Efficacy of a Low-FODMAP Diet for Coeliac Patients with Persistent IBS-like Symptoms despite a Gluten-Free Diet: A Systematic Review.

Background: Persistent symptoms in coeliac disease (CD) can be due to not only poor gluten-free diet (GFD) adherence and complications of CD, but also functional gastrointestinal disorders such as irritable bowel syndrome (IBS). Although the role of a low fermentable oligo-, di-, and monosaccharides and polyols (FODMAP) diet is well-established in IBS, little data are available on its role in coeliac patients with persistent IBS-like symptoms despite a GFD. Methods: We systematically reviewed the literature in accordance with the PRISMA guidelines for studies evaluating the role of FODMAPs and/or a low-FODMAP diet in coeliac patients with persistent symptoms. PubMed and Embase were searched from inception to 16 January 2024 for eligible full-text papers. The study protocol was registered on Open Science Framework. Results: A total of 239 records were identified, and six papers were included. Of these, four were interventional studies comparing a low-FODMAP GFD to a regular GFD for persistent symptoms in 115 total coeliac patients (two randomized controlled trials and two open-label studies). A low-FODMAP GFD for a minimum of 4 weeks was significantly more effective than a regular GFD in reducing symptoms (p < 0.05 in 3/4 studies). Dietary FODMAP content of a conventional GFD was significantly lower than that of non-coeliac patients on a gluten-containing diet (both p < 0.05), especially regarding high-FODMAP grain products. However, coeliac patients consumed more servings of fruits/vegetables high in FODMAP. No relationship between FODMAP intake and persistence of symptoms was reported. Conclusions: A low-FODMAP diet may be beneficial for uncomplicated celiac patients with persistent IBS-like symptoms despite strict adherence to a GFD.

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: 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.

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.

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.

Clinical and laboratory predictors and prevalence of immune reconstitution inflammatory syndrome in patients with Whipple's disease.

OBJECTIVES: Whipple's disease (WD) is a rare and potentially fatal infectious disease caused by Tropheryma whipplei. It is characterized by a long prodromal phase that mimics a rheumatological disease, often leading to immunosuppressant treatment. Immune reconstitution inflammatory syndrome (IRIS) is currently the most important complication of WD, requiring prompt recognition and treatment as it can be fatal. However, epidemiological data on IRIS are scarce. We aimed to identify the clinical and laboratory predictors of IRIS at WD diagnosis and to evaluate whether the prevalence of IRIS has changed over time. METHODS: Forty-five patients with WD (mean age 52 ± 11 years; 10 females) were followed up between January 2000 and December 2021. Clinical and laboratory data at WD diagnosis were retrospectively collected and compared among patients who developed IRIS and those who did not. RESULTS: Erythrocyte sedimentation rate (ESR; 33.4 ± 11.8 mm/h vs 67.1 ± 26.3 mm/h, P < 0.01), platelet (PLT; 234 × 109 /L vs 363 × 109 /L, P < 0.01), and body mass index (22.0 ± 2.0 kg/m2 vs 19.8 ± 3.0 kg/m2 , P = 0.04) differed significantly between patients who subsequently developed IRIS and those who did not. ROC analysis identified ESR ≤46 mm/h (AUROC 0.88, 95% CI 0.72-1.00) and PLT ≤ 327 × 109 /L (AUROC 0.85, 95% CI 0.70-1.00) as optimal cut-off values to discriminate WD patients at a high risk of developing IRIS. Prevalence of IRIS remained stable (22.2%) over time. CONCLUSIONS: Low ESR and PLT count at diagnosis help identify WD patients at high risk of developing IRIS. Instead, a greater inflammatory response suggests a lower risk of IRIS. Prevalence of IRIS did not change over two decades.

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.

Humoral immunogenicity of COVID-19 vaccines in patients with coeliac disease and other noncoeliac enteropathies compared to healthy controls.

OBJECTIVES: Data are lacking on the immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients affected by coeliac disease, Whipple's disease and other noncoeliac enteropathies (NCE), characterised by primary or drug-related immunosuppression. We aimed to assess humoral response to SARS-CoV-2 vaccination in these patients compared to controls. METHODS: Between December 2021 and January 2022, IgG anti-SARS-CoV-2 spike protein antibodies were measured in serum samples of coeliac disease, Whipple's disease and NCE patients attending our gastroenterology outpatient clinic for follow-up, who had received their first SARS-CoV-2 vaccination dose 3-6-9 (±1) months prior. Humoral response was compared with healthy controls (vaccinated healthcare workers undergoing serological screening), matched for gender, age, and time from first vaccine dose at sample collection. RESULTS: A total of 120 patients [107 coeliac disease; 10 Whipple's disease; 2 common-variable immunodeficiency (CVID); 1 idiopathic villous atrophy; 77 F, 42 ± 16 years] and 240 matched controls (154 F, 43 ± 14 years) were enrolled. At 3, 6 and 9 months, humoral response in coeliac patients was not impaired compared to controls. Inadequate humoral response to vaccination was significantly more common among Whipple's disease patients than controls ( P < 0.001). Patients on immunosuppressive therapy had markedly lower IgG anti-SARS-CoV-2 antibody titres (median 14 vs. 520 BAU/mL, P < 0.001). As expected, patients with CVID showed no humoral response to vaccination. CONCLUSIONS: Humoral immunogenicity of SARS-CoV-2 vaccines was not reduced in coeliac disease patients compared to controls, although it was in Whipple's disease and CVID patients. Post-vaccination humoral response should be monitored in patients with Whipple's disease and chronic enteropathies on immunosuppressive therapy in order to schedule vaccine booster doses.

High Prevalence of Functional Gastrointestinal Disorders in Celiac Patients with Persistent Symptoms on a Gluten-Free Diet: A 20-Year Follow-Up Study.

BACKGROUND: Ongoing symptoms in treated celiac disease (CD) are frequent and are commonly thought of as being due to infractions to a gluten-free diet (GFD) or complications. AIMS: To study the etiology and natural history of clinically relevant events (CREs) throughout follow-up and identify predictors thereof to guide follow-up. METHODS: CREs (symptoms/signs requiring diagnostic/therapeutic interventions) occurring in celiac patients between January-2000 and May-2021 were retrospectively collected between June and September 2021 and analysed. RESULTS: One-hundred-and-eighty-nine adult patients (133 F, age at diagnosis 36 ± 13 years, median follow-up 103 months, IQR 54-156) were enrolled. CREs were very common (88/189, 47%), but hardly due to poor GFD adherence (4%) or complications (2%). Interestingly, leading etiologies were functional gastrointestinal disorders (30%), reflux disease (18%) and micronutrient deficiencies (10%). Age at diagnosis ≥ 45 years (HR 1.68, 95%CI 1.05-2.69, p = 0.03) and classical pattern of CD (HR 1.63, 95%CI 1.04-2.54, p = 0.03) were predictors of CREs on a multivariable Cox model. At 5 years, 46% of classical patients ≥ 45 years old at diagnosis were event-free, while this was 62% for non-classical/silent ≥ 45 years, 60% for classical < 45 years, and 80% for non-classical/silent < 45 years. CONCLUSIONS: CREs occurred in almost half of CD patients during follow-up, with functional disorders being very common. New follow-up strategies for adult CD may be developed based on age and clinical pattern at diagnosis.

DQA1*0102 DQB1*0602 haplotype distinguishes coeliac disease and its complications from gluten unrelated enteropathies.

BACKGROUND: Duodenal villous atrophy is due not only to coeliac disease and its complications but also to other rare enteropathies unrelated to gluten consumption, defined as noncoeliac enteropathies. The diagnosis of noncoeliac enteropathies remains challenging, and HLA typing has been widely used to exclude coeliac disease if DQ2 and DQ8 alleles are absent. However, the frequency of the various HLA alleles in noncoeliac enteropathies is still unknown. AIMS: To describe the HLA genetic profile of patients affected by noncoeliac enteropathies who have been evaluated at our centres between 2000 and 2021, and to investigate the diagnostic role of HLA typing. METHODS: Genomic DNA was collected from 44 Italian and 19 British adult patients with noncoeliac enteropathies. Patient genotypes were compared with those of healthy Italian and British populations obtained from HLA bone marrow donors' banks. In addition, genotypes were also compared with those of patients with coeliac disease and complicated coeliac disease. RESULTS: Both in the Italian and in the British group, the DQA1*0102 DQB1*0602 haplotype and related alleles occurred significantly more frequently in patients with noncoeliac enteropathies compared to coeliac disease and complicated coeliac disease. CONCLUSIONS: Together with negative HLA-DQ2 and DQ8 haplotypes, the DQA1*0102 DQB1*0602 haplotype can be used to guide the differential diagnosis between coeliac disease and noncoeliac enteropathies.

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.

Musculoskeletal Ultrasound to Identify Subclinical Joint and Periarticular Involvement in Patients With Inflammatory Bowel Disease: A Systematic Literature Review.

Background: Musculoskeletal ultrasonography identifies subclinical joint and entheseal inflammation, and it might be of value in patients with inflammatory bowel diseases (IBD), which are at higher risk of inflammatory arthropathy and disability. Our aim was to retrieve the evidence on the applications of ultrasound in patients with non-arthropathic IBD. Methods: Studies enrolling patients with IBD without arthritis, undergoing ultrasound of joints, tendons or entheses were eligible. The outcomes of interest encompassed the frequency of ultrasound-detected lesions, their accuracy in diagnosing arthritis, their prognostic role and sensitivity to change. All study types, excluding case reports, case series and narrative reviews, were included. Search strategies were applied in PubMed and Embase. Abstract and full-texts were evaluated by pairs of reviewers. The risk of bias was evaluated through the Newcastle-Ottawa scale or the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) 2. The protocol was registered in PROSPERO (CRD42021264972). Results: Out of 2,304 records, eight studies were included, all reporting the frequency of lesions, while only three evaluated also the diagnostic accuracy. All studies had a cross-sectional design, with no evidence on prediction or follow-up. All studies evaluated the entheses, while only three the joints. The most common chronic lesions were entheseal thickening (up to 81.5%) and enthesophytes (67.9%), while entheseal erosions were present in 16%-17% of patients. Among inflammatory lesions, power Doppler was reported in 14%-67% of patients. There were no differences among Crohn's disease or ulcerative colitis and depending on disease activity, while there were contrasting results on different disease durations. When evaluating the diagnostic performance, the best specificity for a diagnosis if IBD was 0.88 (95%CI, 0.8-0.94) for joint abnormalities. Also, the best sensitivity was 0.88 (95%CI, 0.76-0.95) for entheseal lesions. No studies assessed of the combination of lesions. Due to the limited number of studies, meta-analyses were not performed. Conclusions: Despite the possible value of ultrasound in IBD, there is limited evidence deriving from cross-sectional studies. Longitudinal studies are needed to clarify the role of this technique, while its current placement might be that of complementing clinical assessment, in particular in early intestinal disease.

Is it time to rethink the burden of non-coeliac gluten sensitivity? A systematic review.

INTRODUCTION: Non-coeliac gluten sensitivity (NCGS) is still a poorly defined clinical condition. This review aims to describe the clinical features of subjects with a symptomatic response to gluten intake, and to estimate the prevalence of NCGS. EVIDENCE ACQUISITION: Literature search was conducted in accordance with PRISMA recommendations. The PubMed database was searched for original articles until 1st June 2020. EVIDENCE SYNTHESIS: We identified 30 relevant articles, including 14 studies that investigated NCGS through a double-blind, placebo-controlled crossover trial (DBPCC), and 16 that examined the role of gluten in causing symptoms without a DBPCC. We found that regardless of the diagnostic work up, gluten-sensitive patients were predominately middle-aged females complaining of abdominal pain, bloating and diarrhea. The pooled prevalence of NCGS after DBPCC was 24% (5-34%). Subjects with irritable bowel syndrome or self-reporting gluten intolerance accounted for the vast majority of the patients who did not start a DBPCC. A symptomatic response to a gluten-free diet (GFD) occurred in between 7% and 93% of patients. No data on long-term outcomes of NCGS individuals were reported. CONCLUSIONS: Clinical features of NCGS patients did not differ among all the included studies, whereas prevalence figures are rather heterogeneous. Long-term benefit of a GFD on these patients still needs to be ascertained.

Determinants and Trends of Adherence to a Gluten-Free Diet in Adult Celiac Patients on a Long-term Follow-up (2000-2020).

BACKGROUND & AIMS: Data on factors governing long-term adherence to a gluten-free diet (GFD) in celiac disease (CD) are scarce. We aimed to determine trends and clinical predictors of long-term GFD adherence in adult CD. METHODS: Initial and long-term (>3 years) GFD adherence, clinical characteristics at baseline and follow-up were collected retrospectively from celiac patients followed-up over 20 years (2000-2020). Predictors of long-term GFD adherence at diagnosis, and follow-up were evaluated by multivariate logistic regression. RESULTS: 248 patients (37 ± 12 years, 186F, median time on a GFD 90 months) were included. Twenty-five (10.1%) had only short-term follow-up (<3 years) while 223 (89.9%) had initial and long-term dietary assessment. 187/223 (83.9%) patients were initially adherent and 36/223 (16.1%) were not. 17/36 (47.2%) patients initially not adherent become adherent, while only 4/187 (2.1%) initially adherent patients became not adherent. In the long-term, 200/223 (89.7%) were adherent and 21/223 (9.4%) patients were not. Adherence improved more frequently than worsened (OR, 39.5; 95% CI, 11.4-178.5; P < .01). Classical symptoms (diarrhea, weight loss) at diagnosis of CD predicted stricter long-term GFD adherence (OR, 3.27; 95% CI, 1.21-8.81; P = .02), while anemia (OR, 0.31; 95% CI, 0.12-0.82; P = .02) and dermatitis herpetiformis (OR, 0.23; 95% CI, 0.06-0.91; P = .04) predicted poorer long-term adherence. At follow-up, initial GFD adherence (OR, 42.70; 95% CI, 10.70-171.00; P = .04) was the major determinant of long-term GFD adherence. CONCLUSIONS: GFD adherence changes over time in <10% of patients, generally improving when it does. Major determinants of long-term GFD adherence are classical symptoms at diagnosis and initial adherence to a GFD. Patients with anemia or dermatitis herpetiformis at diagnosis require stricter dietetic input.

Long-Term Adherence to a Gluten-Free Diet and Quality of Life of Celiac Patients After Transition to an Adult Referral Center.

BACKGROUND: Modalities for the transition to adult care of celiac patients diagnosed during childhood/adolescence and their impact on long-term adherence to a gluten-free diet (GFD-A), quality of life (QOL) and maintenance of follow-up in adulthood are unknown. AIMS: To evaluate whether timing of transition affects long-term GFD-A, QOL, and continuity of follow-up in adulthood and to identify predictors of long-term GFD-A. METHODS: Clinical and demographic data about pediatric care and adult follow-up at our center were retrospectively collected from clinical notes of celiac patients diagnosed during childhood/adolescence and then referred to our tertiary center. QOL and adult long-term GFD-A were prospectively evaluated with validated questionnaires. These parameters were studied by means of univariate and multivariate statistical analysis. RESULTS: 183 patients (130F, mean age at diagnosis 7.6 ± 5.8 years) were enrolled. Median age at transition to adult care was 20 years (IQR 17-25). There was no relationship between age at transition to adult care, long-term GFD-A, QOL, and continuity of follow-up. GFD-A tended to improve overall from pediatric care to adult referral (OR 2.92, 95% CI 1.13-7.87, p = 0.02) and also throughout adult follow-up (OR 9.0, 95% CI 4.2-19.7, p < 0.01). On multivariable logistic regression analysis, classical symptoms at diagnosis of celiac disease (p = 0.02) and good GFD-A at adult referral (p < 0.01) predicted good long-term GFD-A, while being lost to follow-up predicted poorer long-term GFD-A (p = 0.02). CONCLUSIONS: Clinical characteristics can guide development of personalized strategies for implementing long-term GFD-A and ensure maintenance of regular follow-up in celiac patients diagnosed in childhood/adolescence and transitioning to adult care.

The GLU-10: a validated ten-point score to identify poorly instructed celiac patients in need of dietary interventions.

BACKGROUND: A standard tool to assess patients' knowledge about gluten and the gluten-free diet (GFD) is lacking. METHODS: We aimed to develop and validate a questionnaire to assess GFD knowledge. A 10-point questionnaire (GLU10) covering different aspects of knowledge about gluten content in food/non-food products and the gluten-free living was developed. To validate this questionnaire, it was administered to adult celiac patients already instructed on gluten and the GFD and non-celiac controls. Patients were prospectively recruited at our Gastroenterology Outpatient Clinic between August 2020 and February 2021. RESULTS: One hundred and six patients (52 celiac patients and 54 controls) participated in the validation phase. Celiac patients scored significantly higher than controls on the GLU10 Questionnaire (median 6 points vs. 2 points, P<0.001). Higher self-reported knowledge of the GFD was related to a higher score (P<0.001). ROC curve confirmed the ability of the GLU10 Questionnaire to discriminate between subjects with good and poor GFD knowledge (AUC=0.94, 95% CI: 0.90-0.98). A score of 5 was identified as the best cut-off (sensitivity 80.8%, specificity 94.4%). On multivariable logistic regression analysis, being a celiac patient (P<0.001) and having a university degree (P=0.04) were associated to a high GLU10 Score (≥5). CONCLUSIONS: GLU10 is the first validated questionnaire for assessing knowledge of a GFD in celiac patients and the general population.

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.