|
1
|
Kolkova Z, Suroviakova S, Grendar M, Havlicekova Z, Hornakova A, Holubekova V, Halasova E, Banovcin P. Altered miRNA expression in duodenal tissue of celiac patients and the impact of a gluten-free diet: a preliminary study. Mol Biol Rep 2025; 52:441. [PMID: 40304865 PMCID: PMC12043776 DOI: 10.1007/s11033-025-10534-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Accepted: 04/22/2025] [Indexed: 05/02/2025]
Abstract
BACKGROUND MicroRNAs (miRNAs) are crucial regulators of gene expression, impacting a wide range of biological processes. Their dysregulation can result in pathological changes and contribute to the development of various disorders. This study aims to evaluate the expression of selected miRNAs in duodenal tissue of paediatric patients with active celiac disease (CD), investigate the role of dysregulated miRNAs in disease pathogenesis and assess the changes in their expression profile in response to a gluten-free diet (GFD). METHODS AND RESULTS The study included newly diagnosed celiac patients (n = 20), celiac patients adhering to a GFD (n = 17) and a control group (n = 29). The miRNA expression in duodenal samples was quantified by real-time PCR. Dysregulated miRNAs were analysed for functional enrichment in molecular pathways. Our results identified 8 dysregulated miRNAs in celiac patients: miR-155-5p (upregulated) and hsa-miR-22-5p, hsa-miR-192-5p, hsa-miR-338-3p, hsa-miR-31-5p, hsa-miR-31-3p, hsa-miR-215-5p and hsa-miR-378d (downregulated). Pathway analysis implicated these miRNAs in regulating various signaling pathways related to inflammation, immune response and intercellular junctions, all of which are relevant to the pathogenesis of CD. Moreover, miR-31-3p was upregulated in CD patients on a GFD, exhibiting a negative correlation with the duration of GFD. For other miRNAs, the level of expression in CD patients adhering to a GFD was restored to levels similar to those observed in the control group. CONCLUSION This preliminary study reveals significant changes in miRNA expression in duodenal biopsies from paediatric CD patients and how these patterns shift with dietary intervention. Understanding the interactions among dysregulated miRNAs may lead to novel therapeutic strategies for managing CD.
Collapse
Affiliation(s)
- Zuzana Kolkova
- Laboratory of Genomics and Prenatal Diagnostics, Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Stanislava Suroviakova
- Department of Pediatrics, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia.
- Department of Pediatrics, University Hospital Martin, Martin, Slovakia.
| | - Marian Grendar
- Laboratory of Bioinformatics and Biostatistics, Biomedical Center in Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
| | - Zuzana Havlicekova
- Department of Pediatrics, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
- Department of Pediatrics, University Hospital Martin, Martin, Slovakia
| | - Andrea Hornakova
- Laboratory of Genomics and Prenatal Diagnostics, Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Veronika Holubekova
- Laboratory of Genomics and Prenatal Diagnostics, Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Erika Halasova
- Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Peter Banovcin
- Department of Pediatrics, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
- Department of Pediatrics, University Hospital Martin, Martin, Slovakia
| |
Collapse
|
|
2
|
Shiha MG, Sanders DS. What is new in the management of coeliac disease? Eur J Intern Med 2025; 134:1-8. [PMID: 39894725 DOI: 10.1016/j.ejim.2025.01.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 01/25/2025] [Accepted: 01/29/2025] [Indexed: 02/04/2025]
Abstract
Coeliac disease is the most common immune-mediated enteropathy, affecting approximately 1 % of the population worldwide. Currently, the vast majority of individuals remain undiagnosed. Coeliac disease is triggered by gluten ingestion in genetically predisposed individuals carrying the human leukocyte antigen (HLA) genes; HLA-DQ2 and HLA-DQ8. Patients with coeliac disease present with a wide spectrum of gastrointestinal and extraintestinal manifestations and, in some cases, without any symptoms. The diagnosis of coeliac disease in adults is based on a combination of clinical suspicion, positive serological markers and histological evidence of small intestinal atrophy on duodenal biopsies. The only effective treatment is a strict, lifelong gluten-free diet. However, up to 20 % of patients report persistent or recurrent symptoms. In this review, we provide a comprehensive update on coeliac disease, focusing on its relevance to the different medical specialities and highlighting the need for a multidisciplinary approach to its diagnosis and management. Clinicians practicing internal medicine have a unique opportunity to diagnose this multisystem autoimmune disease. By doing so, they would avoid delays in diagnosis for these patients. A low threshold for serological testing is recommended.
Collapse
Affiliation(s)
- Mohamed G Shiha
- Academic Unit of Gastroenterology, Sheffield Teaching Hospitals, Sheffield, UK; Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK.
| | - David S Sanders
- Academic Unit of Gastroenterology, Sheffield Teaching Hospitals, Sheffield, UK; Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK
| |
Collapse
|
|
3
|
Griffin M, Gruver AM, Shah C, Wani Q, Fahy D, Khosla A, Kirkup C, Borders D, Brosnan-Cashman JA, Fulford AD, Credille KM, Jayson C, Najdawi F, Gottlieb K. A feasibility study using quantitative and interpretable histological analyses of celiac disease for automated cell type and tissue area classification. Sci Rep 2024; 14:29883. [PMID: 39622903 PMCID: PMC11612272 DOI: 10.1038/s41598-024-79570-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 11/11/2024] [Indexed: 12/06/2024] Open
Abstract
Histological assessment is essential for the diagnosis and management of celiac disease. Current scoring systems, including modified Marsh (Marsh-Oberhuber) score, lack inter-pathologist agreement. To address this unmet need, we aimed to develop a fully automated, quantitative approach for histology characterisation of celiac disease. Convolutional neural network models were trained using pathologist annotations of hematoxylin and eosin-stained biopsies of celiac disease mucosa and normal duodenum to identify cells, tissue and artifact regions. Biopsies of duodenal mucosa of varying celiac disease severity, and normal duodenum were collected from a large central laboratory. Celiac disease slides (N = 318) were split into training (n = 230; 72.3%), validation (n = 60; 18.9%) and test (n = 28; 8.8%) datasets. Normal duodenum slides (N = 58) were similarly divided into training (n = 40; 69.0%), validation (n = 12; 20.7%) and test (n = 6; 10.3%) datasets. Human interpretable features were extracted and the strength of their correlation with Marsh scores were calculated using Spearman rank correlations. Our model identified cells, tissue regions and artifacts, including distinguishing intraepithelial lymphocytes and differentiating villous epithelium from crypt epithelium. Proportional area measurements representing villous atrophy negatively correlated with Marsh scores (r = - 0.79), while measurements indicative of crypt hyperplasia positively correlated (r = 0.71). Furthermore, features distinguishing celiac disease from normal duodenum were identified. Our novel model provides an explainable and fully automated approach for histology characterisation of celiac disease that correlates with modified Marsh scores, potentially facilitating diagnosis, prognosis, clinical trials and treatment response monitoring.
Collapse
Affiliation(s)
- Michael Griffin
- PathAI, Inc., 1325 Boylston Street, Suite 10000, Boston, MA, 02215, USA
| | | | - Chintan Shah
- PathAI, Inc., 1325 Boylston Street, Suite 10000, Boston, MA, 02215, USA
| | - Qasim Wani
- PathAI, Inc., 1325 Boylston Street, Suite 10000, Boston, MA, 02215, USA
| | - Darren Fahy
- PathAI, Inc., 1325 Boylston Street, Suite 10000, Boston, MA, 02215, USA
| | - Archit Khosla
- PathAI, Inc., 1325 Boylston Street, Suite 10000, Boston, MA, 02215, USA
| | - Christian Kirkup
- PathAI, Inc., 1325 Boylston Street, Suite 10000, Boston, MA, 02215, USA
| | - Daniel Borders
- PathAI, Inc., 1325 Boylston Street, Suite 10000, Boston, MA, 02215, USA
| | | | | | | | - Christina Jayson
- PathAI, Inc., 1325 Boylston Street, Suite 10000, Boston, MA, 02215, USA
| | - Fedaa Najdawi
- PathAI, Inc., 1325 Boylston Street, Suite 10000, Boston, MA, 02215, USA.
| | | |
Collapse
|
|
4
|
Bildstein T, Charbit-Henrion F, Azabdaftari A, Cerf-Bensussan N, Uhlig HH. Cellular and molecular basis of proximal small intestine disorders. Nat Rev Gastroenterol Hepatol 2024; 21:687-709. [PMID: 39117867 DOI: 10.1038/s41575-024-00962-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/28/2024] [Indexed: 08/10/2024]
Abstract
The proximal part of the small intestine, including duodenum and jejunum, is not only dedicated to nutrient digestion and absorption but is also a highly regulated immune site exposed to environmental factors. Host-protective responses against pathogens and tolerance to food antigens are essential functions in the small intestine. The cellular ecology and molecular pathways to maintain those functions are complex. Maladaptation is highlighted by common immune-mediated diseases such as coeliac disease, environmental enteric dysfunction or duodenal Crohn's disease. An expanding spectrum of more than 100 rare monogenic disorders inform on causative molecular mechanisms of nutrient absorption, epithelial homeostasis and barrier function, as well as inflammatory immune responses and immune regulation. Here, after summarizing the architectural and cellular traits that underlie the functions of the proximal intestine, we discuss how the integration of tissue immunopathology and molecular mechanisms can contribute towards our understanding of disease and guide diagnosis. We propose an integrated mechanism-based taxonomy and discuss the latest experimental approaches to gain new mechanistic insight into these disorders with large disease burden worldwide as well as implications for therapeutic interventions.
Collapse
Affiliation(s)
- Tania Bildstein
- Great Ormond Street Hospital for Children, Department of Paediatric Gastroenterology, London, UK
| | - Fabienne Charbit-Henrion
- Department of Genomic Medicine for Rare Diseases, Necker-Enfants Malades Hospital, APHP, University of Paris-Cité, Paris, France
- INSERM UMR1163, Intestinal Immunity, Institut Imagine, Paris, France
| | - Aline Azabdaftari
- Translational Gastroenterology Unit, Nuffield Department of Medicine, Oxford, UK
| | | | - Holm H Uhlig
- Translational Gastroenterology Unit, Nuffield Department of Medicine, Oxford, UK.
- Department of Paediatrics, University of Oxford, Oxford, UK.
- National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre, Oxford, UK.
| |
Collapse
|
|
5
|
Carreras J. Celiac Disease Deep Learning Image Classification Using Convolutional Neural Networks. J Imaging 2024; 10:200. [PMID: 39194989 DOI: 10.3390/jimaging10080200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 08/09/2024] [Accepted: 08/10/2024] [Indexed: 08/29/2024] Open
Abstract
Celiac disease (CD) is a gluten-sensitive immune-mediated enteropathy. This proof-of-concept study used a convolutional neural network (CNN) to classify hematoxylin and eosin (H&E) CD histological images, normal small intestine control, and non-specified duodenal inflammation (7294, 11,642, and 5966 images, respectively). The trained network classified CD with high performance (accuracy 99.7%, precision 99.6%, recall 99.3%, F1-score 99.5%, and specificity 99.8%). Interestingly, when the same network (already trained for the 3 class images), analyzed duodenal adenocarcinoma (3723 images), the new images were classified as duodenal inflammation in 63.65%, small intestine control in 34.73%, and CD in 1.61% of the cases; and when the network was retrained using the 4 histological subtypes, the performance was above 99% for CD and 97% for adenocarcinoma. Finally, the model added 13,043 images of Crohn's disease to include other inflammatory bowel diseases; a comparison between different CNN architectures was performed, and the gradient-weighted class activation mapping (Grad-CAM) technique was used to understand why the deep learning network made its classification decisions. In conclusion, the CNN-based deep neural system classified 5 diagnoses with high performance. Narrow artificial intelligence (AI) is designed to perform tasks that typically require human intelligence, but it operates within limited constraints and is task-specific.
Collapse
Affiliation(s)
- Joaquim Carreras
- Department of Pathology, School of Medicine, Tokai University, 143 Shimokasuya, Isehara 259-1193, Japan
| |
Collapse
|
|
6
|
Robert ME, Ciacci C, Lebwohl B. Opportunities for Improving Biopsy and Non-Biopsy-Based Diagnosis of Celiac Disease. Gastroenterology 2024; 167:79-89. [PMID: 38302007 DOI: 10.1053/j.gastro.2024.01.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Revised: 01/17/2024] [Accepted: 01/24/2024] [Indexed: 02/03/2024]
Abstract
The accumulating data regarding a non-biopsy diagnosis of celiac disease has led to its adoption in certain scenarios, although debate on whether and when to use non-biopsy criteria in clinical practice is ongoing. Despite the growing popularity and evidence basis for a biopsy-free approach to diagnosis in the context of highly elevated serologies, there will continue to be a role for a biopsy in some groups. This review summarizes the current evidence supporting a non-biopsy approach and arguments supporting continued reliance on biopsy, and focuses on opportunities to improve both approaches.
Collapse
Affiliation(s)
- Marie E Robert
- Department of Pathology, Medicine (Digestive Diseases) and Human and Translational Immunology, Yale University School of Medicine, New Haven, Connecticut
| | - Carolina Ciacci
- Department of Medicine, Surgery, Dentistry, Scuola Medica Salernitana, University of Salerno, Baronissi, Salerno, Italy.
| | - Benjamin Lebwohl
- Department of Medicine, Columbia University Irving Medical Center, New York, New York; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York
| |
Collapse
|
|
7
|
Khalighi M, Javaherizadeh H, Hakimzadeh M, Ahmadi M, Torabizadeh M, Fayezi A. IgE to wheat, prick test, and Patch test among children with celiac disease. BMC Pediatr 2024; 24:367. [PMID: 38807087 PMCID: PMC11131244 DOI: 10.1186/s12887-024-04844-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 05/20/2024] [Indexed: 05/30/2024] Open
Abstract
INTRODUCTION AND AIM Celiac disease is one of the most common autoimmune disorders. This study aimed to evaluate the relationship between celiac disease and wheat sensitization. SUBJECTS AND METHODS In the current study, children aged < 18 years with confirmed celiac disease were included. Data were analyzed using SPSS. RESULTS Gastrointestinal problems were the most common indication for evaluation in terms of celiac disease. Prick and patch tests were positive in 43.4% and 34% respectively. CONCLUSION Prick test and patch test for wheat sensitization were positive in about 30-45% of the children for celiac disease.
Collapse
Affiliation(s)
- Marjaneh Khalighi
- Alimentary Tract Research Center, Clinical Sciences Research Institute, Imam Khomeini Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hazhir Javaherizadeh
- Alimentary Tract Research Center, Clinical Sciences Research Institute, Imam Khomeini Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| | - Mehran Hakimzadeh
- Alimentary Tract Research Center, Clinical Sciences Research Institute, Imam Khomeini Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mitra Ahmadi
- Alimentary Tract Research Center, Clinical Sciences Research Institute, Imam Khomeini Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mehdi Torabizadeh
- Department of Allergy and Clinical Immunology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Abbas Fayezi
- Department of Allergy and Clinical Immunology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| |
Collapse
|
|
8
|
Jansson-Knodell CL, Rubio-Tapia A. Gluten-related Disorders From Bench to Bedside. Clin Gastroenterol Hepatol 2024; 22:693-704.e1. [PMID: 37879521 DOI: 10.1016/j.cgh.2023.09.042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 09/26/2023] [Accepted: 09/29/2023] [Indexed: 10/27/2023]
Abstract
Celiac disease, non-celiac gluten sensitivity, and wheat allergy comprise 3 of the main conditions with wheat- and gluten-containing foods as the symptom trigger. Distinguishing between these entities can be daunting. In this review, we compare and contrast celiac disease, non-celiac gluten sensitivity, and wheat allergy to allow clinicians to determine which diagnosis fits their patient to facilitate high-quality management and longitudinal care.
Collapse
Affiliation(s)
- Claire L Jansson-Knodell
- Celiac Disease Program, Division of Gastroenterology, Hepatology, and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio
| | - Alberto Rubio-Tapia
- Celiac Disease Program, Division of Gastroenterology, Hepatology, and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio.
| |
Collapse
|
|
9
|
Inchingolo AD, Dipalma G, Viapiano F, Netti A, Ferrara I, Ciocia AM, Mancini A, Di Venere D, Palermo A, Inchingolo AM, Inchingolo F. Celiac Disease-Related Enamel Defects: A Systematic Review. J Clin Med 2024; 13:1382. [PMID: 38592254 PMCID: PMC10932357 DOI: 10.3390/jcm13051382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 02/22/2024] [Accepted: 02/25/2024] [Indexed: 04/10/2024] Open
Abstract
INTRODUCTION This systematic review aims to elucidate the intricate correlation between celiac disease (CD) and dental enamel defects (DED), exploring pathophysiological mechanisms, oral health implications, and a dentist's role in early diagnosis. MATERIALS AND METHODS Following PRISMA guidelines, a comprehensive search from 1 January 2013 to 1 January 2024 across PubMed, Cochrane Library, Scopus, and Web of Science identified 153 publications. After exclusions, 18 studies met the inclusion criteria for qualitative analysis. Inclusion criteria involved study types (RCTs, RCCTs, case series), human participants, English language, and full-text available. RESULTS The search yielded 153 publications, with 18 studies meeting the inclusion criteria for qualitative analysis. Notable findings include a high prevalence of DED in CD patients, ranging from 50 to 94.1%. Symmetrical and chronological defects, according to Aine's classification, were predominant, and significant associations were observed between CD severity and enamel defect extent. CONCLUSIONS The early recognition of oral lesions, particularly through Aine's classification, may signal potential CD even in the absence of gastrointestinal symptoms. Correlations between CD and dental health conditions like molar incisor hypomineralization (MIH) emphasize the dentist's crucial role in early diagnosis. Collaboration between dentists and gastroenterologists is essential for effective monitoring and management. This review consolidates current knowledge, laying the groundwork for future research and promoting interdisciplinary collaboration for improved CD-related oral health outcomes. Further large-scale prospective research is recommended to deepen our understanding of these issues.
Collapse
Affiliation(s)
- Alessio Danilo Inchingolo
- Department of Interdisciplinary Medicine, School of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (A.D.I.); (G.D.); (F.V.); (A.N.); (I.F.); (A.M.C.); (A.M.); (D.D.V.); (A.M.I.)
| | - Gianna Dipalma
- Department of Interdisciplinary Medicine, School of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (A.D.I.); (G.D.); (F.V.); (A.N.); (I.F.); (A.M.C.); (A.M.); (D.D.V.); (A.M.I.)
| | - Fabio Viapiano
- Department of Interdisciplinary Medicine, School of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (A.D.I.); (G.D.); (F.V.); (A.N.); (I.F.); (A.M.C.); (A.M.); (D.D.V.); (A.M.I.)
| | - Anna Netti
- Department of Interdisciplinary Medicine, School of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (A.D.I.); (G.D.); (F.V.); (A.N.); (I.F.); (A.M.C.); (A.M.); (D.D.V.); (A.M.I.)
| | - Irene Ferrara
- Department of Interdisciplinary Medicine, School of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (A.D.I.); (G.D.); (F.V.); (A.N.); (I.F.); (A.M.C.); (A.M.); (D.D.V.); (A.M.I.)
| | - Anna Maria Ciocia
- Department of Interdisciplinary Medicine, School of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (A.D.I.); (G.D.); (F.V.); (A.N.); (I.F.); (A.M.C.); (A.M.); (D.D.V.); (A.M.I.)
| | - Antonio Mancini
- Department of Interdisciplinary Medicine, School of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (A.D.I.); (G.D.); (F.V.); (A.N.); (I.F.); (A.M.C.); (A.M.); (D.D.V.); (A.M.I.)
| | - Daniela Di Venere
- Department of Interdisciplinary Medicine, School of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (A.D.I.); (G.D.); (F.V.); (A.N.); (I.F.); (A.M.C.); (A.M.); (D.D.V.); (A.M.I.)
| | - Andrea Palermo
- College of Medicine and Dentistry, Birmingham B4 6BN, UK;
| | - Angelo Michele Inchingolo
- Department of Interdisciplinary Medicine, School of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (A.D.I.); (G.D.); (F.V.); (A.N.); (I.F.); (A.M.C.); (A.M.); (D.D.V.); (A.M.I.)
| | - Francesco Inchingolo
- Department of Interdisciplinary Medicine, School of Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy; (A.D.I.); (G.D.); (F.V.); (A.N.); (I.F.); (A.M.C.); (A.M.); (D.D.V.); (A.M.I.)
| |
Collapse
|
|
10
|
Denholm J, Schreiber BA, Jaeckle F, Wicks MN, Benbow EW, Bracey TS, Chan JYH, Farkas L, Fryer E, Gopalakrishnan K, Hughes CA, Kirkwood KJ, Langman G, Mahler-Araujo B, McMahon RFT, Myint KLW, Natu S, Robinson A, Sanduka A, Sheppard KA, Tsang YW, Arends MJ, Soilleux EJ. CD, or not CD, that is the question: a digital interobserver agreement study in coeliac disease. BMJ Open Gastroenterol 2024; 11:e001252. [PMID: 38302475 PMCID: PMC10870791 DOI: 10.1136/bmjgast-2023-001252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 12/11/2023] [Indexed: 02/03/2024] Open
Abstract
OBJECTIVE Coeliac disease (CD) diagnosis generally depends on histological examination of duodenal biopsies. We present the first study analysing the concordance in examination of duodenal biopsies using digitised whole-slide images (WSIs). We further investigate whether the inclusion of immunoglobulin A tissue transglutaminase (IgA tTG) and haemoglobin (Hb) data improves the interobserver agreement of diagnosis. DESIGN We undertook a large study of the concordance in histological examination of duodenal biopsies using digitised WSIs in an entirely virtual reporting setting. Our study was organised in two phases: in phase 1, 13 pathologists independently classified 100 duodenal biopsies (40 normal; 40 CD; 20 indeterminate enteropathy) in the absence of any clinical or laboratory data. In phase 2, the same pathologists examined the (re-anonymised) WSIs with the inclusion of IgA tTG and Hb data. RESULTS We found the mean probability of two observers agreeing in the absence of additional data to be 0.73 (±0.08) with a corresponding Cohen's kappa of 0.59 (±0.11). We further showed that the inclusion of additional data increased the concordance to 0.80 (±0.06) with a Cohen's kappa coefficient of 0.67 (±0.09). CONCLUSION We showed that the addition of serological data significantly improves the quality of CD diagnosis. However, the limited interobserver agreement in CD diagnosis using digitised WSIs, even after the inclusion of IgA tTG and Hb data, indicates the importance of interpreting duodenal biopsy in the appropriate clinical context. It further highlights the unmet need for an objective means of reproducible duodenal biopsy diagnosis, such as the automated analysis of WSIs using artificial intelligence.
Collapse
Affiliation(s)
- James Denholm
- Department of Pathology, University of Cambridge, Cambridge, UK
- Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge, UK
- Lyzeum Ltd, Cambridge, UK
| | - Benjamin A Schreiber
- Department of Pathology, University of Cambridge, Cambridge, UK
- Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge, UK
| | - Florian Jaeckle
- Department of Pathology, University of Cambridge, Cambridge, UK
- Lyzeum Ltd, Cambridge, UK
| | - Mike N Wicks
- Department of Pathology, The University of Edinburgh College of Medicine and Veterinary Medicine, Edinburgh, UK
| | - Emyr W Benbow
- Division of Medical Education, The University of Manchester, Manchester, UK
- Department of Histopathology, Manchester University NHS Foundation Trust, Manchester, UK
| | - Tim S Bracey
- Department of Diagnostic and Molecular Pathology, Royal Cornwall Hospitals NHS Trust, Truro, UK
- University Hospitals Plymouth NHS Trust, Plymouth, UK
| | - James Y H Chan
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Lorant Farkas
- Department of Pathology, Akershus University Hospital, Nordbyhagen, Norway
- Institute of Clinical Medicine, University of Oslo, Nordbyhagen, Norway
| | - Eve Fryer
- Department of Cellular Pathology, Oxford University Hospitals NHS foundation Trust, Oxford, UK
| | - Kishore Gopalakrishnan
- Department of Histopathology, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
| | - Caroline A Hughes
- Department of Cellular Pathology, Oxford University Hospitals NHS foundation Trust, Oxford, UK
| | | | - Gerald Langman
- Department of Cellular Pathology, Heartlands Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Betania Mahler-Araujo
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- MRC Institute of Metabolic Science, Wellcome Trust, Cambridge, UK
| | - Raymond F T McMahon
- Division of Medical Education, The University of Manchester, Manchester, UK
- Department of Histopathology, Manchester University NHS Foundation Trust, Manchester, UK
| | - Khun La Win Myint
- Department of Pathology, Queen Elizabeth University Hospital, Glasgow, UK
| | - Sonali Natu
- University Hospital of North Tees, North Tees and Hartlepool NHS Foundation Trust, Stockton on Tees, UK
| | - Andrew Robinson
- Department of Histopathology, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
| | - Ashraf Sanduka
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Katharine A Sheppard
- Department of Cellular Pathology, Oxford University Hospitals NHS foundation Trust, Oxford, UK
| | - Yee Wah Tsang
- Department of Histopathology, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
| | - Mark J Arends
- Division of Pathology, University of Edinburgh, Edinburgh, UK
| | - Elizabeth J Soilleux
- Department of Pathology, University of Cambridge, Cambridge, UK
- Lyzeum Ltd, Cambridge, UK
| |
Collapse
|
|
11
|
Scarmozzino F, Pizzi M, Pelizzaro F, Angerilli V, Dei Tos AP, Piazza F, Savarino EV, Zingone F, Fassan M. Refractory celiac disease and its mimickers: a review on pathogenesis, clinical-pathological features and therapeutic challenges. Front Oncol 2023; 13:1273305. [PMID: 38023263 PMCID: PMC10662059 DOI: 10.3389/fonc.2023.1273305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Accepted: 10/20/2023] [Indexed: 12/01/2023] Open
Abstract
Refractory celiac disease (RCD) and enteropathy-associated T-cell lymphoma (EATL) are rare, yet severe complications of celiac disease (CD). Over the last decades, several studies have addressed the biology and clinical-pathological features of such conditions, highlighting unique disease patterns and recurrent genetic events. Current classification proposals identify two forms of RCD, namely: (i) type 1 RCD (RCD-I), characterized by phenotypically normal intra-epithelial lymphocytes (IELs); and (ii) type 2 RCD (RCD-II), featuring phenotypically aberrant IELs. While RCD-I likely represents a gluten-independent dysimmune reaction against small bowel epithelial cells, RCD-II is better considered an in situ aggressive T-cell lymphoma, with high rates of progression to overt EATL. The diagnosis of RCD and EATL is often challenging, due to misleading clinical-pathological features and to significant overlap with several CD-unrelated gastro-intestinal disorders. Similarly, the treatment of RCD and EATL is an unmet clinical need for both gastroenterologists and hematologists. Moving from such premises, this review aims to provide a comprehensive view of RCD and EATL, specifically considering their pathogenesis and the many still open issues concerning their diagnosis and clinical management.
Collapse
Affiliation(s)
- Federico Scarmozzino
- Surgical Pathology and Cytopathology Unit, Department of Medicine-DIMED, University of Padua School of Medicine, Padua, Italy
| | - Marco Pizzi
- Surgical Pathology and Cytopathology Unit, Department of Medicine-DIMED, University of Padua School of Medicine, Padua, Italy
| | - Filippo Pelizzaro
- Gastroenterology Unit, Department of Surgical, Gastroenterological and Oncological Sciences -DISCOG, University of Padua School of Medicine, Padua, Italy
| | - Valentina Angerilli
- Surgical Pathology and Cytopathology Unit, Department of Medicine-DIMED, University of Padua School of Medicine, Padua, Italy
| | - Angelo Paolo Dei Tos
- Surgical Pathology and Cytopathology Unit, Department of Medicine-DIMED, University of Padua School of Medicine, Padua, Italy
| | - Francesco Piazza
- Hematology & Clinical Immunology Unit, Department of Medicine-DIMED, University of Padua School of Medicine, Padua, Italy
| | - Edoardo Vincenzo Savarino
- Gastroenterology Unit, Department of Surgical, Gastroenterological and Oncological Sciences -DISCOG, University of Padua School of Medicine, Padua, Italy
| | - Fabiana Zingone
- Gastroenterology Unit, Department of Surgical, Gastroenterological and Oncological Sciences -DISCOG, University of Padua School of Medicine, Padua, Italy
| | - Matteo Fassan
- Surgical Pathology and Cytopathology Unit, Department of Medicine-DIMED, University of Padua School of Medicine, Padua, Italy
- Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy
| |
Collapse
|
|
12
|
Seitz V, Gennermann K, Elezkurtaj S, Groth D, Schaper S, Dröge A, Lachmann N, Berg E, Lenze D, Kühl AA, Husemann C, Kleo K, Horst D, Lennerz V, Hennig S, Hummel M, Schumann M. Specific T-cell receptor beta-rearrangements of gluten-triggered CD8 + T-cells are enriched in celiac disease patients' duodenal mucosa. Clin Immunol 2023; 256:109795. [PMID: 37769786 DOI: 10.1016/j.clim.2023.109795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 09/12/2023] [Accepted: 09/25/2023] [Indexed: 10/02/2023]
Abstract
Celiac disease (CeD) is an autoimmune disorder affecting the small intestine with gluten as disease trigger. Infections including Influenza A, increase the CeD risk. While gluten-specific CD4+ T-cells, recognizing HLA-DQ2/DQ8 presented gluten-peptides, initiate and sustain the celiac immune response, CD8+ α/β intraepithelial T-cells elicit mucosal damage. Here, we subjected TCRs from a cohort of 56 CeD patients and 22 controls to an analysis employing 749 published CeD-related TCRβ-rearrangements derived from gluten-specific CD4+ T-cells and gluten-triggered peripheral blood CD8+ T-cells. We show, that in addition to TCRs from gluten-specific CD4+ T-cells, TCRs of gluten-triggered CD8+ T-cells are significantly enriched in CeD duodenal tissue samples. TCRβ-rearrangements of gluten-triggered CD8+ T-cells were even more expanded in patients than TCRs from gluten-specific CD4+ T-cells (p < 0.0002) and highest in refractory CeD. Sequence alignments with TCR-antigen databases suggest that a subgroup of these most likely indirectly gluten-triggered TCRs recognize microbial, viral, and autoantigens.
Collapse
Affiliation(s)
- V Seitz
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; HS Diagnomics GmbH, Berlin, Germany
| | | | - S Elezkurtaj
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - D Groth
- Bioinformatics, Institute of Biochemistry and Biology, University of Potsdam, Potsdam, Germany
| | | | - A Dröge
- HS Diagnomics GmbH, Berlin, Germany
| | - N Lachmann
- Centre for Tumor Medicine, Histocompatibility & Immunogenetics Laboratory, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - E Berg
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - D Lenze
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - A A Kühl
- iPATH.Berlin - Core Unit of the Charité Universitätsmedizin Berlin, corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - C Husemann
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; German Cancer Consortium (DKTK), Partner Site Berlin, Berlin, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - K Kleo
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - D Horst
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | | | - S Hennig
- HS Diagnomics GmbH, Berlin, Germany
| | - M Hummel
- Institute of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; German Cancer Consortium (DKTK), Partner Site Berlin, Berlin, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - M Schumann
- Medizinische Klinik m. S. Gastroenterologie, Infektiologie und Rheumatologie, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
| |
Collapse
|
|
13
|
Ciacci C, Bai JC, Holmes G, Al-Toma A, Biagi F, Carroccio A, Ciccocioppo R, Di Sabatino A, Gingold-Belfer R, Jinga M, Makharia G, Niveloni S, Norman GL, Rostami K, Sanders DS, Smecuol E, Villanacci V, Vivas S, Zingone F. Serum anti-tissue transglutaminase IgA and prediction of duodenal villous atrophy in adults with suspected coeliac disease without IgA deficiency (Bi.A.CeD): a multicentre, prospective cohort study. Lancet Gastroenterol Hepatol 2023; 8:1005-1014. [PMID: 37696284 DOI: 10.1016/s2468-1253(23)00205-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 06/30/2023] [Accepted: 06/30/2023] [Indexed: 09/13/2023]
Abstract
BACKGROUND Whether coeliac disease in adults can be diagnosed with serology alone remains controversial. We aimed to evaluate the accuracy of serum anti-tissue transglutaminase IgA (tTG-IgA) in the diagnosis of coeliac disease. METHODS In this multicentre, prospective cohort study, adult participants (aged ≥18 years) with suspected coeliac disease without IgA deficiency who were not on a gluten-free diet and who had a local serum tTG-IgA measurement, were enrolled from Feb 27, 2018, to Dec 24, 2020, by 14 tertiary referral centres (ten from Europe, two from Asia, one from Oceania, and one from South America) to undergo local endoscopic duodenal biopsy. Local serum tTG-IgA was measured with 14 different test brands and concentration expressed as a multiple of each test's upper limit of normal (ULN), and defined as positive when greater than 1 times the ULN. The main study outcome was the reliability of serum tests for the diagnosis of coeliac disease, as defined by duodenal villous atrophy (Marsh type 3 or Corazza-Villanacci grade B). Histology was evaluated by the local pathologist, with discordant cases (positive tTG-IgA without duodenal villous atrophy or negative tTG-IgA with duodenal villous atrophy) re-evaluated by a central pathologist. The reliability of serum tests for the prediction of duodenal villous atrophy was evaluated according to sensitivity, specificity, positive predictive value, negative predictive value, and the area under the receiver operating characteristic curve (AUC) for categorical and continuous data. FINDINGS We enrolled 436 participants with complete local data on serum tTG-IgA and duodenal histology (296 [68%] women and 140 [32%] men; mean age 40 years [SD 15]). Positive serum tTG-IgA was detected in 363 (83%) participants and negative serum tTG-IgA in 73 (17%). Of the 363 participants with positive serum tTG-IgA, 341 had positive histology (true positives) and 22 had negative histology (false positives) after local review. Of the 73 participants with negative serum tTG-IgA, seven had positive histology (false negatives) and 66 had negative histology (true negatives) after local review. The positive predictive value was 93·9% (95% CI 89·2-98·6), the negative predictive value was 90·4% (85·5-95·3), sensitivity was 98·0% (95·3-100·0), and specificity was 75·0% (66·6-83·4). After central re-evaluation of duodenal histology in 29 discordant cases, there were 348 true positive cases, 15 false positive cases, 66 true negative cases, and seven false negative cases, resulting in a positive predictive value of 95·9% (92·0-99·8), a negative predictive value of 90·4% (85·5-95·3), a sensitivity of 98·0% (95·3-100·0), and a specificity of 81·5% (73·9-89·1). Either using the local or central definition of duodenal histology, the positive predictive value of local serum tTG-IgA increased when the serological threshold was defined at increasing multiples of the ULN (p<0·0001). The AUC for serum tTG-IgA for the prediction of duodenal villous atrophy was 0·87 (95% CI 0·81-0·92) when applying the categorical definition of serum tTG-IgA (positive [>1 × ULN] vs negative [≤1 × ULN]), and 0·93 (0·89-0·96) when applying the numerical definition of serum tTG-IgA (multiples of the ULN). Additional endoscopic findings included peptic gastritis (nine patients), autoimmune atrophic gastritis (three), reflux oesophagitis (31), gastric or duodenal ulcer (three), and Barrett's oesophagus (one). In the 1-year follow-up, a midgut ileum lymphoma was diagnosed in a woman on a gluten-free diet. INTERPRETATION Our data showed that biopsy could be reasonably avoided in the diagnosis of coeliac disease in adults with reliable suspicion of coeliac disease and high serum tTG-IgA. FUNDING None.
Collapse
Affiliation(s)
- Carolina Ciacci
- Centre for Coeliac Disease, AOU San Giovanni Di Dio e Ruggi d'Aragona, Salerno, Italy; Department of Medicine, Surgery, and Dentistry, Scuola Medica Salernitana, University of Salerno, Baronissi, Italy.
| | - Julio Cesar Bai
- Research Institutes, Universidad del Salvador, Buenos Aires, Argentina; Small Bowel Section, Dr C Bonorino Udaondo Gastroenterology Hospital, Buenos Aires, Argentina
| | - Geoffrey Holmes
- Department of Gastroenterology, Royal Derby Hospital, Derby, UK
| | - Abdulbaqi Al-Toma
- Department of Gastroenterology and Hepatology, St Antonius Hospital, Nieuwegein, Netherlands
| | - Federico Biagi
- Department of Internal Medicine and Medical Therapy, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy; Gastroenterology Unit of Pavia Institute, Istituti Clinici Scientifici Maugeri, IRCCS, Pavia, Italy
| | - Antonio Carroccio
- Unit of Internal Medicine, Cervello Hospital, University of Palermo, Palermo, Italy
| | - Rachele Ciccocioppo
- Gastroenterology Unit, Department of Medicine, AOUI Policlinico GB Rossi, University of Verona, Verona, Italy
| | - Antonio Di Sabatino
- Department of Internal Medicine and Medical Therapy, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Rachel Gingold-Belfer
- Gastroenterology Division, Rabin Medical Centre, Beilinson Hospital, Petah Tikva, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Mariana Jinga
- Gastroenterology Department, Carol Davila University of Medicine and Pharmacy, Central Military Emergency University Hospital, Bucharest, Romania
| | - Govind Makharia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Sonia Niveloni
- Small Bowel Section, Dr C Bonorino Udaondo Gastroenterology Hospital, Buenos Aires, Argentina
| | - Gary L Norman
- Research and Development, Headquarters and Technology Centre for Autoimmunity, Werfen, San Diego, CA, USA
| | - Kamran Rostami
- Gastroenterology Unit, MidCentral DHB, Palmerston North, New Zealand
| | - David S Sanders
- Academic Unit of Gastroenterology, Sheffield Teaching Hospital NHS Foundation Trust, Sheffield, UK
| | - Edgardo Smecuol
- Small Bowel Section, Dr C Bonorino Udaondo Gastroenterology Hospital, Buenos Aires, Argentina
| | - Vincenzo Villanacci
- Institute of Pathology, Spedali Civili University of Brescia, Brescia, Italy
| | - Santiago Vivas
- Gastroenterology Unit, University Hospital of Leon, Leon, Spain
| | - Fabiana Zingone
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| |
Collapse
|
|
14
|
Nagarajappa P, Chavali SM, Mylavarapu M. Pathological Manifestations of Gluten-Related Neuro-Psychiatric Disorders and the Impact of Gluten-Free Diet in a Pediatric Age Group: A Systematic Review. Cureus 2023; 15:e47062. [PMID: 38022342 PMCID: PMC10644809 DOI: 10.7759/cureus.47062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/15/2023] [Indexed: 12/01/2023] Open
Abstract
Gluten, as a term, causes unease among a vast majority of the population. The reason is the body's inability to process gluten, causing various pathological manifestations. While celiac disease is predominantly a gastrointestinal disease, it also has various extra-intestinal manifestations. Many children receive diagnoses of idiopathic neuropsychiatric symptoms such as epilepsy, attention-deficit hyperactivity disorder (ADHD), restless leg syndrome (RLS), and peripheral neuropathy without ever finding the root cause. A majority of these cases may be associated with celiac disease if only their antibody titers and other appropriate investigations were conducted. The treatment of these manifestations may be eliminated or at least controllable with dietary modification to a gluten-free diet (GFD). In this paper, we will discuss the pathology of celiac disease and the impact of GFD on the neuropsychiatric aspects of this disease, which is of higher prevalence in the pediatric population. A comprehensive literature search was conducted in prominent databases, namely PubMed and Google Scholar, to include studies that provided individual-level data on the neuropathological manifestations and the impact of a GFD on extra-intestinal manifestations of celiac disease. The research protocol was registered in the PROSPERO database (International Prospective Register of Systematic Reviews) with the registration ID: CRD42023415100. Based on the inclusion and exclusion criteria, we included prospective studies, observational studies, and case reports on pediatric patients with biopsy-proven celiac disease, serologically positive celiac disease, celiac disease with neuropsychiatric manifestations, and studies reporting the impact of GFD. After a rigorous quality assessment to remove the risk of bias, we finally included 20 studies to be discussed. In 6 (30%) studies, patients with neuropsychiatric manifestations had positive serology findings and a relatively higher grade of biopsy results. Seven studies discussed the positive impact of GFD. Five of these seven studies reported statistically significant results (p ≤ 0.001). Our study suggests that gluten plays a role in the severity of neuropsychiatric manifestations of celiac disease. Considering the results of our study, we can see that GFD does impact the prognosis of the disease. Neuropsychiatric findings without gastrointestinal manifestations are more common in the pediatric age group. We have clear evidence that several neurological conditions (neuropathy, ADHD, epilepsy, and RLS) have not only a significant association with gluten but can also potentially benefit from GFD. Thus, screening, with a combination of serological, biopsy, and imaging techniques, must be adapted into the guidelines for early detection and induction of GFD. Furthermore, studies should aim at introducing GFD in the pediatric population as a mode of primary prevention. In conclusion, our review underscores the importance of gluten while dealing with idiopathic neurological conditions in children and hopes to shed light on this commonly misdiagnosed and easily manageable disease.
Collapse
Affiliation(s)
- Prajwala Nagarajappa
- Department of Pathology, Mysore Medical College and Research Institute, Mysore, IND
| | | | | |
Collapse
|
|
15
|
Menotti L, Silvello G, Atzori M, Boytcheva S, Ciompi F, Di Nunzio GM, Fraggetta F, Giachelle F, Irrera O, Marchesin S, Marini N, Müller H, Primov T. Modelling digital health data: The ExaMode ontology for computational pathology. J Pathol Inform 2023; 14:100332. [PMID: 37705689 PMCID: PMC10495665 DOI: 10.1016/j.jpi.2023.100332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 07/14/2023] [Accepted: 08/16/2023] [Indexed: 09/15/2023] Open
Abstract
Computational pathology can significantly benefit from ontologies to standardize the employed nomenclature and help with knowledge extraction processes for high-quality annotated image datasets. The end goal is to reach a shared model for digital pathology to overcome data variability and integration problems. Indeed, data annotation in such a specific domain is still an unsolved challenge and datasets cannot be steadily reused in diverse contexts due to heterogeneity issues of the adopted labels, multilingualism, and different clinical practices. Material and methods This paper presents the ExaMode ontology, modeling the histopathology process by considering 3 key cancer diseases (colon, cervical, and lung tumors) and celiac disease. The ExaMode ontology has been designed bottom-up in an iterative fashion with continuous feedback and validation from pathologists and clinicians. The ontology is organized into 5 semantic areas that defines an ontological template to model any disease of interest in histopathology. Results The ExaMode ontology is currently being used as a common semantic layer in: (i) an entity linking tool for the automatic annotation of medical records; (ii) a web-based collaborative annotation tool for histopathology text reports; and (iii) a software platform for building holistic solutions integrating multimodal histopathology data. Discussion The ontology ExaMode is a key means to store data in a graph database according to the RDF data model. The creation of an RDF dataset can help develop more accurate algorithms for image analysis, especially in the field of digital pathology. This approach allows for seamless data integration and a unified query access point, from which we can extract relevant clinical insights about the considered diseases using SPARQL queries.
Collapse
Affiliation(s)
- Laura Menotti
- Department of Information Engineering, University of Padua, Padova, Italy
| | - Gianmaria Silvello
- Department of Information Engineering, University of Padua, Padova, Italy
| | - Manfredo Atzori
- Information Systems Institute, University of Applied Sciences Western Switzerland, Delémont, Switzerland
- Department of Neuroscience, University of Padua, Padova, Italy
| | | | - Francesco Ciompi
- Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
| | | | | | - Fabio Giachelle
- Department of Information Engineering, University of Padua, Padova, Italy
| | - Ornella Irrera
- Department of Information Engineering, University of Padua, Padova, Italy
| | - Stefano Marchesin
- Department of Information Engineering, University of Padua, Padova, Italy
| | - Niccolò Marini
- Information Systems Institute, University of Applied Sciences Western Switzerland, Delémont, Switzerland
| | - Henning Müller
- Information Systems Institute, University of Applied Sciences Western Switzerland, Delémont, Switzerland
| | | |
Collapse
|
|
16
|
Popp A, Laurikka P, Czika D, Kurppa K. The role of gluten challenge in the diagnosis of celiac disease: a review. Expert Rev Gastroenterol Hepatol 2023; 17:691-700. [PMID: 37243608 DOI: 10.1080/17474124.2023.2219893] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 05/12/2023] [Accepted: 05/26/2023] [Indexed: 05/29/2023]
Abstract
INTRODUCTION Duodenal biopsy is the gold standard in the diagnosis of celiac disease, with increasing utilization of serology. A gluten challenge may be required, for example, when dietary gluten reduction precedes appropriate diagnostic evaluations. Evidence on the best challenge protocol is currently sparse. Pharmaceutical trials in recent years may have provided new insights into the challenge and advanced the development of novel sensitive histological and immunological methods. AREAS COVERED This review outlines the current perspectives on the use of gluten challenge in the diagnosis of celiac disease and explores future directions in this area. EXPERT OPINION Comprehensive elimination of celiac disease before dietary gluten restriction is essential to avoid diagnostic uncertainties. Gluten challenge continues to have an important role in certain clinical scenarios, although it is important to understand its limitations in the diagnostic evaluation. The evidence so far permits no unequivocal recommendation considering the timing, duration, and amount of gluten used in the challenge. Thus, these decisions should be made on a case-by-case basis. Further studies with more standardized protocols and outcome measures are called for. In the future novel immunological methods may help to shorten or even avoid gluten challenge.
Collapse
Affiliation(s)
- Alina Popp
- Department of Pediatrics, University of Medicine and Pharmacy Carol Davila and National Institute for Mother and Child Health, Bucharest, Romania
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Pilvi Laurikka
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Internal Medicine, Tampere University Hospital, Tampere, Finland
| | - Diana Czika
- Department of Pediatrics, University of Medicine and Pharmacy Carol Davila and National Institute for Mother and Child Health, Bucharest, Romania
| | - Kalle Kurppa
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Tampere Center for Child, Adolescent and Maternal Health Research, Tampere University and Tampere University Hospital, Tampere, Finland
- The University Consortium of Seinäjoki, Seinäjoki, Finland
| |
Collapse
|
|
17
|
Trovato CM, Montuori M, Leter B, Laudadio I, Russo G, Oliva S. Role of age in dynamics of autoantibodies in pediatric Celiac disease. Ital J Pediatr 2023; 49:38. [PMID: 36959611 PMCID: PMC10037870 DOI: 10.1186/s13052-023-01435-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 03/01/2023] [Indexed: 03/25/2023] Open
Abstract
BACKGROUND Celiac disease (CD) is characterized by elevated serum titers of autoantibodies IgA anti-tissue transglutaminase 2 (TGA-IgA) and IgA anti-endomysial (EMA), with small bowel mucosa atrophy. We evaluated age differences between CD children exhibiting variable antibody titers at diagnosis. METHODS CD children diagnosed between January 2014 and June 2019, according to 2012 ESPGHAN guidelines were studied. All had EMA and TGA-IgA measurements, while a proportion of them underwent esophagogastroduodenoscopy (EGD). Patients were grouped based on serum TGA-IgA titers normalized to the upper limit of normal (ULN) and differences in median age (years) assessed by analysis of variance (ANOVA) and creation of orthogonal contrasts. RESULTS CD was diagnosed in 295 subjects (median age: 4.4 [IQR: 2.60-8.52]) with a biopsy sparing protocol (high titer: ≥ 10xULN) and in 204 by EGD biopsy. Of the latter, 142 (median age: 8.5 [IQR: 5.81-11.06]) and 62 (median age: 9.5 [IQR: 6.26-12.76]) had a low (< 5xULN) and a moderate (≥ 5 < 10xULN) TGA-IgA titer, respectively. Potential CD was diagnosed in 20 patients (median age: 3.6 [IQR: 2.47-6.91]). The median age was significantly lower in the no-biopsy group (ANOVA: F(3, 516) = 25.98, p < .001) than in low- and moderate titer groups (p < 0.0001), while there was no statistical difference between biopsy-sparing and potential CD groups. CONCLUSION CD patients with greatly elevated antibody titers (≥ 10xULN) were diagnosed at an earlier age than those with lower titers. This may indicate that an increase in TGA-IgA is independent of age and suggests a polarization of autoimmunity in younger individuals with higher serum antibody levels.
Collapse
Affiliation(s)
- Chiara Maria Trovato
- Gastroenterology and Nutritional Rehabilitation Unit, I.R.C.C.S. Bambino Gesù Children's Hospital, Piazza Sant'Onofrio 4, 00165, Rome, Italy
| | - Monica Montuori
- Pediatric Gastroenterology and Liver Unit, Maternal and Child Health Department, Sapienza University of Rome, Rome, Italy
| | - Beatrice Leter
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Ilaria Laudadio
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Giusy Russo
- Pediatric Gastroenterology and Liver Unit, Maternal and Child Health Department, Sapienza University of Rome, Rome, Italy
| | - Salvatore Oliva
- Pediatric Gastroenterology and Liver Unit, Maternal and Child Health Department, Sapienza University of Rome, Rome, Italy.
| |
Collapse
|
|
18
|
Faust O, De Michele S, Koh JE, Jahmunah V, Lih OS, Kamath AP, Barua PD, Ciaccio EJ, Lewis SK, Green PH, Bhagat G, Acharya UR. Automated analysis of small intestinal lamina propria to distinguish normal, Celiac Disease, and Non-Celiac Duodenitis biopsy images. COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE 2023; 230:107320. [PMID: 36608429 DOI: 10.1016/j.cmpb.2022.107320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 12/16/2022] [Accepted: 12/18/2022] [Indexed: 06/17/2023]
Abstract
BACKGROUND AND OBJECTIVE Celiac Disease (CD) is characterized by gluten intolerance in genetically predisposed individuals. High disease prevalence, absence of a cure, and low diagnosis rates make this disease a public health problem. The diagnosis of CD predominantly relies on recognizing characteristic mucosal alterations of the small intestine, such as villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. However, these changes are not entirely specific to CD and overlap with Non-Celiac Duodenitis (NCD) due to various etiologies. We investigated whether Artificial Intelligence (AI) models could assist in distinguishing normal, CD, and NCD (and unaffected individuals) based on the characteristics of small intestinal lamina propria (LP). METHODS Our method was developed using a dataset comprising high magnification biopsy images of the duodenal LP compartment of CD patients with different clinical stages of CD, those with NCD, and individuals lacking an intestinal inflammatory disorder (controls). A pre-processing step was used to standardize and enhance the acquired images. RESULTS For the normal controls versus CD use case, a Support Vector Machine (SVM) achieved an Accuracy (ACC) of 98.53%. For a second use case, we investigated the ability of the classification algorithm to differentiate between normal controls and NCD. In this use case, the SVM algorithm with linear kernel outperformed all the tested classifiers by achieving 98.55% ACC. CONCLUSIONS To the best of our knowledge, this is the first study that documents automated differentiation between normal, NCD, and CD biopsy images. These findings are a stepping stone toward automated biopsy image analysis that can significantly benefit patients and healthcare providers.
Collapse
Affiliation(s)
| | - Simona De Michele
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, USA
| | - Joel Ew Koh
- Department of Computer Engineering, Ngee Ann Polytechnic, Singapore, Singapore
| | - V Jahmunah
- Department of Computer Engineering, Ngee Ann Polytechnic, Singapore, Singapore
| | - Oh Shu Lih
- Department of Computer Engineering, Ngee Ann Polytechnic, Singapore, Singapore
| | | | - Prabal Datta Barua
- Cogninet Australia, Sydney, NSW 2010, Australia; School of Management & Enterprise, University of Southern Queensland, Australia; Faculty of Engineering and Information Technology, University of Technology Sydney, Sydney, NSW 2007, Australia
| | - Edward J Ciaccio
- Department of Medicine, Celiac Disease Center, Columbia University Irving Medical Center, USA
| | - Suzanne K Lewis
- Department of Medicine, Celiac Disease Center, Columbia University Irving Medical Center, USA
| | - Peter H Green
- Department of Medicine, Celiac Disease Center, Columbia University Irving Medical Center, USA
| | - Govind Bhagat
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, USA; Department of Medicine, Celiac Disease Center, Columbia University Irving Medical Center, USA
| | - U Rajendra Acharya
- School of Science and Technology, Singapore University of Social Sciences, 463 Clementi Road, 599494, Singapore; Department of Computer Engineering, Ngee Ann Polytechnic, Singapore, Singapore; Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan.
| |
Collapse
|
|
19
|
Villanacci V, Del Sordo R, Casella G, Becheanu G, Oberti A, Belfekih B, Bassotti G, Ravelli A. The correct methodological approach to the diagnosis of celiac disease: the point of view of the pathologist. GASTROENTEROLOGY AND HEPATOLOGY FROM BED TO BENCH 2023; 16:129-135. [PMID: 37554758 PMCID: PMC10404828 DOI: 10.22037/ghfbb.v16i2.2704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 03/01/2023] [Indexed: 08/10/2023]
Abstract
The diagnosis of celiac disease relies on the assessment of serological data and the presence of histological alterations in the duodenal mucosa. The duodenal biopsy is pivotal in adults, and in some circumstances in children, to confirm the clinical suspicion of celiac disease. The correct interpretation of duodenal biopsies is influenced by numerous variables. The aim of this overview is to describe the correct methodological approach including the procedures of biopsy sampling, orientation, processing, staining and histopathological classification in order to avoid or minimize the errors and the variability in duodenal biopsy interpretation. Multiple biopsies taken from different sites of the duodenum during endoscopy maximize the diagnostic yield of duodenal histological sampling. Proper orientation of the biopsy samples is of the utmost importance to assess histological features of pathological duodenal mucosa and to avoid artifacts that may lead even an experienced pathologist to a wrong histological interpretation with subsequent misdiagnosis of celiac disease. An immunohistochemical stain for CD3 can be invaluable to aid the pathologist in obtaining a more accurate intra-epithelial T lymphocytes count. A simplified histological classification facilitates the clinician's work and improves the communication between pathologist and clinician. An integrated clinical and pathological approach is required for a correct diagnosis of celiac disease since a relatively large number of conditions may cause duodenal damage with a histological appearance similar to that of celiac disease.
Collapse
Affiliation(s)
- Vincenzo Villanacci
- Institute of Pathology, ASST Spedali Civili and University of Brescia, Brescia, Italy
| | - Rachele Del Sordo
- Department of Medicine and Surgery, Section of Anatomic Pathology and Histology, Medical School, University of Perugia, Perugia, Italy
| | | | - Gabriel Becheanu
- Department of Pathology, Carol Davila University of Medicine & Pharmacy, 050474 Bucharest, Romania
| | - Arianna Oberti
- Institute of Pathology, ASST Spedali Civili and University of Brescia, Brescia, Italy
| | - Baraa Belfekih
- Institute of Pathology, ASST Spedali Civili and University of Brescia, Brescia, Italy
| | - Gabrio Bassotti
- Gastroenterology and Hepatology Section, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Alberto Ravelli
- Gastroenterology and GI Endoscopy Unit, University Department of Pediatrics, Children's Hospital, ASST Spedali Civili, Brescia, Italy
| |
Collapse
|
|
20
|
KARPUZ D, TEZOL Ö, TÜRKEGÜN M, USTA Y. Comparison of early atherosclerosis markers in children with Celiac disease and their healthy peers. CUKUROVA MEDICAL JOURNAL 2022. [DOI: 10.17826/cumj.1166923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Purpose: We aimed to evaluate carotid intima-media thickness (cIMT) and epicardial adipose tissue thickness (EATT) concurrently as early atherosclerotic markers in pediatric patients with Celiac disease.
Materials and Methods: Patients with Celiac disease (n=54) and healthy peers (n=54) aged 5-18 years were enrolled in this cross-sectional study. Patients who followed gluten free diet at least the past 12 months were included. Anthropometric and biochemical measurements were performed. cIMT and EATT were measured by echocardiography and compared between the patient and control groups.
Results: Body mass index (17.4±3.0 vs. 18.4±3.1 kg/m2), blood pressure (systolic: 100 (85-120) vs. 100 (80-100) mmHg; diastolic: 60 (40-90) vs. 70 (40-90) mmHg), and lipid profile (total cholesterol: 144.6±30.2 vs. 150.8±22.6 mg/dL; triglycerides: 71.5 (27-178) vs. 92.5 (34-203) mg/dL) were not different between the patient and control groups, while there were significant differences in cIMT and EATT. The patient group had higher cIMT (0.50±0.07 vs. 0.45±0.04 mm) and EATT (5.68±0.90 vs. 4.22±0.76 mm) than the control group. The risk of vitamin D insufficiency was 2.68 times higher in the patient group (95% CI=1.19-6.03).
Conclusions: Children with Celiac disease had higher cIMT and EATT than healthy peers. cIMT and/or EATT measurements by echocardiography may present as a reliable and easy method to investigate subclinical atherosclerosis in children with Celiac disease.
Collapse
Affiliation(s)
| | | | | | - Yusuf USTA
- MERSİN ÜNİVERSİTESİ, TIP FAKÜLTESİ, TIP PR
| |
Collapse
|
|
21
|
Quantitative histology as a diagnostic tool for celiac disease in children and adolescents. Ann Diagn Pathol 2022; 61:152031. [DOI: 10.1016/j.anndiagpath.2022.152031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Accepted: 08/21/2022] [Indexed: 11/17/2022]
|
|
22
|
Oktay C, Yavuz S. Evaluation of the Relationship Between Carotid Intima Media Thickness and Dietary Compliance in Pediatric Celiac Patients: A Single-Center Pilot Study. JOURNAL OF ULTRASOUND IN MEDICINE : OFFICIAL JOURNAL OF THE AMERICAN INSTITUTE OF ULTRASOUND IN MEDICINE 2022; 41:2475-2485. [PMID: 34962314 DOI: 10.1002/jum.15934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 12/14/2021] [Accepted: 12/15/2021] [Indexed: 06/14/2023]
Abstract
OBJECTIVES This study aimed to show the relationship between gluten-free diet (GFD) compliance in Celiac Disease (CD) and early atherosclerotic findings in pediatric patients and to test the effectiveness of carotid-intima-media-thickness (cIMT) to possibly predict long-term compliance to the GFD. METHODS Patients from 6 to 18 years of age with a diagnosis of CD confirmed by endoscopic duodenal biopsy who were followed at our hospital's pediatric gastroenterology outpatient clinic between November 2020 and May 2021 were evaluated in this single-center, prospective study. The study patients were divided into two groups according to GFD compliance. Serologic and biochemical tests were conducted routinely during the follow-up period. cIMT was measured using ultrasound for both groups. RESULTS A total of 80 patients (GFD-non-compliant: n = 35, GFD-compliant: n = 45) were evaluated. No significant differences were observed between the groups in terms of demographic data and pathology results. The mean cIMT value was 0.44 ± 0.028 mm for the GFD-compliant group and 0.54 ± 0.036 mm for the GFD-non-compliant group, with a statistically significant between-group difference (P < .001). The receiver operating characteristic curve analysis showed an area under the curve of 0.992 (95% confidence interval [CI]: 0.978-1, P < .001) for discrimination of the groups. In addition, a cutoff value of 0.486 mm for cIMT showed 96% (95% CI: 0.83-0.99) sensitivity and 94% (95% CI: 0.79-0.99) specificity for distinguishing GFD-compliant patients from non-GFD-compliant patients. CONCLUSION In this study, the relationship between long-term GFD compliance and cIMT was demonstrated in CD. Currently used by some authors for the assessment of preclinical atherosclerosis, cIMT can also be used as a long-term indicator of dietary compliance as well as cardiovascular risk.
Collapse
Affiliation(s)
- Cemil Oktay
- Department of Radiology, Adıyaman University Training and Research Hospital, Adıyaman, Turkey
| | - Sibel Yavuz
- Department of Pediatric Gastroenterology, Adıyaman University Training and Research Hospital, Adıyaman, Turkey
| |
Collapse
|
|
23
|
Zingone F, Maimaris S, Auricchio R, Caio GPI, Carroccio A, Elli L, Galliani E, Montagnani M, Valiante F, Biagi F. Guidelines of the Italian societies of gastroenterology on the diagnosis and management of coeliac disease and dermatitis herpetiformis. Dig Liver Dis 2022; 54:1304-1319. [PMID: 35858884 DOI: 10.1016/j.dld.2022.06.023] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 05/11/2022] [Accepted: 06/19/2022] [Indexed: 12/29/2022]
Abstract
INTRODUCTION Coeliac disease and dermatitis herpetiformis are immune-mediated diseases triggered by the consumption of gluten in genetically predisposed individuals. These guidelines were developed to provide general practitioners, paediatricians, gastroenterologists, and other clinicians with an overview on the diagnosis, management and follow-up of coeliac patients and those with dermatitis herpetiformis. METHODS Guidelines were developed by the Italian Societies of Gastroenterology. Following a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the certainty of the evidence. Statements and recommendations were developed by working groups consisting of gastroenterologists and a paediatrician with expertise in this field. RESULTS These guidelines provide a practical guidance for the diagnosis, management and follow-up of coeliac patients and dermatitis herpetiformis in children and adults, both in primary care and in specialist settings. We developed four sections on diagnosis, gluten-free diet, follow-up and risk of complications in adults, one section focused on diagnosis and follow-up in children and one on the diagnosis and management of dermatitis herpetiformis. CONCLUSIONS These guidelines may support clinicians to improve the diagnosis and management of patients with coeliac disease.
Collapse
Affiliation(s)
- Fabiana Zingone
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Italy; Gastroenterology Unit, Azienda Ospedale Università, Padova, Italy.
| | - Stiliano Maimaris
- Dipartimento di Medicina Interna e Terapia Medica, Università di Pavia, Italia
| | - Renata Auricchio
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Giacomo Pietro Ismaele Caio
- Department of Morphology, Surgery and Experimental Medicine, St. Anna Hospital, University of Ferrara, Ferrara, Italy
| | - Antonio Carroccio
- Unit of Internal Medicine, "V. Cervello" Hospital, Ospedali Riuniti "Villa Sofia-Cervello", 90146 Palermo, University of Palermo, Italy
| | - Luca Elli
- Gastroenterology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Ermenegildo Galliani
- UOC Gastroenterologia ed Endoscopia Digestiva, AULSS1 Dolomiti Veneto, Ospedale San Martino, Belluno, Italy
| | - Marco Montagnani
- Department of Medical and Surgical Sciences, University of Bologna, Italy; Gastroenterology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Italy
| | - Flavio Valiante
- UOC Gastroenterologia ed Endoscopia Digestiva, AULSS1 Dolomiti Veneto, Feltre (BL), Italy
| | - Federico Biagi
- Istituti Clinici Maugeri, IRCCS, Unità di Gastroenterologia dell'Istituto di Pavia, Italy
| |
Collapse
|
|
24
|
Virta J, Hannula M, Lindfors K, Tamminen I, Taavela J, Huhtala H, Kaukinen K, Saavalainen P, Hyttinen J, Kurppa K. Validation of the X-ray microtomography in the assessment of duodenal morphometry and surface area in celiac disease. Front Immunol 2022; 13:945197. [PMID: 36211435 PMCID: PMC9539806 DOI: 10.3389/fimmu.2022.945197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 09/01/2022] [Indexed: 11/13/2022] Open
Abstract
Background Duodenal histology remains the diagnostic reference standard in celiac disease. However, traditional methods have suboptimal sensitivity and reproducibility for early mucosal changes and research purposes. We validated a recently introduced micro-CT imaging method for an accurate digital evaluation of duodenal histomorphometry and mucosal surface areas. Methods Endoscopic biopsies from 58 individuals were utilized for the micro-CT imaging, selecting histological changes ranging from normal to severely damaged mucosa. The imaging protocol was optimized for practicability and resolution. The Bland–Altman method was applied to test intra- and interobserver variations in the blinded measurements. Results The 3D micro-CT reconstructions enabled easy and precise digital cutting with optimal orientation and computer-assisted measurement of the surface area. Intraobserver analysis of morphological measurements showed a mean difference of 0.011 with limits of agreement (LA) from -0.397 to 0.375 and a standard deviation (SD) of 0.197. The corresponding figures for interobserver analysis were 0.080, from -0.719 to 0.537 and 0.320, respectively. The intraclass correlation coefficients (ICC) for the intraobserver and interobserver variations were 0.981 and 0.954, respectively. Intraobserver surface area analysis yielded a mean difference of 0.010, LA from -0.764 to 0.785 and an SD of 0.395, and an interobserver analysis mean difference of 0.028, LA from -0.642 to 0.698 and SD of 0.342. The respective ICCs for the intra- and interobserver variations were 0.963 and 0.972. Conclusions Micro-CT showed excellent accuracy and reproducibility in the evaluation of mucosal morphometry and surface areas. The improved sensitivity for histological changes is a powerful tool for the diagnosis of celiac disease and for clinical and pharmacological studies.
Collapse
Affiliation(s)
- Johannes Virta
- Tampere Center for Child Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Pediatrics, Tampere University Hospital, Tampere, Finland
| | - Markus Hannula
- Computational Biophysics and Imaging Group, The Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Katri Lindfors
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Ilmari Tamminen
- Computational Biophysics and Imaging Group, The Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Juha Taavela
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Heini Huhtala
- Faculty of Social Sciences, Tampere University, Tampere, Finland
| | - Katri Kaukinen
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Internal Medicine, Tampere University Hospital, Tampere, Finland
| | - Päivi Saavalainen
- Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
| | - Jari Hyttinen
- Computational Biophysics and Imaging Group, The Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Kalle Kurppa
- Tampere Center for Child Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Pediatrics, Tampere University Hospital, Tampere, Finland
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- The University Consortium of Seinäjoki and Seinäjoki Central Hospital, Seinäjoki, Finland
- *Correspondence: Kalle Kurppa,
| |
Collapse
|
|
25
|
Papparella S, Crescio MI, Baldassarre V, Brunetti B, Burrai GP, Cocumelli C, Grieco V, Iussich S, Maniscalco L, Mariotti F, Millanta F, Paciello O, Rasotto R, Romanucci M, Sfacteria A, Zappulli V. Reproducibility and Feasibility of Classification and National Guidelines for Histological Diagnosis of Canine Mammary Gland Tumours: A Multi-Institutional Ring Study. Vet Sci 2022; 9:357. [PMID: 35878374 PMCID: PMC9325225 DOI: 10.3390/vetsci9070357] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 07/04/2022] [Accepted: 07/06/2022] [Indexed: 11/30/2022] Open
Abstract
Histological diagnosis of Canine Mammary Tumours (CMTs) provides the basis for proper treatment and follow-up. Nowadays, its accuracy is poorly understood and variable interpretation of histological criteria leads to a lack of standardisation and impossibility to compare studies. This study aimed to quantify the reproducibility of histological diagnosis and grading in CMTs. A blinded ring test on 36 CMTs was performed by 15 veterinary pathologists with different levels of education, after discussion of critical points on the Davis-Thompson Foundation Classification and providing consensus guidelines. Kappa statistics were used to compare the interobserver variability. The overall concordance rate of diagnostic interpretations of WP on identification of hyperplasia-dysplasia/benign/malignant lesions showed a substantial agreement (average k ranging from 0.66 to 0.82, with a k-combined of 0.76). Instead, outcomes on ICD-O-3.2 morphological code /diagnosis of histotype had only a moderate agreement (average k ranging from 0.44 and 0.64, with a k-combined of 0.54). The results demonstrated that standardised classification and consensus guidelines can produce moderate to substantial agreement; however, further efforts are needed to increase this agreement in distinguishing benign versus malignant lesions and in histological grading.
Collapse
Affiliation(s)
- Serenella Papparella
- Department of Veterinary Medicine and Animal Production, Unit of Pathology, University of Naples Federico II, 80138 Naples, Italy; (S.P.); (V.B.); (O.P.)
| | - Maria Ines Crescio
- National Reference Center for the Veterinary and Comparative Oncology (CEROVEC), Experimental Zooprophylactic Institute of Piedmont, Liguria and Valle d’Aosta, 10154 Turin, Italy;
| | - Valeria Baldassarre
- Department of Veterinary Medicine and Animal Production, Unit of Pathology, University of Naples Federico II, 80138 Naples, Italy; (S.P.); (V.B.); (O.P.)
| | - Barbara Brunetti
- Department of Veterinary Medical Sciences, University of Bologna, 40126 Bologna, Italy;
| | - Giovanni P. Burrai
- Department of Veterinary Medicine, University of Sassari, 07100 Sassari, Italy;
- Mediterranean Center for Disease Control (MCDC), University of Sassari, 07100 Sassari, Italy
| | - Cristiano Cocumelli
- Experimental Zooprophylactic Institute of Lazio and Toscana M. Aleandri, 00178 Rome, Italy;
| | - Valeria Grieco
- Department of Veterinary Medicine, University of Milan, 26900 Lodi, Italy;
| | - Selina Iussich
- Department of Veterinary Science, University of Turin, 10095 Turin, Italy; (S.I.); (L.M.)
| | - Lorella Maniscalco
- Department of Veterinary Science, University of Turin, 10095 Turin, Italy; (S.I.); (L.M.)
| | - Francesca Mariotti
- School of Bioscience and Veterinary Medicine, University of Camerino, 62032 Camerino, Italy;
| | - Francesca Millanta
- Department of Veterinary Sciences, University of Pisa, 56124 Pisa, Italy;
| | - Orlando Paciello
- Department of Veterinary Medicine and Animal Production, Unit of Pathology, University of Naples Federico II, 80138 Naples, Italy; (S.P.); (V.B.); (O.P.)
| | - Roberta Rasotto
- Independent Researcher, Via Messer Ottonello 1, 37127 Verona, Italy;
| | | | | | - Valentina Zappulli
- Department of Comparative Biomedicine and Food Science, University of Padua, 35020 Padua, Italy
| |
Collapse
|
|
26
|
Trasciatti S, Piras F, Bonaretti S, Marini S, Nencioni S, Biasci E, Egan CG, Nannipieri F. Effect of oral cholecalciferol in a murine model of celiac disease: A dose ranging study. J Steroid Biochem Mol Biol 2022; 220:106083. [PMID: 35257869 DOI: 10.1016/j.jsbmb.2022.106083] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 01/20/2022] [Accepted: 02/18/2022] [Indexed: 12/16/2022]
Abstract
Previous studies have shown a relationship between vitamin D and celiac disease (CD), however little evidence is available examining the direct effects of vitamin D on pathological features of this disease. In this study we evaluated the effect of oral administration of different doses of native vitamin D3 (cholecalciferol) in enteropathic mice. Female non-obese diabetic (NOD)/ShiLt.J mice were fed standard or gluten-free diet and administered gliadin (5 μg/kg) to induce a celiac pathology. Healthy control (gluten-free diet, without gliadin) and control for pathology (standard diet, with gliadin) were administered olive oil. All other experimental groups received gliadin and standard diet plus oral cholecalciferol (5, 10, 20, 50 and 130 μg/kg). Serum levels of 25(OH)D3, calcium and zonulin and expression of vitamin D receptor (VDR), CD3 and zonula occludens-1 (ZO-1) by immunohistochemistry as well as intestinal histological and histomorphometric analyses were undertaken. Although no difference in serum levels of 25(OH)D3, calcium or zonulin was observed in cholecalciferol-treated mice vs. healthy controls, a significant improvement in intestinal mucosa pathological features in mice administered cholecalciferol was observed by histological analysis. Villi length was also significantly increased by cholecalciferol in a dose-dependent manner. Immunohistochemical staining revealed increased expression of CD3 and ZO-1 in celiac mice compared to mice receiving high dose (130 μg/kg) cholecalciferol. These findings show the effect of oral cholecalciferol on signature features of CD in a mouse model of CD. Further dose-ranging studies to investigate the efficacy of cholecalciferol for the treatment of CD are warranted.
Collapse
|
|
27
|
Biomarkers for the diagnosis and monitoring of celiac disease: can you count on me? Curr Opin Gastroenterol 2022; 38:263-269. [PMID: 35645020 DOI: 10.1097/mog.0000000000000825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
PURPOSE OF REVIEW Different markers are available to diagnose and monitor celiac disease (CeD); however, the concordance among them and their efficacy are still controversial. We aim at defining the efficacy of CeD biomarkers, their advantages and limits. RECENT FINDINGS CeD diagnostic criteria are widely accepted, being a positive serology and duodenal atrophy (according to the Marsh-Oberhuber score) the main hallmarks. Flow cytometry and other molecular biomarkers support the diagnosis of refractory CeD. On the other side, CeD monitoring is less defined, as the biomarkers are not always reliable. To date, the reference standard to detect mucosal healing is represented by duodenal histology, but its timing and significance are debated. Novel scores may better define the trend of mucosal damage and MicroRNAs are among the innovative noninvasive biomarkers. The assessment of a correct gluten-free diet (GFD) is another aspect of CeD monitoring, based upon questionnaires and recently developed tools such as dosage of urinary or faecal gluten immunogenic peptides. SUMMARY Clinicians lack of a widely acknowledged tools to monitor CeD and GFD. Here, we present the efficacy of the most used markers.
Collapse
|
|
28
|
Del Sordo R, Volta U, Lougaris V, Parente P, Sidoni A, Facchetti M, Bassotti G, Carosi I, Clemente C, Villanacci V. Histological Features of Celiac-Disease-like Conditions Related to Immune Checkpoint Inhibitors Therapy: A Signal to Keep in Mind for Pathologists. Diagnostics (Basel) 2022; 12:395. [PMID: 35204486 PMCID: PMC8871268 DOI: 10.3390/diagnostics12020395] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/19/2022] [Accepted: 02/02/2022] [Indexed: 11/17/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein (PD-1), and its ligand PDL-1, are finding increasing application in the treatment of malignant neoplasms. The widespread clinical use of these drugs, however, resulted in the discovery of side effects. The occurrence of celiac disease (CD) after ICIs therapy has been reported in the literature, but its incidence remains unknown and the role of ICIs in its onset is not yet clear. In this review, we examine the published data on this topic in order to better understand and define this entity from a histological point of view. We performed an electronic literature search to identify original reports in which CD or pathological CD-like conditions were documented histologically in patients treated with ICIs. We identified ten papers. A total of twenty-five patients were included in these publications, eleven of them receiving a serologic and histological diagnosis of CD, and four a histological diagnosis of CD-like conditions, in which pathogenesis appears to be multifactorial. ICIs can cause a CD-like enteropathy and biopsies with clinical integration are crucial to diagnose this condition. CD rarely has been observed during treatment with ICIs and its morphological aspects are similar to ICIs-CD enteropathy. Moreover, the onset of ICIs-CD may have a distinct immune mechanism compared to classical CD. Thus, the pathologists must make a histological diagnosis of CD with caution and only in adequate clinical and serological context.
Collapse
Affiliation(s)
- Rachele Del Sordo
- Department of Medicine and Surgery, Section of Anatomic Pathology and Histology, Medical School, University of Perugia, 06132 Perugia, Italy; (R.D.S.); (A.S.)
| | - Umberto Volta
- Department of Medical and Surgical Sciences, University of Bologna, 40126 Bologna, Italy;
| | - Vassilios Lougaris
- Pediatrics Clinic, Department of Clinical and Experimental Sciences, University of Brescia and Children’s Hospital, ASST-Spedali Civili, 25123 Brescia, Italy;
| | - Paola Parente
- Pathology Unit, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy; (I.C.); (C.C.)
| | - Angelo Sidoni
- Department of Medicine and Surgery, Section of Anatomic Pathology and Histology, Medical School, University of Perugia, 06132 Perugia, Italy; (R.D.S.); (A.S.)
| | - Mattia Facchetti
- Institute of Pathology, ASST-Spedali Civili Brescia, 25123 Brescia, Italy;
| | - Gabrio Bassotti
- Gastroenterology & Hepatology Section, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy;
| | - Illuminato Carosi
- Pathology Unit, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy; (I.C.); (C.C.)
| | - Celeste Clemente
- Pathology Unit, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, FG, Italy; (I.C.); (C.C.)
| | | |
Collapse
|
|
29
|
Villanacci V, Del Sordo R, Pietrantoni A. IgA deposits in celiac disease. Their immunohistochemistry value in early diagnosis. Dig Liver Dis 2022; 54:198-199. [PMID: 34857488 DOI: 10.1016/j.dld.2021.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 11/10/2021] [Indexed: 12/11/2022]
Affiliation(s)
| | - Rachele Del Sordo
- Department of Medicine and Surgery, Section of Anatomic Pathology and Histology, Medical School, University of Perugia, Perugia, Italy.
| | | |
Collapse
|
|
30
|
Trovato CM, Oliva S, Pietropaoli N, Pignataro MG, Berni S, Tancredi A, Cucchiara S, Giordano C, Montuori M. A new double immunohistochemistry method to detect mucosal anti-transglutaminase IgA deposits in coeliac children. Dig Liver Dis 2022; 54:200-206. [PMID: 34844876 DOI: 10.1016/j.dld.2021.11.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 11/02/2021] [Accepted: 11/08/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Intestinal transglutaminase (TG2) IgA deposits represent early marker of coeliac disease (CeD) and can predict the evolution towards intestinal atrophy. AIMS To validate a double immunohistochemistry method for the determination of intestinal TG2 IgA deposits on formalin-fixed paraffin-embedded biopsies. METHODS Immunohistochemistry was tested on: 1) children with overt CeD [persistently positive serum IgA anti-tissue transglutaminase type 2 (TGA-IgA) with moderate or low titer, and histological findings of CeD]; 2) potential CeD (persistently positive serum TGA-IgA and normal intestinal mucosa) and 3) controls (negative serum TGA-IgA and normal intestinal mucosa). RESULTS Samples from 61 children were analyzed (32 overt CeD, 14 potential CeD, and 15 controls). Deposits appeared as focal, multifocal, or confluent extracellular foci of red and brown staining colocalization in the sub-epithelium and around mucosal vessels. Deposits were present in all 32 children with overt CeD and in 9/14 potential CeD. Deposits were never observed in the 15 controls. Patients with higher serum level of TGA-IgA and with mucosal atrophy showed mostly a multifocal/diffuse pattern of deposits distribution. The bulb appeared most severely involved. In potential CeD deposits showed mainly a focal distribution. CONCLUSION Our results indicate double immunohistochemistry as promising diagnostic tool to improve diagnosis of CeD.
Collapse
Affiliation(s)
- Chiara Maria Trovato
- Maternal and Child Health Department, Sapienza - University of Rome, Rome, Italy; Hepatology Gastroenterology and Nutrition Unit, "Bambino Gesù" Children Hospital, 00165 Rome, Italy
| | - Salvatore Oliva
- Maternal and Child Health Department, Sapienza - University of Rome, Rome, Italy
| | | | - Maria Gemma Pignataro
- Department of Radiology, Oncology and Pathology, Sapienza, University of Rome, Rome, Italy
| | - Silvia Berni
- Department of Radiology, Oncology and Pathology, Sapienza, University of Rome, Rome, Italy
| | - Andrea Tancredi
- Department of Methods and Models for Economy, Territory and Finance, Sapienza, University of Rome, Rome, Italy
| | - Salvatore Cucchiara
- Maternal and Child Health Department, Sapienza - University of Rome, Rome, Italy
| | - Carla Giordano
- Department of Radiology, Oncology and Pathology, Sapienza, University of Rome, Rome, Italy.
| | - Monica Montuori
- Maternal and Child Health Department, Sapienza - University of Rome, Rome, Italy.
| |
Collapse
|
|
31
|
Rossi C, Simoncelli G, Arpa G, Stracuzzi A, Parente P, Fassan M, Vanoli A, Villanacci V. Histopathology of intestinal villi in neonatal and paediatric age: main features with clinical correlation - Part II. Pathologica 2022; 114:22-31. [PMID: 34856605 PMCID: PMC9040546 DOI: 10.32074/1591-951x-338] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 07/30/2021] [Indexed: 11/30/2022] Open
Abstract
In this paper, we will continue the description of histological findings of infantile and paediatric small bowel alterations with the main clinical pictures and differential diagnosis. We emphasise once again the need to evaluate the biopsies in an adequate clinical contest and with a systematic approach, including epithelial alterations, lamina propria changes, mucosal architecture, and the distribution of inflammation, together with other morphological signs more specific of certain diseases. We describe the histological findings of coeliac and Crohn's disease, gastrointestinal food allergic diseases, Langerhans cell histiocytosis, nutritional deficiencies and infections. Finally, we suggest the principal issues in the drafting the pathological report for appropriate interpretation and usefulness in clinical practice.
Collapse
Affiliation(s)
- Chiara Rossi
- Unit of Anatomic Pathology, Department of Molecular Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy
| | | | - Giovanni Arpa
- Unit of Anatomic Pathology, Department of Molecular Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy
| | - Alessandra Stracuzzi
- Pathological Anatomy Unit, Department of Diagnostic and Laboratory Medicine, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
| | - Paola Parente
- Pathology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, Italy
- Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy
| | - Alessandro Vanoli
- Unit of Anatomic Pathology, Department of Molecular Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy
| | | |
Collapse
|
|
32
|
Raiteri A, Granito A, Giamperoli A, Catenaro T, Negrini G, Tovoli F. Current guidelines for the management of celiac disease: A systematic review with comparative analysis. World J Gastroenterol 2022; 28:154-175. [PMID: 35125825 PMCID: PMC8793016 DOI: 10.3748/wjg.v28.i1.154] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 08/08/2021] [Accepted: 12/25/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Wheat and other gluten-containing grains are widely consumed, providing approximately 50% of the caloric intake in both industrialised and developing countries. The widespread diffusion of gluten-containing diets has rapidly led to a sharp increase in celiac disease prevalence. This condition was thought to be very rare outside Europe and relatively ignored by health professionals and the global media. However, in recent years, the discovery of important diagnostic and pathogenic milestones has led to the emergence of celiac disease (CD) from obscurity to global prominence. These modifications have prompted experts worldwide to identify effective strategies for the diagnosis and follow-up of CD. Different scientific societies, mainly from Europe and America, have proposed guidelines based on CD's most recent evidence. AIM To identify the most recent scientific guidelines on CD, aiming to find and critically analyse the main differences. METHODS We performed a database search on PubMed selecting papers published between January 2010 and January 2021 in the English language. PubMed was lastly accessed on 1 March 2021. RESULTS We distinguished guidelines from 7 different scientific societies whose reputation is worldwide recognized and representative of the clinical practice in different geographical regions. Differences were noted in the possibility of a no-biopsy diagnosis, HLA testing, follow-up protocols, and procedures. CONCLUSION We found a relatively high concordance between the guidelines for CD. Important modifications have occurred in the last years, especially about the possibility of a no-biopsy diagnosis in children. Other modifications are expected in the next future and will probably involve the extension of the non-invasive diagnosis to the adult population and the follow-up modalities.
Collapse
Affiliation(s)
- Alberto Raiteri
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| | - Alessandro Granito
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| | - Alice Giamperoli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| | - Teresa Catenaro
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| | - Giulia Negrini
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| | - Francesco Tovoli
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| |
Collapse
|
|
33
|
Ensari A, Ersoz CC, Kirmizi A, Kiremitci S. Histopathologic aspects of gluten-related disorders. GLUTEN-RELATED DISORDERS 2022:113-128. [DOI: 10.1016/b978-0-12-821846-4.00002-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
34
|
Yoosuf S, Therrien A, Leffler DA. Non-dietary therapies for celiac disease. COELIAC DISEASE AND GLUTEN-RELATED DISORDERS 2022:111-160. [DOI: 10.1016/b978-0-12-821571-5.00011-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
35
|
Kurppa K, Agardh D. Pediatric coeliac disease. COELIAC DISEASE AND GLUTEN-RELATED DISORDERS 2022:23-41. [DOI: 10.1016/b978-0-12-821571-5.00002-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
36
|
The Gluten-Free Diet for Celiac Disease and Beyond. Nutrients 2021; 13:nu13113993. [PMID: 34836247 PMCID: PMC8625243 DOI: 10.3390/nu13113993] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 11/02/2021] [Accepted: 11/03/2021] [Indexed: 12/20/2022] Open
Abstract
The gluten-free diet (GFD) has gained popularity beyond its main medical indication as the treatment for gluten-induced immune-mediated disorders such as celiac disease (CD), dermatitis herpetiformis, gluten ataxia, wheat allergy, and non-celiac gluten sensitivity. However, the diet carries some disadvantages such as elevated costs, nutritional deficiencies, and social and psychological barriers. The present work aims to review indications, proven benefits, and adverse events of a gluten-free diet. Close follow-up with patients following the diet is recommended. More data is needed to assess the effectiveness of the diet in managing mental and cognitive disorders and to establish a connection between the brain and gluten.
Collapse
|
|
37
|
Costetti M, Schiepatti A, Fraticelli S, Costa S, Maimaris S, Lenti MV, Villani L, Bianchi PI, Di Sabatino A, Corazza GR, Vanoli A, Biagi F. Clinical and gastro-duodenal histopathological features of enteropathy due to angiotensin II receptor blockers. Dig Liver Dis 2021; 53:1262-1267. [PMID: 34330666 DOI: 10.1016/j.dld.2021.07.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 07/01/2021] [Accepted: 07/04/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Clinical elements differentiating enteropathy due to angiotensin II-receptor-blockers (ARBs-E) from coeliac disease (CD) are poorly defined. The histopathological features on duodenal and gastric biopsies in these patients still need to be investigated. AIMS To describe the clinical phenotype of ARBs-E in comparison to CD, and the histological findings of gastric and duodenal biopsies in ARBs-E. METHODS Clinical data of patients with ARBs-E and CD diagnosed between 2013 and 2020 were retrospectively reviewed. Baseline presenting symptoms and demographics were compared (Fisher's exact test and t-test). Gastric and duodenal histology in ARBs-E were revised by two independent pathologists. RESULTS 14 ARBs-E and 112 CD patients were enroled. Weight loss (p < 0.01), acute onset of diarrhoea (p < 0.01), hospitalization (p < 0.01), and older age at diagnosis (p < 0.01) were more common in ARBs-E. Duodenal histology in ARBs-E showed intraepithelial lymphocytosis in 71%, increased mucosal eosinophilic count in 57%, with preserved neuroendocrine, Paneth and goblet cells in all patients. Gastric histologic lesions at baseline, including lymphocytic gastritis, eosinophilic gastritis, chronic active gastritis, and metaplastic atrophic gastritis patterns were observed in 73% of patients, without Helicobacter pylori infection. CONCLUSIONS ARBs-E showed a severe clinical phenotype, often requiring hospital admission. Gastric involvement at diagnosis is very common, and this could further support this diagnosis.
Collapse
Affiliation(s)
- Martina Costetti
- Gastroenterology Unit of Pavia Institute, IRCCS Pavia, Istituti Clinici Scientifici Maugeri, University of Pavia, Via Salvatore Maugeri 10, Pavia 27100, Italy
| | - Annalisa Schiepatti
- Gastroenterology Unit of Pavia Institute, IRCCS Pavia, Istituti Clinici Scientifici Maugeri, University of Pavia, Via Salvatore Maugeri 10, Pavia 27100, Italy.
| | - Sara Fraticelli
- Unit of Anatomic Pathology, Department of Molecular Medicine, University of Pavia, and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Stefania Costa
- Gastroenterology Unit of Pavia Institute, IRCCS Pavia, Istituti Clinici Scientifici Maugeri, University of Pavia, Via Salvatore Maugeri 10, Pavia 27100, Italy
| | - Stiliano Maimaris
- Gastroenterology Unit of Pavia Institute, IRCCS Pavia, Istituti Clinici Scientifici Maugeri, University of Pavia, Via Salvatore Maugeri 10, Pavia 27100, Italy
| | - Marco Vincenzo Lenti
- Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Italy
| | - Laura Villani
- Pathology Unit, IRCCS Pavia, Istituti Clinici Scientifici Maugeri, University of Pavia, Italy
| | | | - Antonio Di Sabatino
- Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Italy
| | - Gino Roberto Corazza
- Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Italy
| | - Alessandro Vanoli
- Unit of Anatomic Pathology, Department of Molecular Medicine, University of Pavia, and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Federico Biagi
- Gastroenterology Unit of Pavia Institute, IRCCS Pavia, Istituti Clinici Scientifici Maugeri, University of Pavia, Via Salvatore Maugeri 10, Pavia 27100, Italy
| |
Collapse
|
|
38
|
Gandini A, Gededzha MP, De Maayer T, Barrow P, Mayne E. Diagnosing coeliac disease: A literature review. Hum Immunol 2021; 82:930-936. [PMID: 34462157 DOI: 10.1016/j.humimm.2021.07.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 07/14/2021] [Accepted: 07/30/2021] [Indexed: 12/14/2022]
Abstract
Coeliac disease (CD) is an autoimmune gastroenteropathy triggered by gliadin and gliadin-tissue transglutaminase (tTG) complexes. CD is one of the few autoimmune diseases with an accurate, non-invasive serological test. Anti-endomysial, anti-tTG and anti-deaminated gliadin peptides (DGP) antibodies are currently used for serological tests with tTG ELISAs being the superior test. Duodenal biopsy, although invasive, is the gold standard for CD diagnosis. HLA genotyping and flow cytometry can also be used as supplementary tests. The incidence of CD is rising globally although the reasons for this remain unclear. In addition, the true incidence of coeliac disease in African populations remains unknown although recent work suggests that South African populations express the alleles associated with this disease. This review examines the pathogenesis and diagnosis of coeliac disease and considers novel and innovative biomarkers in its diagnosis specifically in an African population.
Collapse
Affiliation(s)
- Anastasia Gandini
- University of Witwatersrand, South Africa; National Health Laboratory Service, South Africa; Department of Immunology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
| | - Maemu P Gededzha
- University of Witwatersrand, South Africa; National Health Laboratory Service, South Africa; Department of Immunology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Tim De Maayer
- University of Witwatersrand, South Africa; Rahima Moosa Mother and Child Hospital, South Africa
| | - Peter Barrow
- University of Witwatersrand, South Africa; Wits University Donald Gordon Medical Centre, South Africa
| | - Elizabeth Mayne
- University of Witwatersrand, South Africa; National Health Laboratory Service, South Africa; Department of Immunology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| |
Collapse
|
|
39
|
Villanacci V, Ciacci C, Salviato T, Leoncini G, Bonetti LR, Ragazzini T, Limarzi F, Saragoni L. Histopathology of Celiac Disease. Position Statements of the Italian Group of Gastrointestinal Pathologists (GIPAD-SIAPEC). TRANSLATIONAL MEDICINE AT UNISA 2021. [PMID: 33457319 PMCID: PMC8370535 DOI: 10.37825/2239-9747.1005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Celiac Disease (CeD) is an immune-mediated inflammatory disorder of the small intestine, affecting genetically susceptible individuals when exposed to gluten. Small intestinal biopsy interpretation has been the “gold standard” for celiac disease (CeD) for over 50 years. Despite today’s availability of sensitive and specific serological tests, the histopathological features from mucosal biopsy play a key role in diagnosing when CeD is suspected. Such a diagnostic approach requires a multidisciplinary team to optimize both tissue sampling and interpretation via the interaction between the pathologist and the gastroenterologist. Pathologists of the Italian Group of Gastrointestinal Pathology (GIPAD-SIAPEC), together with a member (TR) of the Italian Society of Technicians (AITIC) and an expert gastroenterologist (CC), provide position statements as a practical tool for reading and interpreting the report. Moreover, a position statement was formulated about the recently described condition known as Non-Celiac Gluten Sensitivity (NCGS). Within such a diagnostic setting, both the architectural abnormalities of the duodenal mucosa, namely glandular hyperplasia, and villous atrophy and the number of intraepithelial T-lymphocytes should be well highlighted. Ancillary tests such as anti-CD3 stain are useful for an accurate count of the intraepithelial T lymphocytes when CeD or NCGS is suspected. Moreover, anti-CD3 and anti-CD8 stains are recommended in patients not responding to the gluten-free diet (GFD) to confirm a diagnosis of Refractory Celiac Disease (RCeD). Diagnostic clues about the differential diagnosis of both CeD and RCeD have also been rendered.
Collapse
Affiliation(s)
- V Villanacci
- Institute of Pathology ASST-Spedali Civili, Brescia, Italy
| | - C Ciacci
- Celiac Center, AOU San Giovanni di Dio e Ruggi di Aragona, University of Salerno, Department of Medicine, Surgery, and Dentistry Scuola Medica Salernitana, Salerno, Italy
| | - T Salviato
- Department of Diagnostic, Clinic and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - G Leoncini
- Pathology Unit, ASST del Garda, Desenzano del Garda, Brescia, Italy
| | - L Reggiani Bonetti
- Department of Diagnostic, Clinic and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - T Ragazzini
- Department of Pathology, University of Bologna, Italy
| | - F Limarzi
- Department of Pathological Anatomy, AUSL Romagna, Morgagni-Pierantoni Hospital, Forlì, Italy
| | - L Saragoni
- Department of Pathological Anatomy, AUSL Romagna, Morgagni-Pierantoni Hospital, Forlì, Italy
| |
Collapse
|
|
40
|
Villanacci V, Vanoli A, Leoncini G, Arpa G, Salviato T, Bonetti LR, Baronchelli C, Saragoni L, Parente P. Celiac disease: histology-differential diagnosis-complications. A practical approach. Pathologica 2021; 112:186-196. [PMID: 33179621 PMCID: PMC7931573 DOI: 10.32074/1591-951x-157] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 06/24/2020] [Indexed: 02/08/2023] Open
Abstract
Celiac disease is a multi-factorial chronic inflammatory intestinal disease, characterized by malabsorption resulting from mucosal injury after ingestion of wheat gluten or related rye and barley proteins. Inappropriate T-cell-mediated immune response against ingested gluten in genetically predisposed people, leads to characteristic histological lesions, as villous atrophy and intraepithelial lymphocytosis. Nevertheless, celiac disease is a comprehensive diagnosis with clinical, serological and genetic characteristics integrated with histological features. Biopsy of duodenal mucosa remains the gold standard in the diagnosis of celiac disease with the recognition of the spectrum of histological changes and classification of mucosa damage based on updated Corazza-Villanacci system. Appropriate differential diagnosis evaluation and clinical context also for the diagnosis of complications is, moreover, needed for correct histological features interpretation and clinical management.
Collapse
Affiliation(s)
| | - Alessandro Vanoli
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia, Italy.,Anatomic Pathology Unit, IRCCS San Matteo Hospital of Pavia, Italy
| | | | - Giovanni Arpa
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia, Italy.,Anatomic Pathology Unit, IRCCS San Matteo Hospital of Pavia, Italy
| | - Tiziana Salviato
- Department of Diagnostic, Clinic and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Luca Reggiani Bonetti
- Department of Diagnostic, Clinic and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | | | - Luca Saragoni
- Department of Pathological Anatomy, AUSL Romagna, Morgagni-Pierantoni Hospital, Forlì, Italy
| | - Paola Parente
- Pathology Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy
| |
Collapse
|
|
41
|
Taavela J, Viiri K, Välimäki A, Sarin J, Salonoja K, Mäki M, Isola J. Apolipoprotein A4 Defines the Villus-Crypt Border in Duodenal Specimens for Celiac Disease Morphometry. Front Immunol 2021; 12:713854. [PMID: 34394117 PMCID: PMC8358775 DOI: 10.3389/fimmu.2021.713854] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 07/19/2021] [Indexed: 12/18/2022] Open
Abstract
Histological evaluation of the small intestinal mucosa is the cornerstone of celiac disease diagnostics and an important outcome in scientific studies. Gluten-dependent injury can be evaluated either with quantitative morphometry or grouped classifications. A drawback of mucosal readings is the subjective assessment of the border where the crypt epithelium changes to the differentiated villus epithelium. We studied potential immunohistochemical markers for the detection of the villus-crypt border: apolipoprotein A4 (APOA4), Ki-67, glucose transporter 2, keratin 20, cytochrome P450 3A4 and intestinal fatty-acid binding protein. Among these, villus-specific APOA4 was chosen as the best candidate for further studies. Hematoxylin-eosin (H&E)- and APOA4 stained duodenal biopsy specimens from 74 adult patients were evaluated by five observers to determine the villus-to-crypt ratio (VH : CrD). APOA4 delineated the villus to crypt epithelium transition clearly, and the correlation coefficient of VH : CrD values between APOA4 and H&E was excellent (r=0.962). The VH : CrD values were lower in APOA4 staining (p<0.001) and a conversion factor of 0.2 in VH : CrD measurements was observed to make the two methods comparable to each other. In the intraobserver analysis, the doubled standard deviations, representing the error ranges, were 0.528 for H&E and 0.388 for APOA4 staining, and the ICCs were 0.980 and 0.971, respectively. In the interobserver analysis, the average error ranges were 1.017 for H&E and 0.847 for APOA4 staining, and the ICCs were better for APOA4 than for H&E staining in all analyses. In conclusion, the reliability and reproducibility of morphometrical VH : CrD readings are improved with the use of APOA4 staining.
Collapse
Affiliation(s)
- Juha Taavela
- Central Finland Central Hospital, Jyväskylä, Finland.,Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Keijo Viiri
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Anna Välimäki
- Fimlab Laboratories Inc, Tampere, Finland.,Jilab Inc, Tampere, Finland
| | | | | | - Markku Mäki
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.,Tampere University Hospital, Tampere, Finland
| | - Jorma Isola
- Jilab Inc, Tampere, Finland.,Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| |
Collapse
|
|
42
|
Oreshko LS, Bakulin IG, Avalueva EB, Semenova EA, Sitkin SI. Modern understanding of adult celiac disease. EXPERIMENTAL AND CLINICAL GASTROENTEROLOGY 2021:84-95. [DOI: 10.31146/1682-8658-ecg-188-4-84-95] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Abstract
The article presents a modern view of celiac disease within the framework of the classification concept of gluten- associated disorders. The prevalence of the disease, the modern model of the etiopathogenesis of celiac disease, clinical manifestations, and the possibilities of differential diagnosis are discussed. According to the European guidelines, a strategy for monitoring outpatients with celiac disease is presented, based on baseline characteristics of the disease, regular doctor- patient interaction, and prevention of gluten- associated disorders.
Collapse
Affiliation(s)
- L. S. Oreshko
- North- Western State Medical University named after I. I. Mechnikov, Ministry of Health of Russian Federation
| | - I. G. Bakulin
- North- Western State Medical University named after I. I. Mechnikov, Ministry of Health of Russian Federation
| | - E. B. Avalueva
- North- Western State Medical University named after I. I. Mechnikov, Ministry of Health of Russian Federation
| | - E. A. Semenova
- North- Western State Medical University named after I. I. Mechnikov, Ministry of Health of Russian Federation
| | - S. I. Sitkin
- North- Western State Medical University named after I. I. Mechnikov, Ministry of Health of Russian Federation;
Federal State Budgetary Institution “Almazov National Medical Research Centre” of the Ministry of Health of the Russian Federation
| |
Collapse
|
|
43
|
Freiche V, Cordonnier N, Paulin MV, Huet H, Turba ME, Macintyre E, Malamut G, Cerf-Bensussan N, Molina TJ, Hermine O, Bruneau J, Couronné L. Feline low-grade intestinal T cell lymphoma: a unique natural model of human indolent T cell lymphoproliferative disorder of the gastrointestinal tract. J Transl Med 2021; 101:794-804. [PMID: 33692440 DOI: 10.1038/s41374-021-00581-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 02/06/2021] [Accepted: 02/07/2021] [Indexed: 12/20/2022] Open
Abstract
Indolent T cell lymphoproliferative disorder (LPD) of the gastrointestinal tract (GI-TLPD) is a rare human primary gastrointestinal T cell lymphoma that was recently included in the 2016 revision of the World Health Organization classification of lymphoid neoplasms. Low-grade intestinal T cell lymphoma (LGITL), an emerging disease in the domestic cat, shares a number of features with human GI-TLPD. In this prospective study, we determined whether feline LGITL might serve as a model of human GI-TLPD. We analyzed clinical, laboratory, and radiological data and performed histopathological and molecular studies on small intestinal biopsies from 22 domestic cats diagnosed with LGITL. This cancer mostly affects aging cats, is associated with nonspecific gastrointestinal tract signs, and is usually characterized by an indolent course. A histopathological analysis indicated that LGITL was mainly located in the jejunum. The small intestinal lamina propria was infiltrated by large numbers of small CD3+ T cell lymphocytes with various CD4 and CD8 expression profiles (CD4+ CD8- (4 out of 11, 36%), CD4- CD8+ (3 out of 11, 27%), and CD4- CD8- (4 out of 11, 36%)). Intraepithelial lymphocyte (IEL) counts were elevated in all cases. Ki67 was expressed in lamina propria lymphocytes and IELs at a low level (<30%). Most LGITLs were labelled by antibodies against phosphorylated STAT5, but were negative for CD56 and phosphorylated STAT3. T cell receptor gamma chain gene monoclonality was found in 86% of cases. These findings confirmed that feline LGITL shares clinical and histopathological features with human GI-TLPD. Feline LGITL may therefore constitute a relevant model of the human disease.
Collapse
Affiliation(s)
- Valérie Freiche
- Internal Medicine Department, Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, France
- Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, INSERM U1163, Imagine Institute, Paris, France
| | - Nathalie Cordonnier
- Pathology Department, Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, France
| | - Mathieu Victor Paulin
- Internal Medicine Department, Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, France
| | - Hélène Huet
- Pathology Department, Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, France
| | | | - Elizabeth Macintyre
- Laboratory of Onco-Hematology, Hôpital Necker - Enfants Malades, Assistance Publique - Hôpitaux de Paris (AP-HP), University of Paris, Paris, France
- INSERM U1151, Necker-Enfants Malades Institute, Paris, France
| | - Georgia Malamut
- Gastroenterology Department, Hôpital Cochin, Assistance Publique - Hôpitaux de Paris (APHP), University of Paris, Paris, France
- Laboratory of Intestinal Immunity, INSERM U1163, Imagine Institute, Paris, France
| | | | - Thierry Jo Molina
- Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, INSERM U1163, Imagine Institute, Paris, France
- Pathology Department, Hôpital Necker - Enfants Malades, Assistance Publique - Hôpitaux de Paris (APHP), University of Paris, Paris, France
| | - Olivier Hermine
- Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, INSERM U1163, Imagine Institute, Paris, France
- Hematology Department, Hôpital Necker - Enfants Malades, Assistance Publique - Hôpitaux de Paris (APHP), University of Paris, Paris, France
| | - Julie Bruneau
- Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, INSERM U1163, Imagine Institute, Paris, France
- Pathology Department, Hôpital Necker - Enfants Malades, Assistance Publique - Hôpitaux de Paris (APHP), University of Paris, Paris, France
| | - Lucile Couronné
- Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, INSERM U1163, Imagine Institute, Paris, France.
- Laboratory of Onco-Hematology, Hôpital Necker - Enfants Malades, Assistance Publique - Hôpitaux de Paris (AP-HP), University of Paris, Paris, France.
| |
Collapse
|
|
44
|
Fraser-Miller SJ, Rooney JS, Lau M, Gordon KC, Schultz M. Can Coupling Multiple Complementary Methods Improve the Spectroscopic Based Diagnosis of Gastrointestinal Illnesses? A Proof of Principle Ex Vivo Study Using Celiac Disease as the Model Illness. Anal Chem 2021; 93:6363-6374. [PMID: 33844904 DOI: 10.1021/acs.analchem.0c04963] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Spectroscopic methods are a promising approach for providing a point-of-care diagnostic method for gastrointestinal mucosa associated illnesses. Such a tool is desired to aid immediate decision making and to provide a faster pathway to appropriate treatment. In this pilot study, Raman, near-infrared, low frequency Raman, and autofluoresence spectroscopic methods were explored alone and in combination for the diagnosis of celiac disease. Duodenal biopsies (n = 72) from 24 participants were measured ex vivo using the full suite of studied spectroscopic methods. Exploratory principal component analysis (PCA) highlighted the origin of spectral differences between celiac and normal tissue with celiac biopsies tending to have higher protein relative to lipid signals and lower carotenoid spectral signals than the samples with normal histology. Classification of the samples based on the histology and overall diagnosis was carried out for all combinations of spectroscopic methods. Diagnosis based classification (majority rule of class per participant) yielded sensitivities of 0.31 to 0.77 for individual techniques, which was increased up to 0.85 when coupling multiple techniques together. Likewise, specificities of 0.50 to 0.67 were obtained for individual techniques, which was increased up to 0.78 when coupling multiple techniques together. It was noted that the use of antidepressants contributed to false positives, which is believed to be associated with increased serotonin levels observed in the gut mucosa in both celiac disease and the use of selective serotonin reuptake inhibitors (SSRIs); however, future work with greater numbers is required to confirm this observation. Inclusion of two additional spectroscopic methods could improve the accuracy of diagnosis (0.78) by 7% over Raman alone (0.73). This demonstrates the potential for further exploration and development of a multispectroscopic system for disease diagnosis.
Collapse
Affiliation(s)
- Sara J Fraser-Miller
- Dodd-Walls Centre for Photonic and Quantum Technologies, Department of Chemistry, University of Otago, Dunedin 9054, New Zealand
| | - Jeremy S Rooney
- Dodd-Walls Centre for Photonic and Quantum Technologies, Department of Chemistry, University of Otago, Dunedin 9054, New Zealand
| | - Michael Lau
- Southern Community Laboratories, Dunedin 9016, New Zealand
| | - Keith C Gordon
- Dodd-Walls Centre for Photonic and Quantum Technologies, Department of Chemistry, University of Otago, Dunedin 9054, New Zealand
| | - Michael Schultz
- Gastroenterology Research Unit, Department of Medicine, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand.,Mercy Hospital, Dunedin 9010, New Zealand.,Gastroenterology Department, Southern District Health Board, Dunedin 9016, New Zealand
| |
Collapse
|
|
45
|
Delvecchio M, Bizzoco F, Lapolla R, Gentile A, Carrozza C, Barone M, Simonetti S, Giordano P, Dargenio VN, Cristofori F, Francavilla R. Iodine Absorption in Celiac Children: A Longitudinal Pilot Study. Nutrients 2021; 13:808. [PMID: 33804451 PMCID: PMC7998751 DOI: 10.3390/nu13030808] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 02/22/2021] [Accepted: 02/25/2021] [Indexed: 02/07/2023] Open
Abstract
Background: non-autoimmune thyroid disorder is a common finding in celiac patients, more frequent than in the general population. An impairment of iodine absorption has been hypothesized, but it has never been investigated so far. We aimed to evaluate the iodine absorption in children and adolescents with newly diagnosed celiac disease. Methods: 36 consecutive celiac patients (age 7.4 years, range 2.4-14.5 years) before starting a gluten-free diet (GFD) were enrolled. We assayed the urinary iodine concentration (UIC) in a 24-h urine sample, at baseline (T0) after 3 (T1) and 12 months (T2) of GFD. Results: UIC at T0 was 64 μg/L (IQR 45-93.25 μg/L) with an iodine deficiency rate of 77.8%. UIC was not different according to histological damage, clinical presentation (typical vs atypical); we found no correlation with the thyroid function tests and auxological parameters. UIC was not statistically different at T1 (76 μg/L) and T2 (89 μg/L) vs T0. UIC at T2 was similar between patients with positive and negative anti-transglutaminase antibodies at T2. No patients presented overt hypothyroidism during the study. Conclusions: We found that iodine absorption in celiac children is impaired compared to the general population; it increases slightly, but not significantly, during the GFD. We should regularly reinforce the need for a proper iodine intake in celiac disease patients to reduce iodine deficiency risk.
Collapse
Affiliation(s)
- Maurizio Delvecchio
- Metabolic Disorder and Diabetology Unit, “Giovanni XXIII” Children Hospital, 70126 Bari, Italy;
| | - Francesca Bizzoco
- Department of Pediatrics, “Giovanni XXIII” Children Hospital, “Aldo Moro” University of Bari, 70126 Bari, Italy; (F.B.); (P.G.); (V.N.D.); (F.C.); (R.F.)
| | - Rosa Lapolla
- Pediatrics Unit, “San Carlo” Hospital, 85100 Potenza, Italy;
| | - Antonia Gentile
- Pediatrics Unit, “Antonio Perrino” Hospital, 72100 Brindisi, Italy;
| | - Cinzia Carrozza
- UOC Chimica, Biochimica e Biologia Molecolare Clinica, Fondazione Policlinico Universitario “A. Gemelli”, IRCCS, Università Cattolica del Sacro Cuore, 00168 Roma, Italy;
| | - Michele Barone
- Section of Gastroenterology, Department of Emergency and Organ Transplantation, “Aldo Moro” University of Bari, 70125 Bari, Italy
| | - Simonetta Simonetti
- Neonatal Screening Center and Clinical Pathology Unit, “Giovanni XXIII” Children Hospital, 70126 Bari, Italy;
| | - Paola Giordano
- Department of Pediatrics, “Giovanni XXIII” Children Hospital, “Aldo Moro” University of Bari, 70126 Bari, Italy; (F.B.); (P.G.); (V.N.D.); (F.C.); (R.F.)
| | - Vanessa Nadia Dargenio
- Department of Pediatrics, “Giovanni XXIII” Children Hospital, “Aldo Moro” University of Bari, 70126 Bari, Italy; (F.B.); (P.G.); (V.N.D.); (F.C.); (R.F.)
| | - Fernanda Cristofori
- Department of Pediatrics, “Giovanni XXIII” Children Hospital, “Aldo Moro” University of Bari, 70126 Bari, Italy; (F.B.); (P.G.); (V.N.D.); (F.C.); (R.F.)
| | - Ruggiero Francavilla
- Department of Pediatrics, “Giovanni XXIII” Children Hospital, “Aldo Moro” University of Bari, 70126 Bari, Italy; (F.B.); (P.G.); (V.N.D.); (F.C.); (R.F.)
- Interdisciplinary Department of Medicine-Pediatrics Section, “Aldo Moro” University of Bari, 70121 Bari, Italy
| |
Collapse
|
|
46
|
Nonbiopsy Approach for Celiac Disease Is Accurate When Using Exact Duodenal Histomorphometry: Prospective Study in 2 Countries. J Clin Gastroenterol 2021; 55:227-232. [PMID: 32301831 DOI: 10.1097/mcg.0000000000001349] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 03/01/2020] [Indexed: 01/13/2023]
Abstract
GOALS To test the accuracy of serology-based criteria for diagnosing celiac disease utilizing quantitative histomorphometry. BACKGROUND The revised European pediatric guidelines allow noninvasive celiac disease diagnosis for a subgroup of children. However, in some of the studies on this issue, the positive predictive value (PPV) of serology has remained suboptimal, possibly because of challenges of histopathology as the reference standard. STUDY Prospectively enrolled children with transglutaminase 2 antibodies (TGA) above the upper limit of normal (ULN) underwent blood sampling and duodenal biopsy in Finland and Romania. Those with TGA ≥10× ULN, positive endomysium antibodies (EmA), and disease-associated genetics were considered to fulfill triple criteria for celiac disease. Initial histopathologic analysis was conducted using grouped classification, whereupon centralized morphometry was performed. RESULTS Altogether 88 (54%) children were triple positive. In local evaluation, 99% of triple-positive children and 73% of children with TGA <10× ULN had celiac disease. These figures increased to 100% and 85% after more precise morphometric analysis. Triple-positive children had more anemia and higher median EmA and liver enzyme values than those with TGA<10× ULN; the groups were comparable in other clinical features and laboratory parameters. CONCLUSIONS When applied as recommended, the nonbiopsy strategy had already yielded excellent PPV regardless of the site of diagnosis or clinical presentation in the local analysis. PPV further increased to 100% with standardized duodenal morphometry.
Collapse
|
|
47
|
Iron Transporter Protein Expressions in Children with Celiac Disease. Nutrients 2021; 13:nu13030776. [PMID: 33673530 PMCID: PMC7997288 DOI: 10.3390/nu13030776] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 02/24/2021] [Accepted: 02/25/2021] [Indexed: 02/07/2023] Open
Abstract
Anemia is a frequent finding in children with celiac disease but the detailed pathophysiological mechanisms in the intestine remain obscure. One possible explanation could be an abnormal expression of duodenal iron transport proteins. However, the results have so far been inconsistent. We investigated this issue by comparing immunohistochemical stainings of duodenal cytochrome B (DCYTB), divalent metal transporter 1 (DMT1), ferroportin, hephaestin and transferrin receptor 1 (TfR1) in duodenal biopsies between 27 children with celiac disease and duodenal atrophy, 10 celiac autoantibody-positive children with potential celiac disease and six autoantibody-negative control children. Twenty out of these 43 subjects had anemia. The expressions of the iron proteins were investigated with regard to saturation and the percentage of the stained area or stained membrane length of the enterocytes. The results showed the stained area of ferroportin to be increased and the saturation of hephaestin to be decreased in celiac disease patients compared with controls. There were no differences in the transporter protein expressions between anemic and non-anemic patients. The present results suggest an iron status-independent alteration of ferroportin and hephaestin proteins in children with histologically confirmed celiac disease.
Collapse
|
|
48
|
Leonard MM, Lebwohl B, Rubio-Tapia A, Biagi F. AGA Clinical Practice Update on the Evaluation and Management of Seronegative Enteropathies: Expert Review. Gastroenterology 2021; 160:437-444. [PMID: 33010252 DOI: 10.1053/j.gastro.2020.08.061] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 08/25/2020] [Accepted: 08/28/2020] [Indexed: 12/22/2022]
Abstract
DESCRIPTION Our aim was to provide a consensus statement for the best approaches for diagnosis and management of patients with suspected enteropathy, but negative results from serologic tests for celiac disease (seronegative enteropathy). METHODS We collected findings from published cohort, case-control, and cross-sectional studies of diagnosis and case series and descriptive studies of management of patients believed to have celiac disease or other enteropathies unrelated to gluten, but negative results from serologic tests. BEST PRACTICE ADVICE 1: Review histologic findings with experienced pathologists who specialize in gastroenterology. BEST PRACTICE ADVICE 2: Serologic tests are essential for an accurate diagnosis of celiac disease. For patients with suspected celiac disease but negative results from serologic tests, total IgA level should be measured; patients should also be tested for anti-tissue transglutaminase, IgA against deamidated gliadin peptide, and endomysial antibody (IgA). Patients with total IgA levels below the lower limit of detection and IgG against tissue transglutaminase or deamidated gliadin peptide, or endomysial antibody, should be considered to have celiac disease with selective IgA deficiency rather than seronegative celiac disease. BEST PRACTICE ADVICE 3: Patients' diets should be carefully reviewed and duodenal biopsies should be collected and analyzed at the time of serologic testing to determine exposure to gluten and accuracy of test results. BEST PRACTICE ADVICE 4: Thorough medication histories should be collected from patients, with attention to angiotensin II receptor blockers, such as olmesartan, along with travel histories to identify potential etiologies of villous atrophy. This will guide additional testing. BEST PRACTICE ADVICE 5: Patients should be analyzed for disease-associated variants in human leukocyte antigen genes; results must be carefully interpreted. Negative results can be used to rule out celiac disease in seronegative patients. BEST PRACTICE ADVICE 6: Patients with suspected celiac disease who are seronegative but have villous atrophy and genetic risk factors for celiac disease must undergo endoscopic evaluation after 1-3 years on a gluten-free diet to evaluate improvements in villous atrophy. A diagnosis of seronegative celiac disease can then be confirmed based on clinical and histologic markers of improvement on the gluten-free diet. BEST PRACTICE ADVICE 7: Seronegative patients with an identified cause for enteropathy should be treated accordingly; a follow-up biopsy might or might not be necessary. BEST PRACTICE ADVICE 8: Patients with persistent signs and symptoms who do not respond to a gluten-free diet, and for whom no etiology of enteropathy is ultimately identified, should be treated with budesonide. CONCLUSIONS These best practice guidelines will aid in diagnosis and management of patients with suspected celiac disease, but negative results from serologic tests.
Collapse
Affiliation(s)
- Maureen M Leonard
- Center for Celiac Research and Treatment, Division of Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts
| | - Benjamin Lebwohl
- Celiac Disease Center, Columbia University Irving Medical Center, New York, New York
| | - Alberto Rubio-Tapia
- Division of Gastroenterology, Hepatology, and Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
| | - Federico Biagi
- Clinical Scientific Institutes Maugeri Scientific Institute for Research, Hospitalization and Healthcare, Gastroenterology Unit of Pavia Institute, University of Pavia, Italy
| |
Collapse
|
|
49
|
Singaravel S, Tandon R, Vohra P. Morphological evaluation of bulb and distal duodenal biopsies in pediatric celiac disease with clinical and serological correlation. INDIAN J PATHOL MICR 2021; 64:484-489. [PMID: 34341258 DOI: 10.4103/ijpm.ijpm_337_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Background and Aims An early correct diagnosis of celiac disease (CD) is fundamental to reversal of symptoms and prevention of complications in pediatric patients. Our aim was to evaluate the role of duodenal bulb biopsy by studying the degree of mucosal damage in the duodenal bulb (D1) and second part of the duodenum (D2) and correlating the findings with serum IgA anti-tTG levels. Settings and Design Pediatric patients (age <18 years) with clinical suspicion of CD and positive IgA anti-tTG titers were consecutively enrolled over a period of one year. Demographic variables, anthropometry, clinical history, laboratory values and endoscopic findings were studied. Endoscopic biopsies obtained from D1 and D2 were evaluated and assigned histopathologic grades that were correlated with serology. Statistical Analysis Used Descriptive statistics were employed. Results A total of 37 clinically suspected cases of pediatric CD were studied. The mean age was 6.7 years and the M:F ratio was 1:1.3. Thirty-two (32) children had varying degrees of growth impairment. Eight (8) children had only extra-intestinal symptoms. Thirty (30) children were anemic, hypoalbuminemia was seen in five (5) children while transaminitis was seen in two (2) children. IgA anti-tTG >300 U/ml was associated with Marsh-Oberhuber Grade 3 morphology at atleast one site. Conclusions Low positive serology values should be confirmed by histopathology. Biopsies should be taken even in the absence of endoscopic abnormality. Additional D1 biopsies placed in a separate container can increase the diagnostic yield.
Collapse
Affiliation(s)
- Saranya Singaravel
- Department of Pathology, Max Superspeciality Hospital Saket, New Delhi, India
| | - Rajesh Tandon
- Department of Pathology, Max Superspeciality Hospital Saket, New Delhi, India
| | - Pankaj Vohra
- Division of Pediatric Gastroenterology, University of New Mexico, Albuquerque, NM, USA
| |
Collapse
|
|
50
|
Brown I, Bettington M, Rosty C. The role of histopathology in the diagnosis and management of coeliac disease and other malabsorptive conditions. Histopathology 2020; 78:88-105. [PMID: 33382496 DOI: 10.1111/his.14262] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 09/16/2020] [Accepted: 09/20/2020] [Indexed: 12/17/2022]
Abstract
Most absorption of nutrients takes place in the proximal small intestine, and the most common disorders leading to malabsorption are associated with a morphological abnormality in the duodenal mucosa that is appreciable in histological sections of biopsy specimens. Coeliac disease is the most well-known example, causing intraepithelial lymphocytosis, inflammation and villous atrophy in the duodenum. Remarkably similar inflammatory changes can be induced by other processes, including medications, e.g. angiotensin II receptor blockers and immune checkpoint inhibitors, immune dysregulation disorders, e.g. common variable immunodeficiency and autoimmune enteropathy, infections, collagenous sprue, and tropical sprue. However, there are often subtle histological differences from coeliac disease in the type of inflammatory infiltrate, the presence of crypt apoptosis, and the extent and type of inflammation beyond the duodenum. The clinical setting and serological investigation usually allow diagnostic separation, but some cases remain challenging. Histopathology is also important in assessing the response to treatment, such as the change in villous architecture caused by a gluten-free diet, or the response to cessation of a potentially causative medication. This review examines the practical role that histopathology of duodenal biopsy specimens plays in the assessment and management of inflammatory malabsorptive processes of the proximal small intestine, with a particular emphasis on coeliac disease.
Collapse
Affiliation(s)
- Ian Brown
- Envoi Specialist Pathologists, University of Queensland, Brisbane, Queensland, Australia.,Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia
| | - Mark Bettington
- Envoi Specialist Pathologists, University of Queensland, Brisbane, Queensland, Australia.,Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia
| | - Christophe Rosty
- Envoi Specialist Pathologists, University of Queensland, Brisbane, Queensland, Australia.,Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia
| |
Collapse
|