Unrestricted vs 3-day low-residue diet for colonoscopy preparation. Results of a feasibility randomized trial.

AIM: To compare the impact of an unrestricted diet with a 3-day low-residue diet before colonoscopy on bowel preparation quality. METHODS: A randomized, multicenter, researcher-blinded, parallel-group feasibility trial was conducted to assess the efficacy of an unrestricted diet versus a 3-day low-residue diet for colonoscopy preparation. Participants, aged 50 to 69, were enrolled in a colorectal cancer screening program with no factors linked to poor bowel cleansing. The Boston Bowel Preparation Scale was used to evaluate colon preparation during intubation and withdrawal. Secondary outcomes included bowel exploration time, adenoma and polyp detection rates, and preparation and diet tolerability. The trial is registered under Clinical Trials (NCT04664543). RESULTS: One hundred and two individuals (mean age 59.3 ± 5.5 years, 40.1% female) were randomly assigned to each diet. All participants in both groups achieved adequate preparation (Boston scores ≥ 2 in each segment). Complete adherence to preparation was observed in the majority of participants in both groups. No significant differences were noted between groups in withdrawal or cecal intubation times, or in adenoma detection rates. The unrestricted diet was better tolerated than the 3-day low-residue diet (82.5% vs. 32.3%). Preparation assessed during intubation was adequate in 82.5% of the unrestricted diet group and in 90.3% of the 3-day low-residue diet group. CONCLUSIONS: It is feasible to test the impact of an unrestricted diet for adequate bowel preparation. Comparable cleansing results were achieved, but the unrestricted diet showed better tolerability.

Improving the Diagnosis of Dermatitis Herpetiformis Using the Intraepithelial Lymphogram.

Dermatitis herpetiformis is a cutaneous manifestation of celiac disease. Phenotyping of intraepithelial lymphocytes in the small bowel mucosa can strengthen the diagnosis of celiac disease when it is not clear-cut. We aim to evaluate the usefulness of the intraepithelial lymphogram to confirm dermatitis herpetiformis in equivocal cases. We performed a retrospective multicenter study on patients diagnosed with dermatitis herpetiformis and collected data from the intraepithelial lymphogram assessed by flow cytometry. A total of 36 patients were analyzed in relation to the severity of intestinal damage (18 had non-atrophic mucosa) at baseline (N = 28) and/or after the adoption of a gluten-free diet (median follow-up of three years, N = 16). We observed that patients with atrophy more often had positive celiac serology (p = 0.019), celiac clinical symptoms (p = 0.018), and iron-deficiency anemia (p = 0.018), but the severity of skin damage was similar in both groups (p = 0.79). At baseline, increased TCRγδ+ cells were present in 94% of patients with atrophy and 67% with non-atrophic lesions (p = 0.13). After a gluten-free diet, increased TCRγδ+ cells persisted in 100% and 63% of cases, respectively (p = 0.21). We concluded that increased TCRγδ+ cells may be helpful in confirming the diagnosis of dermatitis herpetiformis in equivocal cases, even in patients who were started on a gluten-free diet.

Human Leukocyte Antigen Signatures as Pathophysiological Discriminants of Microscopic Colitis Subtypes.

BACKGROUND AND AIMS: Microscopic colitis [MC] is currently regarded as an inflammatory bowel disease that manifests as two subtypes: collagenous colitis [CC] and lymphocytic colitis [LC]. Whether these represent a clinical continuum or distinct entities is, however, an open question. Genetic investigations may contribute important insight into their respective pathophysiologies. METHODS: We conducted a genome-wide association study [GWAS] meta-analysis in 1498 CC, 373 LC patients, and 13 487 controls from Europe and the USA, combined with publicly available MC GWAS data from UK Biobank and FinnGen [2599 MC cases and 552 343 controls in total]. Human leukocyte antigen [HLA] alleles and polymorphic residues were imputed and tested for association, including conditional analyses for the identification of key causative variants and residues. Genetic correlations with other traits and diagnoses were also studied. RESULTS: We detected strong HLA association with CC, and conditional analyses highlighted the DRB1*03:01 allele and its residues Y26, N77, and R74 as key to this association (best p = 1.4 × 10-23, odds ratio [OR] = 1.96). Nominally significant genetic correlations were detected between CC and pneumonia [rg = 0.77; p = 0.048] and oesophageal diseases [rg = 0.45, p = 0.023]. An additional locus was identified in MC GWAS analyses near the CLEC16A and RMI2 genes on chromosome 16 [rs35099084, p = 2.0 × 10-8, OR = 1.31]. No significant association was detected for LC. CONCLUSION: Our results suggest CC and LC have distinct pathophysiological underpinnings, characterised by an HLA predisposing role only in CC. This challenges existing classifications, eventually calling for a re-evaluation of the utility of MC umbrella definitions.

A Population-Based Cross-Sectional Study of Paediatric Coeliac Disease in Catalonia Showed a Downward Trend in Prevalence Compared to the Previous Decade.

(1) Background: Previous studies showed an increased prevalence and incidence of coeliac disease (CD) over time. The objective is to ascertain whether the CD prevalence in Catalonia (a region of Southern Europe) among children aged 1-5 is as high as previously found in 2004-2009; (2) Methods: From 2013 to 2019, 3659 subjects aged 1-5 years were recruited following the previously used methodology. Factors with a potential impact on CD prevalence were investigated; (3) Results: In 2013-2019, 43/3659 subjects had positive serology, giving a standardised seroprevalence of 12.55/1000 (95% CI: 8.92; 17.40), compared to 23.62 (13.21; 39.40) in 2004-2007. The biopsy-proven crude prevalence was 7.92/1000 (95% CI: 5.50; 11.30), and the crude prevalence based on ESPGHAN criteria was 8.74/1000 (95% CI: 6.20-12.30). In contrast to 2004-2009, we did not find differences in the seroprevalence rates between 1 and 2 years vs. 3 and 4 years of age (age percentage of change -7.0 (-29.5; 22.8) vs. -45.3 (-67.5; -8.0)). Rotavirus vaccination was the most remarkable potential protective factor (48% vs. 9% in 2004-2009; p < 0.0001), but not the time of gluten introduction. (4) Conclusion: The present study did not confirm a worldwide CD prevalence increase and emphasizes the need to perform prevalence studies over time using the same methodology in the same geographical areas.

Persistent villous atrophy predicts development of complications and mortality in adult patients with coeliac disease: a multicentre longitudinal cohort study and development of a score to identify high-risk patients.

OBJECTIVE: Persistent villous atrophy (pVA) in coeliac disease (CD) despite a gluten-free diet (GFD) has unclear meaning. We aimed to (i) study the relationship between pVA and long-term outcomes and (ii) develop a score to identify patients at risk of pVA. DESIGN: This is a multicentre retrospective-prospective study consisting of a study cohort (cohort 1) and an external validation cohort (cohort 2) of patients with biopsy-proven CD diagnosed between 2000 and 2021. Cohort 1 was used to (i) compare long-term outcomes between patients with and without pVA (Marsh ≥3a) at follow-up biopsy and (ii) to develop a score to evaluate the risk of pVA, which was validated in cohort 2. RESULTS: Of 2211 patients, 694 (31%) underwent follow-up duodenal biopsy and were included in the study cohort (491F, 44±16 years). 157/694 (23%) had pVA. Risk of complications (HR 9.53, 95% CI 4.77 to 19.04, p<0.001) and mortality (HR 2.93, 95% CI 1.43 to 6.02, p<0.01) were increased in patients with pVA. A 5-point score was developed and externally validated (receiver operating characteristic area under the curve 0.78, 95% CI 0.68 to 0.89) to stratify patients by risk of pVA: low (0-1 points, 5% pVA), intermediate (2 points, 16% pVA) and high (3-5 points, 73% pVA). Predictors for pVA used in the score were age at diagnosis ≥45 years (OR 2.01, 95% CI 1.21 to 3.34, p<0.01), classical pattern of CD (OR 2.14, 95% CI 1.28 to 3.58, p<0.01), lack of clinical response to GFD (OR 2.40, 95% CI 1.43 to 4.01, p<0.001) and poor GFD adherence (OR 48.9, 95% CI 26.1 to 91.8, p<0.001). CONCLUSIONS: Risk of complications and mortality were increased in patients with pVA. We developed a score to identify patients at risk of pVA and in need of histological reassessment and closer follow-up.

Endoscopic treatment (endoscopic balloon dilation/self-expandable metal stent) vs surgical resection for the treatment of de novo stenosis in Crohn's disease (ENDOCIR study): an open-label, multicentre, randomized trial.

BACKGROUND: Stenosis is one of the most common complications in patients with Crohn's disease (CD). Endoscopic balloon dilation (EBD) is the treatment of choice for a short stenosis adjacent to the anastomosis from previous surgery. Self-expandable metal stents (SEMS) may be a suitable treatment option for longer stenoses. To date, however, there is no scientific evidence as to whether endoscopic (EBD/SEMS) or surgical treatment is the best approach for de novo or primary stenoses that are less than 10 cm in length. METHODS/DESIGN: Exploratory study as "proof-of-concept", multicentre, open-label, randomized trial of the treatment of de novo stenosis in the CD; endoscopic treatment (EBD/SEMS) vs surgical resection (SR). The type of endoscopic treatment will initially be with EDB; if a therapeutic failure occurs, then a SEMS will be placed. We estimate 2 years of recruitment and 1 year of follow-up for the assessment of quality of life, costs, complications, and clinical recurrence. After the end of the study, patients will be followed up for 3 years to re-evaluate the variables over the long term. Forty patients with de novo stenosis in CD will be recruited from 15 hospitals in Spain and will be randomly assigned to the endoscopic or surgical treatment groups. The primary aim will be the evaluation of the patient quality of life at 1 year follow-up (% of patients with an increase of 30 points in the 32-item Inflammatory Bowel Disease Questionnaire (IBDQ-32). The secondary aim will be evaluation of the clinical recurrence rate, complications, and costs of both treatments at 1-year follow-up. DISCUSSION: The ENDOCIR trial has been designed to determine whether an endoscopic or surgical approach is therapeutically superior in the treatment of de novo stenosis in CD. TRIAL REGISTRATION: ClinicalTrials.gov NCT04330846. Registered on 1 April 1 2020. https://clinicaltrials.gov/ct2/home.

BMPR2 as a Novel Predisposition Gene for Hereditary Colorectal Polyposis.

BACKGROUND & AIMS: Colorectal cancer (CRC) is one of the most prevalent tumors worldwide, with incidence quickly increasing (particularly in the context of early-onset cases), despite important prevention efforts, mainly in the form of population-wide screening programs. Although many cases present a clear familial component, the current list of hereditary CRC genes leaves a considerable proportion of the cases unexplained. METHODS: In this work, we used whole-exome sequencing approaches on 19 unrelated patients with unexplained colonic polyposis to identify candidate CRC predisposition genes. The candidate genes were then validated in an additional series of 365 patients. CRISPR-Cas9 models were used to validate BMPR2 as a potential candidate for CRC risk. RESULTS: We found 8 individuals carrying 6 different variants in the BMPR2 gene (approximately 2% of our cohort of patients with unexplained colonic polyposis). CRISPR-Cas9 models of 3 of these variants showed that the p.(Asn442Thrfs∗32) truncating variant completely abrogated BMP pathway function in a similar way to the BMPR2 knockout. Missense variants p.(Asn565Ser), p.(Ser967Pro) had varying effects on cell proliferation levels, with the former impairing cell control inhibition via noncanonical pathways. CONCLUSIONS: Collectively, these results support loss-of-function BMPR2 variants as candidates to be involved in CRC germline predisposition.

Mucosal Interleukin-10 depletion in steroid-refractory Crohn's disease patients.

BACKGROUND: Previous studies suggested that Interleukin-10 (IL-10) depletion in Crohn's disease (CD) could predict outcome. AIM: To determine IL-10 in blood and at different intestinal locations in patients with active CD and to assess its potential prognostic capacity to identify aggressive CD. METHODS: Twenty-three patients with CD were included. Ulcerative colitis (UC), infectious colitis and healthy individuals acted as controls. Serum and mucosal samples were taken at baseline and 1 month after steroid initiation in CD patients. Patients were classified according to steroid response. Control samples were obtained from different intestinal locations. IL-10 expression was measured with real-time polymerase chain reaction, immunofluorescence (intestine) and ELISA (serum, biopsy cultures' supernatants and tissue homogenates). RESULTS: CD and UC showed an increase in IL-10 messenger RNA (mRNA) versus controls (p < .0001) in mucosa, whereas IL-10 protein secretion was increased in all types of intestinal inflammation (p < .001). No differences in IL-10 mRNA were found in CD at baseline regarding steroid response, but levels decreased in non-responders versus responders (p = .027) and were restored with rescue therapy. Serum IL-10 was increased in steroid-refractory CD at baseline and after treatment. CONCLUSIONS: Abnormal IL-10 levels in refractory patients in both mucosa and blood have physiopathological relevance and may have potential clinical applications.

Microscopic colitis: Etiopathology, diagnosis, and rational management.

Microscopic colitis is an inflammatory bowel disease divided into two subtypes: collagenous colitis and lymphocytic colitis. With an increasing incidence of microscopic colitis exceeding those of ulcerative and Crohn's disease among elderly people in some countries, microscopic colitis is a debilitating life experience. Therefore, physicians should be familiar with its clinical features and management strategies because the disease deserves the same attention as the classical inflammatory bowel diseases. Here, state-of-the-art knowledge of microscopic colitis is provided from a global perspective with reference to etiopathology and how to establish the diagnosis with the overall aim to create awareness and improve rational management in clinical practice. The immune system and a dysregulated immune response seem to play a key role combined with risk factors (e.g. cigarette smoking) in genetically predisposed individuals. The symptoms are characterized by recurrent or chronic nonbloody, watery diarrhea, urgency, weight loss, and a female preponderance. As biomarkers are absent, the diagnosis relies on colonoscopy with a histological assessment of biopsy specimens from all parts of the colon. Although the disease is not associated with a risk of colorectal cancer, a recent nationwide, population-based cohort study found an increased risk of lymphoma and lung cancer. Budesonide is the first-line therapy for management, whereas immunomodulatory drugs (including biologics) and drugs with antidiarrheal properties may be indicated in those failing, dependent, or intolerant to budesonide. In microscopic colitis induced by checkpoint inhibitors, a drug class used increasingly for a wide range of malignancies, a more aggressive therapeutic approach with biologics introduced early seems reasonable. However, particular attention needs to be drawn to the existence of incomplete forms of microscopic colitis with the risk of being overlooked in routine clinical settings.

Colonic bacterial diversity and dysbiosis in active microscopic colitis as compared to chronic diarrhoea and healthy controls: effect of polyethylene glycol after bowel lavage for colonoscopy.

BACKGROUND: Most microbiota studies in microscopic colitis patients are performed after diagnostic colonoscopy without considering the potential effect of colonic lavage. Patients may achieve clinical remission after colonoscopy and it is unknown whether lavage-induced changes play a role. AIM: To assess the effect of polyethylene glycol (PEG) colonic lavage on clinical remission rate, microbial diversity, microbial dysbiosis index and specific microbial changes in patients with active microscopic colitis as compared to other diarrhoeal diseases and healthy controls. METHODS: Fifty-five consecutive patients presenting chronic watery diarrhoea and 12 healthy controls were included. Faecal samples were collected three days before and 30 days after PEG in patients and controls for microbiome analysis. RESULTS: Clinical remission was observed in 53% of microscopic colitis patients, and in 32% of non-microscopic colitis patients (p = 0.16). Considering patients with persisting diarrhoea after colonoscopy, 71% of non-microscopic colitis patients had bile acid diarrhoea. Baseline Shannon Index was lower in diarrhoea groups than in healthy controls (p = 0.0025); there were no differences between microscopic colitis, bile-acid diarrhoea and functional diarrhoea. The microbial dysbiosis index was significantly higher in microscopic colitis than in bile acid diarrhoea plus functional diarrhoea (p = 0.0095), but no bacterial species showed a significantly different relative abundance among the diarrheal groups. CONCLUSIONS: Dysbiosis is a feature in active microscopic colitis, but loss of microbial diversity was similar in all diarrheal groups, suggesting that faecal microbial changes are not due to microscopic colitis itself but associated with stool form. A considerable number of microscopic colitis patients achieved clinical remission after colonoscopy, but we were unable to demonstrate related PEG-induced changes in faecal microbiome.

Carbohydrate Maldigestion and Intolerance.

This review summarizes dietary carbohydrate intolerance conditions and recent advances on the possible role of carbohydrate maldigestion and dietary outcomes in patients with functional bowel disease. When malabsorbed carbohydrates reach the colon, they are fermented by colonic bacteria, with the production of short-chain fatty acids and gas lowering colonic pH. The appearance of diarrhoea or symptoms of flatulence depends in part on the balance between the production and elimination of these fermentation products. Different studies have shown that there are no differences in the frequency of sugar malabsorption between patients with irritable bowel disease (IBS) and healthy controls; however, the severity of symptoms after a sugar challenge is higher in patients than in controls. A diet low in 'Fermentable, Oligo-Di- and Monosaccharides and Polyols' (FODMAPs) is an effective treatment for global symptoms and abdominal pain in IBS, but its implementation should be supervised by a trained dietitian. A 'bottom-up' approach to the low-FODMAP diet has been suggested to avoid an alteration of gut microbiota and nutritional status. Two approaches have been suggested in this regard: starting with only certain subgroups of the low-FODMAP diet based on dietary history or with a gluten-free diet.

Usefulness of endoscopic ultrasound in patients with minilithiasis and/or biliary sludge as a cause of symptoms of probable biliary origin after cholecystectomy / Utilidad de la ecoendoscopia en pacientes con minilitiasis y/o barro biliar como causa de síntomas digestivos de probable origen biliar después de la colecistectomía

Introduction: Endoscopic ultrasound (EUS) is a more sensitive technique than transabdominal ultrasound for the diagnosis of gallstones. This greater sensitivity, especially in the diagnosis of microlithiasis/biliary sludge, facilitates the indication of cholecystectomy in patients with symptoms of probable biliary origin but may result in over-indication of this surgery.Objectives: Evaluate the role of EUS in the diagnosis of minilithiasis/biliary sludge in patients with digestive symptoms of probable biliary origin by resolving the symptoms after cholecystectomy. Analyse factors related to the remission of symptoms following cholecystectomy.Patients and methods: Retrospective, longitudinal, single-centre study based on a prospective database of 1.121 patients undergoing EUS. Seventy-four patients were identified as meeting inclusion-exclusion criteria (diagnosed with minilithiasis/sludge by EUS after presenting digestive symptoms of probable biliary origin without a history of complicated cholelithiasis). A telephone questionnaire for symptoms was conducted with cholecystectomized patients. Factors related to a good response were analysed with logistic regression analysis.Results: Of the 74 patients, 50 were cholecystectomized (67.5%), mean age 49 years (SEM 2.26) (41 women). Seventy percent of patients (35/50) presented remission of symptoms with median follow-up 353.5 days (95% CI, 270–632.2). The only variable associated with remission of symptoms was the presence of typical biliary colic with an OR of 7.8 (95% CI, 1.8–34; p=0.006). No complications associated with EUS were recorded. One patient (2%) suffered haemoperitoneum and 18% (9/50) suffered diarrhoea following cholecystectomy.Conclusions: EUS is a very useful technique for the indication of cholecystectomy in patients with minilithiasis/sludge and typical symptoms of biliary colic.

Introducción: La ecoendoscopia (USE) presenta mayor sensibilidad que la ecografía abdominal para el diagnóstico de litiasis biliar. Esta mayor sensibilidad, sobre todo en diagnóstico de microlitiasis/barro biliar, facilitaría una colecistectomía en pacientes con clínica digestiva de probable origen biliar, aunque podría inducir su sobre indicación.ObjetivosEvaluar el papel de la USE en el diagnóstico de minilitiasis-barro biliar en pacientes con clínica digestiva de probable origen biliar y ecografía normal mediante la resolución de los síntomas después de colecistectomía. Analizar los factores relacionados con la remisión de la sintomatología tras colecistectomía.Pacientes y método: Estudio retrospectivo, longitudinal, en un centro, sobre base de datos prospectiva de 1.121 pacientes sometidos a USE. Setenta y cuatro pacientes cumplían criterios inclusión-exclusión (realización USE para estudio de minilitiasis/barro por síntomas digestivos de probable origen biliar, sin historia de colelitiasis complicada). Se realizó cuestionario telefónico de síntomas a los pacientes colecistectomizados. Los factores relacionados con buena evolución se analizaron con análisis de regresión logística.Resultados: De los 74 pacientes, 50 fueron colecistectomizados (67,5%), edad media 49 años (ESM 2,26) (41 mujeres). El 70% de pacientes (35/50) presentó remisión de la sintomatología (mediana de seguimiento 353,5 días) (IC 95%, 270-632,2). La única variable asociada con una remisión de la sintomatología fue la presencia de cólico biliar típico con una OR de 7,8 (IC 95%, 1,8-34; p=0,006). No se registró ninguna complicación asociada a la USE. Un paciente (2%) sufrió hemoperitoneo y un 18% (9/50) presentaron diarrea post-colecistectomía.Conclusiones: La USE es de gran utilidad para la indicación de colecistectomía en los pacientes con minilitiasis-barro biliar y clínica típica de cólico biliar.

Self-expandable metal stents versus endoscopic balloon dilation for the treatment of strictures in Crohn's disease (ProtDilat study): an open-label, multicentre, randomised trial.

BACKGROUND: Endoscopic balloon dilation (EBD) is the established endoscopic treatment for short strictures in Crohn's disease. Fully covered self-expandable metal stents (FCSEMS) have been used for endoscopic treatment of patients for whom EBD was unsuccessful. We aimed to determine the efficacy and safety of the two endoscopic treatments in patients with Crohn's disease with stenosis and compare the mean cost of both treatments. METHODS: This multicentre, open-label, randomised trial was done in 19 tertiary and secondary hospitals in Spain. Patients with Crohn's disease with obstructive symptoms and predominantly fibrotic strictures of less than 10 cm in length were eligible for inclusion. We excluded patients with stenosis treated with SEMS or EBD in the previous year and stenosis not accessible to a colonoscope. Patients were randomly assigned (1:1) to receive either EBD (EBD group) or FCSEMS (FCSEMS group) using a digital en-block randomisation system (block size of four). In the EBD group, dilation was done with a CRE Boston Scientific (Marlborough, MA, USA) pneumatic balloon with the diameter set at the discretion of the endoscopist; a maximum of two sessions of dilation were allowed with a minimum interval of 15-30 days between them. In the FCSEMS group, a 20 mm diameter Taewoong (Gimpo-si, South Korea) fully covered metal stent was placed; stent length was set at the discretion of the endoscopist. The primary outcome was to assess the efficacy of the endoscopic treatment, defined by the proportion of patients free of a new therapeutic intervention (EBD, FCSEMS, or surgery) due to symptomatic recurrence at 1 year of follow-up. Patients were analysed according to the intention-to-treat principle. Adverse events were recorded for all the patients; events were considered associated to be with the procedure when a causal association was possible, probable, or definite. This trial is registered with ClinicalTrials.gov, NCT02395354. FINDINGS: From Aug 28, 2013, to Oct 9, 2017, we assessed the eligibility of 99 patients, of whom 19 (19%) patients were excluded. Thus, 80 (81%) patients were randomly assigned to treatment: 39 (49%) patients to the FCSEMS group and 41 (51%) patients to the EBD group. 33 (80%) of 41 patients in the EBD group and 20 (51%) of 39 patients in the FCSEMS group were free of a new therapeutic intervention at 1 year (odds ratio [OR] 3·9 [95% CI 1·4-10·6]; p=0·0061). Two (3%) of 80 patients had severe adverse events (one [2%] patient in the EBD group and one [3%] patient in the FCSEMS group); both patients had perforations. INTERPRETATION: EBD is more effective than FCSEMS for Crohn's disease strictures, with a good safety profile for both treatments. FUNDING: Spanish National Institute of Health, Foundation of Spanish Society of Digestive Endoscopy, Catalan Society of Gastroenterology, and Taweoong.

Usefulness of endoscopic ultrasound in patients with minilithiasis and/or biliary sludge as a cause of symptoms of probable biliary origin after cholecystectomy.

INTRODUCTION: Endoscopic ultrasound (EUS) is a more sensitive technique than transabdominal ultrasound for the diagnosis of gallstones. This greater sensitivity, especially in the diagnosis of microlithiasis/biliary sludge, facilitates the indication of cholecystectomy in patients with symptoms of probable biliary origin but may result in over-indication of this surgery. OBJECTIVES: Evaluate the role of EUS in the diagnosis of minilithiasis/biliary sludge in patients with digestive symptoms of probable biliary origin by resolving the symptoms after cholecystectomy. Analyse factors related to the remission of symptoms following cholecystectomy. PATIENTS AND METHODS: Retrospective, longitudinal, single-centre study based on a prospective database of 1.121 patients undergoing EUS. Seventy-four patients were identified as meeting inclusion-exclusion criteria (diagnosed with minilithiasis/sludge by EUS after presenting digestive symptoms of probable biliary origin without a history of complicated cholelithiasis). A telephone questionnaire for symptoms was conducted with cholecystectomized patients. Factors related to a good response were analysed with logistic regression analysis. RESULTS: Of the 74 patients, 50 were cholecystectomized (67.5%), mean age 49 years (SEM 2.26) (41 women). Seventy percent of patients (35/50) presented remission of symptoms with median follow-up 353.5 days (95% CI, 270-632.2). The only variable associated with remission of symptoms was the presence of typical biliary colic with an OR of 7.8 (95% CI, 1.8-34; p=0.006). No complications associated with EUS were recorded. One patient (2%) suffered haemoperitoneum and 18% (9/50) suffered diarrhoea following cholecystectomy. CONCLUSIONS: EUS is a very useful technique for the indication of cholecystectomy in patients with minilithiasis/sludge and typical symptoms of biliary colic.

The Process of Developing a Disease Activity Index in Microscopic Colitis.

BACKGROUND AND AIMS: Patient-reported outcome measures [PROMs] aim to measure patients' perception of how their disorder influences everyday functioning. The objective of this study was to develop a PROM to assess disease activity in microscopic colitis [MC] fulfilling the requirements of the Food and Drug Administration [FDA]. METHODS: The European Microscopic Colitis Activity Index [E-MCAI] was developed in four steps. [1] A list of symptoms associated with active MC was created by a group of experts in the field. [2] Content validity of the symptoms was performed by experts [n = 14] and patients [n = 79] using the Content Validity Index. [3] Questions and response alternatives were created for each symptom, and validity of the E-MCAI was evaluated with cognitive interviews with patients [n = 7] and by the experts. [4] A pilot postal survey was performed to ensure usability. RESULTS: Seven of the symptoms related to active MC fulfilled the criteria for content validity and were included in the E-MCAI: stool consistency, stool frequency, stools at night, feel a need to pass more stools shortly after a bowel movement, urgent need to empty the bowel, leakage of stool and abdominal pain. The development and validation process resulted in the current version of the E-MCAI consisting of six questions related to MC. CONCLUSIONS: The E-MCAI was developed using the methods advocated by the FDA. The evaluation indicates good content validity. Further evaluation will be performed to achieve construct validity, reliability and responsiveness in future cross-sectional and longitudinal studies.

Pathogenesis of Microscopic Colitis: A Systematic Review.

BACKGROUND: Whereas the exact aetiology of microscopic colitis [MC] remains unknown, a dysregulated immune response to luminal factors or medications is the most accepted pathogenesis hypothesis. METHODS: We conducted a systematic review of the pathogenesis of MC. We applied the Joanna Briggs Institute methodologies and the PRISMA statement for the reporting of systematic reviews [PROSPERO Trial Identifier: CRD42020145008]. Populations, Exposure of interest, and Outcome [PEO] questions were used to explore the following topics in MC: 1] intestinal luminal factors; 2] autoimmunity; 3] innate immunity; 4] adaptive immunity; 5] extracellular matrix; 6] genetic risk factors; and 7] mechanism of diarrhoea. A search was done in PubMed, Embase, and Web of Science up to February 2020. A narrative description was performed explaining the findings for each aspect of MC aetiopathogenesis. RESULTS: Thirty-eight documents provided evidence for PEO1, 100 for PEO2, 72 for PEO3 and 4, 38 for PEO5, 20 for PEO6, and 23 for PEO7. The majority of documents were cohorts, case reports, and case series, with a few case-control and some experimental studies. Consistency among data provided by different studies was considered to support pathogenetic hypotheses. MC is a multifactorial disease believed to involve innate and adaptive immune responses to luminal factors, genetic risk, autoimmunity, and extracellular matrix alterations, all contributing by varied mechanisms to watery diarrhoea. CONCLUSIONS: This is the first systematic review on the aetiology of MC supporting the notion that MC is a multifactorial disease. However, high-profile studies are lacking, and most evidence derives from small heterogeneous studies.

Intestinal and blood lymphograms as new diagnostic tests for celiac disease.

Accurate celiac disease (CD) diagnosis is still challenging for some specific patients or circumstances. Thus, much effort has been expended last decades focused on seronegative or low grade enteropathy CD and, especially, on enable early diagnosis of individuals on a gluten-free diet (GFD). We discuss here two diagnostic approaches based on immunophenotyping by flow cytometry that we expect to reduce the persistent low diagnostic rates and the common diagnostic delay. The intraepithelial lymphogram is based on determining the percentage of TCRγδ+ and surface CD3- lymphocytes in the intestinal epithelium. The concomitant increase in TCRγδ+ and decrease in surface CD3- intraepithelial lymphocytes has been termed the celiac lymphogram and has been proved to be discriminative in seronegative, low grade enteropathy and potential CD, as well as in most CD patients on a GFD. A blood lymphogram based on the analysis of activated gut-homing CD8+ T cells combined with a 3-day gluten challenge is also considered, which has shown high sensitivity and specificity to diagnose seropositive Marsh 1 and Marsh 3 CD in individuals following a GFD. In addition, flow cytometry can be extremely useful in cases of refractory CD type II to identify aberrant cells. Those approaches represent highly accurate methods for CD diagnosis, being simple, fast, highly reproducible and of easy implementation in clinical practice.

Activated gut-homing CD8+ T cells for coeliac disease diagnosis on a gluten-free diet.

BACKGROUND: The diagnosis of coeliac disease (CD) in individuals that have started a gluten-free diet (GFD) without an adequate previous diagnostic work-out is a challenge. Several immunological assays such as IFN-γ ELISPOT have been developed to avoid the need of prolonged gluten challenge to induce the intestinal damage. We aimed to evaluate the diagnostic accuracy of activated gut-homing CD8+ and TCRγδ+ T cells in blood after a 3-day gluten challenge and to compare it with the performance of IFN-γ ELISPOT in a HLA-DQ2.5 subsample. METHODS: A total of 22 CD patients and 48 non-CD subjects, all of them following a GFD, underwent a 3-day 10-g gluten challenge. The percentage of two T cell subsets (CD8+ CD103+ ß7hi CD38+/total CD8+ and TCRγδ+ CD103+ ß7hi CD38+/total TCRγδ+) in fresh peripheral blood drawn baseline and 6 days after the challenge was determined by flow cytometry. IFN-γ ELISPOT assays were also performed in HLA-DQ2.5 participants. ROC curve analysis was used to assess the diagnostic performance of the CD8+ T cell response and IFN-γ ELISPOT. RESULTS: Significant differences between the percentage of the two studied subsets of CD8+ and TCRγδ+ cells at days 0 and 6 were found only when considering CD patients (p < 10-3 vs. non-CD subjects). Measuring activated CD8+ T cells provided accurate CD diagnosis with 95% specificity and 97% sensitivity, offering similar results than IFN-γ ELISPOT. CONCLUSIONS: The results provide a highly accurate blood test for CD diagnosis in patients on a GFD of easy implementation in daily clinical practice.

Coeliac Disease in Elderly Patients: Value of Coeliac Lymphogram for Diagnosis.

(1) Background: Although a meta-analysis reported that the sensitivity of CD3+ TCRγδ+ cells for coeliac disease diagnosis was >93%, a recent study has suggested that sensitivity decreased to 65% in elderly patients. (2) Aim: To evaluate whether the sensitivity of intraepithelial lymphocyte cytometric patterns for coeliac disease diagnosis changes with advanced age. (3) Methods: We performed a multicentre study including 127 coeliac disease patients ≥ 50 years: 87 with baseline cytometry (45 aged 50-59 years; 23 aged 60-69 years; 19 aged ≥ 70 years), 16 also with a follow-up cytometry (on a gluten-free diet); and 40 with only follow-up cytometry. (4) Results: In Marsh 3 patients, a sensitivity of 94.7%, 88.9% and 86.7% was observed for each age group using a cut-off value of TCRγδ+ >10% (p = 0.27); and a sensitivity of 84.2%, 83.4% and 53.3% for a cut-off value >14% (p = 0.02; 50-69 vs. ≥70 years), with difference between applying a cut-off of 10% or 14% (p = 0.008). The TCRγδ+ count in the ≥70 years group was lower than in the other groups (p = 0.014). (5) Conclusion: In coeliac patients ≥ 70 years, the TCRγδ+ count decreases and the cut-off point of >10% is more accurate than >14%.

Clinical features, therapeutic requirements and evolution of patients with Crohn's disease and upper gastrointestinal involvement (CROHNEX study).

BACKGROUND: Crohn's disease (CD) with upper gastrointestinal involvement (UGI) may have a more aggressive and refractory course. However, evidence on this phenotype of patients is scarce. AIMS: To identify the clinical characteristics, therapeutic requirements and complications associated with UGI in CD METHODS: Nationwide study of cases (UGI, UGI plus ileal/ileocolonic involvement) paired with controls (ileal/ileocolonic involvement) from the ENEIDA registry. Cases were matched to 2 controls by year of diagnosis ± 2.5 years. Patients with exclusive/predominant colonic location or complex perianal fistula were excluded. RESULTS: Of 24 738 patients with CD in the ENEIDA registry, we identified 4058 with UGI (16% of the total CD cohort). Finally, 854 cases and 1708 controls were included. Cases were independently associated to extensive involvement (OR 2.7 [2.2-3.3], P < 0.0001), strictures [OR 1.8 (1.5-2.2), P < 0.0001], chronic iron deficiency anaemia [OR 2.2 (1.3-3.2), P < 0.001] and use of second-line biologics [OR 1.7 (1.1-2.6), P = 0.021]. The median stricture-free time was 14 years (95% CI, 12-16) for cases vs 21 years (95% CI, 19-23) for controls (P < 0.0001). Cases with isolated UGI compared to UGI plus ileal/ileocolonic more frequently had localised disease [OR 0.5(0.3-0.8), P = 0.003] and underwent more endoscopic stricture dilations [OR 2.7(1.3-5.4), P = 0.006]. CONCLUSIONS: The largest cohort of patients with CD and UGI provides information on the natural history of this particular phenotype. Increased awareness of the clinical picture and therapeutic requirements of these patients could lead to earlier diagnosis and treatment of upper gastrointestinal lesions, preventing the structural damage frequently seen in these patients at diagnosis and during follow-up.