ArticlesRefractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma
Introduction
Adult refractory sprue, also known as unclassified, or intractable coeliac sprue, is defined as symptomatic severe small-intestinal villous atrophy mimicking coeliac disease, but not responding primarily or secondarily to at least 6 months of a strict gluten-free diet not accounted for by other causes of villous atrophy or overt intestinal lymphoma.1, 2, 3 Refractory sprue and its possible link with uncommon complications of coeliac disease, such as intestinal ulcerations (ulcerative jejunoileitis),4 mesenteric lymph-node cavitation,5 collagenous sprue,6 and lymphoma7 have mainly been described in case reports. Its precise link with coeliac disease or enteropathy-associated T-cell lymphoma (EATL) remains controversial. Moreover, little is known of its diagnostic criteria and long-term outcome.
We have previously seen8 that refractory sprue may be associated with a clonal intestinal intraepithelial T-lymphocyte (IEL) population with a normal cytological appearance and surface CD103 expression, but with an aberrant phenotype characterised by the presence of intracellular CD3ε, but without the usual surface T-cell markers CD3, CD8, CD4, and T-cell receptor (TCR). These cells also exhibited a clonal TCRγ gene configuration, suggesting that they may precede the onset of a malignant disease.8 This phenotypically abnormal IEL population expressing intracellular CD3 but not CD8 was detected not only on frozen sections, but also on fixed biopsy samples by means of a simplified immunohistochemical method suited to retrospective studies (unpublished observations). Bagdi and colleagues9 confirmed our findings in another small series of patients and suggested that refractory sprue is a neoplastic T-cell disorder. The exact frequency and prognosis of this clonal abnormal IEL population has never been determined in a large series of patients with refractory sprue. We therefore did a national cooperative study of adults with primary or secondary refractory sprue and no initial evidence of overt lymphoma, to correlate clinical and pathological features and outcome with the presence of this intestinal aberrant IEL phenotype. In addition, the presence of circulating abnormal lymphocytes was assessed in several patients.
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Patients
Refractory sprue was defined according to Trier's criteria1, 2 after excluding other causes of villous atrophy and overt intestinal lymphoma at the time of diagnosis. A questionnaire was sent to 56 French gastroenterology referral centres in January 1997, and cases compatible with a diagnosis of refractory sprue and diagnosed between 1974 and 1998 were identified. Six of these cases have been described elsewhere.8
The following data were collected if available: sex, age, and symptoms at clinical
Clinical features
21 patients compatible with a diagnosis of refractory sprue and diagnosed between 1974 and 1998 were identified. There were five men and 16 women, with a mean age of 51 years (29–73 years). Presenting signs and symptoms were diarrhoea (n=18), abdominal pain (n=10), weight loss (n=11), and isolated microcytic anaemia (n=1). 20 controls (15 women, five men, mean age 36 [21–62]) were also identified. In all the patients a diagnosis of coeliac disease was initially given because patients had severe
Discussion
Enteropathy-associated T-cell lymphoma is a well-documented and rare complication of coeliac disease and commonly heralded by a lack of response to a gluten-free diet.3, 9, 16 A minority of patients with clinical and pathological features of coeliac disease but no evidence of overt intestinal lymphoma do not respond, initially or secondarily, to a strict gluten-free diet.3, 16 This rare condition, called refractory or unclassified sprue by Trier,1, 3 might be associated with a monoclonal
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