A small bowel adenocarcinoma harboring a DDR2 mutation in a celiac patient.

We present the case of a 62-year-old man with a history of celiac disease and IgA deficiency, following a strict gluten-free diet that was admitted to our hospital for recurrent abdominal pain, fatigue and melena. Esophagogastroduodenoscopy and colonoscopy with biopsies were normal. A video-capsule endoscopy was performed and revealed a sub-stenosing, vegetating, and bleeding lesion in the first jejunal loop. He underwent laparotomic surgery with resection of the involved segment with loco-regional lymphadenectomy. The pathological report described a poorly differentiated adenocarcinoma of the jejunum, stage IIIA (pT3pN1). Analysis of next-generation sequencing (NGS) of DNA on the surgical sample revealed a likely pathogenetic variant in exon 15 of the DDR2 gene (c.2003G > A) and a TP53 non-frame-shift deletion (c.585_602del). Considering the risk of recurrence, he was candidate to 6 months of adjuvant chemotherapy with platinum salt and fluoropyrimidine. Thirty-eight months after the diagnosis, the patient is still disease free and in good clinical condition. This is the first described case of SBA with DDR2 mutation. Considering the limited therapeutic options beyond surgery for SBA, molecular analyses could become promising for the search for potential targetable alterations for treatments with new available drugs.

Distinguishing Features of Autoimmune Gastritis Depending on Previous Helicobacter pylori Infection or Positivity to Anti-Parietal Cell Antibodies: Results From the Autoimmune gastRitis Italian netwOrk Study grOup (ARIOSO).

INTRODUCTION: To describe the clinical features and the risk of developing gastric tumors in patients with autoimmune gastritis (AIG). METHODS: This was a retrospective, longitudinal, multicenter study conducted at 8 Italian tertiary referral centers. We retrieved clinical data from all histologically proven patients with AIG. Differences between Helicobacter pylori -exposed vs H. pylori -naive and anti-parietal cell antibody (PCA)-positive vs PCA-negative patients were investigated. The rate of gastric adenocarcinoma and type 1 gastric neuroendocrine neoplasm (gNEN) was assessed. A multivariable model for factors associated with gNEN was fitted. RESULTS: A total of 1,598 patients with AIG (median age 58 years, interquartile range 46-68; F:M ratio 2.7:1) were included. H. pylori -naive patients were more likely to have a first-degree family history of AIG (14.7% vs 8.9%; P = 0.012), type 1 diabetes mellitus (4.9% vs 2.3%; P = 0.025), and pernicious anemia (30.9% vs 21.1%; P = 0.003). PCA-positive patients had significantly more associated autoimmune diseases (59.0% vs 42.9%; P < 0.001) and were more likely to have been diagnosed by a case-finding strategy (15.3% vs 2.6%; P < 0.001). Overall, 15 cases (0.9%) of gastric adenocarcinoma and 153 cases (9.6%) of gNEN occurred, with a global rate of 0.12 (95% confidence interval [CI] 0.07-0.20) and 1.22 (95% CI 1.03-1.42) per 100 person/year, respectively. Having a vitamin B12/iron deficiency manifestation at AIG diagnosis was associated with a 16.44 (95% CI 9.94-27.20 P < 0.001) hazard ratio of gNEN. DISCUSSION: The "pure" AIG pattern has typical features of an autoimmune disease and seems to be unrelated to H. pylori . In a tertiary referral setting, the risk of developing overt gastric adenocarcinoma is low, while patients with vitamin B12 deficiency complications at onset may benefit from a more intense endoscopic follow-up for early gNEN detection.

Superior bowel preparation quality for colonoscopy with 1L-PEG compared to 2L-PEG and picosulphate: Data from a large real-world retrospective outpatient cohort.

BACKGROUND: Several randomized clinical trials comparing different bowel preparations (BP) have shown similar efficacy; however, there is a lack of real-world studies on this topic. AIMS: This study aims to identify the most effective BP regimen in a real-world setting and any predictors of inadequate BP. METHODS: A retrospective single-center study was conducted over 14 months at an academic hospital including outpatient colonoscopies in which adult patients did not teach on how to perform BP before colonoscopy. Colonoscopies with 1L-PEG, 2L-PEG and picosulphate mixtures were considered. A multivariable analysis for factors associated to poor BP was fitted. RESULTS: Overall, 1779 patients (51 %F, 60±14) years were included. The 1L-PEG regimen provided a higher rate of BP adequacy at multivariate analysis (adjusted OR 2.30, 95 %CI 1.67-3.16,p < 0.001) and was associated with higher median Boston Bowel Preparation Scale score (p < 0.001), higher rate of right-colon cleansing (p < 0.001) and exam completion (p = 0.04). Furthermore, we identified male sex, history of constipation, active smoking, previous pelvic surgery, concomitant psychiatric/neurological or chronic kidney diseases as predictors of inadequate BP. CONCLUSIONS: This is the largest real-world study comparing 1L-PEG to other BP regimens. Our results suggest 1L-PEG provides better BP in a non-controlled setting, improving clinical practice quality and minimizing the need for repeated colonoscopies and saving healthcare resources.

New entity of adult ultra-short coeliac disease: the first international cohort and case-control study.

BACKGROUND: Ultra-short coeliac disease (USCD) is defined as villous atrophy only present in the duodenal bulb (D1) with concurrent positive coeliac serology. We present the first, multicentre, international study of patients with USCD. METHODS: Patients with USCD were identified from 10 tertiary hospitals (6 from Europe, 2 from Asia, 1 from North America and 1 from Australasia) and compared with age-matched and sex-matched patients with conventional coeliac disease. FINDINGS: Patients with USCD (n=137, median age 27 years, IQR 21-43 years; 73% female) were younger than those with conventional coeliac disease (27 vs 38 years, respectively, p<0.001). Immunoglobulin A-tissue transglutaminase (IgA-tTG) titres at index gastroscopy were lower in patients with USCD versus conventional coeliac disease (1.8×upper limit of normal (ULN) (IQR 1.1-5.9) vs 12.6×ULN (IQR 3.3-18.3), p<0.001).Patients with USCD had the same number of symptoms overall (median 3 (IQR 2-4) vs 3 (IQR 1-4), p=0.875). Patients with USCD experienced less iron deficiency (41.8% vs 22.4%, p=0.006).Both USCD and conventional coeliac disease had the same intraepithelial lymphocytes immunophenotype staining pattern; positive for CD3 and CD8, but not CD4.At follow-up having commenced a gluten-free diet (GFD) (median of 1181 days IQR: 440-2160 days) both USCD and the age-matched and sex-matched controls experienced a similar reduction in IgA-tTG titres (0.5 ULN (IQR 0.2-1.4) vs 0.7 ULN (IQR 0.2-2.6), p=0.312). 95.7% of patients with USCD reported a clinical improvement in their symptoms. INTERPRETATION: Patients with USCD are younger, have a similar symptomatic burden and benefit from a GFD. This study endorses the recommendation of D1 sampling as part of the endoscopic coeliac disease diagnostic workup.

Systematic review with meta-analysis: Cause-specific and all-cause mortality trends across different coeliac disease phenotypes.

BACKGROUND: Data on mortality in coeliac disease are contrasting. AIMS: To systematically review the literature on all-cause and cause-specific mortality in coeliac disease compared to the general population, and evaluate differences across clinical phenotypes, geographical regions, and over time. METHODS: We searched PubMed and Embase from 1 January 1970 to 31 December 2022 for eligible studies reporting on all-cause and cause-specific mortality in coeliac disease compared to the general population or controls. The protocol was registered on Open Science Framework (https://doi.org/10.17605/OSF.IO/852DN). RESULTS: We included 25 studies. All-cause mortality (HR 1.16, 95% CI 1.05-1.27, I2 = 89%), mortality due to malignancies (HR 1.21, 95% CI 1.08-1.36, I2 = 65%) and respiratory disease (HR 1.39, 95% CI 1.04-1.86, I2 = 76%) were increased. Mortality due to non-Hodgkin lymphoma (HR 10.14, 95% CI 2.19-46.88, I2 = 96%) was markedly increased. Mortality significantly decreased in recent decades: 1989-2004 (HR 1.61, 95% CI 1.27-2.03, I2 = 91%), 2005-2014 (HR 1.16, 95% CI 0.99-1.36, I2 = 89%), 2015-2022 (HR 1.19, 95% CI 1.05-1.35, I2 = 93%). All-cause mortality was not increased in dermatitis herpetiformis (HR 0.85, 95% CI 0.73-0.99, I2 = 40%) and undiagnosed coeliac disease (HR 1.09, 95% CI 0.95-1.25, I2 = 0%). Mortality was increased in the UK (HR 1.23, 95% CI 1.03-1.47, I2 = 91%) but not Scandinavia (HR 1.01, 95% CI 0.91-1.13, I2 = 81%). Limitations include high heterogeneity and lack of data for many countries. CONCLUSION: Mortality in coeliac disease is increased, predominantly due to malignancies-particularly non-Hodgkin lymphoma-although differing significantly across disease phenotypes. Mortality of patients with coeliac disease has significantly decreased in recent decades. These results may influence diagnosis and management.

Systematic review: Clinical phenotypes, histopathological features and prognosis of enteropathy due to angiotensin II receptor blockers.

BACKGROUND: Although enteropathy due to angiotensin II receptor blockers (ARBs) has been known for over 10 years, clinicians' awareness of this condition is still low. AIMS: To systematically review the literature about clinical phenotypes, distribution of mucosal changes throughout the gastrointestinal tract and prognosis of enteropathy due to ARBs. METHODS: According to PRISMA guidelines, we searched PubMed and Embase for relevant articles up to November 6, 2023. We included full-text papers, letters, case reports and case series describing enteropathy due to ARBs. Patients were classified into subgroups based on endoscopic and histological findings of different regions of the gastrointestinal tract. The protocol was registered with Open Science Framework (https://doi.org/10.17605/OSF.IO/TK67C). RESULTS: We included 94 articles reporting 183 cases (101 female, mean age at diagnosis 69 ± 10 years). The clinical picture at diagnosis was characterised by severe diarrhoea (97%) and weight loss (84%, median -13 kg), leading to hospital admission in 167 (95%) patients. Olmesartan (90%) was most frequently implicated. Villous atrophy (VA) was reported in 164/183 (89%) patients. One hundred and nine had only VA, 12 had pan-gastrointestinal involvement, 23 had VA and gastric involvement and 19 had VA and colon involvement (predominantly microscopic colitis). Outcomes were reported for 178/183 (97%) patients, who all recovered clinically on ARBs withdrawal. Histological recovery occurred in all 96 patients with VA at baseline who underwent follow-up duodenal biopsy. CONCLUSIONS: Enteropathy due to ARBs is characterised by severe malabsorption often requiring hospital admission and can involve the entire gastrointestinal tract. Clinician awareness can lead to prompt diagnosis and excellent prognosis.

Whipple's disease: A rare disease that can be spotted by many doctors.

Whipple's disease, an extremely rare, chronic infection caused by Tropheryma whipplei, an actinobacterium ubiquitously present in the environment, is a multisystemic condition that can affect several organs. Therefore, Whipple's disease should always be considered by physicians working across various branches of medicine, including internal medicine, rheumatology, infectious diseases, gastroenterology, haematology, and neurology. Initially, Whipple's disease is challenging to diagnose due to both its rarity and non-specific clinical features, almost indistinguishable from rheumatological conditions. A few years later, the onset of gastrointestinal symptoms increases the specificity of its clinical picture and helps in reaching the correct diagnosis. Diagnosis is typically made by finding PAS-positive macrophages in the lamina propria at duodenal biopsy. PCR for Tropheryma whipplei is nowadays also increasingly available, and represents an undeniable help in diagnosing this condition. However, it may also be misleading as false positives can occur. If not promptly recognized and treated, central nervous system involvement may develop, which can be fatal. The therapeutic gold standard has not yet been fully established, particularly in cases of recurrent disease, neurological involvement, and an immune reconstitution inflammatory syndrome that may arise following the initiation of antibiotic therapy.

Flow cytometry for the assessment and monitoring of aberrant intraepithelial lymphocytes in non-responsive celiac disease and non-celiac enteropathies.

BACKGROUND: Few data are available on flow cytometry (FC) for monitoring intraepithelial lymphocytes (IELs) in refractory celiac disease (RCD), non-responsive celiac disease (NRCD), and non-celiac enteropathies (NCEs). AIMS: 1) To investigate the significance of monitoring IELs immunophenotype with FC in patients with NRCD, RCD and NCEs; 2) to evaluate FC concordance with immunohistochemistry (IHC) and γ-TCR clonality analysis. METHODS: Patients investigated between January-2012 and February-2023 were divided into two groups: 1)confirmed RCD or NRCD being investigated for persistent symptoms and suspected complications of celiac disease (CD); 2)NCEs lacking clinical/histological response. Clinical/molecular features and outcomes were retrospectively collected and analysed according to presence/absence of aberrant IELs on FC (cut-off≥20 % CD103+sCD3-CD8-iCD3+ IELs). RESULTS: 52 patients (18 RCD,21 NRCD,13 NCEs; 38F, 55±13 years; median follow-up 30 months, IQR 2-58) underwent 100 FC IELs determinations. 22/52 had ≥2 FC determinations and IEL phenotype remained unchanged over time in all them (κ=1.00). Aberrant IEL phenotype in CD was associated with increased mortality (HR 4.2, 95 % CI 1.5-11.9, p < 0.01). No patients with NCEs had an aberrant IEL phenotype at FC, although 3/13 developed lymphoma and 4/13 died. Concordance of FC was fair with both IHC (κ=0.40) and γ-TCR clonality analysis (κ=0.22). CONCLUSION: FC is accurate for assessing and monitoring IEL phenotype and providing important prognostic information in celiac patients. Further study is needed on its role in NCEs.

Serum anti-tissue transglutaminase IgA and prediction of duodenal villous atrophy in adults with suspected coeliac disease without IgA deficiency (Bi.A.CeD): a multicentre, prospective cohort study.

BACKGROUND: Whether coeliac disease in adults can be diagnosed with serology alone remains controversial. We aimed to evaluate the accuracy of serum anti-tissue transglutaminase IgA (tTG-IgA) in the diagnosis of coeliac disease. METHODS: In this multicentre, prospective cohort study, adult participants (aged ≥18 years) with suspected coeliac disease without IgA deficiency who were not on a gluten-free diet and who had a local serum tTG-IgA measurement, were enrolled from Feb 27, 2018, to Dec 24, 2020, by 14 tertiary referral centres (ten from Europe, two from Asia, one from Oceania, and one from South America) to undergo local endoscopic duodenal biopsy. Local serum tTG-IgA was measured with 14 different test brands and concentration expressed as a multiple of each test's upper limit of normal (ULN), and defined as positive when greater than 1 times the ULN. The main study outcome was the reliability of serum tests for the diagnosis of coeliac disease, as defined by duodenal villous atrophy (Marsh type 3 or Corazza-Villanacci grade B). Histology was evaluated by the local pathologist, with discordant cases (positive tTG-IgA without duodenal villous atrophy or negative tTG-IgA with duodenal villous atrophy) re-evaluated by a central pathologist. The reliability of serum tests for the prediction of duodenal villous atrophy was evaluated according to sensitivity, specificity, positive predictive value, negative predictive value, and the area under the receiver operating characteristic curve (AUC) for categorical and continuous data. FINDINGS: We enrolled 436 participants with complete local data on serum tTG-IgA and duodenal histology (296 [68%] women and 140 [32%] men; mean age 40 years [SD 15]). Positive serum tTG-IgA was detected in 363 (83%) participants and negative serum tTG-IgA in 73 (17%). Of the 363 participants with positive serum tTG-IgA, 341 had positive histology (true positives) and 22 had negative histology (false positives) after local review. Of the 73 participants with negative serum tTG-IgA, seven had positive histology (false negatives) and 66 had negative histology (true negatives) after local review. The positive predictive value was 93·9% (95% CI 89·2-98·6), the negative predictive value was 90·4% (85·5-95·3), sensitivity was 98·0% (95·3-100·0), and specificity was 75·0% (66·6-83·4). After central re-evaluation of duodenal histology in 29 discordant cases, there were 348 true positive cases, 15 false positive cases, 66 true negative cases, and seven false negative cases, resulting in a positive predictive value of 95·9% (92·0-99·8), a negative predictive value of 90·4% (85·5-95·3), a sensitivity of 98·0% (95·3-100·0), and a specificity of 81·5% (73·9-89·1). Either using the local or central definition of duodenal histology, the positive predictive value of local serum tTG-IgA increased when the serological threshold was defined at increasing multiples of the ULN (p<0·0001). The AUC for serum tTG-IgA for the prediction of duodenal villous atrophy was 0·87 (95% CI 0·81-0·92) when applying the categorical definition of serum tTG-IgA (positive [>1 × ULN] vs negative [≤1 × ULN]), and 0·93 (0·89-0·96) when applying the numerical definition of serum tTG-IgA (multiples of the ULN). Additional endoscopic findings included peptic gastritis (nine patients), autoimmune atrophic gastritis (three), reflux oesophagitis (31), gastric or duodenal ulcer (three), and Barrett's oesophagus (one). In the 1-year follow-up, a midgut ileum lymphoma was diagnosed in a woman on a gluten-free diet. INTERPRETATION: Our data showed that biopsy could be reasonably avoided in the diagnosis of coeliac disease in adults with reliable suspicion of coeliac disease and high serum tTG-IgA. FUNDING: None.

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.

Patients with Whipple's disease have a high prevalence of Helicobacter pylori infection.

INTRODUCTION: Whipple's disease is a rare systemic infection due to an impaired immunological response against T. whipplei in genetically predisposed individuals. Since we previously noted development of H. pylori related complications in some patients with Whipple's disease, our aim was to study the prevalence of H. pylori infection and H. pylori related disorders in Whipple's disease. METHODS: Whipple's disease patients diagnosed from Jan-2002 to Dec-2021 and two controls per patient, matched for age, gender, ethnicity and year of H. pylori testing were enrolled. RESULTS: 34 patients with Whipple's disease and 68 controls were enrolled. H. pylori infection (13/34 vs 8/68, p<0.01), H. pylori-related gastritis (p<0.01) and gastric atrophy (p = 0.01) were significantly more common in patients with Whipple's disease than controls. H. pylori infection and Whipple's disease were diagnosed synchronously in 6/13 patients, and during follow-up in the remaining 7. Interestingly, these last 7 patients were all on trimethoprim-sulfamethoxazole long-term therapy. Two patients developed H. pylori-related gastric malignancies during follow-up. No patients on doxycycline developed H. pylori infection. CONCLUSIONS: H. pylori infection and related disorders are common in patients with Whipple's disease and should always be excluded both at time of diagnosis and during follow-up. These findings should be taken into account when selecting antibiotics for Whipple's disease long-term prophylaxis.

Small bowel villous atrophy due to immune-checkpoint inhibitors: report of two cases and literature review.

The differential diagnosis of non-coeliac enteropathies (NCEs) is challenging and includes a wide range of aetiologies. Drug-induced NCEs are relatively common and characterized by duodenal villous atrophy, which resolves upon suspension of the offending drug. Immune-checkpoint inhibitors (ICIs), targeting molecules involved in the activation of cytotoxic T cells by targeting, for example, PD-1, PD-L1 and CTLA4, are increasingly used for many types of cancers. Adverse events occurring in the gastrointestinal tract have been described, predominantly in the form of immune-mediated colitis mimicking inflammatory bowel disease. Small bowel involvement whilst on ICI therapy is also possible, though less well described. Herein, we describe two cases of enteropathy with villous atrophy and negative coeliac serology due to ICIs: a 65-year-old man affected by stage IV pulmonary adenocarcinoma under treatment with pembrolizumab and an 18-year-old woman affected by stage IV auricular melanoma who was treated with nivolumab. We also provide a review of the current literature describing small bowel involvement during therapy with ICIs, alone or in combination, for different types of solid tumours. Implications for clinical practice include considering the possibility of small bowel involvement in oncological patients treated with ICIs and the inclusion of ICIs amongst the iatrogenic causes of NCE with villous atrophy. Enteropathies due to ICIs may also represent a pathogenetic model for the understanding of the molecular mechanisms leading to villous atrophy in NCE.

Nomenclature and diagnosis of seronegative coeliac disease and chronic non-coeliac enteropathies in adults: the Paris consensus.

OBJECTIVE: Differential diagnosis of villous atrophy (VA) without coeliac antibodies in adults includes seronegative coeliac disease (CD) and chronic enteropathies unrelated to gluten, ie. non-coeliac enteropathies (NCEs). There is currently no international consensus on the nomenclature and diagnostic criteria for these enteropathies. In this work, a Delphi process was conducted to address this diagnostic and clinical uncertainty. DESIGN: An international task force of 13 gastroenterologists from six countries was recruited at the 16th International Coeliac Disease Symposium, Paris, 2019. Between September 2019 and July 2021, a Delphi process was conducted through mail surveys to reach a consensus on which conditions to consider in the differential diagnosis of VA with negative coeliac serology and the clinical diagnostic approaches required for these conditions. A 70% agreement threshold was adopted. RESULTS: Chronic enteropathies characterised by VA and negative coeliac serology can be attributed to two main clinical scenarios: forms of CD presenting with negative serology, which also include seronegative CD and CD associated with IgA deficiency, and NCEs, with the latter recognising different underlying aetiologies. A consensus was reached on the diagnostic criteria for NCEs assisting clinicians in differentiating NCEs from seronegative CD. Although in adults seronegative CD is the most common aetiology in patients with VA and negative serology, discriminating between seronegative CD and NCEs is key to avoid unnecessary lifelong gluten-free diet, treat disease-specific morbidity and contrast poor long-term outcomes. CONCLUSION: This paper describes the Paris consensus on the definitions and diagnostic criteria for seronegative CD and chronic NCEs in adults.

Enteropathies with villous atrophy but negative coeliac serology in adults: current issues.

OBJECTIVE: The differential diagnosis and management of seronegative enteropathies is challenging due to the rarity of these conditions, the overlap of clinical and histopathological features and the current lack of an international consensus on their nomenclature. DESIGN: This is a narrative review providing pragmatic guide on the investigation and clinical management of seronegative enteropathies in adults based on the available literature and our clinical experience. CONCLUSIONS: Seronegative coeliac disease is the most frequent cause among the heterogeneous group of seronegative enteropathies and its diagnosis is confirmed by the clinical and histological response to a gluten-free diet after the exclusion of other causes of villous atrophy. Correct identification and targeted management of seronegative enteropathies is mandatory because of the variation in terms of clinical outcomes and prognosis.

Clinical classification and long-term outcomes of seronegative coeliac disease: a 20-year multicentre follow-up study.

BACKGROUND: Seronegative coeliac disease is poorly defined. AIMS: To study clinical phenotypes and long-term outcomes of seronegative coeliac disease in a multicentre cohort over 20 years. METHODS: Seronegative coeliac disease was diagnosed in HLA-DQ2/DQ8-positive patients with villous atrophy (VA), negative IgA endomysial (EmA), tissue transglutaminase (tTG) and deamidated-gliadin antibodies (DGP), clinical and histological response to a gluten-free diet (GFD), and no alternative causes for VA. In patients with IgA deficiency, coeliac disease was diagnosed through VA, positive IgG EmA/tTG/DGP and clinical/histological response to a GFD (coeliac disease+IgAd). Patients with seropositive coeliac disease served as controls. RESULTS: Of 227 patients previously diagnosed with seronegative coeliac disease, true seronegative coeliac disease was confirmed in 84, coeliac disease+IgAd in 48, and excluded in 55. Lack of follow-up duodenal biopsy precluded diagnosing seronegative coeliac disease in 40 patients. 2084 patients with seropositive coeliac disease served as controls. True seronegative coeliac disease had more severe symptoms at diagnosis and a higher risk of complications (HR 10.87, 95% CI 6.11-19.33, P < 0.001) and mortality (HR 2.18, 95% CI 1.12-4.26, P < 0.01) than seropositive coeliac disease. There were no differences between true seronegative coeliac disease and coeliac disease+IgAd. On multivariate analysis, age at diagnosis, lack of clinical response to a GFD, true seronegative coeliac disease, coeliac disease+IgAd, and classical presentation predicted complications. Age at diagnosis, complications and absence of clinical response to a GFD predicted mortality. CONCLUSIONS: Seronegative coeliac disease has a more aggressive disease phenotype than seropositive coeliac disease. These data argue against over-reliance on serology for the diagnosis of coeliac disease and support a strict clinical and histologic follow-up in seronegative coeliac disease.

Clinical and gastro-duodenal histopathological features of enteropathy due to angiotensin II receptor blockers.

BACKGROUND: Clinical elements differentiating enteropathy due to angiotensin II-receptor-blockers (ARBs-E) from coeliac disease (CD) are poorly defined. The histopathological features on duodenal and gastric biopsies in these patients still need to be investigated. AIMS: To describe the clinical phenotype of ARBs-E in comparison to CD, and the histological findings of gastric and duodenal biopsies in ARBs-E. METHODS: Clinical data of patients with ARBs-E and CD diagnosed between 2013 and 2020 were retrospectively reviewed. Baseline presenting symptoms and demographics were compared (Fisher's exact test and t-test). Gastric and duodenal histology in ARBs-E were revised by two independent pathologists. RESULTS: 14 ARBs-E and 112 CD patients were enroled. Weight loss (p < 0.01), acute onset of diarrhoea (p < 0.01), hospitalization (p < 0.01), and older age at diagnosis (p < 0.01) were more common in ARBs-E. Duodenal histology in ARBs-E showed intraepithelial lymphocytosis in 71%, increased mucosal eosinophilic count in 57%, with preserved neuroendocrine, Paneth and goblet cells in all patients. Gastric histologic lesions at baseline, including lymphocytic gastritis, eosinophilic gastritis, chronic active gastritis, and metaplastic atrophic gastritis patterns were observed in 73% of patients, without Helicobacter pylori infection. CONCLUSIONS: ARBs-E showed a severe clinical phenotype, often requiring hospital admission. Gastric involvement at diagnosis is very common, and this could further support this diagnosis.

AGA Clinical Practice Update on the Evaluation and Management of Seronegative Enteropathies: Expert Review.

DESCRIPTION: Our aim was to provide a consensus statement for the best approaches for diagnosis and management of patients with suspected enteropathy, but negative results from serologic tests for celiac disease (seronegative enteropathy). METHODS: We collected findings from published cohort, case-control, and cross-sectional studies of diagnosis and case series and descriptive studies of management of patients believed to have celiac disease or other enteropathies unrelated to gluten, but negative results from serologic tests. BEST PRACTICE ADVICE 1: Review histologic findings with experienced pathologists who specialize in gastroenterology. BEST PRACTICE ADVICE 2: Serologic tests are essential for an accurate diagnosis of celiac disease. For patients with suspected celiac disease but negative results from serologic tests, total IgA level should be measured; patients should also be tested for anti-tissue transglutaminase, IgA against deamidated gliadin peptide, and endomysial antibody (IgA). Patients with total IgA levels below the lower limit of detection and IgG against tissue transglutaminase or deamidated gliadin peptide, or endomysial antibody, should be considered to have celiac disease with selective IgA deficiency rather than seronegative celiac disease. BEST PRACTICE ADVICE 3: Patients' diets should be carefully reviewed and duodenal biopsies should be collected and analyzed at the time of serologic testing to determine exposure to gluten and accuracy of test results. BEST PRACTICE ADVICE 4: Thorough medication histories should be collected from patients, with attention to angiotensin II receptor blockers, such as olmesartan, along with travel histories to identify potential etiologies of villous atrophy. This will guide additional testing. BEST PRACTICE ADVICE 5: Patients should be analyzed for disease-associated variants in human leukocyte antigen genes; results must be carefully interpreted. Negative results can be used to rule out celiac disease in seronegative patients. BEST PRACTICE ADVICE 6: Patients with suspected celiac disease who are seronegative but have villous atrophy and genetic risk factors for celiac disease must undergo endoscopic evaluation after 1-3 years on a gluten-free diet to evaluate improvements in villous atrophy. A diagnosis of seronegative celiac disease can then be confirmed based on clinical and histologic markers of improvement on the gluten-free diet. BEST PRACTICE ADVICE 7: Seronegative patients with an identified cause for enteropathy should be treated accordingly; a follow-up biopsy might or might not be necessary. BEST PRACTICE ADVICE 8: Patients with persistent signs and symptoms who do not respond to a gluten-free diet, and for whom no etiology of enteropathy is ultimately identified, should be treated with budesonide. CONCLUSIONS: These best practice guidelines will aid in diagnosis and management of patients with suspected celiac disease, but negative results from serologic tests.

Long-term morbidity and mortality in Whipple's disease: a single-center experience over 20 years.

Background: Little is known about long-term morbidity and mortality in Whipple's disease (WD). Aim: To describe morbidity and mortality in patients with WD on a long-term follow-up. Materials & methods: Comorbidities, mortality and causes of death were retrospectively registered. Results: A total of 35 patients with WD (9F, 54 ± 11 years) were followed-up for a median of 104 months. Nine patients developed ten complications; three patients died. A total of 31 severe comorbidities apparently unrelated to WD were found in 20 patients: preneoplastic/neoplastic disorders in seven, thromboembolic and cardiovascular events in seven, pneumonia in four, candidiasis in ten patients. Conclusion: WD is frequently complicated by potentially life-threatening infectious, neoplastic and thromboembolic disorders, thus highlighting the need for a life-long multidisciplinary follow-up.

Low prevalence of upper endoscopic gastrointestinal findings despite high frequency of alarm symptoms at the time of diagnosis in adult coeliac disease.

OBJECTIVES: Exclusion of organic disorders involving the upper gastrointestinal (UGI) is a mandatory step before considering a biopsy-avoidance diagnostic strategy for adult coeliac disease. We aim to evaluate the prevalence of alarm symptoms and coincidental UGI endoscopic findings at the time of diagnosis of coeliac disease. To develop consensus criteria to identify patients with coeliac disease requiring a gastroscopy and to evaluate whether alarm symptoms prompting gastroscopy were predictive of endoscopic findings. METHODS: Presenting symptoms and UGI endoscopic findings at diagnosis of coeliac disease were collected retrospectively in 278 adult patients with coeliac disease diagnosed in Pavia between January 1999 and December 2017. A panel of experts developed criteria to evaluate which clinical scenarios warrant gastroscopy, which was then applied retrospectively to patients diagnosed in Pavia. RESULTS: At least one alarm symptom was present in 177/278 patients, 121/278 met our criteria for gastroscopy. Major UGI endoscopic findings included 3 cases of autoimmune atrophic gastritis, 19 oesophagitis and 20 Helicobacter pylori infections. No organic disorders were found. Prevalence of major endoscopic findings did not differ between patients who met our criteria and those who did not. CONCLUSIONS: Despite the high prevalence of alarm symptoms at diagnosis, coincident major UGI endoscopic findings are rare in adult coeliac disease. These results may be relevant for future developments in coeliac disease diagnosis in adults.

Pitfalls in the Diagnosis of Coeliac Disease and Gluten-Related Disorders.

The spectrum of gluten-related disorders (GRD) has emerged as a relevant phenomenon possibly impacting on health care procedures and costs worldwide. Current classification of GRD is mainly based on their pathophysiology, and the following categories can be distinguished: immune-mediated disorders that include coeliac disease (CD), dermatitis herpetiformis (DH), and gluten ataxia (GA); allergic reactions such as wheat allergy (WA); and non-coeliac gluten sensitivity (NCGS), a condition characterized by both gastrointestinal and extra-intestinal symptoms subjectively believed to be induced by the ingestion of gluten/wheat that has recently gained popularity. Although CD, DH, and WA are well-defined clinical entities, whose diagnosis is based on specific diagnostic criteria, a diagnosis of NCGS may on the contrary be considered only after the exclusion of other organic disorders. Neither allergic nor autoimmune mechanisms have been found to be involved in NCGS. Mistakes in the diagnosis of GRD are still a relevant clinical problem that may result in overtreatment of patients being unnecessary started on a gluten-free diet and waste of health-care resources. On the basis of our clinical experience and literature, we aim to identify the main pitfalls in the diagnosis of CD and its complications, DH, and WA. We provide a practical methodological approach to guide clinicians on how to recognize and avoid them.