Diagnosis and treatment of refractory sprue

Celiac disease is a gluten-sensitive enteropathy characterized by villous atrophy that is reversed by gluten withdrawal. A minority of these patients is resistant to a gluten-free diet or, after a period of remission, they experience relapse despite continued adherence to treatment, which is called unclassified sprue or refractory sprue.The prognosis of refractory sprue may be poor: patients may die of severe malabsorption or from the development of an enteropathy-associated T-cell lymphoma. We report a 72-year-old-woman with a diagnosis of refractory sprue who responded well to treatment with corticosteroids and a gluten-free diet.     

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.     

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.     

Defining gluten refractory enteropathy

OBJECTIVE: The diagnosis of coeliac disease (CD) is based on the responsiveness of the enteropathy to a gluten-free diet (GFD). This implies that terms such as 'non-responsive CD' and 'refractory CD' are almost paradoxical. In spite of this, these terms are commonly used in the literature, often with different and confusing meanings. METHODS: On the basis of both a review of the literature and our clinical experience, we propose the following classification. A condition characterized by a refractory enteropathy, not due to lymphoma, ulcerative jejunoileitis or collagenous sprue, but in which gluten sensitivity has been shown previously or could be shown while the patients were on an immunosuppressive therapy should be indicated as refractory CD. Those patients in whom gluten sensitivity can be excluded should be considered to be affected by non-coeliac refractory sprue. Finally, patients in whom the presence of CD cannot be either confirmed or excluded should be considered to be affected by undefined sprue. RESULTS: Twenty-four certain refractory patients are described in the literature. The data suggest a diagnosis of refractory CD in 13 patients, non-coeliac refractory sprue in three patients, and undefined sprue in eight patients. CONCLUSIONS: We define refractory CD as a form of CD that no longer responds to a GFD. Non-coeliac refractory sprue is a condition unrelated to CD. It could be either an independent condition or a common end point of different enteropathies.     

Refractory sprue syndrome with clonal intraepithelial lymphocytes evolving into overt enteropathy-type intestinal T-cell lymphoma

INTRODUCTION: Recently, patients with refractory sprue have been shown to contain a clonal proliferation of phenotypically abnormal intraepithelial lymphocytes in their intestine. Whether this signifies early enteropathy-type intestinal T-cell lymphoma (EITCL) or a reactive condition is not clear. We report on a patient presenting with the findings of refractory sprue who subsequently developed overt EITCL. MATERIAL AND METHODS: Duodenal biopsies from 1997 (refractory sprue) and duodenal and jejunal biopsies from 1998 (intestinal T-cell lymphoma) were compared by immunohistochemistry and PCR for the detection of T-cell receptor (TCR)-gamma gene rearrangements. Clonal PCR products were sequenced. RESULTS: The duodenal biopsies from both 1997 and 1998 and the jejunal tumor biopsy showed villus atrophy and an increase of intraepithelial lymphocytes with an abnormal immunophenotype (CD3+, CD4-, CD8- and TCR-beta-). In all duodenal specimens including the one from 1997, and the jenunal tumor biopsy, an identical clonal amplificate was detected by enzymatic amplification of the TCR-gamma gene. CONCLUSION: These data suggest that refractory sprue containing a clonal proliferation of phenotypically abnormal intraepithelial lymphocytes may represent an early manifestation of EITCL. The detection of immunohistochemical negativity for several antigens normally found on intraepithelial lymphocytes such as CD8 or the TCR-beta chain in combination with clonal T-cell populations by PCR may be helpful in identifying refractory sprue with a malignant transformation.     

Coeliac disease

Coeliac disease is a genetically-determined chronic inflammatory intestinal disease induced by an environmental precipitant, gluten. Patients with the disease might have mainly non-gastrointestinal symptoms, and as a result patients present to various medical practitioners. Epidemiological studies have shown that coeliac disease is very common and affects about one in 250 people. The disease is associated with an increased rate of osteoporosis, infertility, autoimmune diseases, and malignant disease, especially lymphomas. The mechanism of the intestinal immune-mediated response is not completely clear, but involves an HLA-DQ2 or HLA-DQ8 restricted T-cell immune reaction in the lamina propria as well as an immune reaction in the intestinal epithelium. An important component of the disease is the intraepithelial lymphocyte that might become clonally expanded in refractory sprue and enteropathy-associated T-cell lymphoma. Study of the mechanism of the immune response in coeliac disease could provide insight into the mechanism of inflammatory and autoimmune responses and lead to innovations in treatment.     

Maladie cœliaque

Celiac disease is an enteropathy due to gluten intake in genetically predisposed individuals (HLA DQ2/DQ8). Celiac disease occurs in adults and children at rates approaching 1% of population in Europe and USA. Clinical features observed in celiac disease are extremely various and anaemia, oral aphthous stomatis, amenorrhea or articular symptoms may be the only presenting manifestations. Diagnosis relies on the evidence of histological villous atrophy in proximal small bowel and the presence of specific serum antibodies. Treatment relies on eviction of gluten (wheat, barley, rye) from diet. Gluten free diet allows prevention of malignant complications such as small bowel adenocarcinoma and lymphoma, and osteopenia. The main cause of resistance to gluten free diet is its poor observance. If not the case, serious complications of celiac disease, such as clonal refractory celiac sprue and intestinal T-cell lymphoma should be suspected. Current therapeutic challenges concern alternative to gluten free diet and new efficient treatments of lymphomatous complications.     

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.     

Treatment and management of celiac disease

In most patients the clinical course of celiac disease is unproblematic after the diagnosis has been made and a strict gluten-free diet is established. However, in rare cases complications like refractory sprue or lymphoma can occur. Individual management is required since the clinical presentation of celiac disease can be very heterogeneous. For example, it is a matter of controversy if asymptomatic patients, who have the same typical histological changes in their small bowel like patients with symptomatic celiac disease, should adhere to a gluten-free diet. A major problem is the compliance and the unintentional intake of gluten. A 100 % gluten-free diet is not possible since most food components are contaminated with trace amounts of gluten. Fortunately most patients tolerate these contaminations. Furthermore, the threshold for gluten contamination can differ highly among patients. One central point in patient care is the monitoring of a gluten-free diet and the timely recognition of complications. Therefore, the role of antibodies and duodenal histology in monitoring the course of the disease will be discussed.     

The combination of clinical parameters and immunophenotyping of intraepithelial lymphocytes allows to assess disease severity in refractory celiac disease

BackgroundFlow cytometry of intestinal lymphocytes is discussed to be a stronger predictor of enteropathy-associated T-cell lymphoma development in refractory celiac disease than T-cell clonality analysis.AimsTo investigate possible associations between clinical characteristics of refractory celiac disease patients and aberrant intraepithelial lymphocytes and to evaluate the accuracy of immunophenotyping for the identification of high-risk refractory celiac disease.MethodsFlow cytometry of isolated lymphocytes from duodenal biopsies of controls and celiac disease patients was performed and results were compared to clinical data.ResultsFlow cytometry analysis was performed on 42 controls, 37 non-complicated celiac disease and 30 refractory celiac disease cases with or without T-cell receptor clonality. Elevated aberrant intraepithelial lymphocyte counts were significantly associated with severe malabsorption. A 15% cut-off (aberrant lymphocytes among all lymphocytes) had the best discriminatory ability to identify high-risk patients. However, this technique failed to identify some high-risk cases (sensitivity 63%, specificity 100%). The severity of malabsorption was added to the criteria for high-risk refractory celiac disease, improving the correct patients’ allocation (sensitivity 100%, specificity 96%).ConclusionImmunophenotyping of aberrant intraepithelial lymphocytes is a good predictor for high-risk refractory celiac disease. Furthermore, adding the evaluation of malabsorption to the diagnostic assessment of refractory celiac disease optimizes accuracy.     

Celiac sprue

Celiac sprue, celiac disease, or gluten-sensitive enteropathy, is a malabsorption disorder of the small intestine that occurs after ingestion of wheat gluten in genetically susceptible individuals. This disease is characterized by intestinal malabsorption associated with villous atrophy of the small intestinal mucosa, clinical and histological improvement after adherence to strict gluten free diet, and relapse when gluten is reintroduced. Celiac sprue has a high prevalence in Western Europe and North America where it is estimated to affect 1:120 to 1:300 individuals. The pathogenesis of celiac sprue is related to inappropriate intestinal T-cell activation in HLA-DQ2 positive individuals triggered by antigenic peptides from wheat gluten or prolamins from barley and rye. Although previously thought to be mainly a disease of childhood onset, the diagnosis is increasingly being made in adults. There are a wide variety of presentations, which range from asymptomatic forms to severe diarrhea, weight loss and nutritional deficiencies. Extraintestinal manifestations including anemia, osteopenia or neurological disorders and associated conditions such as diabetes or hypothyroidism are commonly present. The availability of highly sensitive and specific serologic markers has dramatically facilitated the diagnosis of celiac sprue. However, the demonstration of characteristic histological abnormalities in a biopsy specimen of the small intestine remains the mainstay of diagnosis. Treatment consists of life-long avoidance of dietary gluten to control symptoms and to prevent both immediate and long-term complications.     

Heterogeneity of intraepithelial lymphocytes in refractory sprue: potential implications of CD30 expression

BACKGROUND: Refractory sprue is defined as primary or secondary failure to respond to a gluten free diet in patients with coeliac disease-like enteropathy and may signify cryptic or overt enteropathy associated T cell lymphoma. AIMS: To study in detail jejunal morphology and immunophenotypes in patients with refractory sprue in the search for features that might be useful to predict prognosis. PATIENTS: Seven patients are described, representing all such cases identified in our hospital over a 13 year period. METHODS: Biopsy and/or surgical resection specimens were examined by morphology, immunohistochemistry, including enzymatic and immunofluorescent detection, and molecular biology. RESULTS: All patients had phenotypically abnormal intraepithelial lymphocytes (IELs) that lacked CD8, T cell receptor alpha beta (or gamma delta), and/or expressed CD30 in addition to variable expression of the natural killer cell receptor CD94. A monoclonal T cell population was present in six cases, data from the seventh being inconclusive. Three patients had overt lymphoma with CD30+ tumour tissue intervening between intact mucosa that contained neoplastic IELs. Intriguingly, CD30+ IELs were observed both a long way away from, and in direct continuity with, the tumours in these patients. Such CD30+ cells were hardly detected in patients without tumours, two of which are in good health several years after the initial diagnosis. CONCLUSIONS: Our data suggest that abnormal IELs in patients with refractory sprue are phenotypically heterogeneous. CD30 expression by these cells may indicate a worse prognosis, including the occurrence of overt lymphoma.     

Free perforation of the small intestine in collagenous sprue

A 67-year-old man with celiac disease developed recurrent diarrhea, profound weakness and weight loss, with evidence of marked protein depletion. His clinical course was refractory to a strict gluten-free diet and steroid therapy. Postmortem studies led to definition of unrecognized collagenous sprue that caused ulceration and small intestinal perforation. Although PCR showed identical monoclonal T-cell populations in antemortem duodenal biopsies and postmortem jejunum, careful pathological evaluation demonstrated no frank lymphoma. Rarely, overt or even cryptic T-cell lymphoma may complicate collagenous sprue, however, small intestinal ulcers and perforation may also develop independently. The dramatic findings here may reflect an underlying or early molecular event in the eventual clinical appearance of overt T-cell lymphoma.     

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.     

Complication associated with celiac disease

Enteropathy associated T cell lymphoma is the most serious complication of celiac sprue. The incidence of malignancy, in general, is approximately twofold greater in celiac disease than in the general population, but the risk of specific gastrointestinal malignancies is markedly increased. Lymphoma of the small intestine, comprises approximately 50% of the malignancies, and the most are of T-cell origin. We report a case of celiac disease associated T-cell Lymphoma of the jejunum in a woman. At the age of 33 the diagnosis of Celiac sprue was made, after institution of a gluten free diet the patient improved, but, fifteen year later, the patient begin with fever and abdominal pain. Laparotomy showed a perforation of the intestine by a tumour.     

Diabetes and celiac disease

Celiac sprue is permanent lifelong intolerance of gluten which in some sensitive individuals leads to an inflammation of various grades followed by atrophy of jejunum mucosa. Diagnosis of celiac sprue is based on proof of histopathological changes in jejunum mucosa as a result of presence of gluten in food. In recent years, serum endogenous myosin and tissue transglutaminase antibodies were used in a diagnostic algorithm. We distinguish active, silent, latent, and potential celiac sprue. Simultaneous incidence of type I diabetes mellitus and celiac sprue has been documented in a range of studies. Both diseases have common immunology and genetic characters. Prevalence of celiac sprue in patients with type I diabetes is several times higher compared to prevalence of this disease in the population. There is the prevalence of celiac sprue 3.6-5.1% in children with type I diabetes mellitus in the Czech Republic, silent form of the disease is the most frequent one. An effect of a strict gluten free diet on a metabolic control of diabetes has not been proved. It is necessary to assess (at least once per two years) actively and on regular basis endogenous myosin and/or tissue transglutaminase antibodies in patients with type I diabetes.     

Survival in refractory coeliac disease and enteropathy-associated T-cell lymphoma: retrospective evaluation of single-centre experience

BACKGROUND: Coeliac disease may be regarded as refractory disease (RCD) when symptoms persist or recur despite strict adherence to a gluten-free diet. RCD may be subdivided into types I and II with a phenotypically normal and aberrant intraepithelial T-cell population, respectively. RCD I seems to respond well to azathioprine/prednisone therapy. RCD II is usually resistant to any known therapy and transition into enteropathy-associated T-cell lymphoma (EATL) is common. AIM: To provide further insight into RCD and the development of EATL, by reporting on long-term survival and risk of transition of RCD into EATL in a large cohort of patients with complicated coeliac disease. Design and METHODS: Retrospective comparison of responses to therapy in four groups of patients with complicated coeliac disease: 43, RCD I; 50, RCD II (total), of whom 26 with RCD II developed EATL after a period of refractoriness to a gluten-free diet (secondary EATL) and 13 were EATL patients without preceding history of complicated coeliac disease (de novo EATL). RESULTS: No coeliac-disease-related mortality was recognised in the RCD I group. The overall 5-year survival in the RCD I group it was 96%; in the RCD II (total) group was 58%; and in the RCD II group after developing EATL it was only 8%. The 2-year survival in the de novo EATL group was 20% versus 15% in secondary EATL group (p = 0.63). Twenty-eight (56%) of the 50 patients with RCD II died, 23 (46%) due to EATL, 4 due to a progressive refractory state with emaciation and 1 from neurocoeliac disease. CONCLUSION: Remarkably, no patient with RCD I developed RCD II or EATL within the mean follow-up period of 5 years (range 2-15 years). A total of 52% of the RCD II patients developed EATL within 4-6 years after the diagnosis of RCD II. More aggressive and targeted therapies seem necessary in RCD II and EATL.     

The cellular infiltrate of the jejunum in adult coeliac disease and dermatitis herpetiformis following the reintroduction of dietary gluten.

The cellular infiltrate of the jejunal mucosa has been studied in patients with both treated and untreated adult coeliac disease and dermatitis herpetiformis and serially in treated patients before and after the reintroduction of gluten to the diet. In adult coeliac disease and dermatitis herpetiformis the jejunal mucosa showed similar abnormalities of the cellular infiltrate which was characterized by an increase in intraepithelial lymphocytes and lamina propria plasma cells and eosinophils, with the greatest numbers of cells occurring in untreated patients. At 24-48 hours following a single 25-g gluten challenge there was an increase in lamina propria plasma cells, lymphocytes and eosinophils and intraepithelial lymphocytes. This rise was sustained after seven days on a gluten-containing diet for all of these cell groups except lamina propria lymphocytes. These responses were essentially similar in both adult coeliac disease and in those dermatitis herpetiformis patients who had jejunal lesions before treatment. In dermatitis herpetiformis patients with normal jejunal morphology on a normal diet there was an upward trend in lamina propria plasma cells and intraepithelial lymphocytes within one to three weeks of taking extra dietary gluten. These results are compatible with the view that more than one immunological mechanism may be responsible for the pathogenesis of the jejunal lesion of coeliac disease and dermatitis herpetiformis.     

Frequency of clonal intraepithelial T lymphocyte proliferations in enteropathy-type intestinal T cell lymphoma, coeliac disease, and refractory sprue

BACKGROUND: Clonal T cell receptor (TCR) gene rearrangements and loss of T cell antigens such as CD8 and TCR-beta in intraepithelial lymphocytes (IELs) may indicate the development of an enteropathy-type intestinal T cell lymphoma (EITCL) in patients with refractory sprue. AIMS: To define the diagnostic value of these markers in duodenal biopsies from patients with villous atrophy as a result of various underlying disorders. PATIENTS AND METHODS: Duodenal biopsies from eight patients with coeliac disease and five patients with villous atrophy caused by defined disorders were compared with three patients with refractory sprue evolving into overt EITCL, two patients with ulcerative jejunitis, and with eight patients with overt EITCL, for expression of CD3, CD4, CD8, and TCR-beta in IELs using immunohistochemistry and for clonal TCR-gamma gene rearrangements using polymerase chain reaction. In addition, biopsies from six consecutive patients with refractory sprue of uncertain cause were examined. RESULTS: Clonal TCR-gamma gene rearrangements were found in all resected tumours of patients with EITCL, in 3/8 duodenal biopsies of patients with EITCL, in 2/2 patients with ulcerative jejunitis, in 2/3 patients with refractory sprue evolving into overt EITCL, and in 1/6 patients with refractory sprue. No rearrangements were found in biopsies from patients with refractory sprue caused by defined disorders or those with coeliac disease. Clonality in duodenal biopsies was associated with an abnormal phenotype of IELs in all cases and in all but one case in patients with evidence of underlying coeliac disease. Specificity for detection of an EITCL using immunohistology was 77% for CD8 and for TCR-beta staining, and 100% for detection of a clonal TCR-gamma gene rearrangement. Sensitivity was 62% for staining with CD8 and clonality investigation, while sensitivity reached 100% for TCR-beta staining in all investigated patients with EITCL. CONCLUSIONS: Clonal proliferations of phenotypically abnormal IELs in refractory sprue represent an early manifestation of EITCL, for which the term "sprue-like intestinal T cell lymphoma" is proposed. This constellation is also found in duodenal biopsies from patients with an overt EITCL and is not related to other sprue syndromes, resulting in a high specificity for detection of an EITCL or refractory sprue evolving into EITCL. Overt EITCL may develop directly from coeliac disease without a precursor lesion (refractory sprue with clonal IELs) being demonstrable in duodenal biopsies or via a "sprue-like intestinal T cell lymphoma". This latter entity is a complication of coeliac disease.     

Etiology of nonresponsive celiac disease: results of a systematic approach

OBJECTIVES: Nonresponse or relapse of symptoms is common in patients with celiac disease treated with gluten free diet. Refractory sprue (RS) is defined as initial or subsequent failure of a strict gluten-free diet to restore normal intestinal architecture and function in patients who have celiac-like enteropathy. The aims of this study were: 1) to identify causes of persistent symptoms in patients referred with presumed diagnosis of nonresponsive celiac disease (NCD); and 2) to characterize patients with true RS. METHODS: Patients were identified who had been systematically evaluated for NCD between January 1997, and May 2001. Patient records and small bowel biopsy results were reviewed. RESULTS: A total of 55 patients were referred with a presumed diagnosis of NCD. Six did not have celiac disease and had other diseases responsible for their symptoms. Diarrhea, abdominal pain, and weight loss were the most common reasons for evaluation in cases of NCD, whereas weight loss, steatorrhea, and diarrhea were the most common presenting features of RS (nine patients). Of the 49 patients with celiac disease, 25 were identified as having gluten contamination. Additional diagnoses accounting for persistent symptoms included: pancreatic insufficiency, irritable bowel syndrome, bacterial overgrowth, lymphocytic colitis, collagenous colitis, ulcerative jejunitis, T-cell lymphoma, pancreatic cancer, fructose intolerance, protein losing enteropathy, cavitating lymphadenopathy syndrome, and tropical sprue. CONCLUSIONS: Based on this study, we conclude the following: 1) gluten contamination is the leading reason for NCD; 2) of NCD cases, 18% are due to RS; and 3) alternative diseases or those coexistent with celiac disease and gluten contamination should be ruled out before a diagnosis of RS is made.