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Grizzi F, Hegazi MA. Functional foods and celiac disease prevalent in North America and globally. FUNCTIONAL FOODS AND CHRONIC DISEASE 2024:105-114. [DOI: 10.1016/b978-0-323-91747-6.00006-8] [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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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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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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Malamut G, Cording S, Cerf-Bensussan N. Recent advances in celiac disease and refractory celiac disease. F1000Res 2019; 8:F1000 Faculty Rev-969. [PMID: 31297187 PMCID: PMC6600866 DOI: 10.12688/f1000research.18701.1] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/14/2019] [Indexed: 12/21/2022] Open
Abstract
Celiac disease (CeD), defined as gluten-induced enteropathy, is a frequent and largely underdiagnosed disease. Diagnosis relies on the detection of highly specific serum IgA anti-transglutaminase auto-antibodies and on the demonstration of duodenal villous atrophy. Treatment necessitates a strict gluten-free diet, which resolves symptoms and enables histological recovery. However, regular follow-up is necessary to assess mucosal healing, which emerges as an important prognostic factor. Recent work on CeD pathogenesis has highlighted how the cross-talk between gluten-specific CD4 + T cells and interleukin-15 can activate cytotoxic intraepithelial lymphocytes and trigger epithelial lesions. Moreover, acquisition by a subset of intraepithelial lymphocytes of somatic gain-of-function mutations in the JAK-STAT pathway was shown to be a decisive step in the progression toward lymphomas complicating CeD, thus opening new therapeutic perspectives for these rare but life-threatening complications.
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Affiliation(s)
- Georgia Malamut
- Gastroenterology, Hôpital Cochin APHP, Paris, France
- Université Paris Descartes, Paris, France
- Inserm, UMR1163 and Institut Imagine, Laboratory Intestinal Immunity, Paris, France
| | - Sascha Cording
- Université Paris Descartes, Paris, France
- Inserm, UMR1163 and Institut Imagine, Laboratory Intestinal Immunity, Paris, France
| | - Nadine Cerf-Bensussan
- Université Paris Descartes, Paris, France
- Inserm, UMR1163 and Institut Imagine, Laboratory Intestinal Immunity, Paris, France
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Abstract
Refractory celiac disease (RCD) refers to persistence of malnutrition and intestinal villous atrophy for more than 1 to 2 years despite strict gluten-free diet in patients with celiac disease. Diagnosis remains difficult and impacts treatment and follow-up. RCD has been subdivided into 2 subgroups according to the normal (RCDI) or abnormal phenotype of intraepithelial lymphocytes (IELs) (RCDII). RCDII is considered as a low-grade intraepithelial lymphoma and has a poor prognosis due to gastrointestinal and extraintestinal dissemination of the abnormal IELs, and high risk of overt lymphoma.
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Affiliation(s)
- Georgia Malamut
- Paris Descartes University, 15 rue de l'Ecole de Médecine, Paris 75006, France; Gastroenterology Department, Hôpital Européen Georges Pompidou, APHP, 20 rue Leblanc, Paris 75015, France; UMR1163 Institute Imagine, 24 Boulevard du Montparnasse, Paris 75015, France.
| | - Christophe Cellier
- Paris Descartes University, 15 rue de l'Ecole de Médecine, Paris 75006, France; Gastroenterology Department, Hôpital Européen Georges Pompidou, APHP, 20 rue Leblanc, Paris 75015, France; UMR1163 Institute Imagine, 24 Boulevard du Montparnasse, Paris 75015, France
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Parzanese I, Qehajaj D, Patrinicola F, Aralica M, Chiriva-Internati M, Stifter S, Elli L, Grizzi F. Celiac disease: From pathophysiology to treatment. World J Gastrointest Pathophysiol 2017; 8:27-38. [PMID: 28573065 PMCID: PMC5437500 DOI: 10.4291/wjgp.v8.i2.27] [Citation(s) in RCA: 157] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Revised: 03/08/2017] [Accepted: 03/23/2017] [Indexed: 02/06/2023] Open
Abstract
Celiac disease, also known as "celiac sprue", is a chronic inflammatory disorder of the small intestine, produced by the ingestion of dietary gluten products in susceptible people. It is a multifactorial disease, including genetic and environmental factors. Environmental trigger is represented by gluten while the genetic predisposition has been identified in the major histocompatibility complex region. Celiac disease is not a rare disorder like previously thought, with a global prevalence around 1%. The reason of its under-recognition is mainly referable to the fact that about half of affected people do not have the classic gastrointestinal symptoms, but they present nonspecific manifestations of nutritional deficiency or have no symptoms at all. Here we review the most recent data concerning epidemiology, pathogenesis, clinical presentation, available diagnostic tests and therapeutic management of celiac disease.
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Abstract
Refractory coeliac disease (RCD) is a recognised complication, albeit very rare, of coeliac disease (CD). This condition is described when individuals with CD continue to experience enteropathy and subsequent or ongoing malabsorption despite strict adherence to a diet devoid of gluten for at least 12 months and when all other causes mimicking this condition are excluded. Depending on the T-cell morphology and T-cell receptor (TCR) clonality at the β/γ loci, RCD can be subdivided into type 1 (normal intra-epithelial lymphocyte morphology, polyclonal TCR population) and type 2 (aberrant IELs with clonal TCR). It is important to differentiate between the two types as type 1 has an 80% survival rate and is managed with strict nutritional and pharmacological management. RCD type 2 on the other hand has a 5-year mortality of 50% and can be complicated by ulcerative jejunitis or enteropathy-associated T-cell lymphoma (EATL). Management of RCD type 2 has challenged many experts, and different treatment approaches have been adopted with variable results. Some of these treatments include immunomodulation with azathioprine and steroids, methotrexate, cyclosporine, alemtuzumab (an anti CD-52 monoclonal antibody), and cladribine or fludarabine sometimes with autologous stem cell transplantation. In this article, we summarise the management approach to patients with RCD type 2.
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Affiliation(s)
- Ikram Nasr
- Gastroenterology Department, St Thomas' Hospital, London, UK
| | - Iman Nasr
- Department of Allergy and Immunology, Royal Hospital, Muscat, Oman
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Recognising and Managing Refractory Coeliac Disease: A Tertiary Centre Experience. Nutrients 2015; 7:9896-907. [PMID: 26633478 PMCID: PMC4690058 DOI: 10.3390/nu7125506] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Revised: 11/10/2015] [Accepted: 11/16/2015] [Indexed: 12/19/2022] Open
Abstract
Refractory coeliac disease (RCD) is a rare complication of coeliac disease (CD) and involves malabsorption and villous atrophy despite adherence to a strict gluten-free diet (GFD) for at least 12 months in the absence of another cause. RCD is classified based on the T-cells in the intra-epithelial lymphocyte (IEL) morphology into type 1 with normal IEL and type 2 with aberrant IEL (clonal) by PCR (polymerase chain reaction) for T cell receptors (TCR) at the β/γ loci. RCD type 1 is managed with strict nutritional and pharmacological management. RCD type 2 can be complicated by ulcerative jejunitis or enteropathy associated lymphoma (EATL), the latter having a five-year mortality of 50%. Management options for RCD type 2 and response to treatment differs across centres and there have been debates over the best treatment option. Treatment options that have been used include azathioprine and steroids, methotrexate, cyclosporine, campath (an anti CD-52 monoclonal antibody), and cladribine or fluadribine with or without autologous stem cell transplantation. We present a tertiary centre's experience in the treatment of RCD type 2 where treatment with prednisolone and azathioprine was used, and our results show good response with histological recovery in 56.6% of treated individuals.
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Abstract
Within the past 20 years the spectrum of complications of coeliac disease (CD) has been considerably extended. Besides the classic complications, autoimmune diseases and osteopenia, numerous forms of CD non-responsive to a gluten-free diet have been recently identified. Among the non-responsive CD, the majority of patients presents as long term responders. However a small subset of CD patients becomes refractory to a gluten-free diet with persistent malabsorption and intestinal villous atrophy. Whereas refractory coeliac disease type I (RCDI) is hardly distinguishable from active CD, the type II (RCDII) has a severe clinical presentation and a very poor prognosis. Enteropathy Associated T cell Lymphoma (EATL) is even more aggressive with a five year survival of 20%. Classic adriamycin-based chemotherapy is poorly efficient in the lymphomatous complications of CD and current therapeutic strategies focus on more intensive regimen with autologous or allogenic stem cell transplantation. Notable pathogenic advances let us to test targeted therapy both in low (RCDII) and high grade lymphomatous (EATL) complications associated with CD.
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Abstract
A small subset of celiac disease (CD) patients becomes refractory to a gluten-free diet with persistent malabsorption and intestinal villous atrophy. This is a rare (probably less than 2% of adult CD patients), but serious disorder, with a high risk of progression to an overt T-cell lymphoma. Diagnosis of this condition defined as refractory CD (RCD) is made after exclusion of other small bowel diseases with villous atrophy. RCD has been subdivided into two subgroups according to the normal (RCDI) or abnormal phenotype of intraepithelial lymphocytes (RCDII). Whereas RCDI is hardly distinguishable from active noncompliant CD, RCDII has a severe clinical presentation and a very poor prognosis. We precisely describe below the different types of RCD and propose diagnostic and therapeutic guidelines for its clinical management.
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Pascual V, Dieli-Crimi R, López-Palacios N, Bodas A, Medrano LM, Núñez C. Inflammatory bowel disease and celiac disease: Overlaps and differences. World J Gastroenterol 2014; 20:4846-4856. [PMID: 24803796 PMCID: PMC4009516 DOI: 10.3748/wjg.v20.i17.4846] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Accepted: 01/15/2014] [Indexed: 02/06/2023] Open
Abstract
Recent findings demonstrate the common genetic basis for many immune-mediated diseases, and consequently, the partially shared pathogenesis. We collected these findings and reviewed the extension of these overlaps to other disease characteristics. Two autoimmune diseases were selected that also share the specific target organ, the bowel. The etiology and immunopathogenesis of both conditions characterized by chronic intestinal inflammation, inflammatory bowel disease (IBD) and celiac disease (CeD), are not completely understood. Both are complex diseases with genetics and environment contributing to dysregulation of innate and adaptive immune responses, leading to chronic inflammation and disease. CeD constitutes a particular disease because the main environmental and genetic triggers are largely known. IBD comprises two main clinical forms, Crohn’s disease and ulcerative colitis, which most likely involve a complex interplay between some components of the commensal microbiota and other environmental factors in their origin. These multifactorial diseases encompass a broad spectrum of clinical phenotypes and ages of onset, although the clinical presentation often differs depending on childhood or adult onset, with greater heterogeneity commonly observed in adults.
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Malamut G, Meresse B, Kaltenbach S, Derrieux C, Verkarre V, Macintyre E, Ruskone-Fourmestraux A, Fabiani B, Radford-Weiss I, Brousse N, Hermine O, Cerf-Bensussan N, Cellier C. Small intestinal CD4+ T-cell lymphoma is a heterogenous entity with common pathology features. Clin Gastroenterol Hepatol 2014; 12:599-608.e1. [PMID: 24316103 DOI: 10.1016/j.cgh.2013.11.028] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Accepted: 11/19/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Little is known about intestinal CD4+ T-cell lymphoma; this rare malignancy is misdiagnosed frequently. We evaluated diagnostic criteria and factors that might affect its development and outcome. METHODS In a retrospective analysis, we analyzed medical records and intestinal specimens from 10 patients diagnosed with intestinal CD4+ T-cell lymphoma among 115 consecutive patients examined for severe enteropathy with villous atrophy. Samples were analyzed by histology, flow cytometry, and comparative genomic hybridization. RESULTS Small-intestine epithelial and lamina propria tissues from patients who presented with chronic diarrhea and malnutrition had variable levels of infiltration of CD3+ CD4+ T cells. Flow cytometry showed a high frequency of CD4+ intraepithelial cells, which frequently expressed a specific Vβ chain. T-cell receptor β clonality was confirmed by DNA sequencing. Two patients had HLA and serology results compatible with celiac disease and autoimmune enteropathy, respectively. Two patients were found to have antibodies against human T-cell leukemia virus and 2 patients had signs of a recent infection with the herpes viruses. Comparative genomic hybridization analyses showed heterogeneous chromosomal abnormalities. Symptoms were reduced in patients treated with steroids (n = 5), but not in patients given purine analogues or chemotherapy. Antibodies against CD52 produced clinical and histologic responses in 2 of 2 patients, whereas severe adverse effects developed in 1 patient. At the latest follow-up evaluation, all patients were alive. CONCLUSIONS There is much heterogeneity in the onset and genetic features of intestinal CD4+ T-cell lymphomas, despite their common presentation as indolent lymphoproliferations of the intestinal mucosa. Patients should be treated with steroids, and possibly antibodies against CD52 (for the most aggressive forms of this disorder).
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Affiliation(s)
- Georgia Malamut
- Université Paris Descartes-Sorbonne Paris Centre, Paris, France; Gastroenterology Department, Hôpital Européen Georges Pompidou Assistance Publique des Hôpitaux de Paris, Paris, France; Inserm U989, Paris, France; Institute Imagine, Paris, France.
| | - Bertrand Meresse
- Université Paris Descartes-Sorbonne Paris Centre, Paris, France; Inserm U989, Paris, France; Institute Imagine, Paris, France
| | - Sophie Kaltenbach
- Université Paris Descartes-Sorbonne Paris Centre, Paris, France; Cytogenetic Department, Hôpital Necker Enfants Malades Assistance Publique des Hôpitaux de Paris, Paris, France
| | - Coralie Derrieux
- Université Paris Descartes-Sorbonne Paris Centre, Paris, France; Biological Hematology Department, Hôpital Necker Enfants Malades Assistance Publique des Hôpitaux de Paris, Paris, France
| | - Virginie Verkarre
- Université Paris Descartes-Sorbonne Paris Centre, Paris, France; Pathology Department, Hôpital Necker Enfants Malades Assistance Publique des Hôpitaux de Paris, Paris, France
| | - Elizabeth Macintyre
- Université Paris Descartes-Sorbonne Paris Centre, Paris, France; Biological Hematology Department, Hôpital Necker Enfants Malades Assistance Publique des Hôpitaux de Paris, Paris, France
| | - Agnès Ruskone-Fourmestraux
- Gastroenterology Department, Hôpital Saint-Antoine Assistance Publique des Hôpitaux de Paris, Paris, France
| | - Bettina Fabiani
- Pathology Department, Hôpital Saint-Antoine Assistance Publique des Hôpitaux de Paris, Paris, France
| | - Isabelle Radford-Weiss
- Université Paris Descartes-Sorbonne Paris Centre, Paris, France; Cytogenetic Department, Hôpital Necker Enfants Malades Assistance Publique des Hôpitaux de Paris, Paris, France
| | - Nicole Brousse
- Université Paris Descartes-Sorbonne Paris Centre, Paris, France; Pathology Department, Hôpital Necker Enfants Malades Assistance Publique des Hôpitaux de Paris, Paris, France
| | - Olivier Hermine
- Université Paris Descartes-Sorbonne Paris Centre, Paris, France; Institute Imagine, Paris, France; Hematology Department, Hôpital Necker Enfants Malades Assistance Publique des Hôpitaux de Paris, Paris, France
| | - Nadine Cerf-Bensussan
- Université Paris Descartes-Sorbonne Paris Centre, Paris, France; Inserm U989, Paris, France; Institute Imagine, Paris, France
| | - Christophe Cellier
- Université Paris Descartes-Sorbonne Paris Centre, Paris, France; Gastroenterology Department, Hôpital Européen Georges Pompidou Assistance Publique des Hôpitaux de Paris, Paris, France; Inserm U989, Paris, France; Institute Imagine, Paris, France
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Abstract
PURPOSE OF REVIEW Concept of refractory coeliac disease (RCD) emerged in the past decade and refers to persistence of malnutrition and intestinal villous atrophy for more than 1 year strict gluten-free diet in coeliac patients. Diagnosis of this condition remains difficult and conditions treatment and follow-up. RECENT FINDINGS RCD has been subdivided into two subgroups according to the normal [type I RCD (RCDI)] or abnormal phenotype of intraepithelial lymphocytes [type II RCD (RCDII)]. RCDII is considered as a low-grade intraepithelial lymphoma and has a very poor prognosis, leading to intractable ulcerative jejunitis, gastrointestinal and extra-intestinal dissemination of the abnormal intraepithelial lymphocytes, and to their frequent transformation into a high-grade invasive lymphoma. SUMMARY Herein, we review here the distinctive diagnostic features of RCDI and RCDII, the risk of developing overt lymphoma and different therapeutic approaches.
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14
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Abstract
A small subset of celiac disease (CD) patients becomes refractory to a gluten-free diet with persistent malabsorption and intestinal villous atrophy. Diagnosis of this condition defined as refractory celiac disease (RCD) is made after exclusion of other small bowel diseases with villous atrophy. RCD has been subdivided into two subgroups according to the normal or abnormal phenotype of intraepithelial lymphocytes. Whereas normal RCD is hardly distinguishable from active CD, abnormal RCD has a severe clinical presentation and a very poor prognosis. We precisely describe below the different types of RCD and propose diagnostic and therapeutic guidelines for its clinical management.
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Affiliation(s)
- Georgia Malamut
- Université Paris Descartes-Sorbonne Paris Centre, Paris, France
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Verbeek WHM, Schreurs MWJ, Visser OJ, von Blomberg BME, Al-Toma A, Mulder CJJ. Novel approaches in the management of refractory celiac disease. Expert Rev Clin Immunol 2014; 4:205-19. [PMID: 20477051 DOI: 10.1586/1744666x.4.2.205] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- Wieke H M Verbeek
- VU University Medical Center, Department of Gastroenterology and Hepatology, PO Box 7057, 1007 MB, Amsterdam, The Netherlands.
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16
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Abstract
A small subset of patients with celiac disease become refractory to a gluten-free diet, with persistent or recurrent symptoms of malabsorption and intestinal villous atrophy. This condition, defined as refractory celiac disease (RCD), is diagnosed after other small bowel diseases with villous atrophy are excluded. RCD is subdivided into 2 subgroups: type I RCD and type II RCD (RCDII). This latter condition is considered a low-grade intraepithelial lymphoma and has a poor prognosis. This article reviews the clinical and pathologic features of RCD and recent pathogenic findings in RCDII, offering a model to study how inflammation can drive T-cell lymphomagenesis.
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Refractory celiac disease: from bench to bedside. Semin Immunopathol 2012; 34:601-13. [PMID: 22810901 DOI: 10.1007/s00281-012-0322-z] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2012] [Accepted: 06/15/2012] [Indexed: 02/08/2023]
Abstract
Refractory celiac disease is defined by the persistence of symptoms of malnutrition and intestinal villous atrophy for more than 6-12 months despite strict gluten-free diet in celiac patients. Diagnosis of this rare condition is made after excluding other causes of chronic small intestinal inflammation and villous atrophy and inadvertent intake of gluten. Over the past 15 years, multidisciplinary approaches have been developed to assess the mechanism of resistance to the diet, and two distinct entities have been delineated. Type II refractory celiac disease (RCD) can be defined as a low-grade intraepithelial lymphoma. RCD II is characterised by a massive accumulation of abnormal IEL that display an aberrant hybrid NK/T cell phenotype, contain clonal T cell rearrangement(s) and can mediate a cytolytic attack of the gut epithelium. This condition has a severe prognosis, largely due to the frequent transformation of RCDII IEL into overt aggressive enteropathy-type-associated T cell lymphoma. In contrast, in type I RCD, intestinal lymphocytes have a normal phenotype, and this generally milder condition remains often difficult to differentiate from uncomplicated CD except for the resistance to gluten-free diet (GFD). Several mechanisms may underlie resistance to gluten. Herein, we review the distinctive characteristics of RCD I and RCD II, the mechanisms underlying the onset of resistance to GFD, the risk of developing high grade lymphoma and possible clues to improve their treatment.
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Amiot A, Allez M, Treton X, Fieschi C, Galicier L, Joly F, Gornet JM, Oksenhendler E, Lémann M, Bouhnik Y. High frequency of fatal haemophagocytic lymphohistiocytosis syndrome in enteropathy-associated T cell lymphoma. Dig Liver Dis 2012; 44:343-9. [PMID: 22100722 DOI: 10.1016/j.dld.2011.10.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2011] [Revised: 10/09/2011] [Accepted: 10/13/2011] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Enteropathy-associated T-cell lymphoma is a rare form of T-cell lymphoma associated with a poor prognosis and the relative ineffectiveness of standard chemotherapy. The occurrence of haemophagocytic lymphohistiocytosis has been reported only once with this entity. PATIENTS AND METHODS A retrospective study of 15 patients with enteropathy-associated T-cell lymphoma (type 1 in 12), followed-up in our units, since 1985. Two patients died before starting chemotherapy. The remaining 13 patients were treated with standard chemotherapy (n=7) and purine nucleotide analogues (n=6). RESULTS Median follow-up was 8.7 (1-97) months. Surgery was required in 10 patients (66%) for intestinal complications (n=7) or elective small bowel resection (n=3). Survival probability was 40% and 20% at 1 and 5 years, respectively (Kaplan-Meier method). Survival was not significantly different between the two chemotherapy regimens. However, a slight decrease of febrile neutropenia was observed in the purine nucleotide analogues group (p=0.06). Haemophagocytic lymphohistiocytosis occurred in 6/15 (40%) cases. In these six patients, haemophagocytic lymphohistiocytosis was always fatal within 3 months. CONCLUSION Enteropathy-associated T-cell lymphoma is associated with a poor outcome, independently of the chemotherapy regimens administered and frequent occurrence of haemophagocytic lymphohistiocytosis. The latter complication should be considered for urgent rescue therapy.
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Affiliation(s)
- Aurelien Amiot
- Pôle des Maladies de l'Appareil Digestif, Service de Gastroentérologie et d'Assistance Nutritive, Hôpital Beaujon, Clichy et Université Diderot, Paris VII, France.
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19
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Abstract
Refractory coeliac disease (RCD) is defined by persistent or recurrent malabsorptive symptoms and villous atrophy despite strict adherence to a gluten-free diet (GFD) for at least 6-12 months in the absence of other causes of non-responsive treated coeliac disease and overt malignancy. Symptoms are often severe and require additional therapeutic intervention besides a GFD. RCD can be classified as type 1 (normal intraepithelial lymphocyte phenotype), or type 2 (defined by the presence of abnormal (clonal) intraepithelial lymphocyte phenotype). Patients with RCD may never have responded to a GFD or may have relapsed despite adherence and initial response to the GFD. RCD type 1 usually improves after treatment with a combination of aggressive nutritional support, adherence to a GFD, and alternative pharmacological therapies. By contrast, clinical response to alternative therapies in RCD type 2 is less certain and the prognosis is poor. Severe complications such as ulcerative jejunitis and enteropathy-associated T cell lymphoma may occur in a subgroup of patients with RCD. The aims of this article are to (1) review recent advances in the diagnosis and management of patients with RCD, and (2) describe current and novel methods for classification of patients with RCD into categories that are useful to predict outcome and direct treatment.
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Affiliation(s)
- Alberto Rubio-Tapia
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
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20
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Tack GJ, Verbeek WHM, Schreurs MWJ, Mulder CJJ. The spectrum of celiac disease: epidemiology, clinical aspects and treatment. Nat Rev Gastroenterol Hepatol 2010; 7:204-13. [PMID: 20212505 DOI: 10.1038/nrgastro.2010.23] [Citation(s) in RCA: 175] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Celiac disease is a gluten-sensitive enteropathy that affects people of all ages worldwide. This disease has emerged as a major health-care problem, as advances in diagnostic and screening methods have revealed its global prevalence. Environmental factors such as gluten introduction at childhood, infectious agents and socioeconomic features, as well as the presence of HLA-DQ2 and/or HLA-DQ8 haplotypes or genetic variations in several non-HLA genes contribute to the development of celiac disease. Growing insight into the variable clinical and histopathological presentation features of this disease has opened new perspectives for future research. A strict life-long gluten-free diet is the only safe and efficient available treatment, yet it results in a social burden. Alternative treatment modalities focus on modification of dietary components, enzymatic degradation of gluten, inhibition of intestinal permeability and modulation of the immune response. A small group of patients with celiac disease (2-5%), however, fail to improve clinically and histologically upon elimination of dietary gluten. This complication is referred to as refractory celiac disease, and imposes a serious risk of developing a virtually lethal enteropathy-associated T-cell lymphoma.
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Affiliation(s)
- Greetje J Tack
- Department of Gastroenterology and Hepatology, VU University Medical Center, P. O. Box 7057, 1007 MB Amsterdam, The Netherlands.
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Ho-Yen C, Chang F, van der Walt J, Mitchell T, Ciclitira P. Recent advances in refractory coeliac disease: a review. Histopathology 2009; 54:783-95. [PMID: 18700844 DOI: 10.1111/j.1365-2559.2008.03112.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Coeliac disease (CD) is an immune-mediated disease of the small intestine caused by intolerance to gluten. Removal of gluten from the diet results in a return to normal health for the majority of patients. A significant proportion of patients do not respond to a gluten-free diet and are considered to be suffering from refractory coeliac disease (RCD). Two types of RCD are now recognized: type 1 RCD is characterized by a polyclonal population of intraepithelial lymphocytes (IELs) with a normal immunophenotype, and type 2 RCD shows monoclonal IELs with an aberrant immunoprofile. Patients with RCD have a high risk of complications such as ulcerative jejunitis (UJ) and enteropathy-type T-cell lymphoma (ETTL). RCD2 may represent an early stage in the development of overt lymphoma. The diagnosis of RCD, therefore, has important implications, but remains a challenging area. In this paper we review the latest developments in RCD, including the diagnostic approach and a discussion of the key clinical, histological, immunohistochemical and molecular features of RCD and its complications.
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Affiliation(s)
- C Ho-Yen
- Department of Histopathology, Guy's and St Thomas' NHS Foundation Trust, London, UK.
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Malamut G, Afchain P, Verkarre V, Lecomte T, Amiot A, Damotte D, Bouhnik Y, Colombel JF, Delchier JC, Allez M, Cosnes J, Lavergne-Slove A, Meresse B, Trinquart L, Macintyre E, Radford-Weiss I, Hermine O, Brousse N, Cerf-Bensussan N, Cellier C. Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II. Gastroenterology 2009; 136:81-90. [PMID: 19014942 DOI: 10.1053/j.gastro.2008.09.069] [Citation(s) in RCA: 250] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2008] [Revised: 08/27/2008] [Accepted: 09/18/2008] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Refractory celiac disease (RCD) was recently subdivided into 2 subtypes (RCD I and II) based on a normal or abnormal phenotype of intraepithelial lymphocytes (IELs), respectively. It is not clear, however, if these 2 entities differ in their presentation at diagnosis or long-term outcome. We compared the clinical and biological characteristics of RCD I and RCD II at diagnosis, the risk of developing an overt lymphoma, and the predictive factors of survival. METHODS Medical files of 14 patients with RCD I and 43 with RCD II were analyzed retrospectively. Predictive factors of overt lymphoma and survival were studied in univariate and multivariate analyses. RESULTS At diagnosis, malnutrition, ulcerative jejunitis, and lymphocytic gastritis were more common in patients with RCD II than RCD I (P< .05). Overt lymphomas occurred in 2 patients with RCD I and 16 with RCD II. In the univariate analysis, abnormal IEL phenotype and increased age at diagnosis of RCD were predictive factors for overt lymphoma. Abnormal IEL phenotype (P< .01), clonality (P= .01), and overt lymphoma (P= .001) predicted short survival time. Only abnormal IEL phenotype (P= .03) and overt lymphoma (P= .04) were predictive in the multivariate analysis. The 5-year survival rate was 93% in patients with RCD I and 44% with RCD II. CONCLUSIONS RCD II has a much more severe presentation and prognosis than patients with RCD I; <44% of patients with RCD II survive 5 years after diagnosis. Abnormal IEL phenotype is a predictive factor but not a necessary condition for the development of overt lymphoma.
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Crenn P, Messing B, Cynober L. Citrulline as a biomarker of intestinal failure due to enterocyte mass reduction. Clin Nutr 2008; 27:328-339. [PMID: 18440672 DOI: 10.1016/j.clnu.2008.02.005] [Citation(s) in RCA: 302] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2007] [Revised: 02/12/2008] [Accepted: 02/22/2008] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS In human, citrulline (plasma concentration about 40 micromol/L) is an amino acid involved in intermediary metabolism and that is not incorporated in proteins. Circulating citrulline is mainly produced by enterocytes of the small bowel. For this reason plasma or serum citrulline concentration has been proposed as a biomarker of remnant small bowel mass and function. This article reviews this concept and its metabolic basis. METHODS Conditions in which there is a significantly reduced small bowel enterocyte mass and function and a plasma or serum citrulline were measured in adults and children. These studies included patients with a short bowel syndrome, villous atrophy states, Crohn's disease, during monitoring of digestive toxicity of chemotherapy and radiotherapy or follow-up of patients after small bowel transplantation. RESULTS In all these situations, with more than 500 studied patients a decreased level of plasma citrulline correlated with the reduced enterocyte mass independently of nutritional and inflammatory status. A close correlation between small bowel remnant length and citrullinemia was found. In addition, diagnosis of intestinal failure was assessed through plasma citrulline levels in severe small bowel diseases in which there is a marked enterocyte mass reduction. DISCUSSION The threshold for establishing a diagnosis of intestinal failure is lower in villous atrophy disease (10mumol/L) than in short bowel syndrome (20mumol/L). Compromised renal function is an important factor when considering plasma citrulline levels as a marker of intestinal failure as this potentially can increase circulating citrulline values. CONCLUSIONS Reduced plasma citrulline levels are an innovative quantitative biomarker of significantly reduced enterocyte mass and function in different disease states in humans.
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Affiliation(s)
- Pascal Crenn
- Département de Médecine, Hôpital Raymond Poincaré, Assistance Publique-Hôpitaux de Paris, Université de Versailles Saint-Quentin-en-Yvelines, Garches, France.
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Cellier C, Cerf-Bensussan N. Treatment of clonal refractory celiac disease or cryptic intraepithelial lymphoma: A long road from bench to bedside. Clin Gastroenterol Hepatol 2006; 4:1320-1. [PMID: 17110301 DOI: 10.1016/j.cgh.2006.09.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Messing B, Joly F. Insuffisance intestinale chronique : passé, présent, avenir. NUTR CLIN METAB 2006. [DOI: 10.1016/s0985-0562(06)80021-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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