Wieke H. M. Verbeek

The differential diagnosis of diarrhoea in combination with villous atrophy is broad. Coeliac disease heads the list but medication-induced villous atrophy should also be taken into consideration. We report the case of a 63-year-old man presenting with recurrent secretory diarrhoea, acute renal failure and metabolic acidosis. Initial work-up revealed total villous atrophy (Marsh stage IIIC) with intraepithelial lymphocytosis. A gluten-free diet did not have any effect on the diarrhoea. During several periods of hospitalization antihypertensive medications were temporarily stopped due to dehydration; this resulted in reduction of his symptoms. Eventually an association between the enteropathy and the antihypertensive olmesartan was suspected. Indeed, permanent withdrawal of olmesartan resulted in permanent clinical improvement. Olmesartan is frequently prescribed in the Netherlands and it should be included in the differential diagnosis of diarrhoea accompanying villous atrophy.

Background: Refractory coeliac disease (RCD) is characterized by persisting mucosal pathology in spite of a strict gluten free diet (GFD). In RCD type II, phenotypically aberrant (CD7+CD3‐CD4/8‐cytoplasmicCD3+) T‐lymphocytes are present within the intraepitelial lymphocyte (IEL) population in the small intestine, and 50–60% of these patients develops an enteropathy associated T‐cell lymphoma (EATL).Aim: To investigate whether aberrant T‐lymphocytes in RCD II can be detected in other parts of the small intestinal mucosa besides the intraepithelial compartment. Additionally, the presence of aberrant T‐lymphocytes was analyzed in two RCD II patients that developed atypical skin lesions.Methods: Multiparameter flow cytometric immunophenotyping was performed on both IEL and lamina propria lymphocyte (LPL) cell suspensions, isolated from small bowel biopsy specimens of RCD II patients (n = 14), and on cutaneous lymphocytes isolated from skin‐lesion biopsy specimens of RCD II patients (n = 2). In addition, immunofluorescence analysis of frozen RCD II derived small intestinal biopsies was performed.Results: Our results clearly show that aberrant T‐lymphocytes may be present in both the IEL and the LPL compartments of RCD II derived small intestinal biopsies. Although the highest percentages are always present in the IEL compartment, aberrant LPL can exceed 20% of total LPL in half the RCD II patients. Interestingly, cutaneous lymphocytes isolated from atypical skin lesions that developed in some RCD II patients showed a similar aberrant immunophenotype as found in the intestinal mucosa.Conclusions: In RCD II, the aberrant T‐lymphocytes may also reside in the subepithelial layer of the small intestinal mucosa, in the lamina propria, and even in extraintestinal localizations including the skin. Whether this phenomenon represents a passive overflow from the intestinal epithelium or active trafficking towards other anatomical localizations remains to be elucidated. RCD II appears to be a disseminated disease, which may impose the risk of EATL development outside the intestine. © 2009 Clinical Cytometry Society

Celiac disease is a gluten-sensitive enteropathy, which commits the patient to a life-long gluten-free diet. This is sufficient to treat the overwhelming majority of patients. However, a small group of these patients, mainly those diagnosed above 50 years of age, fails to improve histologically and clinically upon elimination of gluten from the diet. These patients are regarded as suffering from refractory celiac disease. In a subgroup of these patients a pre-malignant intraepithelial lymphocyte population can be detected in the small intestinal mucosa (type II). These patients are at a high risk of developing an enteropathy-associated T-cell lymphoma (50-60% within 4-6 years), which has a very poor prognosis and a 5-year survival of only 8%. The therapeutic challenge in these refractory celiac disease type II patients is targeting the aberrant intraepithelial lymphocytes to eventually prevent enteropathy-associated T-cell lymphoma development. Although management of these patients is difficult and therapeutic options are currently limited, novel treatment modalities are being explored.

Enteropathy-associated T-cell lymphomas (EATLs) are T-cell non-Hodgkin lymphomas of the small bowel, which are specifically associated with coeliac disease (CD). To our knowledge no studies have previously reported on the overall incidence of EATLs in the general population. The aim of this study was to investigate the incidence of EATL and the demographic characteristics of patients with EATL in The Netherlands. A survey of the nation-wide network and registry of histo- and cytopathology reports in The Netherlands (PALGA) was performed. We included all T-cell lymphomas detected between January 2000 and December 2006 that initially presented in the small bowel. Crude and world standardized incidence rates were computed as well as gender- and age-specific incidence rates. Finally, the distribution of characteristics such as the localization, the Marsh classification and method of diagnosis are described. Clinicopathological data were gathered for 116 cases of EATL. The mean age at primary presentation of EATL was 64 years. The crude incidence in the total Dutch population was 0.10/100,000 with an incidence of 2.08/100,000 in the over 50-year-olds. Age-specific incidences were 1.44/100,000 in the 50-59 years age group, 2.92/100,000 in the 60-69 years age group, and 2.53/100,000 in the 70-79 years age group. There was a significant predominance of males (64%, p=0.004, CI 54-72); above the age of 50 the gender-specific incidence was 2.95/100,000 in males versus 1.09/100,000 in females. Most EATLs were localized in the proximal small intestine and the diagnosis was made by surgical resection in the majority of cases. EATL is a rare disease with an incidence of 0.10 per 100,000 inhabitants per year, occurring in older age, with a peak incidence in the 7th decade. The tumour is mainly localized in the proximal small intestine. Although uncomplicated CD is twice as frequent in female patients, EATL is more prevalent in males.