Peter J. Wahab

Strict adherence to a gluten-free diet (GFD) is the cornerstone of treatment in coeliac disease, yet gluten cross-contamination in household settings poses a persistent challenge. Guidance from dieticians and patient organizations is often not evidence-based. This study quantified gluten contamination risks associated with common kitchen appliances and evaluated the effectiveness of various cleaning methods in typical Dutch households. We performed a two-phase analysis of 417 samples of 275 chopping boards, 34 toasters/sandwich makers, and 108 deep-fat fryers/air fryers. Gluten levels were assessed on appliances and food items under different cleaning protocols, with Bayesian modeling used to estimate contamination probabilities. Plastic chopping boards showed the highest risks, with probabilities up to 0.868 when rinsed with cold water, compared with 0.147 after dishwasher cleaning. Glass and wooden boards cleaned in dishwashers had the lowest probabilities (0.0102 and 0.0194). Toasters and sandwich makers tested positive in 1 of 34 samples; at the 20 ppm threshold, contamination probability was 0.00001. In fryers, probabilities were 0.125 for deep-fat fryers and 0.070 for air fryers at the 5 ppm threshold, decreasing to 0.0405 and 0.0326 at 20 ppm. Across all appliances, gluten levels seldom exceeded the clinically relevant threshold of 20 ppm. This study highlights the importance of dedicated cleaning protocols and appliance-specific recommendations to mitigate gluten exposure. While complete elimination of gluten is challenging, adopting rigorous practices can substantially mitigate exposure for coeliac patients, enhancing safety and quality of life.

Background and Aims: The patient segmentation model based on disease acceptance and perceived control may guide personalized care in inflammatory bowel disease (IBD). We aimed to investigate the external validity of the segmentation model and its consistency over time. Methods: This is a multicenter longitudinal cohort study of adult IBD patients with questionnaires on disease acceptance and perceived control (6-items, 7-point Likert scale) and health-related quality of life (HRQoL) (Short IBD questionnaire, range 10-70). Segments were created based on mean scores (cut-off>5): (I) high acceptance, high control; (II) high acceptance, low control; (III) low acceptance, high control and; (IV) low acceptance, low control. Results: The external validation cohort included 921 IBD patients. The acceptance and control scale were unidimensional and internally consistent. Segments differed significantly in gender, disease duration, IBD medication and clinical disease activity. High acceptance and/or high control were significantly associated with a higher HRQoL compared with low acceptance and low control (i.e., segment IV) (Beta (95%CI) segment I=11.7 (10.4-13.1), segment II=9.3 (7.7-10.9) and segment III=3.8 (1.6-6.0), p≤0.001). The follow-up cohort included 783 patients: 58% remained in the same segment while 42% differed in segment over time. Changes in segment were positively correlated with changes in HRQoL over time (Spearman rho 0.38, p<0.001). Conclusions: The patient segmentation model based on disease acceptance and perceived control was externally valid and showed consistency over time. The different segments were independently associated with HRQoL. Future interventions should aim to personalize care based on segments and improve disease acceptance and perceived control of IBD patients.

Background: To determine the applicability and sensitivity of a urine self-test to detect gluten-immunogenic-peptides (GIP) in daily-life for patients with coeliac disease and correlate the test results with reported symptoms. Methods: We performed a prospective double-blinded placebo-controlled study, including adults with coeliac disease adhering to a strictly gluten-free diet. Patients were administered gluten in test-cycles of ascending doses of 50, 100, 200, and 500 mg alternated with placebo. Urine portions from 2, 5–17 h after the ingestion were collected and analyzed for GIP using the iVYCHECK-GIP-Urine rapid lateral flow test. Patients completed a diary mapping symptoms (nausea, bloating, diarrhea, abdominal pain, and lower level of energy). Results: We enrolled 15 patients and 7 received all 4 cycles with increasing gluten dosing. GIP was detected from urine in 47% of the patients receiving 50 mg gluten and in 86% with 500 mg gluten. We detected GIP in 20–50% of urine samples after placebo. There was no correlation between symptoms, gluten administration and/or GIP in urine. Conclusions: Gluten intake, even with a dose as low as 50 mg, leads to detectable urinary GIP concentrations. There is no correlation of coeliac disease ascribed symptoms with detection of urinary GIP.

PNAd and MAdCAM-1 addressins on venules are of importance in T-cell homing and potential therapeutic targets in ulcerative colitis (UC). Normally, PNAd⁺ high endothelial venules (HEVs) are only present in lymphoid organs, whereas small numbers of MAdCAM-1⁺ venules can be seen in non-lymphoid tissue. We aimed to study their presence in the intestinal mucosa of UC patients at diagnosis and during follow-up, and their correlation with disease activity. Colonic biopsy specimens of 378 UC patients were analyzed by immunohistochemistry for CD3, CD20, ERG, MECA-79 (PNAd) and MECA-376 (MAdCAM-1) and compared to healthy controls (HC). The proportion of PNAd⁺HEVs in UC at diagnosis was 4.9% (IQR 2.0%–8.3%), while none were detected in HC. During follow-up, PNAd⁺HEVs completely disappeared in remission (n = 93), whereas the proportion in active disease was similar to baseline (n = 285, p = 0.39). The proportion of MAdCAM-1⁺venules in UC at baseline was 5.8% (IQR 2.6–10.0). During follow-up, the proportion in remission was comparable to diagnosis, but upregulated (7.5% (IQR 4.4–10.9), p = 0.001) in active disease. In conclusion, PNAd⁺HEVs appear in UC during active inflammation which could thus serve as a marker for disease activity, whereas MAdCAM-1⁺venules remain present after inflammation is resolved and increase after subsequent flares, reflecting chronicity and potentially serving as a therapeutic target.

Routine duodenal biopsies during upper gastrointestinal endoscopy (UGE) have been suggested to be useful in detecting coeliac disease (CD). However results from previous studies are not conclusive. The aim of this study is to investigate the diagnostic yield and cost-effectiveness of routine duodenal biopsy during UGE. In this retrospective single-centre study, we studied 6442 patients undergoing first-time UGE at the Rijnstate Hospital, Arnhem, the Netherlands, from January 2009 to December 2010. All UGE reports were analysed for indication, duodenal intubation, and endoscopic aspect of duodenal mucosa. Endomysium and tissue transglutaminase antibody titre, when present, were scored as positive or negative. CD was defined as Marsh 3a or higher. Costs of duodenal biopsies and pathology analysis were calculated. Comparisons were done with T-tests for continuous data and Chi-square tests for categorical data. Forty-one patients had newly diagnosed CD; 34 of these 41 patients had definite indications for biopsy prior to UGE, e.g. positive serology or symptoms. Thus, routine duodenal biopsies identified seven patients as having CD, who otherwise would not have been biopsied. The number needed to biopsy was therefore 577, spending more than v 30,000 per case. We do not recommend routine duodenal biopsy to screen for coeliac disease because of the high number needed to biopsy as well as high costs.

Alpha-I antitrypsin (AIAT) is an acute-phase protein that is produced in liver cells. AIAT deficiency is a hereditary disease which is defined by the hepatic production of an abnormal protein that can not be released into the plasma. This leads to deficiency of plasma AIAT and subsequently to an impaired protection against proteases, resulting in pulmonary disease. Accumulation of the abnormal protein in hepatocytes can lead to liver damage. Serum level measurement, phenotyping and liver biopsy can be used for establishing the diagnosis. Homozygous AIAT deficiency can cause neonatal hepatitis; in adults end-stage liver disease, cirrhosis and hepatocellular carcinoma can develop. There are strong arguments to consider heterozygous AIAT deficiency as an important co-factor in the aetiology of chronic liver disease. Studies have shown that AIAT heterozygosity can be considered a modifier for hepatitis C virus, end-stage liver disease, cirrhosis and hepatocellular carcinoma. The accumulation of AIAT in the hepatocytes occurs more profoundly in a diseased liver, and as a consequence it affects the natural course of the liver disease. Therapeutic options include augmentation therapy (infusion of purified human plasma AIAT) in pulmonary disease; in end-stage liver disease liver transplantation is an option. For the future, other interventions such as gene therapy or strategies to inhibit polymerisation are promising.

Background : The continuing flow of scientific development in coeliac disease in the past decade points to the need for the formulation of a new concept of pathophysiology and clinical approach to the coeliac condition. Immunogenetic studies have shown a correlation of the disease to the HLA region on the short arm of chromosome 6; immunological research has led to the concept of a T-cell-driven immunologic response of the small intestine, with the identification of highly sensitive and specific antibodies; and our understanding of the histopathology of coeliac disease has changed dramatically, initiated by the proposition of a spectrum of gluten-sensitive enteropathy by Marsh in 1992. Clinical studies report a significant change in patient characteristics and epidemiology. The incidence of the disease has shifted to a majority of adult coeliacs, and it may present with less severe symptoms of malabsorption. Screening studies suggest an overall prevalence of up to 1 in 200-300. Methods : Update on histopathology concentrating on the work of our research group. Results : We specifically describe the work of our group in Arnhem concerning the identification and validation of the spectrum of intestinal histopathology in gluten-sensitive enteropathy, i.e. lymphocytic enteritis (Marsh I lesion), lymphocytic enteritis with crypt hyperplasia (Marsh II lesion), and villous atrophy, subdivided into partial villous atrophy (Marsh IIIA), subtotal villous atrophy (Marsh IIIB) and total villous atrophy (Marsh IIIC). Special attention is given to a subgroup of 'refractory coeliacs', including the identification of (pre-)malignant aberrant T cells in the intestinal mucosa of these patients. Conclusion : New data on immunogenetics, epidemiology, histopathology and patient characteristics point to a significant change of view on coeliac disease.

Patients with villous atrophy due to coeliac disease have an increased risk of developing small intestinal malignancies. Intestinal glutathione (GSH) and glutathione S‐transferases (GST) are involved in the protection against carcinogenesis. The aim of this study was to evaluate GSH content and GST enzyme activity in small intestinal mucosa of untreated coeliacs compared to controls. We evaluated GSH content and GST enzyme activity, including the levels of GST classes α, μ, π, θ in small intestinal biopsies of untreated coeliacs (flat mucosa, Marsh IHC, n=12) compared to normal subjects (n=23). Next, we evaluated GSH and GST's in coeliacs in remission (Marsh 0‐1, n=11), coeliacs with persisting villous atrophy while on a gluten‐free diet (partial villous atrophy, Marsh IIIA (n=5); subtotal villous atrophy, Marsh IIIB (n=6) and patients with infiltrative/crypt‐hyperplastic Marsh II lesions (n=4). Total GST enzyme activity and content of GSTa are markedly suppressed in Marsh IIIC lesions compared to controls (resp. 220±79 vs. 4641189 nmol/mg protein‐min (P<0.001) and 2.79±2.46 vs. 6.47±2.29 μg/mg protein (P<0.001). In coeliacs in remission these levels normalized. Total GST enzyme activity and GSTα levels are proportionately lowered according to the degree of mucosal pathology in Marsh II, IIIA and IIIB. (Spearman's σ correlation coefficient for total GST, ‐0.596, P<0.001; GSTα, ‐0.620, P<0.001). GSTμ, π and θ and GSH levels are not significantly different in the selected study groups of mucosal pathology compared to controls. Total GST enzyme activity and content of GSTα in small intestinal mucosa are significantly lower in untreated coeliac disease compared to controls. In Marsh II, IIIA and IIIB, GST enzyme activity and GSTα content are proportionally lower according to the degree of mucosal pathology. Normal values are seen in coeliacs in remission. This correlation between coeliac disease and a suppressed GSH/GST detoxification system may explain in part the carcinogenic risk in untreated coeliac disease.

Aim: To evaluate the effect of cyclosporin treatment on clinical and histological parameters in adult patients with refractory coeliac disease.Methods: Thirteen patients were treated with oral cyclosporin for 2 months, aiming at serum levels of 100–200 ng/mL. Seven extended medication intake up to a maximum of 12 months. Before and after treatment, clinical parameters were monitored and small intestinal biopsies taken. Ten of 13 patients were typed for HLA‐DQA1 and ‐DQB1 alleles.Results: Eight of 13 patients responded histologically to cyclosporin treatment. Normalization of villi was demonstrated in five patients, three after prolonged treatment. Eight patients reported a clinical response, of whom six had concomitant histological improvement. No serious side‐effects of cyclosporin were noticed. Nine of 10 patients who were immunogenetically typed carried the coeliac disease associated serologic DQ2 markers, one carried neither DQ2 nor DQ8 markers.Conclusion: In our study group of 13 adult refractory coeliac disease patients, cyclosporin in therapeutic doses induced a histological improvement in eight patients (61%), in five of whom (38%) normalization of villi was demonstrated. Thus, we believe that cyclosporin is a therapeutic option in refractory coeliac disease, although we could not confirm earlier reports of unconditional successful treatment.

The treatment of coeliac disease (CD) is straightforward and simple: life-long adherence to a gluten-free diet. However, in a small subgroup of patients, the clinical and histological abnormalities persist or recur. This non-responsiveness leaves a poorly understood syndrome known as refractory coeliac disease (RCD). A specific definition of RCD is lacking in the literature. We speculate that RCD may appear in a subgroup of coeliacs with persisting histologic abnormalities. In all patients screened for RCD we look for DQ2 and DQ8. In non-DQ2/DQ8 patients we reconsider the diagnosis of CD and of auto-immune enteropathy. Most of the patients referred to us because of suspicion of RCD are affected by other diseases. Probably the commonest cause of non-responsiveness is continued gluten intake. Exocrine pancreas insufficiency, hyperthyroid disease, collagenous colitis are other common explanations. RCD and enteropathy-associated T cell lymphomas (EATL) can be distinguished by intra-epithelial lymphocyte phenotyping and TCR-gamma gene rearrangements. In RCD, an unexplained sustained stimulation of T cell cytotoxic activity is present. Immunosuppressive treatment might moderate this. Cyclosporine has been reported as a resounding success in case reports; however, our results were disappointing. We suggest azathioprine and steroids in RCD without aberrant T-lymphocytes in their mucosa. However, in RCD with aberrant T-lymphocytes we suggest chemotherapy. As the prognosis of EATLs is extremely poor the early detection of RCD with aberrant T cells is crucial.