Tom van Gils

Prevalence and Characterization of Self-Reported Gluten Sensitivity in The Netherlands

Background: A growing number of individuals reports symptoms related to the ingestion of gluten-containing food in the absence of celiac disease. Yet the actual prevalence is not well established. Methods: Between April 2015 and March 2016, unselected adults visiting marketplaces, dental practices and a university in The Netherlands were asked to complete a modified validated questionnaire for self-reported gluten sensitivity (srGS). Results: Among the 785 adults enquired, two had celiac disease. Forty-nine (6.2%) reported symptoms related to the ingestion of gluten-containing food. These individuals were younger, predominantly female and lived more frequently in urban regions compared with the other respondents. Symptoms reported included bloating (74%), abdominal discomfort (49%) and flatulence (47%). A total of 23 (47%) srGS individuals reported having had tried a gluten-free or gluten-restricted diet. Abdominal discomfort related to fermentable oligosaccharide, disaccharide, monosaccharide and polyol (FODMAP)-containing food was more often reported in srGS individuals compared with the other respondents (73.5% vs. 21.7%, p < 0.001). Conclusion: Self-reported GS is common in The Netherlands, especially in younger individuals, females and urban regions, although the prevalence was lower than in a comparable recent UK study. It cannot be excluded that FODMAPs are in part responsible for these symptoms.

Mechanisms and management of refractory coeliac disease

A small subset of patients with coeliac disease become refractory to a gluten-free diet with persistent malabsorption and intestinal villous atrophy. The most common cause of this condition is inadvertent gluten exposure, but concomitant diseases leading to villous atrophy should also be considered and excluded. After exclusion of these conditions, patients are referred to as having refractory coeliac disease, of which two categories are recognized based on the absence (type I) or presence (type II) of a clonal expansion of premalignant intraepithelial lymphocyte population with a high potential for transformation into an overt enteropathy-associated T-cell lymphoma. Type I disease usually has a benign course that can be controlled by mild immunosuppressive treatment, but type II can be more severe with cladribine with or without autologous stem cell transplantation effective as treatment. Patients who fail to respond to cladribine therapy, however, still have a high risk of malignant transformation. Insights into the immunophenotype of these cells and the recognition that type II disease is a low-grade, no-mass lymphoma opens avenues for new treatment strategies, including chemotherapeutic and immunomodulating strategies. This Review will provide an overview of refractory coeliac disease, discussing mechanisms, diagnosis and management.

CD4 T-cell cytokines synergize to induce proliferation of malignant and nonmalignant innate intraepithelial lymphocytes.

Significance Refractory celiac disease type II (RCDII) is a severe variant of celiac disease, an autoimmune disorder of the small intestine caused by inflammatory T-cell responses to gluten, a common food protein. Typical of RCDII is the presence of aberrant lymphocytes in the duodenal epithelium, which often give rise to a lethal lymphoma. A single growth factor promoting the expansion of aberrant cells has been identified: epithelial cell-derived IL-15. The experiments described in this paper identify three additional growth factors—TNF, IL-2, and IL-21—produced by gluten-specific T cells. Thus, these findings suggest a potential mechanism for the contribution of gluten-specific T cells to RCDII. Refractory celiac disease type II (RCDII) is a severe complication of celiac disease (CD) characterized by the presence of an enlarged clonal population of innate intraepithelial lymphocytes (IELs) lacking classical B-, T-, and natural killer (NK)-cell lineage markers (Lin−IELs) in the duodenum. In ∼50% of patients with RCDII, these Lin−IELs develop into a lymphoma for which no effective treatment is available. Current evidence indicates that the survival and expansion of these malignant Lin−IELs is driven by epithelial cell-derived IL-15. Like CD, RCDII is strongly associated with HLA-DQ2, suggesting the involvement of HLA-DQ2–restricted gluten-specific CD4+ T cells. We now show that gluten-specific CD4+ T cells isolated from CD duodenal biopsy specimens produce cytokines able to trigger proliferation of malignant Lin−IEL lines as powerfully as IL-15. Furthermore, we identify TNF, IL-2, and IL-21 as CD4+ T-cell cytokines that synergistically mediate this effect. Like IL-15, these cytokines were found to increase the phosphorylation of STAT5 and Akt and transcription of antiapoptotic mediator bcl-xL. Several small-molecule inhibitors targeting the JAK/STAT pathway blocked proliferation elicited by IL-2 and IL-15, but only an inhibitor targeting the PI3K/Akt/mTOR pathway blocked proliferation induced by IL-15 as well as the CD4+ T-cell cytokines. Confirming and extending these findings, TNF, IL-2, and IL-21 also synergistically triggered the proliferation of freshly isolated Lin−IELs and CD3−CD56+ IELs (NK-IELs) from RCDII as well as non-RCDII duodenal biopsy specimens. These data provide evidence implicating CD4+ T-cell cytokines in the pathogenesis of RCDII. More broadly, they suggest that adaptive immune responses can contribute to innate IEL activation during mucosal inflammation.

The first cases of collagenous sprue successfully treated with thioguanine

Objective Collagenous sprue (CS) is a rare form of small bowel enteropathy characterised by a thickened basement membrane and is, in most of the literature, reported as part of coeliac disease. Multiple treatment strategies are suggested in CS, but there is no standardised therapy. The aim of this series is to describe 4 cases of CS and to propose thioguanine (6-TG) treatment. Design We reviewed 4 cases of CS. Data were obtained from our prospective database of patients referred to our coeliac centre. Evaluation of small bowel biopsies was performed by an expert pathologist. Results None of the patients had ever had coeliac-specific antibodies, and all were negative for HLA-DQ2 and HLA-DQ8 phenotype. Three patients were treated with a combination of 6-TG and budesonide, and 1 patient received 6-TG only. All patients improved remarkably. Normalisation of the thickened basement membrane was found in 2 patients and complete histological improvement including full recovery of villi was found in 1 patient. In the third patient, the thickened basement membrane was only very focally recognised. The thickened membrane persisted in the last patient, probably because of the short time of follow-up. Conclusions CS should be separated from coeliac disease. Based on the lack of typical HLA phenotyping and the absence of coeliac-specific antibodies, there seems to be no relation with coeliac disease in these 4 cases. A promising treatment option might be 6-TG with or without budesonide. Research in a larger cohort is needed to standardise treatment for CS.

Splenic volume differentiates complicated and non-complicated celiac disease

Background Studies in small groups of patients indicated that splenic volume (SV) may be decreased in patients with celiac disease (CD), refractory CD (RCD) type II and enteropathy-associated T-cell lymphoma (EATL). Objective The objective of this article is to evaluate SV in a large cohort of uncomplicated CD, RCD II and EATL patients and healthy controls. Methods The retrospective cohort consisted of 77 uncomplicated CD (of whom 39 in remission), 29 RCD II, 24 EATL and 12 patients with both RCD II and EATL. The control group included 149 healthy living kidney donors. SV was determined on computed tomography. Results The median SV in the uncomplicated CD group was significantly larger than in controls (202 cm3 (interquartile range (IQR): 154–275) versus 183 cm3 (IQR: 140–232), p = 0.02). After correction for body surface area, age and gender, the ratio of SV in uncomplicated CD versus controls was 1.28 (95% confidence interval: 1.20–1.36; p < 0.001). The median SV in RCD II patients (118 cm3 (IQR 83–181)) was smaller than the median SV in the control group (p < 0.001). Conclusion This study demonstrates large inter-individual variation in SV. SV is enlarged in uncomplicated CD. The small SV in RCD II may be of clinical relevance considering the immune-compromised status of these patients.

Risks for lymphoma and gastrointestinal carcinoma in patients with newly diagnosed adult-onset celiac disease: Consequences for follow-up: Celiac disease, lymphoma and GI carcinoma

Background The association between celiac disease (CD) and the development of lymphoid and gastrointestinal (GI) malignancies have been reported. However, data are scarce yet needed to develop evidence-based follow-up programs. Objective The objective of this article is to assess relative (RR) and absolute risks of lymphoma and GI carcinoma for newly diagnosed patients. Methods A case-control design to determine RR was performed with cases (lymphoma or GI carcinoma) and controls (melanoma or basal cell carcinoma) diagnosed 1994–2014, retrieved from the Dutch nationwide population-based pathology database (PALGA). Within this population, individuals with histologically proven CD before or simultaneously diagnosed with the malignancy were identified. Results A total of 349/301,425 cases (0.1%) and 282/576,971 (0.05%) controls were diagnosed with CD. Risk of T-cell lymphoma, predominantly enteropathy-associated T-cell lymphoma (EATL), was strongly associated with CD diagnosis (RR = 35.8 (95% CI 27.1–47.4)). Although most often synchronously diagnosed, T-cell lymphoma RR ≥ 1 year after CD diagnosis was still elevated (RR = 12.7 (95% CI 7.6–21.3)). Other CD-associated malignancies were small bowel adenocarcinoma (RR = 11.9 (95% CI 8.2–17.2)) and esophageal squamous cell carcinoma (RR = 3.5 (95% CI 2.1–5.8)). Absolute risks were relatively low. Other types of lymphomas and GI carcinomas were not associated with CD. Conclusion Increased risk for specific malignancies in CD should alert physicians for EATL (both intestinal and extraintestinal) and small bowel adenocarcinoma in patients with CD diagnosed at age ≥ 50 years.

849 Gamma-Delta T-Lymphocytes As Diagnostic Criterium in Latent Celiac Disease

Introduction Flow cytometry is a validated, easy applicable methodology for the determination of intraepithelial lymphocytes (IEL) phenotype in celiac disease (CD). An increase in Gamma-Delta IEL (CD3+TCRγδ+) is a characteristic finding in CD patients yet cut-off values for CD3+TCRγδ+ IEL in CD have not been determined. A validated cut-off value might be helpful in the establishing the diagnosis of CD, especially in those patients with minimal histological abnormalities (i.e., Marsh I) or individuals with positive serology in the absence of histological abnormalities. Methods Flow cytometric immunophenotyping was performed on IELs isolated from fresh small bowel biopsy specimens obtained from histology and serology proven CD patients (n=219) (active CD: n=92, CD in remission: n=127), healthy controls without CD (n=89) and suspected CD (n=14), the latter being defined as Marsh III and/or positive serology. Thirty-one additional patients with non-celiac villous atrophy were included as a disease control group. Follow-up data were available from thirteen CD patients. Percentages of CD3+TCRγδ+ IEL from CD patients and healthy controls were used to calculate a cut-off value for CD3+TCR γδ+ IEL in suspected CD patients using a receiver operating characteristic (ROC) curve. Results A significantly higher percentage of CD3+TCRγδ+ IEL was found in biopsy and serology proven CD patients (median 19.0%, range 1-58%) compared to healthy controls (median 6.0%, range 1-15%) (p 14% CD3+TCRγδ+ IEL might aid in a diagnosis of CD. Furthermore, Flow cytometric immunophenotyping might be helpful in cases of diagnostic doubt on CD in patients compliant to a GFD without the need for a gluten-challenge.