis. Marsh [9] first hypothesized that formation as to the degree of mucosal improvement or deterioration. the intestinal response to gluten can express as five interrelated lesions Moreover, quantitative histopathology is helpful in case of detection of (preinfiltrative, infiltrative, hyperplastic, destructive, and hypoplastic) non-coeliac villous atrophy. A reduction in villous height to Cd ratio that can be considered as cell-mediated immunologic responses [10]. that is not associated with a substantial increase in IELs can point to an These responses originate in the lamina propria, where a series of an- alternative diagnosis such as peptic duodenitis or auto-immune en- tigen-specificinflammatory processes has now been identified. In this teropathy [15]. perspective, the sequential progression of the intestinal damage in Quantitative histology highlights this important distinction. In coeliac disease should be: normal, pre-infiltrative mucosal (stage 0) can clinical practice these histologic features are most commonly qualita- show an increase of Intraepithelial Lymphocyte (IEL) followed by the tively assessed; however, in the context of clinical research and ther- infiltration of IEL to the lamina propria (stage 1), reported as the number apeutics development, specific, reproducible, and quantitative mea- of IELs per unit area of absorptive epithelium or as number of IELs per sures need to be utilized to monitor responses over time and allow for 100 enterocytes. Perhaps, the most contentious issue in interpretation clear measurement to assess efficacy end points. To date, it is also of the histology of coeliac disease is the significance of Marsh 1 find- difficult to confirm histologically if dietary gluten has been restricted ings. Marsh did not define the number of IELs necessary to constitute an prior to obtaining a diagnostic biopsy, a significant problem given the infiltrative lesion; this was first specified in the modified criteria in current growing popularity of gluten-free diets [16]. which > 40 EILs/100 enterocyte nuclei were considered for diagnosis Most advanced molecular technologies supported even the possibi- [11], although this definition is fluid, recently revised to > 25 IELs/ lity of a correspondence between gene expression patterns and Marsh 100 [12]. The presence of > 25 IELs per 100 enterocytes characterizes score categories, giving the chance to future new diagnostic tools be- this stage but has also a prevalence of 5.4% in the general population yond the traditional histological assessment [17]. [13] and therefore should always be considered in the right setting of serological and clinical expressions. Crypts’ hyperplasia (stage 2) and 3. Challenging duodenitis and confounding factors villous atrophy (stage 3), as reported by the historical definition, are the consequent signs of disease progression. Finally, the advanced stage Despite the availability of both biopsy and serological specific fea- consists of the complete mucosal atrophy (stage 4), composed by villous tures, the diagnosis of coeliac disease sometimes is not so easy as it atrophy, increase of the apoptosis and crypts hyperplasia. Few years seems [18,19]. later, Oberhuber and colleagues [11] proposed a revision of the Marsh On