An unexpected deterrent in diagnosing refractory celiac disease and enteropathy-associated T-cell lymphoma: a gluten-free diet

Background & Aims: In most cases celiac disease (CD) is successfully treated with a gluten-free diet (GFD). However, some patients become refractory to the GFD. Refractory CD (RCD) patients have an increased risk for developing enteropathy associated T-cell lymphoma and early diagnosis is therefore of importance. Currently, RCD diagnosis relies on endoscopy and adequate serological markers are lacking. Antibodies against glycoprotein-2 (GP2A) were described in Crohn's disease (CrD) and active CD but not in ulcerative colitis (UC), suggesting this is a specific marker for small intestinal lesions.Methods: Sera obtained from patients visiting our outpatient clinic for routine serological tests for diagnosis and/or follow-up of inflammatory bowel disease (n=78), active CD (n=45), GFD (n=34) and RCD (n=15) were analysed for GP2A titres.Results: Increased GP2A-IgA levels in CrD and active CD as compared to controls (p<0.001) and lack thereof in UC was confirmed. However, we could not confirm the association with small bowel localization within the CrD patient group. Within CD patients, we demonstrated a significant decrease of GP2A-IgA titres upon a GFD and increased levels in RCD patients as compared to patients on a GFD. Although GP2A-IgA was not associated with the degree of villous atrophy, GP2A-IgA levels were able to distinguish RCD patients from GFD patients (ROC AUC=0.79, p=0.002).Conclusion: Follow-up of GP2A-IgA titres in CD patients on a GFD may help to identify patients at risk for developing RCD.Abbreviations: ABSA: anti-bovine serum albumine; ASCA: anti- Saccharomyces cerevisiae antigen; AU:artificial units; AUC: area under the curve; CD: celiac disease; CrD: Crohn's disease; EATL: enteropathyassociated T-cell lymphoma; EmA: anti-endomysium antibodies; GFD: gluten free diet; GP2A: glycoprotein 2 antibodies; IEL: intraepithelial lymphocytes; RCD: refractory celiac disease; ROC: receiver operator curve; TG2A: transglutaminase-2 antibodies; UC: ulcerative colitis.

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Are Complicated Forms of Celiac Disease Cryptic T-Cell Lymphomas?

Blood ◽

10.1182/blood.v92.10.3879 ◽

1998 ◽

Vol 92 (10) ◽

pp. 3879-3886 ◽

Cited By ~ 94

Author(s):

Franck Carbonnel ◽

Laurence Grollet-Bioul ◽

Jean Claude Brouet ◽

Marie Françoise Teilhac ◽

Jacques Cosnes ◽

...

Keyword(s):

Bone Marrow ◽

Celiac Disease ◽

T Cell ◽

Cell Lymphoma ◽

Large Cell ◽

Cell Receptor ◽

T Cell Lymphoma ◽

Gluten Free Diet ◽

Gluten Free ◽

Duodenal Biopsies

Abstract We assessed the clonality of duodenal mucosal T cells in patients with celiac disease and controls. Fifteen adult patients were studied. Four patients had a complicated celiac disease, 3 did not respond to a gluten-free diet, and 2 had an ulcerative jejunitis (including 1 patient with nonresponsive celiac disease). Seven patients had an untreated celiac disease responsive to a gluten-free diet. Histological examination of duodenal biopsies of these 11 patients showed benign-appearing celiac disease without evidence of lymphoma. Four patients with nonulcer dyspepsia and normal duodenal biopsies served as controls. TCRγ gene rearrangements were analyzed by multiplex polymerase chain reaction on DNA extracted from duodenal biopsies. Major clonal rearrangements of the T-cell receptor were found in 4 cases, all with complicated celiac disease. Monoclonality was confirmed by DNA sequencing of the junctional region in 3 cases and by hybridization with clone-specific oligoprobes. Patients with celiac disease responsive to gluten-free diet had mainly a polyclonal pattern, with 1 of them having an oligoclonal rearrangement. An oligoclonal pattern was also observed in 2 control patients. Three patients with complicated celiac disease evolved to T-cell lymphoma with liver (n = 2) or bone marrow (n = 1) invasion. Identical clones were found in the enteropathic duodenojejunum and peripheral blood in the patient with large-cell lymphoma with bone marrow invasion. This study suggests that complicated celiac disease is a cryptic T-cell lymphoma.

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Are Complicated Forms of Celiac Disease Cryptic T-Cell Lymphomas?

Blood ◽

10.1182/blood.v92.10.3879.422k34_3879_3886 ◽

1998 ◽

Vol 92 (10) ◽

pp. 3879-3886

Author(s):

Franck Carbonnel ◽

Laurence Grollet-Bioul ◽

Jean Claude Brouet ◽

Marie Françoise Teilhac ◽

Jacques Cosnes ◽

...

Keyword(s):

Bone Marrow ◽

Celiac Disease ◽

T Cell ◽

Cell Lymphoma ◽

Large Cell ◽

Cell Receptor ◽

T Cell Lymphoma ◽

Gluten Free Diet ◽

Gluten Free ◽

Duodenal Biopsies

We assessed the clonality of duodenal mucosal T cells in patients with celiac disease and controls. Fifteen adult patients were studied. Four patients had a complicated celiac disease, 3 did not respond to a gluten-free diet, and 2 had an ulcerative jejunitis (including 1 patient with nonresponsive celiac disease). Seven patients had an untreated celiac disease responsive to a gluten-free diet. Histological examination of duodenal biopsies of these 11 patients showed benign-appearing celiac disease without evidence of lymphoma. Four patients with nonulcer dyspepsia and normal duodenal biopsies served as controls. TCRγ gene rearrangements were analyzed by multiplex polymerase chain reaction on DNA extracted from duodenal biopsies. Major clonal rearrangements of the T-cell receptor were found in 4 cases, all with complicated celiac disease. Monoclonality was confirmed by DNA sequencing of the junctional region in 3 cases and by hybridization with clone-specific oligoprobes. Patients with celiac disease responsive to gluten-free diet had mainly a polyclonal pattern, with 1 of them having an oligoclonal rearrangement. An oligoclonal pattern was also observed in 2 control patients. Three patients with complicated celiac disease evolved to T-cell lymphoma with liver (n = 2) or bone marrow (n = 1) invasion. Identical clones were found in the enteropathic duodenojejunum and peripheral blood in the patient with large-cell lymphoma with bone marrow invasion. This study suggests that complicated celiac disease is a cryptic T-cell lymphoma.

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Effect of a Gluten-free Diet on the Risk of Enteropathy-associated T-cell Lymphoma in Celiac Disease

Digestive Diseases and Sciences ◽

10.1007/s10620-007-9952-8 ◽

2007 ◽

Vol 53 (4) ◽

pp. 972-976 ◽

Cited By ~ 50

Author(s):

Marco Silano ◽

Umberto Volta ◽

Alessandro De Vincenzi ◽

Mariarita Dessì ◽

Massimo De Vincenzi ◽

...

Keyword(s):

Celiac Disease ◽

T Cell ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Gluten Free Diet ◽

Gluten Free

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Serendipity in Refractory Celiac Disease: Full Recovery of Duodenal Villi and Clinical Symptoms after Fecal Microbiota Transfer

Journal of Gastrointestinal and Liver Diseases ◽

10.15403/jgld.2014.1121.253.cel ◽

2016 ◽

Vol 25 (3) ◽

pp. 385-388 ◽

Cited By ~ 15

Author(s):

Yvette H. Van Beurden ◽

Tom Van Gils ◽

Nienke A. Van Gils ◽

Zain Kassam ◽

Chris J.J. Mulder ◽

...

Keyword(s):

Celiac Disease ◽

T Cell ◽

Clostridium Difficile ◽

Clostridium Difficile Infection ◽

Cell Lymphoma ◽

Fecal Microbiota ◽

Disease Type ◽

T Cell Lymphoma ◽

Type Ii ◽

Refractory Celiac Disease

Treatment of refractory celiac disease type II (RCD II) and preventing the development of an enteropathy associated T-cell lymphoma in these patients is still difficult. In this case report, we describe a patient with RCD II who received fecal microbiota transfer as treatment for a recurrent Clostridium difficile infection, and remarkably showed a full recovery of duodenal villi and disappearance of celiac symptoms. This case suggests that altering the gut microbiota may hold promise in improving the clinical and histological consequences of celiac disease and/or RCD II. Abbreviations: CDI: Clostridium difficile infection; EATL : enteropathy associated T-cell lymphoma; FMT: fecal microbiota transfer; IEL: intraepithelial lymphocytes; RCD II: refractory celiac disease type II; TPN: total parenteral nutrition.

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Enteropathy-Type T-cell Lymphoma: Its Relationship to Refractory Celiac Disease

Pathology Case Reviews ◽

10.1097/01.pcr.0000015747.87813.27 ◽

2002 ◽

Vol 7 (3) ◽

pp. 110-116

Author(s):

Dennis P. OʼMalley ◽

Margaret L. Gulley ◽

Peter M. Banks

Keyword(s):

Celiac Disease ◽

T Cell ◽

Cell Lymphoma ◽

T Cell Lymphoma ◽

Refractory Celiac Disease

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The Intracellular Intensity of CD3 on Aberrant Intraepithelial Lymphocytes Is a Prognostic Factor of the Progression to Overt Lymphoma in Refractory Celiac Disease Type II (Pre-Enteropathy-Associated T Cell Lymphoma)

Digestive Diseases ◽

10.1159/000506305 ◽

2020 ◽

Vol 38 (6) ◽

pp. 490-499 ◽

Cited By ~ 1

Author(s):

Carlota García-Hoz ◽

Laura Crespo ◽

Natalia Lopez ◽

Ana De Andrés ◽

Raquel Ríos León ◽

...

Keyword(s):

Celiac Disease ◽

T Cell ◽

Cell Lymphoma ◽

Intraepithelial Lymphocytes ◽

Disease Type ◽

T Cell Lymphoma ◽

Control Group ◽

Type Ii ◽

Refractory Celiac Disease ◽

Single Center Study

Background: Refractory celiac disease type II (RCD-II) is a very rare yet severe complication of celiac disease (CD) with a 50% rate of progression to Enteropathy-associated T-cell lymphoma (EATL). Timely diagnosis and treatment of RCD-II is of the essence and requires the identification of a population of frequently clonal, phenotypically aberrant intraepithelial lymphocytes (IELs). Flow Cytometry of intestinal IELs is the recommended method to identify the aberrant surface CD3-negative (sCD3–) intracytoplasmic CD3-positive (icCD3ε+) IELs, and a proportion of >20% is diagnostic of RCD-II. There is substantial heterogeneity in the clinical course of RCD-II, and insufficient information on prognostic factors. Aim: To establish flow cytometric predictors of the clinical evolution of RCD-II, to help guide treatment approaches. Patients and Methods: Retrospective single-center study of clinical and immunological features of 6 RCD-II patients and a control group, both identified from a 2,000-patient cohort over 16 years. IEL subset frequencies and the intensity of staining for surface (s) and intracytoplasmic (ic) CD3ε+ on IEL subsets were quantified and correlated with the clinical outcome. Results: Unexpectedly, the frequency of aberrant sCD3– icCD3ε+ cells at diagnosis did not correlate with histological or clinical affection. However, a higher intensity of icCD3ε+ staining in the aberrant IELs relative to expression on normal IELs correlated with monoclonality and with worse clinical outcomes. Conclusion: The ratio of icCD3ε+ on aberrant IELs vs. normal IELs appears to be a useful indicator of prognosis at the time of diagnosis, and may represent a novel tool in the follow-up of RCD-II patients after therapy.

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