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Schirru E, Rossino R, Jores RD, Corpino M, Muntoni S, Cucca F, Congia M. Clinical settings in which human leukocyte antigen typing is still useful in the diagnosis of celiac disease. World J Gastroenterol 2025; 31:104397. [DOI: 10.3748/wjg.v31.i14.104397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 02/01/2025] [Accepted: 03/21/2025] [Indexed: 04/11/2025] Open
Abstract
Celiac disease (CD) is a systemic autoimmune disorder triggered by gluten ingestion ingenetically predisposed individuals. It is characterized by intestinal histological damage and the production of specific autoantibodies. The latest European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) 2020 guidelines have excluded human leukocyte antigen (HLA) genotyping from the no-biopsy diagnostic approach due to its weak positive predictive value, limited availability, and high cost in some countries. However, HLA genetic testing remains valuable in certain clinical contexts. This study provided practical indications for when to request and how to interpret HLA genotyping, emphasizing its continued relevance for CD diagnosis in specific cases. We also proposed a strategy for monitoring the risk of developing type 1 diabetes (T1D) in patients with CD, based on the risk stratification carried by different HLA genotypes. A retrospective analysis of 746 patients with CD and 627 controls was conducted at our hospital starting in 2012, when HLA genotyping became mandatory for the diagnosis of CD. We identified key clinical scenarios where HLA testing remains useful. Several high risk HLA-DQ genotypes strongly associated with CD were highlighted, including HLA-DQ2.5/HLA-DQ2.2 and HLA-DQ2.5/HLA-DQ2.5. Notably, while the HLA-DQ2.5/HLA-DQ2.2 genotype is linked to CD, it appears to confer protection against T1D. To support clinical practice, we presented a table clarifying commonly used HLA terminology, and another summarized the main clinical situations in which HLA genotyping should still be considered. These findings underscore the dual role of HLA testing: Not only can it help rule out CD in selected cases, but it also identifies patients with CD at risk for T1D, guiding personalized monitoring strategies.
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Affiliation(s)
- Enrico Schirru
- University Service Center for Animal Facility (CeSASt), University of Cagliari, Monserrato 09042, Sardinia, Italy
| | - Rossano Rossino
- Department of Medical Science and Public Health, University of Cagliari, Monserrato 09042, Sardegna, Italy
- Department of Pediatrics, Clinic of Pediatric and Rare Diseases, Microcitemico Pediatric Hospital, A.Cao, ASL8, Cagliari 09121, Sardegna, Italy
| | - Rita D Jores
- Department Outpatient Clinic, ASL8 Outpatient Clinic, Quartu Sant’Elena 09045, Sardegna, Italy
| | - Mara Corpino
- Department of Pediatrics, Clinic of Pediatric and Rare Diseases, Microcitemico Pediatric Hospital, A.Cao, ASL8, Cagliari 09121, Sardegna, Italy
| | - Sandro Muntoni
- Department of Biomedical Science, University of Cagliari, Monserrato 09042, Sardegna, Italy
| | - Francesco Cucca
- Department of Biomedical Science, University of Sassari, Sassari 07100, Sardegna, Italy
| | - Mauro Congia
- Department of Pediatrics, Clinic of Pediatric and Rare Diseases, Microcitemico Pediatric Hospital, A.Cao, ASL8, Cagliari 09121, Sardegna, Italy
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2
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Rao MS, Gaur A, Bharadwaj HR, Imran S, Tan JK, Abbas S, Fuad M, Abuhashem S, Shah MH, Dalal P, Al Khatib AN, Abbasher Hussien Mohamed Ahmed K. The current state of pediatric gastroenterology in under-resourced nations. Ann Med Surg (Lond) 2025; 87:2218-2228. [PMID: 40212147 PMCID: PMC11981426 DOI: 10.1097/ms9.0000000000003141] [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: 11/16/2024] [Accepted: 02/25/2025] [Indexed: 04/13/2025] Open
Abstract
Background Pediatric gastroenterology (GI) care in low- and middle-income countries (LMICs) faces substantial challenges due to limited healthcare infrastructure, inadequate resources, and a shortage of specialized healthcare professionals. These challenges lead to delayed diagnoses and treatment, exacerbating the morbidity and mortality associated with pediatric GI diseases, which include both infectious conditions like diarrhea and chronic conditions such as inflammatory bowel disease (IBD) and liver diseases. Aim The aim of this review is to examine the current state of pediatric GI care in LMICs, identify the key challenges these regions face, and propose strategies to improve healthcare outcomes for children affected by GI disorders. Methods This review synthesizes existing literature from a range of LMICs, analyzing factors such as the economic burden of healthcare, barriers to access, the availability of diagnostic and therapeutic services, and the state of pediatric hepatology and endoscopy. Studies included in the review were sourced from countries in sub-Saharan Africa, South Asia, and other LMIC regions, focusing on pediatric GI disorders and healthcare delivery. Results Economic burden: Families in LMICs face significant economic barriers in accessing pediatric GI care, with treatment costs often exceeding household income, especially in private healthcare settings. Healthcare access: Limited access to healthcare facilities, especially in rural areas, coupled with the shortage of trained pediatric gastroenterologists and necessary medical equipment, leads to delayed diagnoses and inadequate care for conditions like Helicobacter pylori infections and chronic liver diseases. Sanitation and infectious diseases: Poor sanitation and lack of access to clean water contribute to the high prevalence of diarrheal diseases, which can be reduced through better hygiene practices and improved infrastructure. Training gaps: The shortage of trained healthcare workers, particularly pediatric specialists, hinders effective care delivery, with healthcare workers often overburdened due to workforce migration and low salaries. Hepatology and endoscopy: Pediatric hepatology, especially in the context of viral hepatitis, and the availability of pediatric GI endoscopy are severely limited in LMICs, further complicating the management of liver diseases and GI conditions in children. Conclusion Improving pediatric GI care in LMICs requires addressing systemic challenges such as inadequate healthcare infrastructure, limited financial resources, and a shortage of trained professionals. Prevention strategies like vaccination, sanitation improvements, and public health education campaigns are crucial for reducing the prevalence of pediatric GI diseases. In addition, enhancing access to specialized training, healthcare services, and diagnostic tools will improve outcomes for children in resource-limited settings. Continued international collaboration and investment in local healthcare systems are essential for creating sustainable solutions and bridging the gap in pediatric GI care.
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Affiliation(s)
- Medha Sridhar Rao
- School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, United Kingdom
| | - Aditya Gaur
- Yeovil District Hospital, Somerset NHS Foundation Trust, Higher Kingston, Yeovil, United Kingdom
| | | | - Shahzeb Imran
- School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, United Kingdom
| | - Joecelyn Kirani Tan
- Faculty of Biology Medicine and Health, The University of Manchester, Manchester, United Kingdom
| | - Saad Abbas
- Faculty of Biology Medicine and Health, The University of Manchester, Manchester, United Kingdom
| | - Muhtasim Fuad
- Faculty of Biology Medicine and Health, The University of Manchester, Manchester, United Kingdom
| | | | - Muhammad Hamza Shah
- School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, Belfast, United Kingdom
| | - Priyal Dalal
- School of Medicine and Dentistry, University of Central Lancashire, Preston, United Kingdom
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Kalampokis I, Wong CS, Ma J, Smith LM, Masten BJ, Chabot-Richards D, Pisetsky DS. The Limitation of HLA Diversity as a Risk Factor for Pediatric-Onset Autoimmune Rheumatic Disease. J Clin Med 2025; 14:916. [PMID: 39941587 PMCID: PMC11818087 DOI: 10.3390/jcm14030916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 01/22/2025] [Accepted: 01/27/2025] [Indexed: 02/16/2025] Open
Abstract
Background: HLA homozygosity of specific alleles at a single locus is associated with increased risk for autoimmunity and/or more severe clinical phenotypes. However, the contribution of the overall limitation of HLA diversity across multiple loci to autoimmunity risk remains to be determined. Methods: We conducted a proof-of-concept case-control study of 413 individuals (279 cases with pediatric-onset autoimmune rheumatic diseases, 134 matched controls) examining the "Limitation of HLA Diversity" (LoHLAD) across multiple loci as an allele-independent risk factor for autoimmunity. We examined the association of LoHLAD with pediatric-onset autoimmune rheumatic diseases at five HLA loci (A, B, DQB1, DRB1, DRB3/4/5). LoHLAD was defined as (1) homozygosity at any of the examined loci, and/or (2) the presence of a single allele or the complete lack of an allele at the HLA-DRB3/4/5 locus. Results: The frequency of LoHLAD at any locus was significantly higher in cases compared to controls (65.95% vs. 30.60%, OR 4.39 [2.82-6.84], p < 0.0001). Higher frequencies of LoHLAD in cases compared to controls were observed at both class I (19.35% vs. 10.45%, OR 2.06 [1.10-3.86], p = 0.031) and class II (54.48% vs. 20.15%, OR 4.74 [2.92-7.69], p < 0.0001) loci. Specifically, significant differences between cases and controls were observed at the B (OR 8.63 [1.14-65.55], p = 0.016), DQB1 (OR 3.34 [1.27-8.78], p = 0.016), and DRB3/4/5 (OR 4.64 [2.77-7.75], p < 0.0001) loci. Multiple logistic regression models confirmed the ability of LoHLAD to positively predict autoimmunity. Conclusions: LoHLAD is a significant allele-independent risk factor for pediatric-onset autoimmune rheumatic disease.
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Affiliation(s)
- Ioannis Kalampokis
- University of Nebraska Medical Center, Omaha, NE 68198, USA; (J.M.); (L.M.S.)
- University of New Mexico, Albuquerque, NM 87106, USA; (C.S.W.); (B.J.M.); (D.C.-R.)
| | - Craig S. Wong
- University of New Mexico, Albuquerque, NM 87106, USA; (C.S.W.); (B.J.M.); (D.C.-R.)
| | - Jihyun Ma
- University of Nebraska Medical Center, Omaha, NE 68198, USA; (J.M.); (L.M.S.)
| | - Lynette M. Smith
- University of Nebraska Medical Center, Omaha, NE 68198, USA; (J.M.); (L.M.S.)
| | - Barbara J. Masten
- University of New Mexico, Albuquerque, NM 87106, USA; (C.S.W.); (B.J.M.); (D.C.-R.)
- Tricore Reference Laboratories, Albuquerque, NM 87102, USA
| | | | - David S. Pisetsky
- Duke University Medical Center, Durham, NC 27710, USA;
- Durham Veterans Administration Medical Center, Durham, NC 27705, USA
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Sleiman Y, Hadeer RA, Nahle H, Jurdi N, Abs L, Allouch M. Monomorphic epitheliotropic intestinal T-cell lymphoma with obstructive pattern: A rare case of small bowel lymphoma. Int J Surg Case Rep 2024; 124:110327. [PMID: 39317016 PMCID: PMC11456898 DOI: 10.1016/j.ijscr.2024.110327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 09/14/2024] [Accepted: 09/19/2024] [Indexed: 09/26/2024] Open
Abstract
INTRODUCTION Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a very rare and aggressive type of gastrointestinal non-Hodgkin's lymphoma (NHL) with a poor prognosis. CASE PRESENTATION A 59-year-old man presented with a three-days history of diffuse abdominal pain associated with distention and obstipation. Abdominal computed tomography (CT) scan showed small bowel obstruction (SBO) due to moderately thickened jejunal loop. The SBO was treated conservatively, and after a workup, the patient underwent a laparoscopic oncological small bowel resection. The final pathology sampling revealed transmural sheets of atypical lymphoid cells that were identified as MEITL, which is a very rare type of small bowel lymphoma, by the histo-immunopathoplogy studies. He responded to three courses of chemotherapy, and the patient went into remission at the end of the third chemotherapy session. Five months post remission patient was rushed to the emergency with acute mesenteric ischemia and died shortly after. DISCUSSION An extremely uncommon and aggressive type of T-cell lymphoma is called monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL). Gastrointestinal involvement was detected in the majority of the patients. 40 % of the published cases had stage IV disease. Based on morphological classification, the tumors were classified into two groups: Typical (58 %) and atypical (i.e., non-monomorphic or exhibiting necrosis, angiotropism, or starry-sky pattern) (42 %). Mostly caused by driver gene changes that de-regulate JAK/STAT signaling and histone methylation, it is resistant to standard therapy and includes morphologic and genetic variants that carry a very high clinical risk. CONCLUSION We report a case of MEITL detected after jejunal resection in a patient presented initially with SBO. Our patient has a recurrence-free survival of 5 months after chemotherapy, but passed away 5 months after remission due to acute mesenteric ischemia.
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Affiliation(s)
- Youssef Sleiman
- Nini Hospital, Department of General and Visceral Surgery, Tripoli, Lebanon
| | - Ribal Aby Hadeer
- University of Balamand, Department of General Surgery, Beirut, Lebanon.
| | - Hassan Nahle
- University of Balamand, Department of General Surgery, Beirut, Lebanon
| | - Nawaf Jurdi
- Nini Hospital, Department of Pathology, Tripoli, Lebanon
| | - Leila Abs
- Nini Hospital, Department of Radiology, Tripoli, Lebanon
| | - Mustafa Allouch
- Nini Hospital, Department of General and Visceral Surgery, Tripoli, Lebanon; University of Balamand, Department of General Surgery, Beirut, Lebanon
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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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Marchi E, Craig JW, Kalac M. Current and upcoming treatment approaches to uncommon subtypes of PTCL (EATL, MEITL, SPTCL, and HSTCL). Blood 2024; 144:1898-1909. [PMID: 38657272 DOI: 10.1182/blood.2023021788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 04/19/2024] [Accepted: 04/19/2024] [Indexed: 04/26/2024] Open
Abstract
ABSTRACT Rare subtypes of peripheral T-cell lymphoma (PTCL) including enteropathy-associated T-cell lymphoma (EATL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), subcutaneous panniculitis-like T-cell lymphoma (SPTCL), and hepatosplenic T-cell lymphoma (HSTCL) are underrepresented in most registries and clinical studies. Most of the literature is obtained from small case series, single-institution retrospective studies, and subgroup analyses of the largest studies with few recent and ongoing exceptions. Although the pathogenesis and biology of these entities have yet to be fully elucidated, global efforts by the scientific community have started to shed some light on the most frequently deregulated pathways. In this review, we highlight the most pertinent clinical and pathologic features of rare subtypes of PTCL including EATL/MEITL, SPTCL, and HSTCL. We also summarize the results of recent developments identifying potential targets for novel therapeutic strategies based on molecular studies. Finally, we highlight the underrepresentation of these rare subtypes in most clinical trials, making evidence-based therapeutic decisions extremely challenging.
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Affiliation(s)
- Enrica Marchi
- Division of Hematology and Oncology, Department of Medicine, University of Virginia Cancer Center, Charlottesville, VA
| | - Jeffrey W Craig
- Department of Pathology, University of Virginia Cancer Center, Charlottesville, VA
| | - Matko Kalac
- Department of Hematology and Oncology, University of California, Irvine, CA
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7
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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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8
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Kurppa K, Mulder CJ, Stordal K, Kaukinen K. Celiac Disease Affects 1% of Global Population: Who Will Manage All These Patients? Gastroenterology 2024; 167:148-158. [PMID: 38290622 DOI: 10.1053/j.gastro.2023.12.026] [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: 11/03/2023] [Revised: 12/19/2023] [Accepted: 12/19/2023] [Indexed: 02/01/2024]
Abstract
Celiac disease is a common gastrointestinal condition with an estimated global prevalence of up to 1%. Adequate long-term surveillance of patients is imperative to ensure strict adherence to treatment with a gluten-free diet and the ensuing clinical and histologic recovery. Traditionally, this has been accomplished by means of regular on-site attendance at specialist health care facilities, accompanied for most patients by follow-up endoscopic and laboratory tests. However, the rapidly increasing prevalence of celiac disease and the limited health care resources challenge the current centralized and nonindividualized follow-up strategies. The improved noninvasive surveillance tools and online health care services are further changing the landscape of celiac disease management. There is a clear need for more personalized and on-demand follow-up based on early treatment response and patient-related factors associated with long-term prognosis. Additional scientific evidence on the optimal implementation of follow-up for pediatric and adulthood celiac disease is nevertheless called for.
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Affiliation(s)
- Kalle Kurppa
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; Tampere Center for Child, Adolescent, and Maternal Health Research, Tampere University, Tampere, Finland; Department of Pediatrics, Tampere University Hospital, Tampere, Finland; University Consortium of Seinäjoki, Seinäjoki, Finland.
| | - Chris J Mulder
- Department of Gastroenterology, Amsterdam University Medical Center, Amsterdam, The Netherlands; Location Vrije Universiteit, Amsterdam, The Netherlands
| | - Ketil Stordal
- Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway; Department of Pediatric Research, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Katri Kaukinen
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; Department of Internal Medicine, Tampere University Hospital, Tampere, Finland
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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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10
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Iorgulescu JB, Medeiros LJ, Patel KP. Predictive and prognostic molecular biomarkers in lymphomas. Pathology 2024; 56:239-258. [PMID: 38216400 DOI: 10.1016/j.pathol.2023.12.001] [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] [Received: 12/03/2023] [Revised: 12/05/2023] [Accepted: 12/06/2023] [Indexed: 01/14/2024]
Abstract
Recent advances in molecular diagnostics have markedly expanded our understanding of the genetic underpinnings of lymphomas and catalysed a transformation in not just how we classify lymphomas, but also how we treat, target, and monitor affected patients. Reflecting these advances, the World Health Organization Classification, International Consensus Classification, and National Comprehensive Cancer Network guidelines were recently updated to better integrate these molecular insights into clinical practice. We summarise here the molecular biomarkers of lymphomas with an emphasis on biomarkers that have well-supported prognostic and predictive utility, as well as emerging biomarkers that show promise for clinical practice. These biomarkers include: (1) diagnostic entity-defining genetic abnormalities [e.g., B-cell acute lymphoblastic leukaemia (B-ALL) with KMT2A rearrangement]; (2) molecular alterations that guide patients' prognoses (e.g., TP53 loss frequently conferring worse prognosis); (3) mutations that serve as the targets of, and often a source of acquired resistance to, small molecular inhibitors (e.g., ABL1 tyrosine kinase inhibitors for B-ALL BCR::ABL1, hindered by ABL1 kinase domain resistance mutations); (4) the growing incorporation of molecular measurable residual disease (MRD) in the management of lymphoma patients (e.g., molecular complete response and sequencing MRD-negative criteria in multiple myeloma). Altogether, our review spans the spectrum of lymphoma types, from the genetically defined subclasses of precursor B-cell lymphomas to the highly heterogeneous categories of small and large cell mature B-cell lymphomas, Hodgkin lymphomas, plasma cell neoplasms, and T/NK-cell lymphomas, and provides an expansive summary of our current understanding of their molecular pathology.
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Affiliation(s)
- J Bryan Iorgulescu
- Molecular Diagnostics Laboratory, Department of Hematopathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - L Jeffrey Medeiros
- Molecular Diagnostics Laboratory, Department of Hematopathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Keyur P Patel
- Molecular Diagnostics Laboratory, Department of Hematopathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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Pritchard D, Anand A, De'Ath A, Lee H, Rees MT. UK NEQAS and BSHI guideline: Laboratory testing and clinical interpretation of HLA genotyping results supporting the diagnosis of coeliac disease. Int J Immunogenet 2024; 51 Suppl 1:3-20. [PMID: 38153308 DOI: 10.1111/iji.12649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Accepted: 12/08/2023] [Indexed: 12/29/2023]
Abstract
Coeliac disease is a common immune-mediated inflammatory disorder caused by dietary gluten in genetically susceptible individuals. While the diagnosis of coeliac disease is based on serological and histological criteria, HLA-DQ genotyping can be useful, especially in excluding the diagnosis in patients who do not carry the relevant DQ heterodimers: DQA1*05 DQB1*02, DQB1*03:02 or DQA1*02 DQB1*02 (commonly referred to as DQ2.5, DQ8 and DQ2.2, respectively). External quality assessment results for HLA genotyping in coeliac disease have revealed concerning errors in HLA genotyping, reporting and clinical interpretation. In response, these guidelines have been developed as an evidence-based approach to guide laboratories undertaking HLA genotyping for coeliac disease and provide recommendations for reports to standardise and improve the communication of results.
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Affiliation(s)
| | - Arthi Anand
- H&I Laboratory, North West London Pathology, Imperial College Healthcare NHS Trust, London, UK
| | - Amy De'Ath
- UK NEQAS for H&I, Velindre University NHS Trust, Cardiff, UK
| | - Helena Lee
- Transplantation Laboratory, Manchester Royal Infirmary, Manchester University NHS Foundation Trust, Manchester, UK
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12
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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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13
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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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14
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Hitawala AA, Almomani A, Onwuzo S, Boustany A, Kumar P, Asaad I. Prevalence of autoimmune, cholestatic and nonalcoholic fatty liver disease in celiac disease. Eur J Gastroenterol Hepatol 2023; 35:1030-1036. [PMID: 37395201 DOI: 10.1097/meg.0000000000002599] [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] [Indexed: 07/04/2023]
Abstract
BACKGROUND While there is higher prevalence of autoimmune, cholestatic and fatty liver disease in celiac disease (CeD), most data is from small-scale studies. We evaluated the prevalence and risk factors of the same using large cohort data. METHODS A population-based cross-sectional study was conducted using Explorys, a multi-institutional database. Prevalence and risk factors of autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and nonalcoholic fatty liver disease (NAFLD) in CeD were assessed. RESULTS Out of 70 352 325 subjects, 136 735 had CeD (0.19%). The prevalence of AIH (0.32%), PBC (0.15%), PSC (0.004%) and NAFLD (0.7%) were high in CeD. After adjusting for age, gender, Caucasian race and anti-tissue transglutaminase antibody (anti-TTG), CeD subjects had higher odds of AIH [adjusted odds ratio (aOR) 7.06, 95% confidence interval (CI) 6.32-7.89] and PBC (aOR 4.16, 95% CI 3.46-5.0). Even after adjusting for CeD, anti-TTG positivity concurred with higher odds of AIH (aOR 4.79, 95% CI 3.88-5.92) and PBC (aOR 9.22, 95% CI 7.03-12.1). After adjusting for age, gender, Caucasian race, diabetes mellitus (DM), obesity, hypothyroidism and metabolic syndrome, there was higher prevalence of NAFLD in CeD, with the aOR in the presence of DM type 1 being 2.1 (95% CI 1.96-2.25), and in the presence of DM type 2 being 2.92 (95% CI 2.72-3.14). CONCLUSION Subjects with CeD are more likely to have AIH, PBC, PSC and NAFLD. AIH and PBC have higher odds in the presence of anti-TTG. The odds of NAFLD in CeD are high regardless of type of DM.
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Affiliation(s)
- Asif Ali Hitawala
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Ashraf Almomani
- Department of Gastroenterology and Digestive Diseases, Cleveland Clinic Foundation, Weston, Florida
| | - Somtochukwu Onwuzo
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Antoine Boustany
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Prabhat Kumar
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Imad Asaad
- Department of Gastroenterology and Digestive Diseases, Cleveland Clinic Foundation, Cleveland, Ohio, USA
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15
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Bhansali RS, Barta SK. SOHO State of the Art Updates and Next Questions | Challenging Cases in Rare T-Cell Lymphomas. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2023; 23:642-650. [PMID: 37302955 PMCID: PMC10524462 DOI: 10.1016/j.clml.2023.05.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 05/19/2023] [Indexed: 06/13/2023]
Abstract
Mature T- and NK-cell neoplasms (MTNKN) collectively represent a rare disorder, representing less than 15% of all non-Hodgkin lymphoma (NHL) cases and qualifying for orphan disease designation by the U.S. Food and Drug Administration (FDA). These consist of 9 families in the fifth revised WHO classification of lymphoid neoplasms, which are made up of over 30 disease subtypes, underscoring the heterogeneity of clinical features, molecular biology, and genetics across this disease group. Moreover, the 5 most common subtypes (peripheral T-cell lymphoma, not otherwise specified; nodal TFH cell lymphoma, angioimmunoblastic type; extranodal NK-cell/T-cell lymphoma; adult T-cell leukemia/lymphoma; and ALK-positive or -negative anaplastic large cell lymphoma) comprise over 75% of MTNKN cases, so other subtypes are exceedingly rare in the context of all NHL diagnoses and consequently often lack consensus on best practices in diagnosis and management. In this review, we discuss the following entities-enteropathy-associated T-cell lymphoma (EATL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), hepatosplenic T-cell lymphoma (HSTCL), subcutaneous panniculitis-like T-cell lymphoma (SPTCL), and primary cutaneous ɣδ T-cell lymphoma (PCGD-TCL) - with an emphasis on clinical and diagnostic features and options for management.
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Affiliation(s)
- Rahul S Bhansali
- Department of Medicine, Division of Hematology and Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Stefan K Barta
- Department of Medicine, Division of Hematology and Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA.
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16
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Abdullah SAA, Goa P, Vandenberghe E, Flavin R. Update on the Pathogenesis of Enteropathy-Associated T-Cell Lymphoma. Diagnostics (Basel) 2023; 13:2629. [PMID: 37627888 PMCID: PMC10453492 DOI: 10.3390/diagnostics13162629] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 07/18/2023] [Accepted: 07/21/2023] [Indexed: 08/27/2023] Open
Abstract
EATL is an aggressive T-cell non-Hodgkin lymphoma with poor prognosis and is largely localized to the small intestine. EATL is closely associated with coeliac disease (CD) and is seen mostly in patients originating from Northern Europe. Various factors are associated with an increased risk of developing EATL, such as viral infection, advanced age, being male, and the presence of the HLA-DQ2 haplotype. Clonal rearrangements in the TCR-β and γ genes have been reported in all EATL morphological variants with distinctive immunophenotypic characteristics. Although EATL can occur de novo, individuals with RCDII are at a higher risk of developing EATL. The cells of origin of EATL has been postulated to be normal small intestinal intraepithelial T-lymphocytes (IELs), and more recent evidence suggests a link between innate precursor IELs and EATL derived from refractory coeliac disease type II (RCDII). The immune microenvironment of mucosal cells within the small intestine enhances the process of neoplastic transformation of IELs into EATL. Cytokines such as IL-15 can activate and crucially deregulate the JAK-STAT signaling pathway by binding to receptors on the surface of IELs. Furthermore, mutations in the JAK/STAT pathway have been associated with RCDII-derived EATL.
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Affiliation(s)
| | - Patricia Goa
- Department of Histopathology, St. James’s Hospital, D08 NHY1 Dublin, Ireland;
| | - Elisabeth Vandenberghe
- Department of Haematology, St. James’s Hospital, D08 NHY1 Dublin, Ireland;
- Department of Haematology, Trinity College Dublin, D02 PN40 Dublin, Ireland
| | - Richard Flavin
- Department of Histopathology, Trinity College Dublin, D02 PN40 Dublin, Ireland
- Department of Histopathology, St. James’s Hospital, D08 NHY1 Dublin, Ireland;
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17
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Ghazanfar H, Javed N, Lee S, Shaban M, Cordero D, Acherjee T, Hasan KZ, Jyala A, Kandhi S, Hussain AN, Patel H. Novel Therapies for Celiac Disease: A Clinical Review Article. Cureus 2023; 15:e39004. [PMID: 37323330 PMCID: PMC10263194 DOI: 10.7759/cureus.39004] [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: 05/14/2023] [Indexed: 06/17/2023] Open
Abstract
Celiac disease is emerging as an autoimmune disorder with increasing prevalence and incidence. The mean age of presentation is also increasing with the passage of time. The delay in diagnosis is partly attributable to the asymptomatic state in which most patients present. The diagnosis of the disease is primarily based on biopsy, but serology can also be included for possible screening purposes. Although the primary management strategy is to eliminate gluten from the diet of such patients; however, compliance with the diet and follow-up to detect healing might be difficult to maintain. Therefore, there is a need to investigate further management therapies that can be easily administered and monitored. The aim of the review is to discuss the epidemiology, clinical presentation, and novel therapies being investigated for celiac disease.
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Affiliation(s)
| | - Nismat Javed
- Internal Medicine, BronxCare Health System, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Somin Lee
- Internal Medicine, BronxCare Hospital Center, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Mohammed Shaban
- Internal Medicine, BronxCare Hospital Center, Icahn School of Medicine at Mount Sinai, New York, USA
| | | | | | - Khushbu Z Hasan
- Internal Medicine, Mohtarma Benazir Bhutto Shaheed Medical College, Mirpur, PAK
| | | | - Sameer Kandhi
- Internal Medicine, BronxCare Health System, New York, USA
| | - Ali N Hussain
- Premedical, Baruch College, City University of New York, New York, USA
| | - Harish Patel
- Medicine/Gastroenterology, BronxCare Health System, New York, USA
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18
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Martín-Masot R, Herrador-López M, Navas-López VM, Carmona FD, Nestares T, Bossini-Castillo L. Celiac Disease Is a Risk Factor for Mature T and NK Cell Lymphoma: A Mendelian Randomization Study. Int J Mol Sci 2023; 24:ijms24087216. [PMID: 37108375 PMCID: PMC10139431 DOI: 10.3390/ijms24087216] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 04/04/2023] [Accepted: 04/08/2023] [Indexed: 04/29/2023] Open
Abstract
Celiac disease (CeD) is an immune-mediated disorder triggered by gluten ingestion that damages the small intestine. Although CeD has been associated with a higher risk for cancer, the role of CeD as a risk factor for specific malignancies, such as enteropathy-associated T-cell lymphoma (EATL), remains controversial. Using two-sample Mendelian randomization (2SMR) methods and the summarized results of large genome-wide association studies from public repositories, we addressed the causal relationship between CeD and eight different malignancies. Eleven non-HLA SNPs were selected as instrumental variables (IVs), and causality estimates were obtained using four 2SMR methods: random-effects inverse variance-weighted, weighted median estimation, MR-Egger regression, and MR pleiotropy residual sum and outlier (MR-PRESSO). We identified a significant causal relationship between CeD and mature T/NK cell lymphomas. Under a multivariate Mendelian randomization model, we observed that the causal effect of CeD was not dependent on other known lymphoma risk factors. We found that the most instrumental IV was located in the TAGAP locus, suggesting that aberrant T cell activation might be relevant in the T/NK cell malignization process. Our findings provide new insights into the connection between immune imbalance and the development of severe comorbidities, such as EATL, in patients with CeD.
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Affiliation(s)
- Rafael Martín-Masot
- Sección de Gastroenterología y Nutrición Infantil, Hospital Regional Universitario de Málaga, 29011 Málaga, Spain
- Instituto de Nutrición y Tecnología de los Alimentos "José Mataix Verdú" (INYTA), Centro de Investigación Biomédica (CIBM), Universidad de Granada, 18016 Granada, Spain
| | - Marta Herrador-López
- Sección de Gastroenterología y Nutrición Infantil, Hospital Regional Universitario de Málaga, 29011 Málaga, Spain
| | - Víctor Manuel Navas-López
- Sección de Gastroenterología y Nutrición Infantil, Hospital Regional Universitario de Málaga, 29011 Málaga, Spain
| | - Francisco David Carmona
- Departamento de Genética e Instituto de Biotecnología, Centro de Investigación Biomédica (CIBM), Universidad de Granada, 18016 Granada, Spain
- Reproducción Humana y Enfermedades Hereditarias y Complejas (IBS-TEC14), Terapias Avanzadas y Tecnologías Biomédicas, Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain
| | - Teresa Nestares
- Instituto de Nutrición y Tecnología de los Alimentos "José Mataix Verdú" (INYTA), Centro de Investigación Biomédica (CIBM), Universidad de Granada, 18016 Granada, Spain
- Departamento de Fisiología, Facultad de Farmacia, Universidad de Granada, 18071 Granada, Spain
| | - Lara Bossini-Castillo
- Departamento de Genética e Instituto de Biotecnología, Centro de Investigación Biomédica (CIBM), Universidad de Granada, 18016 Granada, Spain
- Reproducción Humana y Enfermedades Hereditarias y Complejas (IBS-TEC14), Terapias Avanzadas y Tecnologías Biomédicas, Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), 18012 Granada, Spain
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19
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Tamai T, Ihara K. Celiac Disease Genetics, Pathogenesis, and Standard Therapy for Japanese Patients. Int J Mol Sci 2023; 24:ijms24032075. [PMID: 36768398 PMCID: PMC9916540 DOI: 10.3390/ijms24032075] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/14/2023] [Accepted: 01/17/2023] [Indexed: 01/21/2023] Open
Abstract
Celiac disease is an autoimmune disease primarily affecting the small intestine that is caused by the ingestion of gluten in genetically susceptible individuals. The development of celiac disease is based on a complex immune response to gluten proteins. The global average prevalence in the general population is about 1%. In recent years, it has become clear that celiac disease is not less common in Asian countries than in Western countries but often remains undiagnosed. Although the number of patients with celiac disease in Asia is expected to increase with improving disease recognition and advances in diagnostic techniques, there remain few reports of celiac disease in the Far East region of Asia, especially in Japan. In this paper, we outline the epidemiology, diagnosis, and treatment of celiac disease. In addition, we summarize the reported Japanese cases of celiac disease with an overview in Japan.
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20
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Meta-Analysis and Systematic Review of HLA DQ2/DQ8 in Adults with Celiac Disease. Int J Mol Sci 2023; 24:ijms24021188. [PMID: 36674702 PMCID: PMC9863503 DOI: 10.3390/ijms24021188] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/23/2022] [Accepted: 10/04/2022] [Indexed: 01/11/2023] Open
Abstract
Although people with human leukocyte antigens (HLA) DQ2 and/or DQ8 are more likely to develop celiac disease (CD), the condition cannot be fully explained by this genetic predisposition alone. Multiple, as yet unidentified, factors contribute to the genesis of CD, including genetics, the environment, and the immune system. In order to provide insight into a prospective possibility and an expanded screening technique, we aim to undertake a comprehensive and meta-analytical study of the assessment and distribution of HLA class II (HLA-DQ2/DQ8) in adult CD patients. A systematic review was conducted using an electronic search of databases (PubMed, Google Scholar, Embase, and Direct Science) from January 2004 to February 2022. DQ2/DQ2 homozygotes have the highest risk of developing CD. DQ2/DQ8 typing is an effective test to exclude CD from the differential diagnosis of a patient with CD symptoms. Although other non-HLA genes have been associated with CD, they are rarely considered at diagnosis because they account for only a small proportion of the heritability of CD. This finding, together with the information gathered previously, may be useful in considering widely available and economically feasible screening options for celiac disease in young people.
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21
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DQA1*0102 DQB1*0602 haplotype distinguishes coeliac disease and its complications from gluten unrelated enteropathies. Eur J Gastroenterol Hepatol 2023; 35:64-72. [PMID: 36468571 DOI: 10.1097/meg.0000000000002480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND Duodenal villous atrophy is due not only to coeliac disease and its complications but also to other rare enteropathies unrelated to gluten consumption, defined as noncoeliac enteropathies. The diagnosis of noncoeliac enteropathies remains challenging, and HLA typing has been widely used to exclude coeliac disease if DQ2 and DQ8 alleles are absent. However, the frequency of the various HLA alleles in noncoeliac enteropathies is still unknown. AIMS To describe the HLA genetic profile of patients affected by noncoeliac enteropathies who have been evaluated at our centres between 2000 and 2021, and to investigate the diagnostic role of HLA typing. METHODS Genomic DNA was collected from 44 Italian and 19 British adult patients with noncoeliac enteropathies. Patient genotypes were compared with those of healthy Italian and British populations obtained from HLA bone marrow donors' banks. In addition, genotypes were also compared with those of patients with coeliac disease and complicated coeliac disease. RESULTS Both in the Italian and in the British group, the DQA1*0102 DQB1*0602 haplotype and related alleles occurred significantly more frequently in patients with noncoeliac enteropathies compared to coeliac disease and complicated coeliac disease. CONCLUSIONS Together with negative HLA-DQ2 and DQ8 haplotypes, the DQA1*0102 DQB1*0602 haplotype can be used to guide the differential diagnosis between coeliac disease and noncoeliac enteropathies.
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22
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Packova B, Kohout P, Dastych M, Prokesova J, Grolich T, Kroupa R. Malignant complications of celiac disease: a case series and review of the literature. J Med Case Rep 2022; 16:460. [PMID: 36503568 PMCID: PMC9743581 DOI: 10.1186/s13256-022-03682-3] [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: 09/21/2022] [Accepted: 11/18/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Celiac disease is an immune-mediated enteropathy triggered by gluten in genetically susceptible individuals. Diagnosis is based on evaluating specific autoantibodies and histopathologic findings of duodenal biopsy specimens. The only therapy for celiac disease is a gluten-free diet. Celiac disease can be complicated by malnutrition, other autoimmune diseases, refractoriness to treatment, and gastrointestinal tumors. This article presents seven cases of malignancies in patients with celiac disease. Its objective is to raise awareness of the malignant complications of celiac disease, leading to earlier diagnosis and improved outcomes. CASE PRESENTATION Seven cases of malignant complications of celiac disease occurred among 190 patients followed at the Department of Internal Medicine and Gastroenterology, University Hospital Brno from 2014 to 2021. We describe these cases and the presentation, diagnostic process, course, management, and outcomes for each, along with proposed potential risk factors of malignant complications. There was one Caucasian man who was 70 years old and six Caucasian women who were 36, 46, 48, 55, 73, and 82 years old in our cohort. Of the seven cases of malignancies in our cohort, four patients were diagnosed with small bowel adenocarcinoma, one with diffuse large B-cell lymphoma, one with carcinoma of the tongue, and one with colorectal carcinoma. CONCLUSIONS Malignancies occurred in 3.7% of patients followed up for celiac disease. Awareness of the malignant complications of celiac disease, risk factors, presentation, and disease course could lead to earlier diagnosis and improved outcomes.
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Affiliation(s)
- Barbora Packova
- Department of Internal Medicine and Gastroenterology, University Hospital Brno, Faculty of Medicine, Masaryk University, Jihlavska 20, 62500 Brno, Czech Republic
| | - Pavel Kohout
- grid.4491.80000 0004 1937 116XDepartment of Internal Medicine, Third Faculty of Medicine, Charles University Prague and Teaching Thomayer Hospital, 14059 Prague, Czech Republic
| | - Milan Dastych
- Department of Internal Medicine and Gastroenterology, University Hospital Brno, Faculty of Medicine, Masaryk University, Jihlavska 20, 62500 Brno, Czech Republic
| | - Jitka Prokesova
- Department of Internal Medicine and Gastroenterology, University Hospital Brno, Faculty of Medicine, Masaryk University, Jihlavska 20, 62500 Brno, Czech Republic
| | - Tomas Grolich
- Department of Surgery, University Hospital Brno, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic
| | - Radek Kroupa
- Department of Internal Medicine and Gastroenterology, University Hospital Brno, Faculty of Medicine, Masaryk University, Jihlavska 20, 62500 Brno, Czech Republic
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23
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Is Celiac Disease (CD) Prevalent in Patients with Multiple Sclerosis (MS): A Systematic Review and Meta-Analysis. Mult Scler Int 2022; 2022:7091140. [DOI: 10.1155/2022/7091140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 11/10/2022] [Accepted: 11/14/2022] [Indexed: 12/14/2022] Open
Abstract
Background. Celiac disease (CD) is an autoimmune disease, and its prevalence reported variously in different studies. The goal of this study is to evaluate the pooled prevalence of CD in subjects with MS. Methods. PubMed, Scopus, EMBASE, Web of Science, and Google Scholar along with gray literature were systematically searched. The search included all relevant studies which were published up to October 2022. Two researchers independently searched all databases and also references of included studies. Results. We found 8211 articles by literature search, and after deleting duplicates, 5594 remained. Fifteen articles remained for meta-analysis. Totally, 31418 patients were evaluated, and the total number of possible/confirmed cases was 124. Studies were published between 2004 and 2020, and the most published studies were from Italy. Five studies provided information regarding controls. The total number of controls was 22394, of whom 22 had CD. Mean age ranged from 35 to 55 years. The pooled prevalence of CD in MS patients was 0 (
%,
). The pooled odds of CD in subjects with MS are 0.46 (95% CI: 0.19-1.1) (
,
). Conclusion. The pooled prevalence of this systematic review showed that CD is not prevalent in MS cases.
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24
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Carreras J. Artificial Intelligence Analysis of Celiac Disease Using an Autoimmune Discovery Transcriptomic Panel Highlighted Pathogenic Genes including BTLA. Healthcare (Basel) 2022; 10:1550. [PMID: 36011206 PMCID: PMC9408070 DOI: 10.3390/healthcare10081550] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 08/09/2022] [Accepted: 08/14/2022] [Indexed: 12/18/2022] Open
Abstract
Celiac disease is a common immune-related inflammatory disease of the small intestine caused by gluten in genetically predisposed individuals. This research is a proof-of-concept exercise focused on using Artificial Intelligence (AI) and an autoimmune discovery gene panel to predict and model celiac disease. Conventional bioinformatics, gene set enrichment analysis (GSEA), and several machine learning and neural network techniques were used on a publicly available dataset (GSE164883). Machine learning and deep learning included C5, logistic regression, Bayesian network, discriminant analysis, KNN algorithm, LSVM, random trees, SVM, Tree-AS, XGBoost linear, XGBoost tree, CHAID, Quest, C&R tree, random forest, and neural network (multilayer perceptron). As a result, the gene panel predicted celiac disease with high accuracy (95-100%). Several pathogenic genes were identified, some of the immune checkpoint and immuno-oncology pathways. They included CASP3, CD86, CTLA4, FASLG, GZMB, IFNG, IL15RA, ITGAX, LAG3, MMP3, MUC1, MYD88, PRDM1, RGS1, etc. Among them, B and T lymphocyte associated (BTLA, CD272) was highlighted and validated at the protein level by immunohistochemistry in an independent series of cases. Celiac disease was characterized by high BTLA, expressed by inflammatory cells of the lamina propria. In conclusion, artificial intelligence predicted celiac disease using an autoimmune discovery gene panel.
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Affiliation(s)
- Joaquim Carreras
- Department of Pathology, School of Medicine, Tokai University, 143 Shimokasuya, Isehara 259-1193, Japan
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25
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Inflammatory auto-immune diseases of the intestine and their management by natural bioactive compounds. Biomed Pharmacother 2022; 151:113158. [PMID: 35644116 DOI: 10.1016/j.biopha.2022.113158] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 05/08/2022] [Accepted: 05/16/2022] [Indexed: 11/20/2022] Open
Abstract
Autoimmune diseases are caused by the overactivity of the immune system towards self-constituents. Risk factors of autoimmune diseases are multiple and include genetic, epigenetic, environmental, and psychological. Autoimmune chronic inflammatory bowel diseases, including celiac and inflammatory diseases (Crohn's disease and ulcerative colitis), constitute a significant health problem worldwide. Besides the complexity of the symptoms of these diseases, their treatments have only been palliative. Numerous investigations showed that natural phytochemicals could be promising strategies to fight against these autoimmune diseases. In this respect, plant-derived natural compounds such as flavonoids, phenolic acids, and terpenoids exhibited significant effects against three autoimmune diseases affecting the intestine, particularly bowel diseases. This review focuses on the role of natural compounds obtained from medicinal plants in modulating inflammatory auto-immune diseases of the intestine. It covers the most recent literature related to the effect of these natural compounds in the treatment and prevention of auto-immune diseases of the intestine.
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Tye‐Din JA. Review article: Follow-up of coeliac disease. Aliment Pharmacol Ther 2022; 56 Suppl 1:S49-S63. [PMID: 35815829 PMCID: PMC9542881 DOI: 10.1111/apt.16847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/12/2022] [Accepted: 02/13/2022] [Indexed: 12/09/2022]
Abstract
Coeliac disease is a lifelong immune-mediated enteropathy with systemic features associated with increased morbidity and modestly increased mortality. Treatment with a strict gluten-free diet improves symptoms and mucosal damage but is not curative and low-level gluten intake is common despite strict attempts at adherence. Regular follow-up after diagnosis is considered best-practice however this is executed poorly in the community with the problem compounded by the paucity of data informing optimal approaches. The aim of dietary treatment is to resolve symptoms, reduce complication risk and improve quality of life. It follows that the goals of monitoring are to assess dietary adherence, monitor disease activity, assess symptoms and screen for complications. Mucosal disease remission is regarded a key measure of treatment success as healing is associated with positive health outcomes. However, persistent villous atrophy is common, even after many years of a gluten-free diet. As the clinical significance of asymptomatic enteropathy is uncertain the role for routine follow-up biopsies remains contentious. Symptomatic non-responsive coeliac disease is common and with systematic follow-up a cause is usually found. Effective models of care involving the gastroenterologist, dietitian and primary care doctor will improve the consistency of long-term management and likely translate into better patient outcomes. Identifying suitable treatment targets linked to long-term health is an important goal.
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Affiliation(s)
- J. A. Tye‐Din
- Immunology DivisionThe Walter and Eliza Hall InstituteParkvilleVictoriaAustralia,Department of Medical BiologyUniversity of MelbourneParkvilleVictoriaAustralia,Department of GastroenterologyThe Royal Melbourne HospitalParkvilleVictoriaAustralia,Centre for Food & Allergy ResearchMurdoch Children’s Research InstituteParkvilleVictoriaAustralia
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Tonsillar Extraintestinal Enteropathy-Associated T-Cell Lymphoma in a Patient With Celiac Disease. ACG Case Rep J 2022; 9:e00824. [PMID: 35811577 PMCID: PMC9263477 DOI: 10.14309/crj.0000000000000824] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 06/06/2022] [Indexed: 11/17/2022] Open
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28
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Anderson RP. Review article: Diagnosis of coeliac disease: a perspective on current and future approaches. Aliment Pharmacol Ther 2022; 56 Suppl 1:S18-S37. [PMID: 35815826 DOI: 10.1111/apt.16840] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Revised: 02/08/2022] [Accepted: 02/08/2022] [Indexed: 12/09/2022]
Abstract
Diagnostics will play a central role in addressing the ongoing dramatic rise in global prevalence of coeliac disease, and in deploying new non-dietary therapeutics. Clearer understanding of the immunopathogenesis of coeliac disease and the utility of serology has led to partial acceptance of non-biopsy diagnosis in selected cases. Non-biopsy diagnosis may expand further because research methods for measuring gluten-specific CD4+ T cells and the acute recall response to gluten ingestion in patients is now relatively straightforward. This perspective on diagnosis in the context of the immunopathogenesis of coeliac disease sets out to highlight current consensus, limitations of current practices, gluten food challenge for diagnosis and the potential for diagnostics that measure the underlying cause for coeliac disease, gluten-specific immunity.
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29
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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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30
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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. Aktualisierte S2k-Leitlinie Zöliakie der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS). 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] [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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31
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Shah S, Majid Z, Tasneem AA, Ahmed Khan S, Hanif F, Luck N. Refractory Coeliac disease-a case series from Pakistan. Trop Doct 2022; 52:413-417. [PMID: 35354312 DOI: 10.1177/00494755221080589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Coeliac disease or gluten intolerance is a frequent cause of chronic diarrhoea leading to malabsorptive symptoms. Refractory coeliac disease is a rare entity, which is not only harder to diagnose but managing it can be challenging. We hereby present three such cases.
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32
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Guandalini S, Discepolo V. Celiac Disease. TEXTBOOK OF PEDIATRIC GASTROENTEROLOGY, HEPATOLOGY AND NUTRITION 2022:525-548. [DOI: 10.1007/978-3-030-80068-0_40] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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33
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Bigas A, Rodriguez-Sevilla JJ, Espinosa L, Gallardo F. Recent advances in T-cell lymphoid neoplasms. Exp Hematol 2021; 106:3-18. [PMID: 34879258 DOI: 10.1016/j.exphem.2021.12.191] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 11/29/2021] [Accepted: 12/02/2021] [Indexed: 12/14/2022]
Abstract
T Cells comprise many subtypes of specified lymphocytes, and their differentiation and function take place in different tissues. This cellular diversity is also observed in the multiple ways T-cell transformation gives rise to a variety of T-cell neoplasms. This review covers the main types of T-cell malignancies and their specific characteristics, emphasizing recent advances at the cellular and molecular levels as well as differences and commonalities among them.
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Affiliation(s)
- Anna Bigas
- Program in Cancer Research, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), CIBERONC, Barcelona, Spain; Institut Josep Carreras contra la Leucemia, Barcelona, Spain.
| | | | - Lluis Espinosa
- Program in Cancer Research, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), CIBERONC, Barcelona, Spain
| | - Fernando Gallardo
- Dermatology Department, Parc de Salut Mar-Hospital del Mar, Barcelona, Spain.
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34
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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:cancers13215288. [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.)
- Correspondence:
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35
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Sahin Y. Celiac disease in children: A review of the literature. World J Clin Pediatr 2021; 10:53-71. [PMID: 34316439 PMCID: PMC8290992 DOI: 10.5409/wjcp.v10.i4.53] [Citation(s) in RCA: 86] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/23/2021] [Accepted: 05/22/2021] [Indexed: 02/06/2023] Open
Abstract
Celiac disease is an immune-mediated systemic disease triggered by intake of gluten in genetically susceptible individuals. The prevalence of celiac disease in the general population is estimated to be 1% in the world. Its prevalence differs depending on geographical and ethnic variations. The prevalence of celiac disease has increased significantly in the last 30 years due to the increased knowledge and awareness of physicians and the widespread use of highly sensitive and specific diagnostic tests for celiac disease. Despite increased awareness and knowledge about celiac disease, up to 95% of celiac patients still remain undiagnosed. The presentations of celiac disease have significantly changed in the last few decades. Classical symptoms of celiac disease occur in a minority of celiac patients, while older children have either minimal or atypical symptoms. Serologic tests for celiac disease should be done in patients with unexplained chronic or intermittent diarrhea, failure to thrive, weight loss, delayed puberty, short stature, amenorrhea, iron deficiency anemia, nausea, vomiting, chronic abdominal pain, abdominal distension, chronic constipation, recurrent aphthous stomatitis, and abnormal liver enzyme elevation, and in children who belong to specific groups at risk. Early diagnosis of celiac disease is very important to prevent long-term complications. Currently, the only effective treatment is a lifelong gluten-free diet. In this review, we will discuss the epidemiology, clinical findings, diagnostic tests, and treatment of celiac disease in the light of the latest literature.
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Affiliation(s)
- Yasin Sahin
- Pediatric Gastroenterology-Hepatology and Nutrition, Medical Park Gaziantep Hospital, Gaziantep 27560, Turkey
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36
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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: 10] [Impact Index Per Article: 2.5] [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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37
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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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38
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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: 8] [Impact Index Per Article: 2.0] [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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39
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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: 3] [Impact Index Per Article: 0.8] [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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40
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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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Yu X, Vargas J, Green PH, Bhagat G. Innate Lymphoid Cells and Celiac Disease: Current Perspective. Cell Mol Gastroenterol Hepatol 2020; 11:803-814. [PMID: 33309944 PMCID: PMC7851184 DOI: 10.1016/j.jcmgh.2020.12.002] [Citation(s) in RCA: 5] [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: 09/18/2020] [Revised: 12/03/2020] [Accepted: 12/04/2020] [Indexed: 12/15/2022]
Abstract
Celiac disease (CD) is a common autoimmune disorder triggered by the ingestion of gluten in genetically susceptible individuals. Although the mechanisms underlying gliadin-mediated activation of adaptive immunity in CD have been well-characterized, regulation of innate immune responses and the functions of certain immune cell populations within the epithelium and lamina propria are not well-understood at present. Innate lymphoid cells (ILCs) are types of innate immune cells that have lymphoid morphology, lack antigen-specific receptors, and play important roles in tissue homeostasis, inflammation, and protective immune responses against pathogens. Information regarding the diversity and functions of ILCs in lymphoid organs and at mucosal sites has grown over the past decade, and roles of different ILC subsets in the pathogenesis of some inflammatory intestinal diseases have been proposed. However, our understanding of the contribution of ILCs toward the initiation and progression of CD is still limited. In this review, we discuss current pathophysiological aspects of ILCs within the gastrointestinal tract, findings of recent investigations characterizing ILC alterations in CD and refractory CD, and suggest avenues for future research.
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Affiliation(s)
- Xuechen Yu
- Department of Medicine, Celiac Disease Center, Columbia University Irving Medical Center, New York, New York
| | - Justin Vargas
- Department of Medicine, Celiac Disease Center, Columbia University Irving Medical Center, New York, New York
| | - Peter H.R. Green
- Department of Medicine, Celiac Disease Center, Columbia University Irving Medical Center, New York, New York
| | - Govind Bhagat
- Department of Medicine, Celiac Disease Center, Columbia University Irving Medical Center, New York, New York,Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York,Correspondence Address correspondence to: Govind Bhagat, MD, Department of Pathology and Cell Biology, Columbia University Irving Medical Center, 630 West 168th Street, VC 14-228, New York, New York 10032. fax: (212) 305-2301.
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Airaksinen L, Laurikka P, Huhtala H, Kurppa K, Salmi T, Saavalainen P, Kaukinen K, Lindfors K. Influence of HLA-DQ2.5 Dose on Clinical Picture of Unrelated Celiac Disease Patients. Nutrients 2020; 12:nu12123775. [PMID: 33317091 PMCID: PMC7764246 DOI: 10.3390/nu12123775] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 12/07/2020] [Indexed: 12/13/2022] Open
Abstract
The clinical phenotype of celiac disease varies considerably among patients and the dosage of HLA-DQ2.5 alleles has been suggested to be a contributing factor. We investigated whether HLA-DQ2.5 allele dosage is associated with distinct clinical parameters at the time of diagnosis and with patients’ response to a gluten-free diet. The final cohort included 605 carefully phenotyped non-related Finnish celiac disease patients grouped as having 0, 1 or 2 copies of HLA-DQ2.5. Clinical data at the time of diagnosis and during gluten-free diet were collected systematically from medical records and supplementary interviews. An increasing HLA-DQ2.5 dose effect was detected for celiac disease antibody positivity at diagnosis (p = 0.021) and for the presence of any first-degree relatives with celiac disease (p = 0.011 and p = 0.031, respectively). Instead, DQ2.5-negative patients were suffering most often from classical symptoms at diagnosis (p = 0.007 between HLA groups). In addition, during follow-up they were most often symptomatic despite a gluten-free diet (p = 0.002 between groups). Our results thus suggest that increasing HLA-DQ2.5 dose only has a minor effect on the clinical picture of celiac disease. However, HLA-DQ2.5-negative patients should not be overlooked in clinical practice and particular attention should be paid to this patient group during gluten-free diet.
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Affiliation(s)
- Laura Airaksinen
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland; (L.A.); (P.L.); (T.S.); (K.K.)
| | - Pilvi Laurikka
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland; (L.A.); (P.L.); (T.S.); (K.K.)
| | - Heini Huhtala
- Faculty of Social Sciences, Tampere University, 33520 Tampere, Finland;
| | - Kalle Kurppa
- Tampere Centre for Child Health Research, Tampere University Hospital and Tampere University, 33521 Tampere, Finland;
- Department of Pediatrics, Seinäjoki Central Hospital and University Consortium of Seinäjoki, 60220 Seinäjoki, Finland
| | - Teea Salmi
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland; (L.A.); (P.L.); (T.S.); (K.K.)
- Department of Dermatology, Tampere University Hospital, 33521 Tampere, Finland
| | - Päivi Saavalainen
- Research Programs Unit, Immunobiology, and Haartman Institute, Department of Medical Genetics, University of Helsinki, 00014 Helsinki, Finland;
| | - Katri Kaukinen
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland; (L.A.); (P.L.); (T.S.); (K.K.)
- Department of Internal Medicine, Tampere University Hospital, 33521 Tampere, Finland
| | - Katri Lindfors
- Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland; (L.A.); (P.L.); (T.S.); (K.K.)
- Correspondence:
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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: 4] [Impact Index Per Article: 0.8] [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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Tye-Din JA, Daveson AJM, Goldstein KE, Hand HL, Neff KM, Goel G, Williams LJ, Truitt KE, Anderson RP. Patient factors influencing acute gluten reactions and cytokine release in treated coeliac disease. BMC Med 2020; 18:362. [PMID: 33239013 PMCID: PMC7690153 DOI: 10.1186/s12916-020-01828-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Accepted: 10/27/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Patients with coeliac disease (CD) commonly report a variety of adverse symptoms to gluten, but descriptions of the symptomatic response in the literature may have been confounded by the presence of food components such as fermentable carbohydrates (FODMAPs) causing symptoms of irritable bowel syndrome independent of gluten. In recent unmasked and masked low FODMAP gluten challenge studies in small groups of treated CD patients, nausea and vomiting were shown to be the key symptoms associated with serum interleukin (IL)-2 release. Our objective was to utilise a large and diverse cohort of people with CD undertaking a standardised gluten food challenge to characterise the demographic, genetic and clinical factors influencing the severity and timing of acute gluten reactions and IL-2 production. METHODS A total of 295 adults treated for CD were observed for 6 h after an unmasked food challenge consisting of 10 g vital wheat gluten (low in FODMAPs) in 100 ml water. Assessments included patient-reported outcomes, serum IL-2 and adverse events. Responses were analysed according to patient characteristics, HLA-DQ genotype, duodenal histology and response to a second gluten challenge. RESULTS Peak symptom severity was at 3 h (median severity 5/10). Peak IL-2 was at 4 h (median 4 pg/ml, range undetectable to 1028 pg/ml). Older age, older age at diagnosis, HLA-DQ2.5 positivity and homozygosity for HLA-DQB1*02 were each significantly associated with IL-2 elevations after gluten. Patients positive for HLA-DQ2.5, DQ8, DQ2.2 or DQ7 showed elevated IL-2 after gluten. Patient factors were not significantly associated with severity of digestive symptoms, but symptoms were correlated to one another and serum IL-2. Gluten challenge after 5 months caused more vomiting and higher IL-2 levels, but responses correlated with the first. CONCLUSIONS Gluten-induced symptoms and cytokine release is common in adults with treated CD. Age, genetics and previous response to gluten predict these acute reactions to gluten challenge. Structured symptom assessment and serum IL-2 after standardised gluten challenge may inform on patient diagnosis, the role of gluten in symptomatology and the need for adjunctive treatment. TRIAL REGISTRATION ClinicalTrials.gov , NCT03644069 Registered 21 May 2018.
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Affiliation(s)
- Jason A Tye-Din
- Immunology Division, The Walter and Eliza Hall Institute, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.,Department of Gastroenterology, The Royal Melbourne Hospital, Parkville, VIC, Australia
| | - A James M Daveson
- Coral Sea Clinical Research Institute, Suite 7, 76 Willetts Road, North Mackay, QLD, 4740, Australia.,University of Queensland, Brisbane, QLD, Australia
| | | | | | | | | | | | | | - Robert P Anderson
- ImmusanT Inc., Cambridge, MA, USA. .,Wesley Medical Research, PO Box 499, Toowong, QLD, 4066, Australia.
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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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Abstract
PURPOSE OF REVIEW To review the epidemiology, pathophysiology, diagnosis, management, and prognosis of refractory celiac disease, with a specific emphasis on recent literature. RECENT FINDINGS While the pathophysiology of type I refractory celiac disease remains unclear, there have been advances in the understanding of the pathophysiology of type II refractory celiac disease. This has included recognition of the significant role of interleukin-15 and somatic mutations in JAK1 or STAT3 in the proliferation of aberrant T cells. This in turn has led to potential novel therapies targeting these factors, one of which has reached the clinical trial stage. The morbidity and mortality associated with type II refractory celiac disease remain significant; however, recent advances in the understanding of the pathophysiology of this condition have led to potential therapeutic options that should be investigated.
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Ciszewski C, Discepolo V, Pacis A, Doerr N, Tastet O, Mayassi T, Maglio M, Basheer A, Al-Mawsawi LQ, Green P, Auricchio R, Troncone R, Waldmann TA, Azimi N, Tagaya Y, Barreiro LB, Jabri B. Identification of a γc Receptor Antagonist That Prevents Reprogramming of Human Tissue-resident Cytotoxic T Cells by IL15 and IL21. Gastroenterology 2020; 158:625-637.e13. [PMID: 31622625 PMCID: PMC7861144 DOI: 10.1053/j.gastro.2019.10.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 10/02/2019] [Accepted: 10/04/2019] [Indexed: 12/23/2022]
Abstract
BACKGROUND & AIMS Gamma chain (γc) cytokines (interleukin [IL]2, IL4, IL7, IL9, IL15, and IL21) signal via a common γc receptor. IL2 regulates the immune response, whereas IL21 and IL15 contribute to development of autoimmune disorders, including celiac disease. We investigated whether BNZ-2, a peptide designed to inhibit IL15 and IL21, blocks these cytokines selectively and its effects on intraepithelial cytotoxic T cells. METHODS We obtained duodenal biopsies from 9 patients with potential celiac disease (positive results from tests for anti-TG2 but no villous atrophy), 30 patients with untreated celiac disease (with villous atrophy), and 5 patients with treated celiac disease (on a gluten-free diet), as well as 43 individuals without celiac disease (controls). We stimulated primary intestinal intraepithelial CD8+ T-cell lines, or CD8+ T cells directly isolated from intestinal biopsies, with γc cytokines in presence or absence of BNZ-2. Cells were analyzed by immunoblots, flow cytometry, or RNA-sequencing analysis for phosphorylation of signaling molecules, gene expression profiles, proliferation, and levels of granzyme B. RESULTS Duodenal tissues from patients with untreated celiac disease had increased levels of messenger RNAs encoding IL15 receptor subunit alpha (IL15RA) and IL21 compared with tissues from patients with potential celiac disease and controls. Activation of intraepithelial cytotoxic T cells with IL15 or IL21 induced separate signaling pathways; incubation of the cells with IL15 and IL21 cooperatively increased their transcriptional activity, proliferation, and cytolytic properties. BNZ-2 specifically inhibited the effects of IL15 and IL21, but not of other γc cytokines. CONCLUSIONS We found increased expression of IL15RA and IL21 in duodenal tissues from patients with untreated celiac disease compared with controls. IL15 and IL21 cooperatively activated intestinal intraepithelial cytotoxic T cells. In particular, they increased their transcriptional activity, proliferation, and cytolytic activity. The peptide BNZ-2 blocked these effects, but not those of other γc cytokines, including IL2. BNZ-2 might be used to prevent cytotoxic T-cell-mediated tissue damage in complex immune disorders exhibiting upregulation of IL15 and IL21.
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Affiliation(s)
| | | | - Alain Pacis
- Department of Genetics, CHU Sainte-Justine Research Center, Montreal, QC, Canada
| | - Nick Doerr
- Bioniz Therapeutics, Inc., Irvine, CA, USA
| | - Olivier Tastet
- Department of Genetics, CHU Sainte-Justine Research Center, Montreal, QC, Canada
| | - Toufic Mayassi
- Department of Medicine, University of Chicago, Chicago, IL, USA.,Committee on Immunology, University of Chicago, Chicago, IL, USA
| | - Mariantonia Maglio
- Department of Translational Medical Science and European Laboratory for the Investigation of Food Induced Diseases (ELFID), Università degli Studi di Napoli Federico II, Napoli, Italy
| | | | | | - Peter Green
- Celiac Disease Center, Columbia University, New York, NY, USA
| | - Renata Auricchio
- Department of Translational Medical Science and European Laboratory for the Investigation of Food Induced Diseases (ELFID), Università degli Studi di Napoli Federico II, Napoli, Italy
| | - Riccardo Troncone
- Department of Translational Medical Science and European Laboratory for the Investigation of Food Induced Diseases (ELFID), Università degli Studi di Napoli Federico II, Napoli, Italy
| | - Thomas A. Waldmann
- Lymphoid Malignancies Branch, National Cancer Institute, Bethesda, Maryland, USA
| | | | - Yutaka Tagaya
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Luis B. Barreiro
- Department of Medicine, University of Chicago, Chicago, IL, USA.,Committee on Genetics, Genomics and Systems Biology, University of Chicago, Chicago, IL, USA
| | - Bana Jabri
- Department of Medicine, University of Chicago, Chicago, Illinois; Committee on Immunology, University of Chicago, Chicago, Illinois; Department of Pathology and Pediatrics, University of Chicago, Chicago, Illinois.
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Soderquist CR, Bhagat G. Gastrointestinal T- and NK-cell lymphomas and indolent lymphoproliferative disorders. Semin Diagn Pathol 2020; 37:11-23. [DOI: 10.1053/j.semdp.2019.08.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Marchi E, O'Connor OA. The rapidly changing landscape in mature T-cell lymphoma (MTCL) biology and management. CA Cancer J Clin 2020; 70:47-70. [PMID: 31815293 DOI: 10.3322/caac.21589] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 10/01/2019] [Accepted: 10/15/2019] [Indexed: 02/06/2023] Open
Abstract
Historical advances in the care of patients with non-Hodgkin lymphoma (NHL) have been restricted largely to patients with B-cell lymphoma. The peripheral T-cell lymphomas (PTCLs), which are rare and heterogeneous in nature, have yet to experience the same degree of improvement in outcome over the past 20 to 30 years. It is estimated that there are approximately 80,000 and 14,000 cases, respectively, of NHL and Hodgkin lymphoma per year in the United States. As a subgroup of NHL, the PTCLs account for 6% to 10% of all cases of NHL, making them exceedingly rare. In addition, the World Health Organization 2017 classification describes 29 distinct subtypes of PTCL. This intrinsic diversity, coupled with its rarity, has stymied progress in the disease. In addition, most subtypes carry an inferior prognosis compared with their B-cell counterparts, an outcome largely attributed to the fact that most treatment paradigms for patients with PTCL have been derived from B-cell neoplasms, a radically different disease. In fact, the first drug ever approved for patients with PTCL was approved only a decade ago. The plethora of recent drug approvals in PTCL, coupled with a deeper understanding of the molecular pathogenesis of the disease, has stimulated the field to pursue new avenues of research that are now largely predicated on the development of novel, targeted small molecules, which include a host of epigenetic modifiers and biologics. There is an expectation these advances may begin to favorably challenge the chemotherapy paradigms that have been used in the T-cell malignancies.
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Affiliation(s)
- Enrica Marchi
- Department of Medicine, Center for Lymphoid Malignancies, Columbia University Medical Center, College of Physicians and Surgeons, New York, New York
| | - Owen A O'Connor
- Department of Medicine, Center for Lymphoid Malignancies, Columbia University Medical Center, College of Physicians and Surgeons, New York, New York
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50
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van Vliet C, Spagnolo DV. T- and NK-cell lymphoproliferative disorders of the gastrointestinal tract: review and update. Pathology 2019; 52:128-141. [PMID: 31727264 DOI: 10.1016/j.pathol.2019.10.001] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2019] [Revised: 10/08/2019] [Accepted: 10/08/2019] [Indexed: 12/13/2022]
Abstract
T- and NK-cell lymphoproliferative disorders of the gastrointestinal (GI) tract are uncommon, but are important to recognise as there may be morphological and immunophenotypic overlap between lymphoid lesions with vastly different clinical outcomes. Recent data have led to the reclassification of some lymphomas and inclusion of new entities in the 2016 revision of World Health Organization (WHO) classification of lymphoid neoplasms. It has become clear that enteropathy associated T-cell lymphoma (EATL), formerly thought to be composed of two subtypes known as type I and type II, are distinct entities. Type I EATL is now simply classified as EATL; it is strongly associated with coeliac disease and occurs mainly in Western populations. Type II EATL has been renamed monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL); it shows no definite association with coeliac disease and occurs worldwide with a predominance in Asian populations. There is also a group of aggressive intestinal T-cell lymphomas which do not meet criteria for EATL, MEITL, extranodal NK/T-cell lymphoma of nasal type or anaplastic large cell lymphoma. These neoplasms are now designated intestinal T-cell lymphoma, not otherwise specified. Indolent T-cell lymphoproliferative disorder of the GI tract has been included as a provisional entity in the most recent WHO classification. It is a clonal T-cell lymphoproliferative disorder (CD4+ or CD8+) with an indolent clinical course. Finally, benign NK-cell proliferations of the GI tract, variably designated 'NK-cell enteropathy' and 'lymphomatoid gastropathy' have also been recognised in the last two decades but have not been included in the WHO classification as their neoplastic nature is not established. This review covers the aforementioned lymphoid proliferations, emphasising their salient clinicopathological features and genetic abnormalities. It also provides practical insights into resolving difficult differential diagnoses in daily surgical pathology practice.
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Affiliation(s)
- Chris van Vliet
- Anatomical Pathology, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, WA, Australia.
| | - Dominic V Spagnolo
- Anatomical Pathology, PathWest Laboratory Medicine, QEII Medical Centre, Nedlands, WA, Australia; University of Western Australia, School of Pathology and Laboratory Medicine, Nedlands, WA, Australia
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