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1
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Shapiro M, Niv Y. Diagnostic Yield of Video Capsule Endoscopy (VCE) in Celiac Disease (CD): A Systematic Review and Meta-analysis. J Clin Gastroenterol 2025:00004836-990000000-00452. [PMID: 40434820 DOI: 10.1097/mcg.0000000000002204] [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] [Indexed: 05/29/2025]
Abstract
BACKGROUND Celiac disease is an immune-mediated disorder triggered by the ingestion of gluten in genetically susceptible individuals. CD mainly involves the proximal small intestine and has diverse clinical features ranging from severe gastrointestinal symptoms to no symptoms. Diagnosis is based on CD-specific serology and small bowel biopsy. Video capsule endocopy (VCE) is a relatively safe method that provides high-resolution imaging of the entire small intestine mucosa. Today, VCE assists in CD diagnosis in many circumstances. METHODS We systematically searched the medical literature databases up to December 31, 2023, for English-language studies on CD diagnosis by the VCE. Our inclusion criteria comprised complete articles with extractable data and focused on the VCE yield of known celiac patients. Following data extraction, a Meta-Analysis was performed using Comprehensive Meta-Analysis Software (version 4; Biostat Inc., Englewood, NJ). RESULTS We found 22 studies and 46 substudies published up to 31.12.2023 of VCE performed in CD and met our inclusion criteria. Together 1585 patients were studied, of whom 1253 (79.05%) were women. The average age of the patients was 51.94±9.98 SD. A complete small bowel investigation was achieved in 1533 (96.72%) of the patients. Any diagnostic pathology's effect size (ES) was 0.601, 95% CI: 0.518-0.678. Specific findings of villous atrophy, scalloping, mosaic pattern, fissuring, ulcers, or erosions were demonstrated with ES of 0.604, 0.571, 0.440, 0.445, and 0.252 of the cases, and as expected higher in refractory celiac disease. CONCLUSIONS Our findings demonstrate pathognomonic features and supported CE diagnosis in about 60% of the patients.
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Affiliation(s)
- Maya Shapiro
- Adelson Faculty of Medicine, Ariel University, Israel
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2
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Bakhtiari S, Ahmadi B, Asri N, Rezaei‐Tavirani M, Jahani‐Sherafat S, Masotti A, Rostami‐Nejad M. Unraveling the Serum Protein Landscape in Celiac Disease: Current Evidence and Future Directions. Immun Inflamm Dis 2025; 13:e70169. [PMID: 40325942 PMCID: PMC12052852 DOI: 10.1002/iid3.70169] [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: 10/23/2024] [Revised: 01/18/2025] [Accepted: 02/27/2025] [Indexed: 05/07/2025] Open
Abstract
BACKGROUND Celiac disease (CD) is a chronic autoimmune disorder characterized by an abnormal immune response to gluten, leading to intestinal inflammation and various clinical manifestations. Serum proteins are increasingly recognized as potential biomarkers in CD, reflecting inflammation, malabsorption, and immune activation. OBJECTIVE This review aims to elucidate the role of serum proteins in the pathogenesis, diagnosis, and management of CD, emphasizing their potential as noninvasive biomarkers and therapeutic targets. METHODS A comprehensive review of current literature was conducted, focusing on key serum proteins such as albumin, transthyretin (TTR), transferrin, β2-microglobulin (β2M), C-reactive protein (CRP), and immunoglobulins. Their alterations in CD and their relevance to disease activity, nutritional status, and treatment response were examined. RESULTS CD-related inflammation leads to increased acute-phase proteins (e.g., CRP) and decreased transport proteins (e.g., albumin, TTR, transferrin), contributing to malnutrition and anemia. TTR serves as a sensitive marker of nutritional status, while transferrin levels correlate with iron deficiency, a common CD complication. Immunoglobulin profiles reflect immune responses to gluten. These proteins provide insights into CD pathophysiology and offer potential utility for diagnosis and monitoring. CONCLUSION Serum proteins represent promising biomarkers for CD diagnosis and management, with potential for integration into clinical practice. Further research is necessary to validate their utility in routine patient care and explore their role in personalized therapeutic strategies.
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Affiliation(s)
- Sajjad Bakhtiari
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver DiseasesShahid Beheshti University of Medical SciencesTehranIran
| | - Behrooz Ahmadi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver DiseasesShahid Beheshti University of Medical SciencesTehranIran
| | - Nastaran Asri
- Celiac Disease and Gluten Related Disorders Research Center, Research Institute for Gastroenterology and Liver DiseasesShahid Beheshti University of Medical SciencesTehranIran
| | - Mostafa Rezaei‐Tavirani
- Proteomics Research Center, Faculty of Paramedical SciencesShahid Beheshti University of Medical SciencesTehranIran
| | - Somayeh Jahani‐Sherafat
- Laser Application in Medical Sciences Research CenterShahid Beheshti University of Medical SciencesTehranIran
| | - Andrea Masotti
- Bambino Gesù Children's Hospital‐IRCCS, Research LaboratoriesRomeItaly
| | - Mohammad Rostami‐Nejad
- Celiac Disease and Gluten Related Disorders Research Center, Research Institute for Gastroenterology and Liver DiseasesShahid Beheshti University of Medical SciencesTehranIran
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3
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Aggarwal N, Bhatia U, Dwarakanathan V, Singh AD, Singh P, Ahuja V, Makharia GK. Prevalence and etiologies of non-responsive celiac disease: A systematic review and meta-analysis. J Gastroenterol Hepatol 2025; 40:101-107. [PMID: 39557631 DOI: 10.1111/jgh.16808] [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: 07/22/2024] [Accepted: 10/30/2024] [Indexed: 11/20/2024]
Abstract
BACKGROUND AND AIM Non-responsive celiac disease (NRCD) is defined as ongoing symptoms despite 6-12 months of gluten-free diet (GFD), the only known treatment for celiac disease (CeD). There is inconsistency in studies describing the proportion of patients having NRCD and its various causes among patients with CeD. We therefore conducted a systematic review and meta-analysis to determine the prevalence and causes of NRCD. METHODS The PubMed, Embase, Cochrane Library, Scopus, and Web of Science databases were searched for original studies reporting the proportion of patients with persistent symptoms after ≥ 6 months of GFD. Studies reporting the etiologies of NRCD were also identified. The systematic review was conducted as per the Meta-analysis of Observational Studies in Epidemiology guidelines. Statistical analysis was performed in STATA. RESULTS Of 2965 search results, nine studies met the inclusion and exclusion criteria. Five studies (n = 4414) reported data on prevalence, and seven studies (n = 790) reported the causes of NRCD. The pooled prevalence of NRCD was 22% (95% confidence interval, 11-35%). Among patients with NRCD, inadvertent exposure to gluten was the most common cause (33%), followed by functional gastrointestinal disorders including irritable bowel syndrome in 16%. Refractory CeD type II along with its premalignant and malignant sequelae was observed in 7% of patients with NRCD. CONCLUSION One in five patients with CeD may not respond to GFD and would likely be classified as NRCD. Inadvertent gluten exposure was the cause of ongoing symptoms in one-third of patients with NRCD. Improving adherence to GFD along with developing novel therapeutics to mitigate symptoms due to ongoing gluten exposure is critical.
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Affiliation(s)
- Nishant Aggarwal
- Department of Internal Medicine, William Beaumont University Hospital, Royal Oak, Michigan, USA
| | - Unnati Bhatia
- Department of Internal Medicine, William Beaumont University Hospital, Royal Oak, Michigan, USA
| | - Vignesh Dwarakanathan
- Department of Community Medicine, Employees' State Insurance Corporation Hospital, Chennai, India
| | - Achintya Dinesh Singh
- Department of Gastroenterology and Hepatology, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio, USA
| | - Prashant Singh
- Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA
| | - Vineet Ahuja
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Govind K Makharia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
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Muhammed EG, Davies M, Hamza A, Wall M. Progressive Symptoms in an Older Patient Recently Diagnosed With Coeliac Disease and Rapid Progression to Enteropathy-Associated T-cell Lymphoma (EATL). Cureus 2024; 16:e74215. [PMID: 39583592 PMCID: PMC11583275 DOI: 10.7759/cureus.74215] [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: 11/22/2024] [Indexed: 11/26/2024] Open
Abstract
Coeliac disease (CD) is an immune-mediated condition that causes damage to the small intestine upon gluten consumption by genetically susceptible individuals. To determine whether there is an active coeliac disease or the presence of additional pathologies, patients must undergo regular evaluations, including repeat endoscopy. In this analysis, we present a case study of a 75-year-old woman from England who was diagnosed with coeliac disease later in life. She carries the HLA-DQ2 genetic marker and developed type 2 enteropathy-associated T-cell lymphoma (EATL) 12 months after her diagnosis of coeliac disease.
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Affiliation(s)
- Eslam G Muhammed
- Gastroenterology and Hepatology, Blackpool Victoria Hospital, Liverpool, GBR
| | - Michael Davies
- Gastroenterology and Hepatology, Countess of Chester Hospital NHS Trust, Chester, GBR
| | - Asim Hamza
- Gastroenterology, Countess of Chester Hospital NHS Trust, Chester, GBR
| | - Michael Wall
- Histopathology, Countess of Chester Hospital NHS Trust, Chester, GBR
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Verdelho Machado M. Refractory Celiac Disease: What the Gastroenterologist Should Know. Int J Mol Sci 2024; 25:10383. [PMID: 39408713 PMCID: PMC11477276 DOI: 10.3390/ijms251910383] [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: 09/02/2024] [Revised: 09/20/2024] [Accepted: 09/25/2024] [Indexed: 10/20/2024] Open
Abstract
Fewer than 1% of patients with celiac disease (CD) will develop refractory CD (RCD). As such, most gastroenterologists might never need to manage patients with RCD. However, all gastroenterologists must be familiarized with the basic concepts of RCD and non-responsive CD (NRCD), since it can present as a severe disease with high mortality, not only due to intestinal failure, but also due to progression to enteropathy-associated T cell lymphoma (EATL) and a higher susceptibility to life-threatening infections. The diagnostic workup and differential diagnosis with other causes of gastrointestinal symptoms and villous atrophy, as well as the differentiation between type I and II RCD, are complex, and may require specialized laboratories and reference hospitals. Immunosuppression is efficient in the milder RCDI; however, the treatment of RCDII falls short, with current options probably only providing transient clinical improvement and delaying EATL development. This review summarizes the current diagnostic and therapeutic approach for patients with RCD that all doctors that manage patients with CD should know.
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Affiliation(s)
- Mariana Verdelho Machado
- Gastroenterology Department, Hospital de Vila Franca de Xira, 2600-009 Lisbon, Portugal; ; Tel.: +351-912620306
- Gastroenterology Department, Faculdade de Medicina, Lisbon University, 1649-028 Lisboa, Portugal
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6
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Tye‐Din JA. Evolution in coeliac disease diagnosis and management. JGH Open 2024; 8:e13107. [PMID: 38957478 PMCID: PMC11217771 DOI: 10.1002/jgh3.13107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 05/04/2024] [Accepted: 05/28/2024] [Indexed: 07/04/2024]
Abstract
The traditional gut-centric view of coeliac disease is evolving as immune and genetic insights underscore the central importance of a systemic, T cell immune response to gluten in disease pathogenesis. As the field increasingly recognize the limitations of small intestinal histology as the diagnostic standard, data supporting the accuracy of an immune (serologic) diagnosis of coeliac disease - well demonstrated in children - are growing for adults. Novel biomarkers such as interleukin-2 that identify the gluten-specific T cell demonstrate high sensitivity and specificity for coeliac disease and offer the potential for a diagnostic approach that avoids the need for gluten challenge. Asymptomatic disease and manifestations outside the gut pose considerable challenges for diagnosis using a case-finding strategy and enthusiasm for population screening is growing. The gluten-free diet remains a highly restrictive treatment and there is a paucity of controlled data to inform a safe gluten intake threshold. Ongoing symptoms and enteropathy are common and require systematic evaluation. Slowly-responsive disease is prevalent in the older patient diagnosed with coeliac disease, and super-sensitivity to gluten is an emerging concept that may explain many cases of nonresponsive disease. While there is great interest in developing novel therapies for coeliac disease, no drug has yet been registered. Efficacy studies are generally assessing drugs in patients with treated coeliac disease who undergo gluten challenge or in patients with nonresponsive disease; however, substantial questions remain around specific endpoints relevant for patients, clinicians and regulatory agencies and optimal trial design. Novel immune tools are providing informative readouts for clinical trials and are now shaping their design.
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Affiliation(s)
- Jason A Tye‐Din
- Immunology DivisionWalter and Eliza Hall InstituteParkvilleVictoriaAustralia
- Department of Medical BiologyUniversity of MelbourneParkvilleVictoriaAustralia
- Department of GastroenterologyThe Royal Melbourne HospitalParkvilleVictoriaAustralia
- Centre for Food & Allergy ResearchThe Murdoch Children's Research InstituteParkvilleVictoriaAustralia
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Hujoel IA, Hujoel MLA. The Rising Incidence and Poor Outcomes of Enteropathy-Associated T-Cell Lymphoma. Am J Gastroenterol 2024; 119:1412-1416. [PMID: 38235779 DOI: 10.14309/ajg.0000000000002666] [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] [Received: 11/20/2023] [Accepted: 01/15/2024] [Indexed: 01/19/2024]
Abstract
INTRODUCTION Enteropathy-associated T-cell lymphoma (EATL) is associated with celiac disease. With the rising prevalence of celiac disease, we hypothesized that the prevalence of EATL is also increasing. METHODS We used the Surveillance, Epidemiology, and End Results database, which is a population-based US cancer surveillance program. We used the ICD-0-3 code 9717/3 to identify patients with EATL diagnosed between 2000 and 2020. Incidence rates were calculated using the SEER*Stat software, and annual percent change was calculated using the Joinpoint software. Log-rank tests were used to evaluate for significant difference in survival curves between groups. A Cox proportional hazards regression model was used for continuous variables and quantifying association strength of predictors. RESULTS A total of 463 cases of EATL were identified (273 male, 190 female) with a median age of 65 (range 23-90+) years. Most of the cases were at an advanced stage at diagnosis and were treated with a combination of surgery and chemotherapy. The median survival time was 6 months. The 2000-2020 age-adjusted incidence rate per 100,000 people was 0.014, and the incidence increased between 2000 and 2020, with an annual percent change of 2.58 ( P < 0.05). Increased age at diagnosis and lack of treatment had significant impacts on survival while sex, year of diagnosis, race, and time between diagnosis and treatment had no significant impact on survival. DISCUSSION There was a significant increase in the incidence of EATL in the United States between 2000 and 2020. Survival in this cancer remains poor and unchanged over the past 2 decades.
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Affiliation(s)
- Isabel A Hujoel
- Division of Gastroenterology, University of Washington, Seattle, Washington, USA
| | - Margaux L A Hujoel
- Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
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Malamut G, Soderquist CR, Bhagat G, Cerf-Bensussan N. Advances in Nonresponsive and Refractory Celiac Disease. Gastroenterology 2024; 167:132-147. [PMID: 38556189 DOI: 10.1053/j.gastro.2024.02.048] [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: 11/10/2023] [Revised: 02/04/2024] [Accepted: 02/20/2024] [Indexed: 04/02/2024]
Abstract
Nonresponsive celiac disease (CeD) is relatively common. It is generally attributed to persistent gluten exposure and resolves after correction of diet errors. However, other complications of CeD and disorders clinically mimicking CeD need to be excluded. Novel therapies are being evaluated to facilitate mucosal recovery, which might benefit patients with nonresponsive CeD. Refractory CeD (RCeD) is rare and is divided into 2 types. The etiology of type I RCeD is unclear. A switch to gluten-independent autoimmunity is suspected in some patients. In contrast, type II RCeD represents a low-grade intraepithelial lymphoma. Type I RCeD remains a diagnosis of exclusion, requiring ruling out gluten intake and other nonmalignant causes of villous atrophy. Diagnosis of type II RCeD relies on the demonstration of a clonal population of neoplastic intraepithelial lymphocytes with an atypical immunophenotype. Type I RCeD and type II RCeD generally respond to open-capsule budesonide, but the latter has a dismal prognosis due to severe malnutrition and frequent progression to enteropathy-associated T-cell lymphoma; more efficient therapy is needed.
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Affiliation(s)
- Georgia Malamut
- Department of Gastroenterology, Assistance Publique-Hôpitaux de Paris Centre-Université Paris Cité, Hôpital Cochin, Paris, France; Laboratory of Intestinal Immunity, INSERM UMR 1163-Institut Imagine, Université Paris Cité, Paris, France.
| | - Craig R Soderquist
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
| | - Govind Bhagat
- Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
| | - Nadine Cerf-Bensussan
- Laboratory of Intestinal Immunity, INSERM UMR 1163-Institut Imagine, Université Paris Cité, Paris, France.
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9
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Kojima K, Chambers JK, Nakashima K, Uchida K. Pro-inflammatory cytokine expression and the STAT1/3 pathway in canine chronic enteropathy and intestinal T-cell lymphoma. Vet Pathol 2024; 61:382-392. [PMID: 37906531 DOI: 10.1177/03009858231207017] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2023]
Abstract
The accumulation of intraepithelial lymphocytes (IELs) is a histopathological feature of canine chronic enteropathy (CE), and IELs are considered the cells of origin of intestinal T-cell lymphoma (ITCL). However, the pathogenic mechanism of IEL activation in CE remains unclear. This study hypothesized that the expression of proinflammatory cytokines, associated with cytotoxic T/NK-cell activation, is upregulated in CE and ITCL, and examined the expression of IFN-γ, IL-2, IL-12p35, IL-12p40, IL-15, and IL-21 and the downstream signal transducers and activators of transcription (STAT) pathway in the duodenal mucosa of dogs without lesions (n = 11; NC), with IEL-CE (n = 19; CE without intraepithelial lymphocytosis), IEL+CE (n = 29; CE with intraepithelial lymphocytosis), and with ITCL (n = 60). Quantitative polymerase chain reaction (PCR) revealed that IFN-γ and IL-21 were higher in IEL+CE than in IEL-CE or NC. Western blot revealed upregulation of STAT1 and STAT3 in IEL+CE. Double-labeling immunohistochemistry revealed a positive correlation between the Ki67 index of CD3+ T-cells and IFN-γ expression levels. Immunohistochemistry revealed a higher ratio of p-STAT1-positive villi in IEL+CE and ITCL than IEL-CE and NC, which positively correlated with IFN-γ expression levels. Among the 60 ITCL cases, neoplastic lymphocytes were immunopositive for p-STAT1 in 28 cases and p-STAT3 in 29 cases. These results suggest that IFN-γ and IL-21 contribute to the pathogenesis of IEL+CE, and IFN-γ may be involved in T-cell activation and mucosal injury in CE. STAT1 and STAT3 activation in ITCL cells suggests a role for the upregulation of the STAT pathway in the pathogenesis of ITCL.
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Affiliation(s)
| | | | - Ko Nakashima
- Japan Small Animal Medical Center, Tokorozawa, Japan
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10
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Schiepatti A, Maimaris S, Scarcella C, Pignatti P, Betti E, Shoval Y, Arpa G, Ciccocioppo R, Biagi F. Flow cytometry for the assessment and monitoring of aberrant intraepithelial lymphocytes in non-responsive celiac disease and non-celiac enteropathies. Dig Liver Dis 2024; 56:795-801. [PMID: 37968145 DOI: 10.1016/j.dld.2023.10.025] [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: 07/22/2023] [Revised: 10/19/2023] [Accepted: 10/27/2023] [Indexed: 11/17/2023]
Abstract
BACKGROUND Few data are available on flow cytometry (FC) for monitoring intraepithelial lymphocytes (IELs) in refractory celiac disease (RCD), non-responsive celiac disease (NRCD), and non-celiac enteropathies (NCEs). AIMS 1) To investigate the significance of monitoring IELs immunophenotype with FC in patients with NRCD, RCD and NCEs; 2) to evaluate FC concordance with immunohistochemistry (IHC) and γ-TCR clonality analysis. METHODS Patients investigated between January-2012 and February-2023 were divided into two groups: 1)confirmed RCD or NRCD being investigated for persistent symptoms and suspected complications of celiac disease (CD); 2)NCEs lacking clinical/histological response. Clinical/molecular features and outcomes were retrospectively collected and analysed according to presence/absence of aberrant IELs on FC (cut-off≥20 % CD103+sCD3-CD8-iCD3+ IELs). RESULTS 52 patients (18 RCD,21 NRCD,13 NCEs; 38F, 55±13 years; median follow-up 30 months, IQR 2-58) underwent 100 FC IELs determinations. 22/52 had ≥2 FC determinations and IEL phenotype remained unchanged over time in all them (κ=1.00). Aberrant IEL phenotype in CD was associated with increased mortality (HR 4.2, 95 % CI 1.5-11.9, p < 0.01). No patients with NCEs had an aberrant IEL phenotype at FC, although 3/13 developed lymphoma and 4/13 died. Concordance of FC was fair with both IHC (κ=0.40) and γ-TCR clonality analysis (κ=0.22). CONCLUSION FC is accurate for assessing and monitoring IEL phenotype and providing important prognostic information in celiac patients. Further study is needed on its role in NCEs.
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Affiliation(s)
- Annalisa Schiepatti
- Department of Internal Medicine and Therapeutics, University of Pavia, Italy; Istituti Clinici Scientifici Maugeri IRCCS, Gastroenterology Unit of Pavia Institute, Italy.
| | - Stiliano Maimaris
- Department of Internal Medicine and Therapeutics, University of Pavia, Italy; Istituti Clinici Scientifici Maugeri IRCCS, Gastroenterology Unit of Pavia Institute, Italy
| | - Chiara Scarcella
- Department of Internal Medicine and Therapeutics, University of Pavia, Italy
| | - Patrizia Pignatti
- Allergy and Immunology Unit Istituti Clinici Scientifici Maugeri, IRCCS, Pavia, Italy
| | - Elena Betti
- Department of Internal Medicine, San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Yiftach Shoval
- Department of Internal Medicine and Therapeutics, University of Pavia, Italy
| | - Giovanni Arpa
- Department of Molecular Medicine, Unit of Anatomic Pathology, University of Pavia, Italy; Unit of Anatomic Pathology, ICS Maugeri-IRCCS SpA SB, 27100 Pavia, Italy
| | - Rachele Ciccocioppo
- Gastroenterology Unit, Department of Medicine, Azienda Ospedaliera Universitaria Integrata Policlinico G.B. Rossi and University of Verona, Verona, Italy
| | - Federico Biagi
- Department of Internal Medicine and Therapeutics, University of Pavia, Italy; Istituti Clinici Scientifici Maugeri IRCCS, Gastroenterology Unit of Pavia Institute, Italy
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Lenti MV, Broglio G, Lucioni M, Corazza GR. Refractory celiac disease and lymphomagenesis. PEDIATRIC AND ADULT CELIAC DISEASE 2024:207-227. [DOI: 10.1016/b978-0-443-13359-6.00007-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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12
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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.
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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
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13
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Valvano M, Fabiani S, Monaco S, Calabrò M, Mancusi A, Frassino S, Rolandi C, Mosca M, Faenza S, Sgamma E, Cesaro N, Latella G. Old and New Adjunctive Therapies in Celiac Disease and Refractory Celiac Disease: A Review. Int J Mol Sci 2023; 24:12800. [PMID: 37628981 PMCID: PMC10454405 DOI: 10.3390/ijms241612800] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 07/13/2023] [Accepted: 08/12/2023] [Indexed: 08/27/2023] Open
Abstract
Celiac disease (CD) is a chronic enteropathy caused by the ingestion of gluten in a genetically susceptible individual. Currently, a gluten-free diet (GFD) is the only recommended treatment. However, unintentional gluten ingestion or a persistent villous atrophy with malabsorption (regardless of a strict GFD) as in the case of Refractory Celiac Disease (RCD) represents a major issue. In this review, we have analysed and discussed data from both randomized controlled trials and observational studies concerning adjunctive therapies as well as novel therapies for the treatment of CD and RCD. The literature search was carried out through Medline and Scopus. In total, 2268 articles have been identified and 49 were included in this review (36 studies resulting from the search strategy and 13 from other sources). Today, GFD remains the only effective treatment, although steroids, mesalamine, and more recently biological therapies have found space in the complex management of RCD. Currently, studies evaluating the effectiveness of novel therapies are still limited and preliminary results have been controversial.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Giovanni Latella
- Gastroenterology Unit, Division of Gastroenterology, Hepatology and Nutrition, Department of Life, Health and Environmental Sciences, University of L’Aquila, Piazzale Salvatore Tommasi 1, 67100 L’Aquila, Italy; (M.V.); (S.F.); (S.M.); (M.C.); (A.M.); (S.F.); (C.R.); (M.M.); (S.F.); (E.S.); (N.C.)
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14
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Schiepatti A, Maimaris S, Lusetti F, Scalvini D, Minerba P, Cincotta M, Fazzino E, Biagi F. High Prevalence of Functional Gastrointestinal Disorders in Celiac Patients with Persistent Symptoms on a Gluten-Free Diet: A 20-Year Follow-Up Study. Dig Dis Sci 2023; 68:3374-3382. [PMID: 36401140 PMCID: PMC10352160 DOI: 10.1007/s10620-022-07727-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 07/20/2022] [Indexed: 11/19/2022]
Abstract
BACKGROUND Ongoing symptoms in treated celiac disease (CD) are frequent and are commonly thought of as being due to infractions to a gluten-free diet (GFD) or complications. AIMS To study the etiology and natural history of clinically relevant events (CREs) throughout follow-up and identify predictors thereof to guide follow-up. METHODS CREs (symptoms/signs requiring diagnostic/therapeutic interventions) occurring in celiac patients between January-2000 and May-2021 were retrospectively collected between June and September 2021 and analysed. RESULTS One-hundred-and-eighty-nine adult patients (133 F, age at diagnosis 36 ± 13 years, median follow-up 103 months, IQR 54-156) were enrolled. CREs were very common (88/189, 47%), but hardly due to poor GFD adherence (4%) or complications (2%). Interestingly, leading etiologies were functional gastrointestinal disorders (30%), reflux disease (18%) and micronutrient deficiencies (10%). Age at diagnosis ≥ 45 years (HR 1.68, 95%CI 1.05-2.69, p = 0.03) and classical pattern of CD (HR 1.63, 95%CI 1.04-2.54, p = 0.03) were predictors of CREs on a multivariable Cox model. At 5 years, 46% of classical patients ≥ 45 years old at diagnosis were event-free, while this was 62% for non-classical/silent ≥ 45 years, 60% for classical < 45 years, and 80% for non-classical/silent < 45 years. CONCLUSIONS CREs occurred in almost half of CD patients during follow-up, with functional disorders being very common. New follow-up strategies for adult CD may be developed based on age and clinical pattern at diagnosis.
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Affiliation(s)
- Annalisa Schiepatti
- Dipartimento di Medicina Interna e Terapia Medica, University of Pavia, 27100 Pavia, Italy
- Istituti Clinici Scientifici Maugeri, IRCCS, Gastroenterology Unit of Pavia Institute, Via Salvatore Maugeri 10, 27100 Pavia, Italy
| | - Stiliano Maimaris
- Dipartimento di Medicina Interna e Terapia Medica, University of Pavia, 27100 Pavia, Italy
- Istituti Clinici Scientifici Maugeri, IRCCS, Gastroenterology Unit of Pavia Institute, Via Salvatore Maugeri 10, 27100 Pavia, Italy
| | - Francesca Lusetti
- Dipartimento di Medicina Interna e Terapia Medica, University of Pavia, 27100 Pavia, Italy
| | - Davide Scalvini
- Dipartimento di Medicina Interna e Terapia Medica, University of Pavia, 27100 Pavia, Italy
| | - Paolo Minerba
- Dipartimento di Medicina Interna e Terapia Medica, University of Pavia, 27100 Pavia, Italy
| | - Marta Cincotta
- Dipartimento di Medicina Interna e Terapia Medica, University of Pavia, 27100 Pavia, Italy
| | - Erica Fazzino
- Dipartimento di Medicina Interna e Terapia Medica, University of Pavia, 27100 Pavia, Italy
| | - Federico Biagi
- Dipartimento di Medicina Interna e Terapia Medica, University of Pavia, 27100 Pavia, Italy
- Istituti Clinici Scientifici Maugeri, IRCCS, Gastroenterology Unit of Pavia Institute, Via Salvatore Maugeri 10, 27100 Pavia, Italy
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15
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Rouvroye MD, Bontkes HJ, Bol JGJM, Lissenberg-Witte B, Byrnes V, Bennani F, Jordanova ES, Wilhelmus MMM, Mulder CJ, van der Valk P, Rozemuller AJM, Bouma G, Van Dam AM. Cerebellar presence of immune cells in patients with neuro-coeliac disease. Acta Neuropathol Commun 2023; 11:51. [PMID: 36966322 PMCID: PMC10040112 DOI: 10.1186/s40478-023-01538-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 03/01/2023] [Indexed: 03/27/2023] Open
Abstract
Although various neurodegenerative disorders have been associated with coeliac disease (CD), the underlying neuropathological link between these brain and gut diseases remains unclear. We postulated that the neuronal damage sporadically observed in CD patients is immune-mediated. Our aim was to determine if the loss of neurons, especially Purkinje cells, coincides with microglia activation and T- and B-cell infiltration in the cerebellum of patients with CD and a concomitant idiopathic neurological disease affecting the cerebellum (NeuroCD). Post-mortem cerebellar tissue was collected of validated NeuroCD cases. Gender- and age-matched genetic spinocerebellar ataxia (SCA) controls and non-neurological controls (NNC) were selected based on clinical reports and pathological findings. Cerebellar tissue of seventeen patients was included (6 NeuroCD, 5 SCA, 6 NNC). In SCA cases we found that the Purkinje cell layer was 58.6% reduced in comparison with NNC. In NeuroCD cases this reduction was even more prominent with a median reduction of 81.3% compared to NNC. Marked increased numbers of both CD3+ and CD8+ cells were observed in the NeuroCD but not in SCA patients. This coincided with significantly more microglial reactivity in NeuroCD patients. These findings demonstrate that the massive loss of Purkinje cells in the cerebellum of neuro CD patients is accompanied by local innate and T-cell mediated immune responses.
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Affiliation(s)
- Maxine D Rouvroye
- Department of Gastroenterology and Hepatology, AGEM Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Department of Anatomy and Neurosciences, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Spaarne Gasthuis, Boerhavelaan 22, 2035 RC, Haarlem, The Netherlands
| | - Hetty J Bontkes
- Medical Immunology Laboratory, Department of Clinical Chemistry, Amsterdam Infection and Immunity Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - John G J M Bol
- Department of Anatomy and Neurosciences, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands
| | - Birgit Lissenberg-Witte
- Department of Epidemiology and Data Science, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Valerie Byrnes
- Department of Gastroenterology and Hepatology, Galway University Hospitals, Galway, Ireland
| | - Fadel Bennani
- Department of Pathology, Mayo University Hospital, National University of Ireland Galway Affiliated Hospital, Galway, Ireland
| | - Ekaterina S Jordanova
- Department of Gynecology and Obstetrics, Center for Gynecologic Oncology Amsterdam, Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherlands
| | - Micha M M Wilhelmus
- Department of Anatomy and Neurosciences, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands
| | - Chris J Mulder
- Department of Gastroenterology and Hepatology, AGEM Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Paul van der Valk
- Department of Pathology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Annemieke J M Rozemuller
- Department of Pathology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Gerd Bouma
- Department of Gastroenterology and Hepatology, AGEM Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Anne-Marie Van Dam
- Department of Anatomy and Neurosciences, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.
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16
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Donnelly SC. Extensive Mucosal Disease: Coeliac Disease and Eosinophilic Enteritis. INTESTINAL FAILURE 2023:161-175. [DOI: 10.1007/978-3-031-22265-8_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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17
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Branchi F, Wiese JJ, Heldt C, Manna S, Dony V, Loddenkemper C, Bojarski C, Siegmund B, Schneider T, Daum S, Hummel M, Moos V, Schumann M. The combination of clinical parameters and immunophenotyping of intraepithelial lymphocytes allows to assess disease severity in refractory celiac disease. Dig Liver Dis 2022; 54:1649-1656. [PMID: 35850920 DOI: 10.1016/j.dld.2022.06.024] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 06/03/2022] [Accepted: 06/21/2022] [Indexed: 12/30/2022]
Abstract
BACKGROUND Flow cytometry of intestinal lymphocytes is discussed to be a stronger predictor of enteropathy-associated T-cell lymphoma development in refractory celiac disease than T-cell clonality analysis. AIMS To investigate possible associations between clinical characteristics of refractory celiac disease patients and aberrant intraepithelial lymphocytes and to evaluate the accuracy of immunophenotyping for the identification of high-risk refractory celiac disease. METHODS Flow cytometry of isolated lymphocytes from duodenal biopsies of controls and celiac disease patients was performed and results were compared to clinical data. RESULTS Flow cytometry analysis was performed on 42 controls, 37 non-complicated celiac disease and 30 refractory celiac disease cases with or without T-cell receptor clonality. Elevated aberrant intraepithelial lymphocyte counts were significantly associated with severe malabsorption. A 15% cut-off (aberrant lymphocytes among all lymphocytes) had the best discriminatory ability to identify high-risk patients. However, this technique failed to identify some high-risk cases (sensitivity 63%, specificity 100%). The severity of malabsorption was added to the criteria for high-risk refractory celiac disease, improving the correct patients' allocation (sensitivity 100%, specificity 96%). CONCLUSION Immunophenotyping of aberrant intraepithelial lymphocytes is a good predictor for high-risk refractory celiac disease. Furthermore, adding the evaluation of malabsorption to the diagnostic assessment of refractory celiac disease optimizes accuracy.
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Affiliation(s)
- Federica Branchi
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Hindenburgdamm 30, 12203 Berlin, Germany; Center for the Diagnosis and Prevention of Celiac Disease - Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, via Francesco Sforza 35, 20122 Milan, Italy
| | - Jakob Johann Wiese
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Claudia Heldt
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Subhakankha Manna
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Violaine Dony
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Christoph Loddenkemper
- PathoTres Gemeinschaftspraxis für Pathologie und Neuropathologie, Teltowkanalstrasse 2, 12247 Berlin, Germany
| | - Christian Bojarski
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Britta Siegmund
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Thomas Schneider
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Severin Daum
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Michael Hummel
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institut für Pathologie, Molekularpathologie, Charitéplatz 1, 10117 Berlin, Germany
| | - Verena Moos
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Michael Schumann
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Medizinische Klinik für Gastroenterologie, Infektiologie und Rheumatologie, Hindenburgdamm 30, 12203 Berlin, Germany.
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18
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Green PHR, Paski S, Ko CW, Rubio-Tapia A. AGA Clinical Practice Update on Management of Refractory Celiac Disease: Expert Review. Gastroenterology 2022; 163:1461-1469. [PMID: 36137844 DOI: 10.1053/j.gastro.2022.07.086] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 07/21/2022] [Accepted: 07/23/2022] [Indexed: 12/02/2022]
Abstract
DESCRIPTION The purpose of this expert review is to summarize the diagnosis and management of refractory celiac disease. It will review evaluation of patients with celiac disease who have persistent or recurrent symptoms, differential diagnosis, nutritional support, potential therapeutic options, and surveillance for complications of this condition. METHODS This expert review was commissioned and approved by the American Gastroenterological Association (AGA) Institute Clinical Practice Updates Committee (CPUC) and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership and underwent internal peer review by the CPUC and external peer review through standard procedures of Gastroenterology. These Best Practice Advice (BPA) statements were drawn from a review of the published literature and from expert opinion. Since systematic reviews were not performed, these BPA statements do not carry formal ratings of the quality of evidence or strength of the presented considerations. Best Practice Advice Statements BEST PRACTICE ADVICE 1: In patients believed to have celiac disease who have persistent or recurrent symptoms or signs, the initial diagnosis of celiac disease should be confirmed by review of prior diagnostic testing, including serologies, endoscopies, and histologic findings. BEST PRACTICE ADVICE 2: In patients with confirmed celiac disease with persistent or recurrent symptoms or signs (nonresponsive celiac disease), ongoing gluten ingestion should be excluded as a cause of these symptoms with serologic testing, dietitian review, and detection of immunogenic peptides in stool or urine. Esophagogastroduodenoscopy with small bowel biopsies should be performed to look for villous atrophy. If villous atrophy persists or the initial diagnosis of celiac disease was not confirmed, consider other causes of villous atrophy, including common variable immunodeficiency, autoimmune enteropathy, tropical sprue, and medication-induced enteropathy. BEST PRACTICE ADVICE 3: For patients with nonresponsive celiac disease, after exclusion of gluten ingestion, perform a systematic evaluation for other potential causes of symptoms, including functional bowel disorders, microscopic colitis, pancreatic insufficiency, inflammatory bowel disease, lactose or fructose intolerance, and small intestinal bacterial overgrowth. BEST PRACTICE ADVICE 4: Use flow cytometry, immunohistochemistry, and T-cell receptor rearrangement studies to distinguish between subtypes of refractory celiac disease and to exclude enteropathy-associated T-cell lymphoma. Type 1 refractory celiac disease is characterized by a normal intraepithelial lymphocyte population and type 2 is defined by the presence of an aberrant, clonal intraepithelial lymphocyte population. Consultation with an expert hematopathologist is necessary to interpret these studies. BEST PRACTICE ADVICE 5: Perform small bowel imaging with capsule endoscopy and computed tomography or magnetic resonance enterography to exclude enteropathy-associated T-cell lymphoma and ulcerative jejunoileitis at initial diagnosis of type 2 refractory celiac disease. BEST PRACTICE ADVICE 6: Complete a detailed nutritional assessment with investigation of micronutrient and macronutrient deficiencies in patients diagnosed with refractory celiac disease. Check albumin as an independent prognostic factor. BEST PRACTICE ADVICE 7: Correct deficiencies in macro- and micronutrients using oral supplements and/or enteral support. Consider parenteral nutrition for patients with severe malnutrition due to malabsorption. BEST PRACTICE ADVICE 8: Corticosteroids, most commonly open-capsule budesonide or, if unavailable, prednisone, are the medication of choice and should be used as first-line therapy in either type 1 or type 2 refractory celiac disease. BEST PRACTICE ADVICE 9: Patients with refractory celiac disease require regular follow-up by a multidisciplinary team, including gastroenterologists and dietitians, to assess clinical and histologic response to therapy. Identify local experts with expertise in celiac disease to assist with management. BEST PRACTICE ADVICE 10: Patients with refractory celiac disease without response to steroids may benefit from referral to a center with expertise for management or evaluation for inclusion in clinical trials.
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Affiliation(s)
| | - Shirley Paski
- Cedars-Sinai Medical Center, Los Angeles, California
| | - Cynthia W Ko
- Department of Medicine, University of Washington, Seattle, Washington.
| | - Alberto Rubio-Tapia
- Celiac Disease Program, Division of Gastroenterology, Hepatology, and Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
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Ching CK, Lebwohl B. Celiac Disease in the Elderly. CURRENT TREATMENT OPTIONS IN GASTROENTEROLOGY 2022; 20:238-249. [PMID: 36818495 PMCID: PMC9937540 DOI: 10.1007/s11938-022-00397-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 06/29/2022] [Indexed: 10/16/2022]
Abstract
Purpose of review This review highlights literature from the past several years and explores the impact on current understanding of celiac disease diagnosis, complications, and management in older adults. Recent findings Celiac disease in the elderly is becoming increasingly prevalent but remains underdiagnosed, with a high potential burden of downstream morbidity and modestly increased risk of mortality. Clinical presentations are often related to extraintestinal symptoms and can be subtle. Duodenal biopsy remains the gold-standard for diagnosis in older adults, along with supporting serologies. Refractory celiac disease is a particular concern in the aging population, and treatment for this rare condition remains unsatisfactory. Older adults exhibit lower rates of mucosal healing, though the reasons for this are poorly understood. Summary Current understanding of celiac disease in the elderly continues to advance, though significant knowledge gaps persist. Large, prospective studies are needed to further characterize celiac disease pathogenesis, complications, and management in older adults.
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Affiliation(s)
- Charlotte K. Ching
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Benjamin Lebwohl
- Division of Digestive and Liver Diseases, Columbia University Irving Medical Center, New York, NY, USA
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20
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Levescot A, Malamut G, Cerf-Bensussan N. Immunopathogenesis and environmental triggers in coeliac disease. Gut 2022; 71:gutjnl-2021-326257. [PMID: 35879049 PMCID: PMC9554150 DOI: 10.1136/gutjnl-2021-326257] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 07/07/2022] [Indexed: 12/21/2022]
Abstract
Coeliac disease (CD) is a frequent immune enteropathy induced by gluten in genetically predisposed individuals. Its pathogenesis has been extensively studied and CD has emerged as a model disease to decipher how the interplay between environmental and genetic factors can predispose to autoimmunity and promote lymphomagenesis. The keystone event is the activation of a gluten-specific immune response that is driven by molecular interactions between gluten, the indispensable environmental factor, HLA-DQ2/8, the main predisposing genetic factor and transglutaminase 2, the CD-specific autoantigen. The antigluten response is however not sufficient to induce epithelial damage which requires the activation of cytotoxic CD8+ intraepithelial lymphocytes (IEL). In a plausible scenario, cooperation between cytokines released by gluten-specific CD4+ T cells and interleukin-15 produced in excess in the coeliac gut, licenses the autoimmune-like attack of the gut epithelium, likely via sustained activation of the Janus kinase-signal transducer and activator of transcription (JAK/STAT) pathway in IEL. Demonstration that lymphomas complicating CD arise from IEL that have acquired gain-of-function JAK1 or STAT3 mutations stresses the key role of this pathway and explains how gluten-driven chronic inflammation may promote this rare but most severe complication. If our understanding of CD pathogenesis has considerably progressed, several questions and challenges remain. One unsolved question concerns the considerable variability in disease penetrance, severity and presentation, pointing to the role of additional genetic and environmental factors that remain however uneasy to untangle and hierarchize. A current challenge is to transfer the considerable mechanistic insight gained into CD pathogenesis into benefits for the patients, notably to alleviate the gluten-free diet, a burden for many patients.
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Affiliation(s)
- Anais Levescot
- Université Paris Cité, Institut Imagine, INSERM UMR1163, Laboratory Intestinal Immunity, Paris, France
| | - Georgia Malamut
- Université Paris Cité, Institut Imagine, INSERM UMR1163, Laboratory Intestinal Immunity, Paris, France
- Université Paris Cité, APHP Centre, Gastroenterology Department, Hôpital Cochin, Paris, France
| | - Nadine Cerf-Bensussan
- Université Paris Cité, Institut Imagine, INSERM UMR1163, Laboratory Intestinal Immunity, Paris, France
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Ailioaie LM, Ailioaie C, Litscher G, Chiran DA. Celiac Disease and Targeting the Molecular Mechanisms of Autoimmunity in COVID Pandemic. Int J Mol Sci 2022; 23:7719. [PMID: 35887067 PMCID: PMC9322892 DOI: 10.3390/ijms23147719] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 07/06/2022] [Accepted: 07/11/2022] [Indexed: 12/16/2022] Open
Abstract
Celiac disease (CD) comprises over 1% of the world's population and is a chronic multisystem immune-mediated condition manifested by digestive and/or extradigestive symptoms caused by food intake of gluten. This review looked at the risk of children diagnosed with CD developing SARS-CoV-2 infection and possible severe forms of COVID-19. A better understanding of the interaction and effects of SARS-CoV-2 infection in CD is very important, as is the role of environmental and genetic factors, but especially the molecular mechanisms involved in modulating intestinal permeability with impact on autoimmunity. CD inspired the testing of a zonulin antagonist for the fulminant form of multisystem inflammatory syndrome in children (MIS-C) and paved the way for the discovery of new molecules to regulate the small intestine barrier function and immune responses. Original published works on COVID-19 and CD, new data and points of view have been analyzed because this dangerous virus SARS-CoV-2 is still here and yet influencing our lives. Medical science continues to focus on all uncertainties triggered by SARS-CoV-2 infection and its consequences, including in CD. Although the COVID-19 pandemic seems to be gradually extinguishing, there is a wealth of information and knowledge gained over the last two years and important life lessons to analyze, as well as relevant conclusions to be drawn to deal with future pandemics. Zonulin is being studied extensively in immunoengineering as an adjuvant to improving the absorption of new drugs and oral vaccines.
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Affiliation(s)
- Laura Marinela Ailioaie
- Department of Medical Physics, Alexandru Ioan Cuza University, 11 Carol I Boulevard, 700506 Iasi, Romania; (L.M.A.); (C.A.)
| | - Constantin Ailioaie
- Department of Medical Physics, Alexandru Ioan Cuza University, 11 Carol I Boulevard, 700506 Iasi, Romania; (L.M.A.); (C.A.)
| | - Gerhard Litscher
- Research Unit of Biomedical Engineering in Anesthesia and Intensive Care Medicine, Research Unit for Complementary and Integrative Laser Medicine, Traditional Chinese Medicine (TCM) Research Center Graz, Department of Anesthesiology and Intensive Care Medicine, Medical University of Graz, Auenbruggerplatz 39, 8036 Graz, Austria
| | - Dragos Andrei Chiran
- Department of Morpho-Functional Sciences I, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii St., 700115 Iasi, Romania;
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22
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Ailioaie LM, Ailioaie C, Litscher G, Chiran DA. Celiac Disease and Targeting the Molecular Mechanisms of Autoimmunity in COVID Pandemic. Int J Mol Sci 2022. [PMID: 35887067 DOI: 10.3390/ijms23147719.pmid:35887067;pmcid:pmc9322892] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/12/2023] Open
Abstract
Celiac disease (CD) comprises over 1% of the world's population and is a chronic multisystem immune-mediated condition manifested by digestive and/or extradigestive symptoms caused by food intake of gluten. This review looked at the risk of children diagnosed with CD developing SARS-CoV-2 infection and possible severe forms of COVID-19. A better understanding of the interaction and effects of SARS-CoV-2 infection in CD is very important, as is the role of environmental and genetic factors, but especially the molecular mechanisms involved in modulating intestinal permeability with impact on autoimmunity. CD inspired the testing of a zonulin antagonist for the fulminant form of multisystem inflammatory syndrome in children (MIS-C) and paved the way for the discovery of new molecules to regulate the small intestine barrier function and immune responses. Original published works on COVID-19 and CD, new data and points of view have been analyzed because this dangerous virus SARS-CoV-2 is still here and yet influencing our lives. Medical science continues to focus on all uncertainties triggered by SARS-CoV-2 infection and its consequences, including in CD. Although the COVID-19 pandemic seems to be gradually extinguishing, there is a wealth of information and knowledge gained over the last two years and important life lessons to analyze, as well as relevant conclusions to be drawn to deal with future pandemics. Zonulin is being studied extensively in immunoengineering as an adjuvant to improving the absorption of new drugs and oral vaccines.
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Affiliation(s)
- Laura Marinela Ailioaie
- Department of Medical Physics, Alexandru Ioan Cuza University, 11 Carol I Boulevard, 700506 Iasi, Romania
| | - Constantin Ailioaie
- Department of Medical Physics, Alexandru Ioan Cuza University, 11 Carol I Boulevard, 700506 Iasi, Romania
| | - Gerhard Litscher
- Research Unit of Biomedical Engineering in Anesthesia and Intensive Care Medicine, Research Unit for Complementary and Integrative Laser Medicine, Traditional Chinese Medicine (TCM) Research Center Graz, Department of Anesthesiology and Intensive Care Medicine, Medical University of Graz, Auenbruggerplatz 39, 8036 Graz, Austria
| | - Dragos Andrei Chiran
- Department of Morpho-Functional Sciences I, Faculty of Medicine, Grigore T. Popa University of Medicine and Pharmacy, 16 Universitatii St., 700115 Iasi, Romania
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23
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Penny HA, Rej A, Baggus EMR, Coleman SH, Ward R, Wild G, Bouma G, Trott N, Snowden JA, Wright J, Cross SS, Hadjivassiliou M, Sanders DS. Non-Responsive and Refractory Coeliac Disease: Experience from the NHS England National Centre. Nutrients 2022; 14:nu14132776. [PMID: 35807956 PMCID: PMC9268848 DOI: 10.3390/nu14132776] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 06/21/2022] [Accepted: 06/27/2022] [Indexed: 02/04/2023] Open
Abstract
We characterised the aetiology of non-responsive coeliac disease (NRCD) and provided contemporary mortality data in refractory coeliac disease (RCD) from our centre. We also measured urine gluten immunogenic peptides (GIPs) in patients with established RCD1 to evaluate gluten exposure in these individuals. Methods: This was a longitudinal cohort study conducted in Sheffield, UK. Between 1998 and 2019, we evaluated 285 adult (≥16 years) patients with NRCD or RCD. Patients with established RCD1 and persisting mucosal inflammation and/or ongoing symptoms provided three urine samples for GIP analysis. Results: The most common cause of NRCD across the cohort was gluten exposure (72/285; 25.3%). RCD accounted for 65/285 patients (22.8%), 54/65 patients (83.1%) had RCD1 and 11/65 patients (16.9%) had RCD2. The estimated 5-year survival was 90% for RCD1 and 58% for RCD2 (p = 0.016). A total of 36/54 (66.7%) patients with RCD1 underwent urinary GIP testing and 17/36 (47.2%) had at least one positive urinary GIP test. Conclusion: The contemporary mortality data in RCD2 remains poor; patients with suspected RCD2 should be referred to a recognised national centre for consideration of novel therapies. The high frequency of urinary GIP positivity suggests that gluten exposure may be common in RCD1; further studies with matched controls are warranted to assess this further.
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Affiliation(s)
- Hugo A. Penny
- Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK; (A.R.); (E.M.R.B.); (S.H.C.); (R.W.); (G.W.); (N.T.); (S.S.C.)
- Correspondence: (H.A.P.); (D.S.S.); Tel.: +44-0114-271-1900 (H.A.P. & D.S.S.)
| | - Anupam Rej
- Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK; (A.R.); (E.M.R.B.); (S.H.C.); (R.W.); (G.W.); (N.T.); (S.S.C.)
| | - Elisabeth M. R. Baggus
- Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK; (A.R.); (E.M.R.B.); (S.H.C.); (R.W.); (G.W.); (N.T.); (S.S.C.)
| | - Sarah. H. Coleman
- Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK; (A.R.); (E.M.R.B.); (S.H.C.); (R.W.); (G.W.); (N.T.); (S.S.C.)
| | - Rosalie Ward
- Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK; (A.R.); (E.M.R.B.); (S.H.C.); (R.W.); (G.W.); (N.T.); (S.S.C.)
| | - Graeme Wild
- Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK; (A.R.); (E.M.R.B.); (S.H.C.); (R.W.); (G.W.); (N.T.); (S.S.C.)
| | - Gerd Bouma
- Department of Gastroenterology, Vrije Universiteit Medical Center, 1117 Amsterdam, The Netherlands;
| | - Nick Trott
- Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK; (A.R.); (E.M.R.B.); (S.H.C.); (R.W.); (G.W.); (N.T.); (S.S.C.)
| | - John A. Snowden
- Department of Haematology, Royal Hallamshire Hospital, Sheffield Teaching Hospital NHS Foundation Trust, Sheffield S10 2JF, UK; (J.A.S.); (J.W.)
| | - Josh Wright
- Department of Haematology, Royal Hallamshire Hospital, Sheffield Teaching Hospital NHS Foundation Trust, Sheffield S10 2JF, UK; (J.A.S.); (J.W.)
| | - Simon S. Cross
- Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK; (A.R.); (E.M.R.B.); (S.H.C.); (R.W.); (G.W.); (N.T.); (S.S.C.)
| | - Marios Hadjivassiliou
- Department of Neurology, Royal Hallamshire Hospital, Sheffield Teaching Hospital NHS Foundation Trust, Sheffield S10 2JF, UK;
| | - David S. Sanders
- Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK; (A.R.); (E.M.R.B.); (S.H.C.); (R.W.); (G.W.); (N.T.); (S.S.C.)
- Correspondence: (H.A.P.); (D.S.S.); Tel.: +44-0114-271-1900 (H.A.P. & D.S.S.)
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24
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Hue SSS, Ng SB, Wang S, Tan SY. Cellular Origins and Pathogenesis of Gastrointestinal NK- and T-Cell Lymphoproliferative Disorders. Cancers (Basel) 2022; 14:2483. [PMID: 35626087 PMCID: PMC9139583 DOI: 10.3390/cancers14102483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 05/08/2022] [Accepted: 05/13/2022] [Indexed: 11/25/2022] Open
Abstract
The intestinal immune system, which must ensure appropriate immune responses to both pathogens and commensal microflora, comprises innate lymphoid cells and various T-cell subsets, including intra-epithelial lymphocytes (IELs). An example of innate lymphoid cells is natural killer cells, which may be classified into tissue-resident, CD56bright NK-cells that serve a regulatory function and more mature, circulating CD56dim NK-cells with effector cytolytic properties. CD56bright NK-cells in the gastrointestinal tract give rise to indolent NK-cell enteropathy and lymphomatoid gastropathy, as well as the aggressive extranodal NK/T cell lymphoma, the latter following activation by EBV infection and neoplastic transformation. Conventional CD4+ TCRαβ+ and CD8αβ+ TCRαβ+ T-cells are located in the lamina propria and the intraepithelial compartment of intestinal mucosa as type 'a' IELs. They are the putative cells of origin for CD4+ and CD8+ indolent T-cell lymphoproliferative disorders of the gastrointestinal tract and intestinal T-cell lymphoma, NOS. In addition to such conventional T-cells, there are non-conventional T-cells in the intra-epithelial compartment that express CD8αα and innate lymphoid cells that lack TCRs. The central feature of type 'b' IELs is the expression of CD8αα homodimers, seen in monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), which primarily arises from both CD8αα+ TCRαβ+ and CD8αα+ TCRγδ+ IELs. EATL is the other epitheliotropic T-cell lymphoma in the GI tract, a subset of which arises from the expansion and reprograming of intracytoplasmic CD3+ innate lymphoid cells, driven by IL15 and mutations of the JAK-STAT pathway.
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Affiliation(s)
- Susan Swee-Shan Hue
- Department of Pathology, National University Hospital, Singapore 119074, Singapore; (S.S.-S.H.); (S.W.)
| | - Siok-Bian Ng
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore;
- Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore
| | - Shi Wang
- Department of Pathology, National University Hospital, Singapore 119074, Singapore; (S.S.-S.H.); (S.W.)
| | - Soo-Yong Tan
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore;
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25
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Felber J, Bläker H, Fischbach W, Koletzko S, Laaß M, Lachmann N, Lorenz P, Lynen P, Reese I, Scherf K, Schuppan D, Schumann M, Aust D, Baas S, Beisel S, de Laffolie J, Duba E, Holtmeier W, Lange L, Loddenkemper C, Moog G, Rath T, Roeb E, Rubin D, Stein J, Török H, Zopf Y. [Not Available]. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2022; 60:790-856. [PMID: 35545109 DOI: 10.1055/a-1741-5946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Jörg Felber
- Medizinische Klinik II - Gastroenterologie, Hepatologie, Endokrinologie, Hämatologie und Onkologie, RoMed Klinikum Rosenheim, Rosenheim, Deutschland
| | - Hendrik Bläker
- Institut für Pathologie, Universitätsklinikum Leipzig AöR, Leipzig, Deutschland
| | | | - Sibylle Koletzko
- Kinderklinik und Kinderpoliklinik im Dr. von Haunerschen Kinderspital, LMU-Klinikum München, München, Deutschland
- Department of Pediatrics, Gastroenterology and Nutrition, School of Medicine Collegium Medicum University of Warmia and Mazury, 10-719 Olsztyn, Polen
| | - Martin Laaß
- Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden, Dresden, Deutschland
| | - Nils Lachmann
- Institut für Transfusionsmedizin, Charité - Universitätsmedizin Berlin, Berlin, Deutschland
| | - Pia Lorenz
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS), Berlin, Deutschland
| | - Petra Lynen
- Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS), Berlin, Deutschland
| | - Imke Reese
- Ernährungsberatung und -therapie Allergologie, München, Deutschland
| | - Katharina Scherf
- Institute of Applied Biosciences Department of Bioactive and Functional Food Chemistry, Karlsruhe Institute of Technology (KIT), Karlsruhe, Deutschland
| | - Detlef Schuppan
- Institut für Translationale Immunologie, Johannes Gutenberg-Universität Mainz, Mainz, Deutschland
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Michael Schumann
- Medizinische Klinik I für Gastroenterologie, Infektiologie und Rheumatologie, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Deutschland
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26
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Grewal JK, Kassardjian A, Weiss GA. Successful novel use of tofacitinib for type II refractory coeliac disease. BMJ Case Rep 2022; 15:e244692. [PMID: 35418371 PMCID: PMC9013952 DOI: 10.1136/bcr-2021-244692] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/25/2022] [Indexed: 01/03/2023] Open
Abstract
Refractory coeliac disease (RCD) occurs when patients with confirmed CD have continuous or recurrent malabsorption and enteropathy after at least 12 months on a gluten-free diet. Differentiating between type I and type II RCD is key as the latter is associated with T-cell aberrancy and considered prelymphoma, with high mortality rates. Current treatment regimens for type II RCD include corticosteroids, biologics and chemotherapy, but there are no proven therapies for this serious condition. Our patient is a middle-aged woman who developed postpartum type II RCD. When she failed multiple drug classes, we did a trial of tofacitinib. Our clinical experience with use of a janus kinase inhibitor was successful, with no associated adverse events. This is the first report in the literature of RCD remission in response to tofacitinib. The use of this novel agent shows promise in reversing this potentially fatal condition.
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Affiliation(s)
- Jasleen Kaur Grewal
- Division of Gastroenterology, Deparment of Medicine, Southern California Kaiser Permanente, San Diego, California, USA
| | | | - Guy A Weiss
- Celiac Disease Program, University of California Los Angeles David Geffen School of Medicine, Los Angeles, California, USA
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27
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Ciacchi L, Reid HH, Rossjohn J. Structural bases of T cell antigen receptor recognition in celiac disease. Curr Opin Struct Biol 2022; 74:102349. [PMID: 35272251 DOI: 10.1016/j.sbi.2022.102349] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 01/15/2022] [Accepted: 01/30/2022] [Indexed: 12/16/2022]
Abstract
Celiac disease (CeD) is a human leukocyte antigen (HLA)-linked autoimmune-like disorder that is triggered by the ingestion of gluten or related storage proteins. The majority of CeD patients are HLA-DQ2.5+, with the remainder being either HLA-DQ8+ or HLA-DQ2.2+. Structural studies have shown how deamidation of gluten epitopes engenders binding to HLA-DQ2.5/8, which then triggers an aberrant CD4+ T cell response. HLA tetramer studies, combined with structural investigations, have demonstrated that repeated patterns of TCR usage underpins the immune response to some HLADQ2.5/8 restricted gluten epitopes, with distinct TCR motifs representing common landing pads atop the HLA-gluten complexes. Structural studies have provided insight into TCR specificity and cross-reactivity towards gluten epitopes, as well as cross-reactivity to bacterial homologues of gluten epitopes, suggesting that environmental factors may directly play a role in CeD pathogenesis. Collectively, structural immunology-based studies in the CeD axis may lead to new therapeutics/diagnostics to treat CeD, and also serve as an exemplar for other T cell mediated autoimmune diseases.
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Affiliation(s)
- Laura Ciacchi
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia
| | - Hugh H Reid
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia
| | - Jamie Rossjohn
- Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, 3800, Australia; Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, CF14 4XN, United Kingdom.
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28
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Murray JA. Several faces of refractory coeliac disease type 2. Gut 2022; 71:449-450. [PMID: 33785554 DOI: 10.1136/gutjnl-2021-324251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 03/21/2021] [Indexed: 12/08/2022]
Affiliation(s)
- Joseph A Murray
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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29
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Cording S, Lhermitte L, Malamut G, Berrabah S, Trinquand A, Guegan N, Villarese P, Kaltenbach S, Meresse B, Khater S, Dussiot M, Bras M, Cheminant M, Tesson B, Bole-Feysot C, Bruneau J, Molina TJ, Sibon D, Macintyre E, Hermine O, Cellier C, Asnafi V, Cerf-Bensussan N, CELAC network
BouhnikYoramCuenodCharles-AndréBrechignacSabineAllezMatthieuCosnesJacquesFourmestrauxAgnèsDelchierJean-CharlesDupuisJehanHaiounCorinneGnaouiTaoufik ElLereboursEricSavoyeGuillaumeTillyHerveFlourieBernardCoiffierBertrandHebuterneXavierArabNadiaFilippiJérômeSchneiderStéphaneZerbibFrankMilpiedNoelBouabdallahKrimoTabriziRezaVigourouxStéphanePigneuxArnaudLeguayThibautDilhuydyMarie-SarahDauriacCharlesBolognaSergeHulinCyrilleBonmatiCarolineMagninFrédericRantaDanaMatysiakbudnikTamaraDeconinckEricPouderouxPhilippeBonazBrunoGressinRemyCarbonnelFranckGornetJean-MarcBrancheJulienSaint-GeorgesGeorgetteReimundJean-MarieNanceyStéphaneNachuryMariaViennotStéphanieZallotCamilleFabianiBettinaMartheyLysianeJuvinKarineBaleurYann LeKwiatekSandySaillardEricLouvelDominiqueRoblinXavierBeauPhilippeFeugierPierrePeyrin-BirouletLaurentZanaldiHélèneBrixi-BenmansourHediaCadiotGuillaumeLecomteThierryBretagneJean-FrancoisCasasnovasOlivierCaillotDenisBedenneLaurentBayJacques-OlivierBouteloupCorinneDuclosBernardFoucaudCarine. Oncogenetic landscape of lymphomagenesis in coeliac disease. Gut 2022; 71:497-508. [PMID: 33579790 PMCID: PMC8862029 DOI: 10.1136/gutjnl-2020-322935] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 01/26/2021] [Accepted: 01/27/2021] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Enteropathy-associated T-cell lymphoma (EATL) is a rare but severe complication of coeliac disease (CeD), often preceded by low-grade clonal intraepithelial lymphoproliferation, referred to as type II refractory CeD (RCDII). Knowledge on underlying oncogenic mechanisms remains scarce. Here, we analysed and compared the mutational landscape of RCDII and EATL in order to identify genetic drivers of CeD-associated lymphomagenesis. DESIGN Pure populations of RCDII-cells derived from intestinal biopsies (n=9) or sorted from blood (n=2) were analysed by whole exome sequencing, comparative genomic hybridisation and RNA sequencing. Biopsies from RCDII (n=50), EATL (n=19), type I refractory CeD (n=7) and uncomplicated CeD (n=18) were analysed by targeted next-generation sequencing. Moreover, functional in vitro studies and drug testing were performed in RCDII-derived cell lines. RESULTS 80% of RCDII and 90% of EATL displayed somatic gain-of-functions mutations in the JAK1-STAT3 pathway, including a remarkable p.G1097 hotspot mutation in the JAK1 kinase domain in approximately 50% of cases. Other recurrent somatic events were deleterious mutations in nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) regulators TNFAIP3 and TNIP3 and potentially oncogenic mutations in TET2, KMT2D and DDX3X. JAK1 inhibitors, and the proteasome inhibitor bortezomib could block survival and proliferation of malignant RCDII-cell lines. CONCLUSION Mutations activating the JAK1-STAT3 pathway appear to be the main drivers of CeD-associated lymphomagenesis. In concert with mutations in negative regulators of NF-κB, they may favour the clonal emergence of malignant lymphocytes in the cytokine-rich coeliac intestine. The identified mutations are attractive therapeutic targets to treat RCDII and block progression towards EATL.
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Affiliation(s)
- Sascha Cording
- Université de Paris, Imagine Institute, Laboratory of Intestinal Immunity, INSERM UMR 1163, Paris, France
| | - Ludovic Lhermitte
- Université de Paris, Institut Necker-Enfants Malades, INSERM UMR 1151, Paris, France,Laboratory of Onco-Haematology, AP-HP, Hôpital Necker Enfants-Malades, Paris, France
| | - Georgia Malamut
- Université de Paris, Imagine Institute, Laboratory of Intestinal Immunity, INSERM UMR 1163, Paris, France,Department of Gastroenterology, AP-HP, Hôpital Cochin, Paris, France
| | - Sofia Berrabah
- Université de Paris, Imagine Institute, Laboratory of Intestinal Immunity, INSERM UMR 1163, Paris, France
| | - Amélie Trinquand
- Université de Paris, Imagine Institute, Laboratory of Intestinal Immunity, INSERM UMR 1163, Paris, France,Haematology Department, National Children’s Research Centre, Children’s Health Ireland at Crumlin, Dublin, Ireland
| | - Nicolas Guegan
- Université de Paris, Imagine Institute, Laboratory of Intestinal Immunity, INSERM UMR 1163, Paris, France
| | - Patrick Villarese
- Université de Paris, Institut Necker-Enfants Malades, INSERM UMR 1151, Paris, France,Laboratory of Onco-Haematology, AP-HP, Hôpital Necker Enfants-Malades, Paris, France
| | - Sophie Kaltenbach
- Department of Cytogenetics, AP-HP, Hôpital Necker Enfants-Malades, Paris, France
| | - Bertrand Meresse
- Université de Lille, CHU Lille, INSERM UMR 1286 – INFINITE – Institute for Translational Research in Inflammation, Lille, France
| | - Sherine Khater
- Department of Gastroenterology, AP-HP, Hôpital Européen Georges Pompidou, Paris, France
| | - Michael Dussiot
- Université de Paris, Imagine Institute, Laboratory of Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, INSERM UMR 1163, Paris, France
| | - Marc Bras
- Université de Paris, Imagine Institute, Bioinformatics Platform, Paris, France
| | - Morgane Cheminant
- Université de Paris, Imagine Institute, Laboratory of Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, INSERM UMR 1163, Paris, France,Clinical Haematology, AP-HP, Hôpital Necker Enfants-Malades, Paris, France
| | | | | | - Julie Bruneau
- Department of Pathology, AP-HP, Hôpital Necker Enfants-Malades, Paris, France
| | - Thierry Jo Molina
- Université de Paris, Imagine Institute, Laboratory of Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, INSERM UMR 1163, Paris, France,Department of Pathology, AP-HP, Hôpital Necker Enfants-Malades, Paris, France
| | - David Sibon
- Clinical Haematology, AP-HP, Hôpital Necker Enfants-Malades, Paris, France
| | - Elizabeth Macintyre
- Université de Paris, Institut Necker-Enfants Malades, INSERM UMR 1151, Paris, France,Laboratory of Onco-Haematology, AP-HP, Hôpital Necker Enfants-Malades, Paris, France
| | - Olivier Hermine
- Université de Paris, Imagine Institute, Laboratory of Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, INSERM UMR 1163, Paris, France,Clinical Haematology, AP-HP, Hôpital Necker Enfants-Malades, Paris, France
| | - Christophe Cellier
- Department of Gastroenterology, AP-HP, Hôpital Européen Georges Pompidou, Paris, France
| | - Vahid Asnafi
- Université de Paris, Institut Necker-Enfants Malades, INSERM UMR 1151, Paris, France,Laboratory of Onco-Haematology, AP-HP, Hôpital Necker Enfants-Malades, Paris, France
| | - Nadine Cerf-Bensussan
- Université de Paris, Imagine Institute, Laboratory of Intestinal Immunity, INSERM UMR 1163, Paris, France
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30
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Lebwohl B, Green PHR, Emilsson L, Mårild K, Söderling J, Roelstraete B, Ludvigsson JF. Cancer Risk in 47,241 Individuals With Celiac Disease: A Nationwide Cohort Study. Clin Gastroenterol Hepatol 2022; 20:e111-e131. [PMID: 34033925 DOI: 10.1016/j.cgh.2021.05.034] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 05/11/2021] [Accepted: 05/17/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Celiac disease (CD) is associated with increased mortality, in part due to cancer. Most studies investigating this cancer risk involved patients diagnosed before widespread increases in CD diagnosis rates and access to gluten-free food. We performed a population-based study of the risk of cancer in CD. METHODS We identified all patients in Sweden with CD as defined as duodenal/jejunal villus atrophy, using the Epidemiology Strengthened by histoPathology Reports in Sweden cohort. Each patient was matched to ≤5 controls by age, sex, and county. We used stratified Cox proportional hazards model, following patients from diagnosis until first cancer, or by December 31, 2016. RESULTS Among 47,241 patients with CD, 30,080 (64%) were diagnosed since 2000. After a median follow-up of 11.5 years, the incidence of cancer was 6.5 and 5.7 per 1000 person-years in CD patients and controls, respectively. The overall risk of cancer was increased (hazard ratio [HR], 1.11; 95% confidence interval [CI], 1.07-1.15), but it was only significantly elevated in the first year after CD diagnosis (HR, 2.47; 95% CI, 2.22-2.74) and not subsequently (HR, 1.01; 95% CI, 0.97-1.05), although the risks of hematologic, lymphoproliferative, hepatobiliary, and pancreatic cancers persisted. The overall risk was highest in those diagnosed with CD after age 60 years (HR, 1.22; 95% CI, 1.16-1.29) and was not increased in those diagnosed before age 40. The cancer risk was similar among those diagnosed with CD before or after the year 2000. CONCLUSIONS There is an increased risk of cancer in CD even in recent years, but this risk increase is confined to those diagnosed with CD after age 40 and is primarily present within the first year of diagnosis.
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Affiliation(s)
- Benjamin Lebwohl
- Celiac Disease Center, Department of Medicine, Columbia University Medical Center, New York, New York; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York
| | - Peter H R Green
- Celiac Disease Center, Department of Medicine, Columbia University Medical Center, New York, New York
| | - Louise Emilsson
- School of Medical Science, University of Örebro, Örebro, Sweden; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Värmlands Nysäter Health Care Center and Centre for Clinical Research, County Council of Värmland, Sweden; Department of General Practice, Institute of Health and Society, University of Oslo, Oslo, Norway
| | - Karl Mårild
- Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg, Sweden; Department of Pediatric Gastroenterology, Queen Silvia Children's Hospital, Gothenburg, Sweden
| | - Jonas Söderling
- Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Bjorn Roelstraete
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Jonas F Ludvigsson
- Celiac Disease Center, Department of Medicine, Columbia University Medical Center, New York, New York; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Pediatrics, Örebro University Hospital, Örebro University, Örebro, Sweden.
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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: 83] [Impact Index Per Article: 27.7] [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.
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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
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Primary Gastrointestinal T-Cell Lymphoma and Indolent Lymphoproliferative Disorders: Practical Diagnostic and Treatment Approaches. Cancers (Basel) 2021; 13:cancers13225774. [PMID: 34830926 PMCID: PMC8616126 DOI: 10.3390/cancers13225774] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 11/15/2021] [Accepted: 11/16/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary It is challenging for pathologists to diagnose primary gastrointestinal T-cell neoplasms. Besides the rarity of the diseases, the small biopsy material makes it more difficult to differentiate between non-neoplastic inflammation and secondary involvement of extra gastrointestinal lymphoma. Since this group of diseases ranges from aggressive ones with a very poor prognosis to indolent ones that require caution to avoid overtreatment, the impact of the diagnosis on the patient is enormous. Although early treatment of aggressive lymphoma is essential, the treatment strategy is not well established, which is a problem for clinicians. This review provides a cross-sectional comparison of histological findings. Unlike previous reviews, we summarized up-to-date clinically relevant information including the treatment strategies as well as practical differential diagnosis based on thorough literature review. Abstract Primary gastrointestinal (GI) T-cell neoplasms are extremely rare heterogeneous disease entities with distinct clinicopathologic features. Given the different prognoses of various disease subtypes, clinicians and pathologists must be aware of the key characteristics of these neoplasms, despite their rarity. The two most common aggressive primary GI T-cell lymphomas are enteropathy-associated T-cell lymphoma and monomorphic epitheliotropic intestinal T-cell lymphoma. In addition, extranodal natural killer (NK)/T-cell lymphoma of the nasal type and anaplastic large cell lymphoma may also occur in the GI tract or involve it secondarily. In the revised 4th World Health Organization classification, indolent T-cell lymphoproliferative disorder of the GI tract has been incorporated as a provisional entity. In this review, we summarize up-to-date clinicopathological features of these disease entities, including the molecular characteristics of primary GI T-cell lymphomas and indolent lymphoproliferative disorders. We focus on the latest treatment approaches, which have not been summarized in existing reviews. Further, we provide a comprehensive review of available literature to address the following questions: How can pathologists discriminate subtypes with different clinical prognoses? How can primary GI neoplasms be distinguished from secondary involvement? How can these neoplasms be distinguished from non-specific inflammatory changes at an early stage?
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Kojima K, Chambers JK, Nakashima K, Goto-Koshino Y, Uchida K. Immunophenotyping of intraepithelial lymphocytes in canine chronic enteropathy and intestinal T-cell lymphoma using endoscopic samples. Vet Pathol 2021; 59:227-235. [PMID: 34794367 DOI: 10.1177/03009858211057220] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Human enteropathy-associated T-cell lymphoma (EATL) is considered to be derived from intraepithelial lymphocytes (IELs); however, the origin of canine intestinal T-cell lymphoma (ITCL) remains unclear. Histological, immunohistochemical, and clonality examinations were performed using endoscopically collected canine duodenum samples of mucosal lesions of chronic enteropathy (CE; 73 cases) and ITCL without transmural neoplastic mass lesions (64 cases). Histopathological examinations revealed the intraepithelial accumulation of lymphocytes (called "intraepithelial lymphocytosis") in 54/73 CE cases (74%) and the epitheliotropism of neoplastic lymphocytes in 63/64 ITCL cases (98%). Immunohistochemically, IELs in CE with intraepithelial lymphocytosis (IEL+CE) were diffusely immunopositive for CD3, with scattered immunopositivity for CD5, CD8, CD20, and granzyme B (GRB). The percentage of CD8+ in CD3+ IELs was significantly lower in IEL+CE than in CE without intraepithelial lymphocytosis (IEL-CE). Double-labeling immunohistochemistry revealed a high percentage of GRB expression in CD8- IEL among IEL+CE. Among 64 ITCL cases, CD3 was immunopositive in 64 (100%), CD5 in 22 (34%), CD8 in 8 (13%), CD20 in 12 (19%), CD30 in 13 (20%), and GRB in 49 (77%). In CD3+ cells, Ki67 immunopositivity was highest in ITCL, intermediate in IEL+CE, and lower in IEL-CE. A clonal TCR gene rearrangement was detected in 1/19 IEL-CE cases (5%), 15/54 IEL+CE (28%), and 38/58 ITCL (66%). These results indicate that the immunophenotype of canine ITCL (CD8-GRB+) is similar to that of the increased IELs in CE. The high proliferative activity and clonality of T cells in IEL+CE suggest that canine ITCL originates from these IELs, similar to human EATL.
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Affiliation(s)
| | | | - Ko Nakashima
- Japan Small Animal Medical Center, Tokorozawa, Saitama, Japan
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Pelizzaro F, Marsilio I, Fassan M, Piazza F, Barberio B, D’Odorico A, Savarino EV, Farinati F, Zingone F. The Risk of Malignancies in Celiac Disease-A Literature Review. Cancers (Basel) 2021; 13:5288. [PMID: 34771450 PMCID: PMC8582432 DOI: 10.3390/cancers13215288] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2021] [Revised: 10/15/2021] [Accepted: 10/19/2021] [Indexed: 12/14/2022] Open
Abstract
Celiac disease (CeD) is an immune-mediated enteropathy precipitated by ingestion of gluten in genetically predisposed individuals. Considering that CeD affects approximately 1% of the Western population, it may be considered a global health problem. In the large majority of cases, CeD has a benign course, characterized by the complete resolution of symptoms and a normal life expectancy after the beginning of a gluten-free-diet (GFD); however, an increased risk of developing malignancies, such as lymphomas and small bowel carcinoma (SBC), has been reported. In particular, enteropathy-associated T-cell lymphoma (EATL), a peculiar type of T-cell lymphoma, is characteristically associated with CeD. Moreover, the possible association between CeD and several other malignancies has been also investigated in a considerable number of studies. In this paper, we aim to provide a comprehensive review of the current knowledge about the associations between CeD and cancer, focusing in particular on EATL and SBC, two rare but aggressive malignancies.
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Affiliation(s)
- Filippo Pelizzaro
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University Hospital of Padova, 35128 Padova, Italy; (F.P.); (I.M.); (B.B.); (A.D.); (E.V.S.); (F.F.)
| | - Ilaria Marsilio
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University Hospital of Padova, 35128 Padova, Italy; (F.P.); (I.M.); (B.B.); (A.D.); (E.V.S.); (F.F.)
| | - Matteo Fassan
- Surgical Pathology and Cytopathology Unit, Department of Medicine (DIMED), University Hospital of Padova, 35128 Padova, Italy;
- Veneto Oncology Institute, IOV-IRCCS, 35128 Padova, Italy
| | - Francesco Piazza
- Department of Medicine, Hematology, University Hospital of Padova, 35128 Padova, Italy;
| | - Brigida Barberio
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University Hospital of Padova, 35128 Padova, Italy; (F.P.); (I.M.); (B.B.); (A.D.); (E.V.S.); (F.F.)
| | - Anna D’Odorico
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University Hospital of Padova, 35128 Padova, Italy; (F.P.); (I.M.); (B.B.); (A.D.); (E.V.S.); (F.F.)
| | - Edoardo V. Savarino
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University Hospital of Padova, 35128 Padova, Italy; (F.P.); (I.M.); (B.B.); (A.D.); (E.V.S.); (F.F.)
| | - Fabio Farinati
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University Hospital of Padova, 35128 Padova, Italy; (F.P.); (I.M.); (B.B.); (A.D.); (E.V.S.); (F.F.)
| | - Fabiana Zingone
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University Hospital of Padova, 35128 Padova, Italy; (F.P.); (I.M.); (B.B.); (A.D.); (E.V.S.); (F.F.)
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Wang M, Yu M, Kong WJ, Cui M, Gao F. Association between intestinal neoplasms and celiac disease: A review. World J Gastrointest Oncol 2021; 13:1017-1028. [PMID: 34616509 PMCID: PMC8465454 DOI: 10.4251/wjgo.v13.i9.1017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 06/02/2021] [Accepted: 07/30/2021] [Indexed: 02/06/2023] Open
Abstract
Celiac disease (CD) is a chronic immune-mediated intestinal disease with genetic susceptibility. It is characterized by inflammatory damage to the small intestine after ingestion of cereals and products containing gluten protein. In recent years, the global prevalence rate of CD has been approximately 1%, and is gradually increasing. CD patients adhere to a gluten-free diet (GFD) throughout their entire life. However, it is difficult to adhere strictly to a GFD. Untreated CD may be accompanied by gastrointestinal symptoms, such as diarrhea, abdominal pain, and extraintestinal symptoms caused by secondary malnutrition. Many studies have suggested that CD is associated with intestinal tumors such as enteropathy-associated T-cell lymphoma (EATL), small bowel cancer (SBC), and colorectal cancer. In this study, we reviewed related studies published in the literature to provide a reference for the prevention and treatment of intestinal tumors in patients with CD. Compared with the general population, CD patients had a high total risk of SBC and EATL, but not colorectal cancer. The protective effect of GFD on CD-related malignancies is controversial. Further studies are needed to confirm whether GFD treatment can reduce the risk of intestinal neoplasms in CD.
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Affiliation(s)
- Man Wang
- Department of Gastroenterology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830001, Xinjiang Uygur Autonomous Region, China
| | - Ming Yu
- Department of General Practice, Xiangyang Central Hospital, The Affiliated Hospital of Hubei University of Arts and Science, Xiangyang 441021 Hubei Province, China
| | - Wen-Jie Kong
- Department of Gastroenterology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830001, Xinjiang Uygur Autonomous Region, China
| | - Mei Cui
- Department of Pathology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830001, Xinjiang Uygur Autonomous Region, China
| | - Feng Gao
- Department of Gastroenterology, People’s Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830001, Xinjiang Uygur Autonomous Region, China
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Dilmaghani S, Sawas T, Sweetser S. Cystic Lesions of Celiac Disease. Gastroenterology 2021; 161:425-426. [PMID: 33964267 DOI: 10.1053/j.gastro.2021.04.071] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 04/26/2021] [Accepted: 04/29/2021] [Indexed: 12/02/2022]
Affiliation(s)
- Saam Dilmaghani
- Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota.
| | - Tarek Sawas
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Seth Sweetser
- Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota; Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota
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37
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Kojima K, Chambers JK, Ii T, Nibe K, Mizuno T, Uchida K. Histopathological features and immunophenotyping of canine transmural gastrointestinal lymphoma using full-thickness biopsy samples. Vet Pathol 2021; 58:1033-1043. [PMID: 34282671 DOI: 10.1177/03009858211030523] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
To elucidate the histopathological characteristics and immunophenotypes of canine transmural "mass-forming" gastrointestinal lymphomas and plasmacytomas, 83 surgically resected biopsy samples were examined. All lymphomas and plasmacytomas were located in the small or large intestine except for 1 plasmacytoma which was in the stomach. According to the World Health Organization (WHO) classification, B-cell neoplasms (17 cases) included lymphoplasmacytic lymphoma (6/17), plasmacytoma (5/17), follicular lymphoma (3/17), and diffuse large B-cell lymphoma (3/17). Based on nuclear sizes, T-cell neoplasms (66 cases) were broadly divided into large cell lymphoma (LCL; 48/66) and small cell lymphoma (SCL; 18/66). According to the WHO classification, T-cell neoplasms included anaplastic large T-cell lymphoma (ALCL; 10/66), angiotropic T-cell lymphoma (3/66), mixed inflammatory type peripheral T-cell lymphoma (mixed inflammatory type PTCL; 33/66), and PTCL-not otherwise specified (PTCL-NOS; 20/66). Mixed inflammatory type PTCLs were further divided into histiocyte- (27/33) and eosinophil- (6/33) dominant types. Immunohistochemically, lymphoplasmacytic lymphomas were positive for Pax5 (6/6) and IgM (5/6), while plasmacytomas were positive for IgG (5/6) and negative for Pax5. LCLs were immunopositive for granzyme B in 31/48 cases (65%) and CD8 in 9/48 cases (19%), while SCLs were immunopositive for granzyme B in 3/18 cases (17%) and CD8 in 3/18 cases (17%). Furthermore, 8/10 cases (80%) of ALCL and 19/27 cases (70%) of histiocyte-dominant PTCL were immunopositive for granzyme B, whereas 6/20 cases (30%) of PTCL-NOS, 1/6 cases (17%) of eosinophil-dominant PTCL, and no cases of angiotropic T-cell lymphomas were immunopositive for granzyme B. The present study describes the immunophenotypes in different histological types of transmural gastrointestinal lymphomas in the dog.
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38
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Montoro-Huguet MA, Belloc B, Domínguez-Cajal M. Small and Large Intestine (I): Malabsorption of Nutrients. Nutrients 2021; 13:1254. [PMID: 33920345 PMCID: PMC8070135 DOI: 10.3390/nu13041254] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 04/06/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023] Open
Abstract
Numerous disorders can alter the physiological mechanisms that guarantee proper digestion and absorption of nutrients (macro- and micronutrients), leading to a wide variety of symptoms and nutritional consequences. Malabsorption can be caused by many diseases of the small intestine, as well as by diseases of the pancreas, liver, biliary tract, and stomach. This article provides an overview of pathophysiologic mechanisms that lead to symptoms or complications of maldigestion (defined as the defective intraluminal hydrolysis of nutrients) or malabsorption (defined as defective mucosal absorption), as well as its clinical consequences, including both gastrointestinal symptoms and extraintestinal manifestations and/or laboratory abnormalities. The normal uptake of nutrients, vitamins, and minerals by the gastrointestinal tract (GI) requires several steps, each of which can be compromised in disease. This article will first describe the mechanisms that lead to poor assimilation of nutrients, and secondly discuss the symptoms and nutritional consequences of each specific disorder. The clinician must be aware that many malabsorptive disorders are manifested by subtle disorders, even without gastrointestinal symptoms (for example, anemia, osteoporosis, or infertility in celiac disease), so the index of suspicion must be high to recognize the underlying diseases in time.
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Affiliation(s)
- Miguel A. Montoro-Huguet
- Departamento de Medicina, Psiquiatría y Dermatología, Facultad de Ciencias de la Salud y del Deporte, University of Zaragoza, 50009 Zaragoza, Spain
- Unidad de Gastroenterología, Hepatología y Nutrición, Hospital Universitario San Jorge de Huesca, 22004 Huesca, Spain; (B.B.); (M.D.-C.)
- Aragonese Institute of Health Sciences (IACS), 50009 Zaragoza, Spain
| | - Blanca Belloc
- Unidad de Gastroenterología, Hepatología y Nutrición, Hospital Universitario San Jorge de Huesca, 22004 Huesca, Spain; (B.B.); (M.D.-C.)
- Aragonese Institute of Health Sciences (IACS), 50009 Zaragoza, Spain
| | - Manuel Domínguez-Cajal
- Unidad de Gastroenterología, Hepatología y Nutrición, Hospital Universitario San Jorge de Huesca, 22004 Huesca, Spain; (B.B.); (M.D.-C.)
- Aragonese Institute of Health Sciences (IACS), 50009 Zaragoza, Spain
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Smithson G, Siegelman J, Oki T, Maxwell JR, Leffler DA. The Evolving Landscape of Biomarkers in Celiac Disease: Leading the Way to Clinical Development. Front Immunol 2021; 12:665756. [PMID: 33897715 PMCID: PMC8060282 DOI: 10.3389/fimmu.2021.665756] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 03/19/2021] [Indexed: 12/17/2022] Open
Abstract
Celiac disease is a common immune-mediated disease characterized by abnormal T-cell responses to gluten. For many patients, symptoms and intestinal damage can be controlled by a gluten-free diet, but, for some, this approach is not enough, and celiac disease progresses, with serious medical consequences. Multiple therapies are now under development, increasing the need for biomarkers that allow identification of specific patient populations and monitoring of therapeutic activity and durability. The advantage of identifying biomarkers in celiac disease is that the underlying pathways driving disease are well characterized and the histological, cellular, and serological changes with gluten response have been defined in gluten challenge studies. However, there is room for improvement. Biomarkers that measure histological changes require duodenal biopsies and are invasive. Less invasive peripheral blood cell and cytokine biomarkers are transient and dependent upon gluten challenge. Here, we discuss established biomarkers and new approaches for biomarkers that may overcome current limitations.
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Affiliation(s)
- Glennda Smithson
- Research and Development, Takeda Pharmaceuticals Inc. Co., Cambridge, MA, United States
| | - Jenifer Siegelman
- Research and Development, Takeda Pharmaceuticals Inc. Co., Cambridge, MA, United States
| | - Toshihiko Oki
- Research and Development, Takeda Pharmaceuticals Inc. Co., Cambridge, MA, United States
| | - Joseph R Maxwell
- Research and Development, Takeda Pharmaceuticals Inc. Co., Cambridge, MA, United States
| | - Daniel A Leffler
- Research and Development, Takeda Pharmaceuticals Inc. Co., Cambridge, MA, United States.,Celiac Disease Research Program, Harvard Medical School, Boston, MA, United States
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Susan SSH, Ng SB, Wang S, Tan SY. Diagnostic approach to T- and NK-cell lymphoproliferative disorders in the gastrointestinal tract. Semin Diagn Pathol 2021; 38:21-30. [PMID: 34016481 DOI: 10.1053/j.semdp.2021.03.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 03/11/2021] [Accepted: 03/22/2021] [Indexed: 12/13/2022]
Abstract
Most gastrointestinal NK and T cell lymphomas are aggressive in behavior, although in recent years a subset of indolent lymphoproliferative disorders have been described, which must be distinguished from their more malignant mimics. Intestinal T-cell lymphomas may arise from intra-epithelial lymphocytes and display epitheliotropism, such as enteropathy-associated T-cell lymphoma and monomorphic epitheliotropic intestinal T-cell lymphoma. They are both aggressive in behavior but differ in their clinic-pathological features. On the other hand, intra-epithelial lymphocytes are not prominent in intestinal T-cell lymphoma, NOS, which is a diagnosis of exclusion and probably represents a heterogeneous group of entities. Indolent lymphoproliferative disorders of NK- and T-cells of both CD8 and CD4 subsets share a chronic, recurring clinical course but display differences from each other. CD8+ T-cell lymphoproliferative disorder of GI tract has a low proliferative fraction and does not progress nor undergo large cell transformation. Whilst NK-cell enteropathy runs an indolent clinical course, it may display a high proliferation fraction. On the other hand, CD4+ indolent T-cell lymphoproliferative disorder displays variable proliferation rates and may progress or transform after a number of years. In Asia and South America, it is not uncommon to see involvement of the gastrointestinal tract by EBV-associated extranodal NK/T cell lymphoma, nasal type, which must be distinguished from NK cell enteropathy and EBV-associated mucocutaneous ulcers.
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Affiliation(s)
- Swee-Shan Hue Susan
- Department of Pathology, National University Hospital Health Service, Singapore, Singapore; Department of Pathology, National University of Singapore Yong Loo Lin School of Medicine, Singapore, Singapore
| | - Siok-Bian Ng
- Department of Pathology, National University of Singapore Yong Loo Lin School of Medicine, Singapore, Singapore
| | - Shi Wang
- Department of Pathology, National University Hospital Health Service, Singapore, Singapore
| | - Soo-Yong Tan
- Department of Pathology, National University of Singapore Yong Loo Lin School of Medicine, Singapore, Singapore.
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Zammit SC, Elli L, Scaramella L, Sanders DS, Tontini GE, Sidhu R. Small bowel capsule endoscopy in refractory celiac disease: a luxury or a necessity? Ann Gastroenterol 2021; 34:188-195. [PMID: 33654358 PMCID: PMC7903573 DOI: 10.20524/aog.2021.0586] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Accepted: 10/27/2020] [Indexed: 12/11/2022] Open
Abstract
Background Small bowel capsule endoscopy (SBCE) has an established role in the management of refractory celiac disease (RCD) for the detection of complications. The aim of this study was to define the role of SBCE in the management of patients with RCD. Method Patients with histologically confirmed RCD who underwent successive SBCEs were recruited retrospectively from 2 tertiary centers. Results Sixty patients with RCD were included. The percentage extent of the affected small bowel (SB) mucosa improved on repeating a second SBCE in 26 patients (49.1%) (median 27.6% vs. 18.1%, P=0.007). Patients with RCD type II had more extensive disease than those with RCD type I on first (41.4% vs. 19.2%, P=0.004) and second (29.8% vs. 12.0%, P=0.016) SBCE. Patients with RCD type I tended to show a greater improvement in percentage of abnormal SB involved on repeat SBCE compared to those with RCD type II (P=0.049). Nine patients (15%) had RCD-related complications. Five patients developed ulcerative jejunoileitis, 3 patients developed enteropathy-associated T-cell lymphoma, and 1 patient developed cutaneous T-cell lymphoma. Conclusions SBCE can be a useful tool for monitoring the effects of treatment, primarily following its initiation. Patients with RCD type II have more extensive SB disease, equating to a more aggressive disease pattern.
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Affiliation(s)
- Stefania Chetcuti Zammit
- Gastroenterology Department, Sheffield Teaching Hospitals, United Kingdom (Stefania Chetcuti Zammit, David S. Sanders, Reena Sidhu)
| | - Luca Elli
- Centre for Prevention and Diagnosis of Coeliac Disease, Gastroenterology and Endoscopy Unit, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Italy (Luca Elli, Lucia Scaramella, Gian Eugenio Tontini)
| | - Lucia Scaramella
- Centre for Prevention and Diagnosis of Coeliac Disease, Gastroenterology and Endoscopy Unit, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Italy (Luca Elli, Lucia Scaramella, Gian Eugenio Tontini)
| | - David S Sanders
- Gastroenterology Department, Sheffield Teaching Hospitals, United Kingdom (Stefania Chetcuti Zammit, David S. Sanders, Reena Sidhu)
| | - Gian Eugenio Tontini
- Centre for Prevention and Diagnosis of Coeliac Disease, Gastroenterology and Endoscopy Unit, Department of Pathophysiology and Transplantation, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Italy (Luca Elli, Lucia Scaramella, Gian Eugenio Tontini)
| | - Reena Sidhu
- Gastroenterology Department, Sheffield Teaching Hospitals, United Kingdom (Stefania Chetcuti Zammit, David S. Sanders, Reena Sidhu)
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van Wanrooij RLJ, Bontkes HJ, Neefjes-Borst EA, Mulder CJ, Bouma G. Immune-mediated enteropathies: From bench to bedside. J Autoimmun 2021; 118:102609. [PMID: 33607573 DOI: 10.1016/j.jaut.2021.102609] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 01/22/2021] [Accepted: 01/23/2021] [Indexed: 12/13/2022]
Abstract
Immune-mediated enteropathies are caused by excessive reactions of the intestinal immune system towards non-pathogenic molecules. Enteropathy leads to malabsorption-related symptoms and include (severe) chronic diarrhea, weight loss and vitamin deficiencies. Parenteral feeding and immunosuppressive therapy are needed in severe cases. Celiac disease has long been recognized as the most common immune-mediated enteropathy in adults, but the spectrum of immune-mediated enteropathies has been expanding. Histological and clinical features are sometimes shared among these enteropathies, and therefore it may be challenging to differentiate between them. Here, we provide an overview of immune-mediated enteropathies focused on clinical presentation, establishing diagnosis, immunopathogenesis, and treatment options.
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Affiliation(s)
- Roy L J van Wanrooij
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Gastroenterology and Hepatology, AGEM Research Institute, Amsterdam, the Netherlands.
| | - Hetty J Bontkes
- Amsterdam UMC, Laboratory Medical Immunology, Department of Clinical Chemistry, AI & I Institute, AGEM Research Institute, Amsterdam, the Netherlands
| | | | - Chris J Mulder
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Gastroenterology and Hepatology, AGEM Research Institute, Amsterdam, the Netherlands
| | - Gerd Bouma
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Gastroenterology and Hepatology, AGEM Research Institute, Amsterdam, the Netherlands
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43
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Cellular and molecular bases of refractory celiac disease. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2021; 358:207-240. [PMID: 33707055 DOI: 10.1016/bs.ircmb.2020.12.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Refractory celiac disease (RCD) encompasses biologically heterogeneous disorders that develop in a small proportion (0.3%) of individuals with celiac disease that are associated with high morbidity. Two broad categories are currently recognized, type I (RCD I) and type II (RCD II), based on immunophenotypic and molecular features of the intraepithelial lymphocytes (IELs). RCD I is characterized by a polyclonal expansion of IELs displaying a normal immunophenotype, while RCD II represents a clonal proliferation of immunophenotypically "aberrant" IELs, and is considered a low-grade lymphoproliferative disorder. The pathogenesis of RCD I has not been clarified, but limited studies suggest multifactorial etiology. On the other hand, recent immunologic, molecular and immunophenotypic analyses have proposed lineage-negative innate IELs to be the cell of origin of a proportion of RCD II cases. Furthermore, sequencing studies have identified frequent, recurrent, activating mutations in members of the JAK-STAT pathway in RCD II. This finding, in conjunction with prior in vitro experimental observations, suggests roles of deregulated cytokine signaling in disease pathogenesis. In this review, we describe current understanding of environmental, immune and genetic factors associated with the development of RCD and briefly discuss diagnostic and therapeutic considerations.
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44
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D'Avino P, Serena G, Kenyon V, Fasano A. An updated overview on celiac disease: from immuno-pathogenesis and immuno-genetics to therapeutic implications. Expert Rev Clin Immunol 2021; 17:269-284. [PMID: 33472447 DOI: 10.1080/1744666x.2021.1880320] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Celiac disease (CD) is an autoimmune enteropathy triggered by ingestion of gluten. While presenting many similarities with other autoimmune diseases, celiac disease is unique in that the external trigger, gluten, and the genetic background necessary for disease development (HLA DQ2/DQ8) are well described. The prevalence of celiac disease is dramatically increasing over the years and new epidemiologic data show changes regarding age of onset and symptoms. A better understanding of CD-pathogenesis is fundamental to highlight the reasons of this rise of celiac diagnoses. AREAS COVERED In this review we describe CD-pathogenesis by dissecting all the components necessary to lose tolerance to gluten (ingestion of gluten, genetic predisposition, loss of barrier function and immune response). Additionally, we also highlight the role that microbiome plays in celiac disease as well as new proposed therapies and experimental tools. EXPERT OPINION Prevalence of autoimmune diseases is increasing around the world. As a result, modern society is strongly impacted by a social and economic burden. Given the unique characteristics of celiac disease, a better understanding of its pathogenesis and the factors that contribute to it may shed light on other autoimmune diseases for which external trigger and genetic background are not known.
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Affiliation(s)
- Paolo D'Avino
- Division of Pediatric Gastroenterology and Nutrition, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Mucosal Immunology and Biology Research Center, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Celiac Research Program, Harvard Medical School, Boston, MA, USA.,Vita-Salute San Raffaele University, Milan, Italy
| | - Gloria Serena
- Division of Pediatric Gastroenterology and Nutrition, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Mucosal Immunology and Biology Research Center, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Celiac Research Program, Harvard Medical School, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
| | - Victoria Kenyon
- Division of Pediatric Gastroenterology and Nutrition, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Mucosal Immunology and Biology Research Center, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Celiac Research Program, Harvard Medical School, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
| | - Alessio Fasano
- Division of Pediatric Gastroenterology and Nutrition, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Mucosal Immunology and Biology Research Center, Mass General Hospital for Children, Harvard Medical School, Boston, MA, USA.,Celiac Research Program, Harvard Medical School, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA.,European Biomedical Research Institute of Salerno (EBRIS), Salerno, Italy
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45
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Tarar ZI, Zafar MU, Farooq U, Basar O, Tahan V, Daglilar E. The Progression of Celiac Disease, Diagnostic Modalities, and Treatment Options. J Investig Med High Impact Case Rep 2021; 9:23247096211053702. [PMID: 34693776 PMCID: PMC8767653 DOI: 10.1177/23247096211053702] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 09/20/2021] [Accepted: 09/28/2021] [Indexed: 01/15/2023] Open
Abstract
Celiac disease (CD) is an autoimmune disorder that affects genetically predisposed individuals who are sensitive to gluten and related proteins. It affects children and adults with increasing prevalence in the older age groups. Both adaptive and innate immune responses play role in CD pathogenesis which results in damage of lamina propria and deposition of intraepithelial lymphocytes. There are other proposed mechanisms of CD pathogenesis like gastrointestinal infections, intestinal microbiota, and early introduction of gluten. The diagnosis of CD is based on clinical symptoms and serological testing, though a majority of cases are asymptomatic, and small intestinal biopsies are required to confirm the diagnosis. Celiac disease is generally associated with other autoimmune diseases, and it is advisable to test these patients for diseases like type 1 diabetes mellitus, Addison's disease, thyroid diseases, inflammatory bowel disease, and autoimmune hepatitis. The patient with a new diagnosis of CD requires close follow-up after starting treatment to see symptom improvement and check dietary compliance. A newly diagnosed patient is advised to follow with a dietitian to better understand the dietary restrictions as about 20% of patients stay symptomatic even after starting treatment due to noncompliance or poor understanding of diet restrictions. The most effective treatment for CD is a gluten-free diet, but work on non-dietary therapy is in process and few medications are in the clinical trial phase.
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Affiliation(s)
| | | | - Umer Farooq
- Loyola Medicine/MacNeal Hospital, Berwyn, IL, USA
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Chibbar R, Nostedt J, Mihalicz D, Deschenes J, McLean R, Dieleman LA. Refractory Celiac Disease Type II: A Case Report and Literature Review. Front Med (Lausanne) 2020; 7:564875. [PMID: 33344468 PMCID: PMC7746862 DOI: 10.3389/fmed.2020.564875] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 11/03/2020] [Indexed: 12/11/2022] Open
Abstract
We present an unusual case of 68-year-old male, who presented with acute abdomen, ulcerative jejunitis with perforation, and 2 months later with perforation of the sigmoid colon. We will also discuss difficulties in the delay in diagnosis of refractory celiac disease (RCD), specifically the atypical presentation, multiple surgeries, the consecutive failure of distinct therapeutic options, and multiple complications that occurred within the 3 months since first presentation.
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Affiliation(s)
- Richa Chibbar
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, AB, Canada.,Division of Gastro, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States
| | - Jordan Nostedt
- Division of General Surgery, Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Dana Mihalicz
- Division of General Surgery, Department of Surgery, University of Alberta, Edmonton, AB, Canada
| | - Jean Deschenes
- Department of Laboratory Medicine and Pathology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada
| | - Ross McLean
- Department of Laboratory Medicine, Royal Alexandra Hospital, University of Alberta, Edmonton, AB, Canada
| | - Levinus A Dieleman
- Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
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Rej A, Aziz I, Sanders DS. Coeliac disease and noncoeliac wheat or gluten sensitivity. J Intern Med 2020; 288:537-549. [PMID: 32573000 DOI: 10.1111/joim.13120] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 04/15/2020] [Accepted: 04/21/2020] [Indexed: 12/15/2022]
Abstract
Coeliac disease (CD) and noncoeliac wheat or gluten sensitivity (NCWS/NCGS) are common gluten-related disorders. Both conditions can present with gastrointestinal and extraintestinal manifestations, which can be a challenge for physicians to discern between. Whilst coeliac serology and histological assessment are required for the diagnosis of CD, there are no clear biomarkers for the diagnosis of NCGS. The management of both conditions is with a gluten-free diet (GFD), although the duration, as well as strictness of adherence to a GFD in NCGS, is unclear. Adherence to a GFD in CD can also be challenging, with recent developments of noninvasive assessments, although histological assessment via duodenal biopsies remains the gold standard. The management of refractory coeliac disease remains particularly challenging, often requiring specialist input. Whilst wheat is noted to be a trigger for symptom generation in NCGS, it is unclear which components of wheat are responsible for symptom generation in this group, with further research required to elucidate the pathophysiology.
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Affiliation(s)
- A Rej
- From the, Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Sheffield Teaching Hospital NHS Foundation Trust, Sheffield, UK
| | - I Aziz
- From the, Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Sheffield Teaching Hospital NHS Foundation Trust, Sheffield, UK.,Department of Infection, Immunity and Cardiovascular Disease, Academic Unit of Gastroenterology, University of Sheffield, Sheffield, UK
| | - D S Sanders
- From the, Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Sheffield Teaching Hospital NHS Foundation Trust, Sheffield, UK.,Department of Infection, Immunity and Cardiovascular Disease, Academic Unit of Gastroenterology, University of Sheffield, Sheffield, UK
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What is the role of small bowel capsule endoscopy in established coeliac disease? Clin Res Hepatol Gastroenterol 2020; 44:753-761. [PMID: 31928969 DOI: 10.1016/j.clinre.2019.11.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 11/22/2019] [Accepted: 11/25/2019] [Indexed: 02/04/2023]
Abstract
INTRODUCTION Patients with established coeliac disease (CD) can present with signs and symptoms requiring small bowel capsule endoscopy (SBCE) to assess for persistent disease beyond the duodenum and to rule out complications. There is paucity of data on extent of disease on SBCE in relation to histology, clinical and serological parameters. The aim of this study was to assess the relationship between symptoms, CD serology and Marsh classification of disease and extent of disease on SBCE in patients with established CD. METHODS Hundred patients with established CD and 200 controls underwent a SBCE. SBCEs were reviewed by expert reviewers. Extent of disease on SBCE, CD findings and small bowel transit were recorded. RESULTS Considering duodenal histology (D2; Marsh 3a or above) as the gold standard for diagnosing CD activity, the sensitivity of SBCE to delineate active disease was 87.2%. The specificity was 89.0%. Age at SBCE (P=0.006), albumin (P=0.004) and haemoglobin (P=0.0001), Marsh score of histology from the duodenal bulb (D1) (P=0.0001) and the second part of the duodenum (P=0.0001), refractory CD (P=0.007) on histology correlated with extent of affected small bowel (SB) mucosa on univariate analysis. On multiple regression analysis, albumin (P=0.036) and Marsh score of histology (D1) (P=0.019), vitamin B12 (P=0.001) and folate levels (P=0.008) were statistically significant. Extent of affected SB mucosa (11.0% vs 1.35%) was greater in patients with complications including those with refractory CD (P=0.008). CONCLUSIONS This is the first study showing correlation between extent of disease and severity of duodenal histology, markers of malabsorption such as folate levels and vitamin B12 and complications of CD.
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Serena G, D'Avino P, Fasano A. Celiac Disease and Non-celiac Wheat Sensitivity: State of Art of Non-dietary Therapies. Front Nutr 2020; 7:152. [PMID: 33015123 PMCID: PMC7506149 DOI: 10.3389/fnut.2020.00152] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 07/28/2020] [Indexed: 12/12/2022] Open
Abstract
Gluten related disorders (GRD), which include celiac disease, non-celiac wheat sensitivity and wheat allergy are heterogeneous conditions triggered by ingestion of gluten-containing grains. Together, their prevalence is estimated to be ~5% in the general population, however, in the last years the number of diagnoses has been rapidly increasing. To this day, the gold standard treatment for these disorders is the complete removal of gluten-containing grains from the diet. Although this therapy results effective in the majority of patients, up to 30% of individuals affected by GRD continue to present persistent symptoms. In addition, gluten-free diet has been shown to have poor nutritional quality and to cause a socio-economic burden in patients' quality of life. In order to respond to these issues, the scientific community has been focusing on finding additional and adjuvant non-dietary therapies. In this review, we focus on two main gluten related disorders, celiac disease and non-celiac wheat sensitivity. We delineate the actual knowledge about potential treatments and their relative efficacy in pre-clinical and clinical trials.
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Affiliation(s)
- Gloria Serena
- Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, United States
| | - Paolo D'Avino
- Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, United States.,Vita-Salute San Raffaele University, Milan, Italy
| | - Alessio Fasano
- Division of Pediatric Gastroenterology and Nutrition, Center for Celiac Research, Mucosal Immunology and Biology Research Center, Massachusetts General Hospital, Boston, MA, United States.,European Biomedical Research Institute of Salerno (EBRIS), Salerno, Italy
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Abstract
PURPOSE OF REVIEW The aim of this review is to provide insight into the diagnosis and management of patients with refractory coeliac disease (RCD) and highlight recent advances in this field. RECENT FINDINGS The diagnosis of RCD can be more accurately confirmed with flow cytometry in addition to immunohistochemistry. Dietary input and excretion of gluten immunogenic peptides can help rule out gluten contamination, and therefore, substantiate a diagnosis of RCD type I. Small bowel capsule endoscopy (SBCE) is important at diagnosis and follow-up in addition to duodenal histology. Apart from ruling out complications, it can give information on extent of disease in the small bowel, and therefore, help assess response to therapy. Those patients with a poor response can have earlier intensification of therapy, which may result in an improved outcome. RCD also occurs in patients with serology negative coeliac disease but with an increased mortality compared with patients with serology-positive coeliac disease. SUMMARY Patients with RCD can present with persistent symptoms of malnutrition but can also be completely asymptomatic. Serology is not a reliable marker to detect refractory disease. Immunostaining and flow cytometry are necessary for a diagnosis of RCD. Small bowel endoscopy enables disease extent to be assessed and allows for small bowel biopsies to be taken in case of suspicious lesions. Small bowel radiology can be complementary to small bowel endoscopy.
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