The Diagnostic Utility of Flow Cytometry in Celiac Disease Presented Isolated Iron Deficiency Anemia

Background: Flow cytometric analysis of intestinal intraepithelial lymphocytes contributes to the diagnosis of celiac disease. Celiac disease may present with iron deficiency anemia alone which is considered as one of the forms of atypical celiac disease. In this study, we have aimed to investigate the diagnostic utility of flow cytometric analysis of intraepithelial lymphocytes in this atypical form.Methods: Three groups were formed: the patients with unexplained iron deficiency (group 1), the patients with celiac disease (group 2), and the patients who underwent gastroduodenoscopy for other reasons (group 0). Duodenal biopsy samples were used for flow cytometric analysis of intraepithelial lymphocytes. T cell receptor gammadelta intraepithelial lymphocytes and CD3−/CD103+ intraepithelial lymphocytes were determined with relevant monoclonal antibodies. Sensitivity–specificity calculation was performed to evaluate the usability of flow cytometric variables as diagnostic tests.Results: Group 1 had 22 patients, group 2 had 14 patients, and group 0 had 56 patients. In the comparison of the 3 groups, CD3+/TCRγδ+ intraepithelial lymphocytes were found to be higher in celiac patients than other cases. CD3+/TCRγδ+ intraepithelial lymphocyte was evaluated for its usability as a diagnostic test. The cut-off value of CD3+/TCRγδ+ intraepithelial lymphocyte as 16.39% according to receiver operating characteristics curve analysis determined celiac disease in 14 of 22 patients in group 1 with 91.7% sensitivity and 80.4% specificity.Conclusions: Although celiac disease is diagnosed with serologic tests and histologic examination, successively, the increase in intestinal CD3+/TCRγδ+ intraepithelial lymphocytes may be used as a diagnostic test, and it may assist in revealing atypical forms of celiac disease.     

Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease

BACKGROUND & AIMS: The mechanism of intraepithelial lymphocyte hyperplasia, a hallmark of celiac disease, is unknown. We have investigated the role of epithelium-derived interleukin (IL)-15 in the alterations of epithelial homeostasis in refractory celiac sprue, a privileged situation to study the first step of lymphoid transformation and the contribution of intraepithelial lymphocytes to villous atrophy in celiac disease. METHODS: IL-15 expression was assessed in biopsy specimens and isolated enterocytes by combining immunohistochemistry, flow cytometry, and real-time quantitative polymerase chain reaction. The ability of IL-15 to induce growth and survival of clonal intraepithelial lymphocytes lacking surface CD3 and to induce their cytotoxicity and secretion of interferon gamma was tested using soluble IL-15 and coculture in the presence of epithelial cell lines expressing membrane IL-15. RESULTS: IL-15 was massively overexpressed not only in lamina propria but also in the intestinal epithelium of patients with active celiac disease and refractory celiac sprue. IL-15 was not secreted but delivered at the surface of enterocytes. IL-15 specifically induced the expansion and survival of the clonal abnormal intraepithelial lymphocytes that characterize refractory celiac sprue and triggered their secretion of interferon gamma and their cytotoxicity against intestinal epithelial cells. Comparable activating signals could be delivered by IL-15 expressed at the membrane of the T84 enterocyte cell line. CONCLUSIONS: These data provide strong evidence that uncontrolled overexpression of IL-15 in refractory celiac sprue perpetuates epithelial damage and promotes the emergence of T-cell clonal proliferations. Blocking IL-15 might prove useful to treat this severe complication of celiac disease.     

Refractory sprue

Celiac disease is a T cell-mediated disorder that results from intolerance to gluten. The major cause of failure to respond to a gluten-free diet is continuing gluten ingestion. In poorly responsive patients diagnosis of refractory sprue can be established after exclusion of a limited number of conditions. Refractory sprue may occur after an initial response to the diet or without evidence of preexisting celiac disease. The detection of aberrant, clonally expanded, intraepithelial lymphocytes has led to better definition and classification of patients with refractory sprue. Only a few series of patients with well-characterized refractory sprue have been reported in the literature. The prognosis is poor, though some patients respond to corticosteroids and immunosuppressive agents. The presence of an aberrant clonal intraepithelial T-cell population has led to the designation of refractory sprue as a cryptic intestinal T-cell lymphoma.     

Refractory coeliac disease

A small proportion of coeliac disease (CD) patients fail to improve after a gluten-free diet (GFD) and may be considered as atypical regarding their outcome (refractory coeliac disease). The aim of this study is to diagnose and manage patients with CD who fail to improve after a GFD. Refractory coeliac disease (RCD) is a malabsorption syndrome defined by persisting villous atrophy with, usually, an increase of intraepithelial lymphocytes (IELs) in the small bowel in spite of a strict GFD and comprises a heterogenous group of diseases. Some of these diseases have to be excluded and can be treated by specific therapies like antibiotics in tropical sprue and giardiasis and immune globulin substitution in common variable immunodeficiency, while other malabsorption syndromes are less well defined and may require immunosuppressive therapy. Standardized treatment, however, has not been evaluated in such patients so far. In a subgroup of patients with RCD, an abnormal intraepithelial lymphocyte (IEL) population may be observed with the lack of surface expression of usual T-cell markers (CD3-CD8 and/or the T-cell receptor (TCR)) on IELs associated with T-cell clonality pattern suggest the presence of an early enteropathy-associated T-cell lymphoma (EATL) in a subgroup of patients with RCD. This hypothesis has been supported by studies, which revealed progression into overt intestinal T-cell lymphomas in a subgroup of RCD. Steroid treatment has been reported effective even in patients with underlying early EATL. However, long-term results are unsatisfactory in most of these patients with RCD and parenteral nutrition has to be applied in some of these cases. First results with more aggressive chemotherapies and use of cytokines are under way. Due to the difficulty of diagnostic and therapeutic regimens patients should be referred to tertiary centres for coeliac disease.     

Refractory celiac disease

The main cause of lack of response to a gluten-free diet is continued, usually inadvertent, gluten intake. Diagnosis of refractory celiac disease is established on the basis of exclusion of other disorders, persistence of malabsorption and villous atrophy. Refractory celiac disease affects a heterogeneous group of patients, usually adults and, fortunately, is infrequent (<5% of the population). Detection of alterations in the intraepithelial lymphocyte population is essential for diagnosis. Some alterations in these lymphocytes, such as the absence of T cell surface receptor expression (CD3 and CD), indicate an aggressive form of the disease with the potential for malignant transformation (type II refractory celiac disease). Treatment is based on adequate nutritional support and on the use of corticosteroids and/or immunosuppressive agents (mainly azathioprine and infliximab). Because of the high risk of progression to intestinal T cell lymphoma, patients diagnosed with type 2 refractory disease require different -generally more aggressive- therapeutic strategies. At present, no treatment has been demonstrated to be effective in the long term, but two options that should be considered in type II disease are immunotherapy with anti-CD52 or similar agents, and autologous bone marrow transplantation. Trials with antibodies that block epithelial secretion of interleukin-15, a key molecule in the pathogenesis of the disease, are promising.     

Is TCRgamma clonality assay useful to detect early celiac disease?

BACKGROUND: Although histology is considered the gold standard for the diagnosis of celiac disease, the early stages (latent or potential) of this disease are difficult to diagnose, because of the negativity of laboratory tests and the lack of villous atrophy. Thus, markers of early disease are needed. AIMS: We investigated the possibility to detect latent or potential celiac disease by means of TCRgamma clonality assay in intraepithelial T cells in patients with suspected disease, negative laboratory tests, and an increased number of intraepithelial lymphocytes. PATIENTS AND METHODS: Duodenal biopsies were obtained from 35 patients with nonspecific duodenitis (controls), 13 latent or potential celiac disease subjects, 28 well-defined celiac patients, and 8 celiac patients in gluten-free diet. Histologic and immunohistochemical quantification of intraepithelial lymphocytes, as well as TCRgamma clonality assay, were carried out in all subjects by means of standard techniques. RESULTS: Intraepithelial lymphocytes and TCRgamma clonality were significantly increased in potential and defined celiac patients with respect to the controls, even though the increase in TCRgamma clonality was lesser with respect to that of intraepithelial lymphocytes. No significant differences were found concerning this variable between the potential and defined celiac subjects. CONCLUSIONS: TCRgamma clonality does not represent a marker of early disease. However, it might be useful to help in distinguishing celiac disease from other causes of nonspecific duodenitis.     

Mucosal intra-epithelial lymphocytes in enteropathy-associated T-cell lymphoma, ulcerative jejunitis, and refractory celiac disease constitute a neoplastic population.

Loss of response to a gluten-free diet (refractory sprue) and ulcerative jejunitis are complications of celiac disease that may progress to enteropathy-associated T-cell lymphoma (EATL). Both conditions are characterized by the presence of a nonlymphomatous monoclonal T-cell population in the enteropathic mucosa. In EATL, a similar monoclonal population that shows clonal identity with the lymphoma itself is also present in the enteropathic mucosa. In this study we show that in all three circumstances the monoclonal T-cell population is constituted by cytologically normal, noninvasive intraepithelial T lymphocytes that share an identical aberrant immunophenotype with EATL. Patients with refractory sprue and/or ulcerative jejunitis are, therefore, suffering from a neoplastic T-cell disorder for which hematological treatment strategies need to be devised.     

The management of complicated celiac disease

Refractory celiac disease (RCD) is being defined as persisting or recurring villous atrophy with crypt hyperplasia and increased intraepithelial lymphocytes (IELs) in spite of a strict gluten-free diet (GFD) for >12 months or when severe persisting symptoms necessitate intervention independent of the duration of the GFD. RCD may not respond primarily or secondarily to GFD. All other causes of malabsorption must be excluded and additional features supporting the diagnosis of CD must be looked for, including the presence of antibodies in the untreated state and the presence of celiac-related HLA-DQ markers. In contrast to patients with a high percentage of aberrant T-cells, patients with RCD I seem to profit from an immunosuppressive treatment. RCD II is usually resistant to medical therapies. Response to corticosteroid treatment does not exclude underlying enteropathy-associated T-cell lymphoma. Cladribine seems to have a role, although it is less than optimal in the treatment of these patients. It may be considered, however, as the only treatment thus far studied that showed significant reduction of aberrant T cells, seems to be well tolerated, and may have beneficial long-term effects in a subgroup of patients showing significant reduction of the aberrant T-cell population. Autologous stem cell transplantation (ASCT) seems promising in those patients with persisting high percentages of aberrant T cells. The first group of patients treated with ASCT showed improvement in the small intestinal histology, together with an impressive clinical improvement. However, it remains to be proven if this therapy delays or prevents lymphoma development.     

Budesonide in the treatment of refractory celiac disease

OBJECTIVE: Corticosteroids are used in patients with refractory celiac disease. In order to minimize their systemic side effects, we assessed the role of a locally active sustained release corticosteroid with minimal systemic bioavailability in patients with refractory celiac disease in an open labeled noncontrolled study. METHODS: Patients who received budesonide for refractory celiac disease were classified according to whether they were primarily or secondarily unresponsive to the diet, and whether they had a polyclonal (type I) or clonal (type II) expansion of intraepithelial lymphocytes. The response to budesonide was assessed globally and by reduction in bowel movements. RESULTS: Patients (N = 29, 72% female) received budesonide for a mean of 6.7 +/- 8.5 months, 5 patients (18%) had type II disease (clonal T-cell population); 76% responded to the medication, 55% completely. Response occurred when budesonide was used alone or with oral corticosteroids and/or azathioprine. There was an objective improvement in the number of bowel movements in those that responded. Response occurred in those with either primary or secondary refractory disease and in those with type II disease, irrespective of the presence of microscopic colitis (N = 7). There was no improvement in the duodenal biopsy over the study period and there were no side effects of budesonide. CONCLUSIONS: Budesonide may be of value in the management of refractory celiac disease.     

Flow cytometric analysis of intestinal intraepithelial lymphocytes in the diagnosis of refractory celiac sprue

The etiology of refractory celiac sprue (RCS) is unclear. In a high proportion of cases, the clonal nature of intestinal intraepithelial lymphocytes (IEL) can be demonstrated and a pathogenetic implication of intestinal IEL has been postulated. The prognosis of this subgroup of RCS is poor, with a high risk to develop an overt lymphoma and uncontrolled malabsorption despite steroid/immunosuppressive therapy. Cases with a relatively indolent clinical course, however, exist and their early diagnosis may be difficult. To gain insight into the pathogenic implication of intestinal IEL in refractory celiac sprue, we have performed an extensive phenotypic and functional characterization of clonal intestinal IEL in a patient with an indolent form of refractory celiac sprue, using multiparametric flow cytometry. The abnormal lymphocyte infiltrate lacked surface membrane expression of CD3/T-cell receptor (TCR) complexes (TCR(-), CD4(-), CD8(-), sCD3(-)), but contained intracellular CD3(epsilon) (CyCD3(+)) and surface CD103(+) and CD7(+). In particular, these cells showed a unique spontaneous ex-vivo cytokine secretion profile with an increased percentage of CD3(-) IEL containing TNF-alpha and IL-10, in the absence of IL-2, IL-4 and IFN-gamma. Altogether our results suggest that flow cytometry immunophenotyping of intestinal IEL, in cases suspected of celiac disease and their complicated forms, could be of great help in the correct diagnosis of RCS and the understanding of the immunopathogenic mechanisms of the disease and their clinical and/or therapeutical implications.     

Original research: Diagnosis of coeliac disease by flow cytometry of intraepithelial lymphocytes: a new ‘gold’ standard?

ObjectiveThe analysis of intraepithelial lymphocytes (IELs) by flow cytometry of duodenal biopsies—the ‘IEL’ lymphogram—has been proposed as a diagnostic test for coeliac disease. However, its clinical applicability has been limited due to variability in methods and definitions. This study set out to define useful parameters for the application of the IEL lymphogram to the diagnosis of coeliac disease.DesignFlow cytometry was performed on 117 sets of duodenal biopsies in 107 adult patients with active coeliac disease, long-term coeliac disease on a gluten free diet and a control group. The initial 95 samples were used for hypothesis generation for the subsequent samples comprising 12 patients with coeliac disease and 10 controls.ResultsRather than using single linear cut-offs for CD3 and T-cell receptor γδ (TCRγδ)+ve IELs, a discriminant function was identified as %CD3+ve IELs+2x(%TCRγδ+IELs)>100. This differentiated coeliac disease from control biopsies in the hypothesis generating group. These results were replicated in the validation group and found to be independent of histology in patients on long-term gluten free diet up to 12 years (combined sensitivity, 98.5%; specificity, 97.7%).ConclusionsFlow cytometric analysis of IELs is a highly sensitive and specific adjunct to serology and histological examination for the diagnosis of coeliac disease, even in individuals with coeliac disease following a gluten free diet who exhibit normal duodenal histology.     

Enteropathy associated T cell lymphoma in celiac disease: A large retrospective study

IntroductionPrognosis of enteropathy-associated T cell lymphoma is poor but predictors of survival remain ill-defined. How clinical presentation, pathological features and therapies influence outcome was evaluated in 37 thoroughly characterized patients with celiac disease and T-cell lymphoma.Patients and methodsMedical files were studied retrospectively. Lymphoma and intestinal mucosa were analysed by histopathology, multiplex PCR and intestinal intraepithelial lymphocytes phenotyping. Survival and prognostic factors were analysed using Kaplan–Meier curves with Logrank test and Cox Model.ResultsLymphoma complicated non clonal enteropathy, celiac disease (n = 15) and type I refractory celiac disease (n = 2) in 17 patients and clonal type II refractory celiac disease in 20 patients. Twenty-five patients underwent surgery with resection of the main tumour mass in 22 cases. In univariate analysis, non clonal celiac disease, serum albumin level > 21.6 g/L at diagnosis, chemotherapy and surgical resection predicted good survival (p = 0.0007, p < 0.0001, p < 0.0001, p < 0.0001, respectively). In multivariate analysis, serum albumin level > 21.6 g/L, chemotherapy and reductive surgery were all significantly associated with increased survival (p < 0.002, p < 0.03, p < 0.03, respectively).ConclusionsOur study underlines the prognostic value of celiac disease type in patients with T-cell lymphoma, and suggests that a combination of nutritional, chemotherapy and reductive surgery may improve survival.     

Defective synthesis or association of T-cell receptor chains underlies loss of surface T-cell receptor-CD3 expression in enteropathy-associated T-cell lymphoma

Enteropathy-associated T-cell lymphoma, an often fatal complication of celiac disease, can result from expansion of aberrant intraepithelial lymphocytes in refractory celiac disease type II (RCD II). Aberrant intraepithelial lymphocytes and lymphoma cells are intracellularly CD3epsilon(+) but lack expression of the T-cell receptor (TCR)-CD3 complex on the cell surface. It is unknown what causes the loss of TCR-CD3 expression. We report the isolation of a cell line from an RCD II patient with the characteristic phenotype of enteropathy-associated T-cell lymphoma. We demonstrate that in this cell line the TCR-alpha and -beta chains as well as the CD3gamma, CD3delta, CD3epsilon, and zeta-chains are present intracellularly and that assembly of the CD3gammaepsilon, CD3deltaepsilon, and zetazeta-dimers is normal. However, dimerization of the TCR chains and proper assembly of the TCR-CD3 complex are defective. On introduction of exogenous TCR-beta chains, but not of TCR-alpha chains, assembly and functional cell surface expression of the TCR-CD3 complex were restored. Defective synthesis of both TCR chains was found to underlie loss of TCR expression in similar cell lines isolated from 2 additional patients. (Pre)malignant transformation in RCD II thus correlates with defective synthesis or defective association of the TCR chains, resulting in loss of surface TCR-CD3 expression.     

Refractory celiac disease

Celiac disease is a gluten-sensitive enteropathy, characterized by villous atrophy, which is reversed by gluten withdrawal. A minority of patients with celiac-like enteropathy are resistant to gluten-free diet, so-called refractory sprue, or unclassified sprue. Refractory sprue is a diagnosis of exclusion; all other causes of a celiac-like enteropathy must be eliminated before a diagnosis of refractory sprue can be made. Recent evidence suggests that refractory sprue comprises a heterogenous group of patients with diverse underlying causes. A small proportion of these patients seem to have an adult form of autoimmune enteropathy, characterized by the presence of antienterocyte antibodies. However, a larger group of patients with refractory sprue now seem to have a cryptic intestinal T-cell lymphoma, characterized by the presence of phenotypically abnormal, monoclonal intraepithelial lymphocytes, despite benign cytology. Current therapeutic options include nutritional support and immunosuppressive therapy, but response is variable. The prognosis of refractory sprue may be poor; patients may die of severe malabsorption, or through synchronous or metachronous development of an enteropathy-associated T-cell lymphoma. Based on this recent evidence, patients with refractory sprue should be screened for antienterocyte antibodies and have T-cell receptor and monoclonal antibody studies performed; this could facilitate identification of cases of adult-onset autoimmune enteropathy and those of cryptic T-cell lymphoma. Moreover, early recognition of the malignant nature of the intestinal infiltrate in some cases of refractory sprue could permit the development of novel chemotherapeutic regimens for this condition.     

Cladribine therapy in refractory celiac disease with aberrant T cells.

BACKGROUND & AIMS: Refractory celiac disease (RCD) may be subdivided into RCD types I and II with phenotypically normal and aberrant intraepithelial T-cell populations, respectively. In RCD II, transition into enteropathy-associated T-cell lymphoma (EATL) is seen frequently. We have evaluated the effect of cladribine (2-CDA), a purine analogue inducing T-cell depletion, on clinical, histopathologic, and immunologic parameters, as well as the toxicity and side effects in a group of RCD II patients. METHODS: Between 2000 and 2005, 17 patients were included (8 men, 9 women). All patients had a clonal rearrangement of the T-cell receptor gamma gene and immunophenotyping showed an aberrant T-cell population lacking surface expression of CD3, CD8, and T-cell receptor alphabeta, in the presence of expression of surface CD103 and intracytoplasmic CD3. Treatment consisted of 2-CDA (0.1 mg/kg/day) intravenously for 5 days, given in 1-3 courses every 6 months depending on the response. RESULTS: All patients tolerated 2-CDA without serious side effects. Six patients (35.8%) showed a clinical improvement (weight gain, improvement of diarrhea, and hypoalbuminemia). In 10 patients (58.8%) a significant histologic improvement and in 6 patients (35.2%) a significant decrease in aberrant T cells was seen. Seven patients (41.1%) developed EATL and died subsequently. One patient died of progressive refractory state with emaciation. CONCLUSIONS: Treatment with 2-CDA in RCD II is feasible, well tolerated, and can induce clinical and histologic improvement as well as a significant decrease of aberrant T cells in a subgroup of patients, albeit it does not prevent EATL development. However, the earlier reported potential risk of precipitating an overt lymphoma should be taken into consideration.     

High tissue-transglutaminase antibody level predicts small intestinal villous atrophy in adult patients at high risk of celiac disease

BackgroundDuodenal biopsy may be unnecessary to confirm celiac disease in patients with high tissue-transglutaminase antibody level.AimsTo define a cut-off value of tissue-transglutaminase antibody with high positive likelihood ratio for duodenal atrophy in patients with suspected celiac disease.MethodsWe retrospectively identified 945 patients with suspected celiac disease and classified according to the method used for tissue-transglutaminase antibody assay: Group A (n = 393, Eu-tTG^® Eurospital), Group B (n = 263; Eu-tTG^® Eurospital) and Group C (n = 289; Celikey^® Phadia). Duodenal histology was graded according to Marsh. Sensitivity, specificity, and positive likelihood ratio were used to evaluate cut-off points of tissue-transglutaminase antibody as predictor of villous atrophy.Results100% specificity and ∞ positive likelihood ratio for duodenal atrophy was observed at a cut-off value of tissue-transglutaminase antibody 5 times higher than the upper limit of normal. CD diagnosis was confirmed by concordance with antiendomysial antibodies, and by reduction of t-TG titre in all patients and improvement of duodenal histology in 80% during gluten-free diet.ConclusionsTissue-transglutaminase antibody level 5-folds the upper limit of normal is 100% specific for duodenal atrophy and using this cut-off biopsy could by avoided in 1/3 of patients. Diagnostic criteria of celiac disease in adults need revision.     

Effect of elemental diet on mucosal immunopathology and clinical symptoms in type 1 refractory celiac disease.

BACKGROUND & AIMS: Patients with celiac disease (CD) who do not improve or exhibit villous atrophy on a gluten-free diet may have type 1 refractory CD (RCD) with a polyclonal mucosal T-cell infiltrate, or type 2 RCD with a monoclonal infiltrate, also termed cryptic T-cell lymphoma. Both conditions are difficult to treat. Here we describe the effects of a nonimmunogenic elemental diet on clinical symptoms and mucosal immunopathology in type 1 RCD. METHODS: Ten CD patients on a strict gluten-free diet were diagnosed with type 1 RCD after extensive clinical evaluation in a tertiary referral hospital. A 4-week amino-acid-based liquid elemental diet regimen was given with no other treatment, except in 1 patient who also received methotrexate. Duodenal biopsy specimens were obtained before and after treatment for histologic assessment, immunophenotyping of intraepithelial lymphocytes, T-cell receptor clonality, mucosal interleukin (IL)-15 expression, flow-cytometric analysis of interferon (IFN)-gamma-secreting T cells, and whole biopsy specimen IFN-gamma messenger RNA determination. RESULTS: Nine patients completed the treatment; however, 1 patient did not tolerate the diet. Histologic improvement and reduced epithelial IL-15 were seen in 8 patients, whereas IFN-gamma-secreting mucosal T cells and IFN-gamma messenger RNA levels decreased in 4 and 7 patients, respectively. Clinical improvement was noted in 6 patients, with 1 patient showing normalization of hypoalbuminemia. Three patients could discontinue their total parenteral nutrition. CONCLUSIONS: Persistent mucosal IFN-gamma and IL-15 production often occurs in type 1 RCD despite conventional treatment. Elemental diet is a therapeutic option that can provide long-term immunopathologic and clinical improvement of this difficult condition.     

Celiac disease and hypothyroidism

BackgroundCeliac disease is more common in patients with hypothyroidism. Malabsorption of levothyroxine has not been studied in this population. We sought to determine if levothyroxine dosing was influenced by the presence and treatment of celiac disease.MethodsThis retrospective study was conducted at an academic medical center. Cases had hypothyroidism and celiac disease. Controls had hypothyroidism alone and were selected randomly through the endocrinology clinic records. Celiac disease was defined as representative pathology with positive serology. Age, sex, height, weight, body mass index, creatinine, and medical comorbidity were assessed for cases and controls. The levothyroxine dose and weight-based levothyroxine dose necessary to maintain a euthyroid state was evaluated for controls, and before and after celiac disease therapy for cases.ResultsCeliac disease was identified in 152 patients, and 22 patients had concomitant hypothyroidism (14.5%). Seven cases met inclusion criteria. Overall, 200 control patients were identified. The mean celiac disease pretreatment levothyroxine dose and weight-based levothyroxine dose needed to maintain a euthyroid state were higher in cases than in controls (154 μg vs 106 μg, P = .007, and 2.6 μg/kg vs 1.3 μg/kg, P <.001). Doses decreased significantly after treatment of celiac disease (154 μg vs 111 μg, P = .03; and 2.64 μg/kg vs 1.89 μg/kg, P = .04). All cases required at least 125 μg of levothyroxine initially to maintain a euthyroid state.ConclusionsLevothyroxine malabsorption likely occurs with hypothyroidism and untreated celiac disease. Absorption may improve after celiac disease treatment. Screening for celiac disease in patients with hypothyroidism requiring elevated levothyroxine doses warrants further investigation.     

Multiple cerebral lesions in a patient with refractory celiac disease: A case report

BACKGROUNDEnteropathy-associated T cell lymphoma (EATL) is an aggressive intestinal T cell lymphoma derived from intraepithelial lymphocytes, which occurs in individuals with celiac disease (CD). Cerebral involvement is an extremely rare condition and as described so far, lymphoma lesions may present as parenchymal predo-minantly supratentorial or leptomeningeal involvement. We describe a case of EATL with multifocal supra- and infratentorial brain involvement in a patient with refractory celiac disease (RCD).CASE SUMMARYA 58-years old man with known CD developed ulcerative jejunitis and was diagnosed with RCD type II. Six months later he presented with subacute cerebellar symptoms (gait ataxia, double vision, dizziness). Cranial magnetic resonance imaging (MRI) revealed multifocal T2 hyperintense supra- and infratentorial lesions. Laboratory studies of blood and cerebrospinal fluid were inconspicuous for infectious, inflammatory or autoimmune diseases. ¹⁸F-fluorodeoxyglucose-positron emission tomography/computed tomography (¹⁸FDG-PET/CT) scan showed a suspect hypermetabolic lesion in the left upper abdomen and consequent surgical jejunal resection revealed the diagnosis of EATL. During the diagnostic work-up, neurological symptoms aggravated and evolved refractory to high-dosage cortisone. Recurrent MRI scans showed progressive cerebral lesions, highly suspicious for lymphoma and methotrexate chemotherapy was initiated. Unfortunately, clinically the patient responded only transiently. Finally, cerebral biopsy confirmed the diagnosis of cerebral involvement of EATL. Considering the poor prognosis and deterioration of the performance status, best supportive care was started. The patient passed away three weeks after diagnosis.CONCLUSIONEATL with cerebral involvement must be considered as a possible differential diagnosis in patients with known RCD presenting with neurological symptoms.     

Le syndrome de cavitation ganglionnaire mésentérique,complication rare de la maladie cœliaque de l’adulte : à propos de quatre cas et revue de la littérature

IntroductionMesenteric lymph node cavitation is an exceptional complication of celiac disease. We report four original observations of this syndrome, completed by a literature review.DiscussionThe analysis of 38 cases showed that this complication occurred exclusively in adults, with a mean age at diagnosis of 54 years. It revealed the celiac disease in the majority of cases. Hyposplenism was almost systematically associated. The risk of lymphoma appeared higher, especially enteropathy-associated T-cell lymphoma. The prognosis was poor with nearly 50% mortality and seemed related to the clinical response to the gluten-free diet.ConclusionThe severity of this complication deserves to be known and should lead to its research in celiac patients, especially in cases diagnosed in adulthood or in case of refractory disease.