Cerebellar presence of immune cells in patients with neuro-coeliac disease.

Although various neurodegenerative disorders have been associated with coeliac disease (CD), the underlying neuropathological link between these brain and gut diseases remains unclear. We postulated that the neuronal damage sporadically observed in CD patients is immune-mediated. Our aim was to determine if the loss of neurons, especially Purkinje cells, coincides with microglia activation and T- and B-cell infiltration in the cerebellum of patients with CD and a concomitant idiopathic neurological disease affecting the cerebellum (NeuroCD). Post-mortem cerebellar tissue was collected of validated NeuroCD cases. Gender- and age-matched genetic spinocerebellar ataxia (SCA) controls and non-neurological controls (NNC) were selected based on clinical reports and pathological findings. Cerebellar tissue of seventeen patients was included (6 NeuroCD, 5 SCA, 6 NNC). In SCA cases we found that the Purkinje cell layer was 58.6% reduced in comparison with NNC. In NeuroCD cases this reduction was even more prominent with a median reduction of 81.3% compared to NNC. Marked increased numbers of both CD3+ and CD8+ cells were observed in the NeuroCD but not in SCA patients. This coincided with significantly more microglial reactivity in NeuroCD patients. These findings demonstrate that the massive loss of Purkinje cells in the cerebellum of neuro CD patients is accompanied by local innate and T-cell mediated immune responses.

Insight in the diagnosis and treatment of coeliac disease in general practice: A survey and case vignette study among 106 general practitioners.

BACKGROUND: Coeliac disease (CD) is a highly prevalent (∼1%) disease that allegedly remains undiagnosed in over 80% of the cases because of atypical symptoms or silent disease. Currently, it is unknown how GPs deal with (suspected) CD. OBJECTIVES: This study aimed to better understand the diagnostic approach and the clinical reasoning process of GPs concerning CD and concurrently address diagnostic pitfalls. METHODS: A questionnaire with case vignettes to assess the knowledge, diagnostic reasoning pattern and practice for CD by GPs was developed. It was sent through academic GP research networks (encompassing over 1500 GPs) in two large cities and to smaller practices in rural areas. The questionnaire was composed of seven background questions, 13 questions related to four case vignettes and six additional CD-related questions. RESULTS: Responses were received from 106 GPs. Knowledge on risk factors for CD and appropriate testing of at-risk populations was limited. Twenty-two percent would diagnose CD in adults exclusively based on serology, without histopathological confirmation. In total, 99% would refer a newly diagnosed patient to a dietitian to initiate a gluten-free diet (GFD). In the absence of symptoms, only 33% would initiate a GFD. CONCLUSION: The results of this study have given us insight into the diagnostic process of GPs encountering patient with gluten-related complaints. Multiple serology test is available and used, while a positive serology test is not always followed up by a gastroduodenal biopsy to confirm the diagnosis. Most GPs would refer a symptomatic CD patient to a dietician for a GFD.

Testing for coeliac disease rarely leads to a diagnosis: a population-based study.

BACKGROUND: Coeliac disease (CD) has an estimated prevalence of ∼1% in Europe with a significant gap between undiagnosed and diagnosed CD. Active case finding may help to bridge this gap yet the diagnostic yield of such active case finding in general practice by serological testing is unknown. OBJECTIVE: The aim of this study was to determine (1) the frequency of diagnosed CD in the general population, and (2) to investigate the yield of active case finding by general practitioners. METHODS: Electronic medical records of 207.200 patients registered in 49 general practices in The Netherlands in 2016 were analysed. An extensive search strategy, based on International Classification of Primary Care codes, free text and diagnostic test codes was performed to search CD- or gluten-related contacts. RESULTS: The incidence of CD diagnosis in general practice in 2016 was 0.01%. The prevalence of diagnosed CD reported in the general practice in the Netherlands was 0.19%, and considerably higher than previously reported in the general population. During the one year course of the study 0.95% of the population had a gluten-related contact with their GP; most of them (72%) were prompted by gastrointestinal complaints. Serological testing was performed in 66% (n = 1296) of these patients and positive in only 1.6% (n = 21). CONCLUSION: The number of diagnosed CD patients in the Netherlands is substantially higher than previously reported. This suggests that the gap between diagnosed and undiagnosed patients is lower than generally assumed. This may explain that despite a high frequency of gluten-related consultations in general practice the diagnostic yield of case finding by serological testing is low.Key pointsThe diagnostic approach of GPs regarding CD and the diagnostic yield is largely unknownCase finding in a primary health care practice has a low yield of 1.6%CD testing was mostly prompted by consultation for gastrointestinal symptomsThere is a heterogeneity in types of serological test performed in primary care.

The Neuropathology of Gluten-Related Neurological Disorders: A Systematic Review.

Gluten-related neurological disorders (GRND) represent a spectrum of neurological manifestations that are triggered by gluten. In coeliac disease, a T-cell mediated enteropathy is triggered by gluten in genetically predisposed individuals. The underlying pathological mechanism of the neurological dysfunction is not yet clear. The aim of this review is to collate existing neuropathological findings in GRND as a means of aiding the understanding of the pathophysiology. A systematic search of the Pubmed Database yielded 188 articles, of which 32 were included, containing 98 eligible cases with a description of pathological findings in GRND. In gluten ataxia, loss of Purkinje cells, atrophy, gliosis and astrocytosis were apparent, as well as diffuse lymphocytic infiltration and perivascular cuffing with lymphocytes. In patients with large-fiber neuropathy, nerve biopsies revealed axonopathy, loss of myelinated fibers and focal and perivascular infiltration by inflammatory cells. Inflammatory infiltrate was also observed in muscle in myopathy and in cerebrum of patients with encephalopathy and patients with epilepsy. Such changes were not seen in skin biopsies from patients with small fiber neuropathies. The findings from this systematic review suggest an immune mediated pathogenesis for GRND. Future research should focus on the characterization of the inflammatory cell infiltrates and identifying target epitopes.

Vulvar and vaginal neoplasia in women with inflammatory bowel disease.

Immunosuppressive drugs are the cornerstone in the treatment of inflammatory bowel disease (IBD), however they are associated with an increased risk of extra-intestinal cancer. Whether the risk for female genital tract malignancies, including vulvar and vaginal cancer, is increased is less clear. Our aim was to investigate the risk of these malignancies in IBD-patients. Histopathological data of all IBD patients with a vulvar or vaginal (pre-)cancerous lesion were retrieved from the Dutch nationwide network and registry of histopathology and cytopathology from 1991 to 2015. Medical history was retrieved from patient records. Data from the Central Office for Statistics, the Dutch comprehensive cancer organization, and the IBDSL cohort were obtained to calculate the standardized, and age-adjusted incidence rates. Fifty-five patients met the inclusion criteria. A standardized incidence rate of 1.2(95% CI:0.8-1.7) for vulvar and vaginal carcinoma among adult female IBD was calculated, which did not significantly differ from the general population. The use of immunosuppressive therapy did not increase the occurrence of vulvovaginal malignancy, nor did it influence the recurrence rate. However, immunosuppressive drugs ever-users were on average 11 years younger at the time of their gynaecological diagnosis. Overall, our data do not support intensified screening for vulvar or vaginal malignancies in female IBD patients.

Faecal Scent as a Novel Non-Invasive Biomarker to Discriminate between Coeliac Disease and Refractory Coeliac Disease: A Proof of Principle Study.

Currently, the gold standard for diagnosis of coeliac disease (CD) is based on serology and gastroduodenoscopy with histology of duodenal mucosal biopsies. The aim of this study was to evaluate the potential of faecal volatile organic compounds (VOCs) analysis as a novel, non-invasive tool to discriminate between CD in remission in patients on a gluten-free diet (GFD), refractory coeliac disease (RCD) and controls without CD. Patients with an established diagnosis of CD on a GFD, RCD and healthy controls (HC) were instructed to collect a faecal sample. All subjects completed questionnaires on clinical symptoms, lifestyle and dietary information. Faecal VOCs were measured using gas chromatography-ion mobility spectrometry. A total of 13 CD, 7 RCD and 10 HC were included. A significant difference in VOC profiles between CD and RCD patients (area under the curve (AUC) ± 95% CI: 0.91 (0.79-1) p = 0.000) and between CD and HC (AUC ± 95% CI: 0.71 (0.51-0.91) p = 0.0254) was observed. We found no significant differences between faecal VOC patterns of HC and RCD. Based on faecal VOCs, CD could be discriminated from RCD and HC. This implies that faecal VOC analysis may hold potential as a novel non-invasive biomarker for RCD. Future studies should encompass a larger cohort to further investigate and validate this prior to application in clinical practice.

HLA-DQ Typing Kits in Diagnosis and Screening for Celiac Disease.

Aim: Celiac disease (CD) is strongly associated with HLA-DQ2.2, HLA-DQ2.5, and HLA-DQ8. Up to 99.7% of all CD patients are positive for either one or two of these genetic markers, demonstrating a high negative predictive value. This has led to the development of diagnostic kits that, instead of providing a full HLA-DQ typing, detect only these three HLA-DQ types. Our aim was to compare three different kits for their performance, utilization, and costs. Because 0.4-3.6% of all CD patients test positive for HLA-DQ7 and negative for the aforementioned types, information provided by the kits regarding DQ7 alpha and beta chains was evaluated as well. Materials and Methods: Fifty DNA samples previously typed with the SSCP method were analyzed using three commercial kits. Results and Discussion: All kits report hetero- or homozygosity for HLA-DQ2.5. The XeliGen kit directly detects HLA-DQ7, but is relatively expensive. The MLPA kit is the least expensive in terms of reagents and may indirectly detect HLA-DQ7. The CeliaSCAN kit is easy to use and provides indirect information about HLA-DQ7.5. Conclusion: All kits correctly identify the CD risk genes. The resources of the laboratory and the intended use should determine the preference for any of the HLA-DQ typing kits herein described.