Type 1 diabetes, thyroid, gastric and adrenal humoral autoantibodies are present altogether in almost one third of adult celiac patients at diagnosis, with a higher frequency than children and adolescent celiac patients.

Background: No data are available on the frequency of organ-specific humoral autoimmunity at diagnosis of adult celiac disease (CD).Aim: To evaluate the humoral immunoreactivities specific of type 1 diabetes (T1D), thyroid (THD), atrophic-gastritis (AG) and Addison's (AD) diseases in 92 adult CD patients at diagnosis and 237 adult healthy subjects (CTRL).Methods: T1D, THD and AD specific autoantibodies were analyzed by radioimmunoprecipitation assays. AG autoantibodies were detected by enzyme-linked immunosorbent assay.Results: Of 92 CD patients, 31.5% were positive for at least one of the organ-specific autoantibodies investigated (p < .0001 vs CTRL). Thyroid, diabetes, gastric and adrenal-autoantibodies, that increase with age at diagnosis, were detected in 12.0%, 10.9%, 10.9%, 2.2% of CD patients, respectively. Gastric- and diabetes- rather than thyroid- and adrenal-autoimmunity seem to be specifically related to presence of CD.Conclusions: One third of adult CD patients at diagnosis is target of at least one organ-specific autoantibody. A systematic organ-specific autoantibody screening in these patients might be of value to promptly identify, prevent or treat the relative diseases.

Robotic colonoscopy: efficacy, tolerability and safety. Preliminary clinical results from a pilot study.

BACKGROUND: Robotic colonoscopy (RC) is a pneumatically-driven self-propelling platform (Endotics System®) able to investigate the colon, in order to reduce pain and discomfort. AIMS: (1) to describe the progress in gaining experience and skills of a trainee in RC; (2) to show the clinical outcomes of RC. METHODS: Pilot study. An experienced endoscopist started a training on RC whose progress was assessed comparing the results of 2 consecutive blocks of 27 (Group A) and 28 (Group B) procedures. CIR (Cecal Intubation Rate), CIT (Cecal Intubation Time) and Withdrawal Time (WT) were measured. Polyp Detection Rate (PDR), Adenoma Detection Rate (ADR) and Advanced Neoplasia Detection Rate (ANDR) were calculated. Possible adverse events were recorded. At the end of the procedure all patients completed a visual analog scale (VAS) to measure their perceived pain during RC and reported their willingness to repeat RC. RESULTS: General CIR was 92.7%, reaching 100% in Group B. Comparing the two groups, CIT significantly decreased from 55 to 22 min (p value 0.0007), whereas procedures with CIT ≤ 20 min increased (p value 0.037). WT significatively reduced from 21 to 16 min (p value 0.0186). PDR was 40% (males 62.5%, females 14.3%). ADR was 26.7% (males 27.5%, females 14.3%). Most of patients judged the procedure as mild or no distress, with high willingness-to-repeat the RC (92.7%). CONCLUSIONS: Our results about RC are encouraging as preliminary experience, with clear individual learning progress, accurate diagnosis in a painless or comfortable procedure and with possibility to remove polypoid lesions. Studies with larger populations are needed to confirm obtained results.

Efficacy of Sedation by Midazolam in Association With Meperidine or Fentanyl and Role of Patient Distress During Elective Colonoscopy.

Meperidine and fentanyl are opioids currently used in addition to midazolam for sedation and analgesia during colonoscopy in Italy. The aim of the study was to assess the impact of patients' psychological state before elective colonoscopy on the efficacy of the sedation regimens. Eighty outpatients who underwent an elective colonoscopy were included in our study. The Hospital Anxiety and Depression Scale questionnaire was self-administered to evaluate basal anxiety and depression state. The rate of baseline discomfort was evaluated by a standard 100-mm visual analog scale. Sedation was obtained alternatively with a midazolam-meperidine or midazolam-fentanyl combination. There were no statistically significant differences between the fentanyl and meperidine groups on body mass index, age, and gender composition. Patients in the meperidine group reported less pain during colonoscopy than patients in the fentanyl group. There were statistically significant positive correlations in the meperidine group with the distress, anxiety, and depression. Our study has pointed out greater effectiveness of the midazolam plus meperidine regimen, equal recovery times, and no significant differences in the duration of the endoscopic examinations. The evaluation of patients' psychological status seems to predict the efficacy of sedation when the nociceptive component of pain is well controlled.

One-step immunochromatographic visual assay for anti-transglutaminase detection in organ culture system: An easy and prompt method to simplify the in vitro diagnosis of celiac disease.

BACKGROUND: Anti-tissue transglutaminase (anti-tTG) and endomysium antibodies (EMA) are detectable in duodenal culture media of celiac disease (CD) patients. To improve the management of this organ culture system, we evaluated the anti-tTG occurrence by immunochromatographic assay (ICA). METHODS: A total of 103 CD patients and 41 disease controls underwent duodenal biopsy for the organ culture. In culture supernatants, IgA anti-tTG were tested by both enzyme-linked immunosorbent assay (ELISA) and ICA, IgA EMA were searched by indirect immunofluorescence analysis (iIFA). RESULTS: Endomysium antibodies and anti-tTG measured by ELISA were positive in culture media of all CD patients, while anti-tTG detected by ICA were positive in culture media of 87/103 CD patients. Anti-tTG ICA scores significantly correlated with anti-tTG ELISA values (r=.71, P<.0001). Sensitivity, specificity and diagnostic accuracy of anti-tTG detected by ICA were 84.5%, 100% and 88.9%, respectively. CONCLUSIONS: Using ICA, anti-tTG are detectable in duodenal culture media of most CD patients and the intensity of indicative lines depends on the anti-tTG concentration. Sensitivity and diagnostic accuracy achieved with ICA are lower than those obtained with ELISA but, given that the first is a more easy and prompt method, data suggest the possibility of utilizing it in the in vitro diagnosis of CD.

Intestinal, Systemic, and Oral Gluten-related Alterations in Patients With Nonceliac Gluten Sensitivity.

BACKGROUND: Nonceliac gluten sensitivity (NCGS) is an emergent condition, the framework of which is yet unclear, whereas the diagnosis is suggested only by gluten-dependent symptoms after excluding wheat allergy and celiac disease (CD). Our goal was to highlight intestinal, systemic, and oral alterations to clarify the NCGS pathogenesis and identify new diagnostic tools. STUDY: A total of 60 NCGS patients, 20 untreated CD, 20 treated CD, and 20 healthy volunteers were recruited. The differential diagnosis among gluten-related disorders was performed by serological, allergy, and histologic tools. NCGS patients were also subjected to antigliadin antibody (AGA) detection and HLA typing. All participants underwent an oral mucosa patch test for gluten (GOMPT), whereas an oral provocation test (OPT) for gluten was performed in 26 NCGS patients. RESULTS: About 6/60 (10%) NCGS patients showed IgG AGA-positive results, whereas 45/60 (75%) patients carried HLA-DQ2 and/or HLA-DQ8 genes. GOMPT showed positive results in 45/60 (75%) NCGS patients, 3/20 (15%) untreated CD patients, 5/20 (25%) treated CD patients, and in no healthy volunteers. No significant difference was found between the severity of symptoms reported by NCGS patients subjected to OPT with gluten-containing croissants and those who underwent OPT with gluten-free croissants. CONCLUSIONS: GOMPT seems to be a specific tool for NCGS diagnosis, although further investigations are needed to overcome limits due to the small population studied and to contextualize GOMPT false-positive results.

In Vitro Gluten Challenge Test for Celiac Disease Diagnosis.

OBJECTIVES: The in vitro gluten challenge test is an important diagnostic modality in celiac disease (CD), especially in patients who begin treatment with a gluten-free diet before adequate diagnostic workup or in cases with atypical CD. Available literature was reviewed regarding the accuracy of the in vitro gluten challenge test for CD diagnosis. METHODS: MEDLINE, Scopus, and Google Scholar were searched, and studies that used serology and bowel biopsy as the criterion standard for diagnosis were included in our study. Data on authors, publication year, characteristics of the patient and control groups, patients' diet, duration of the gluten challenge test, histology findings, endomysial antibody (EMA) and anti-tissue transglutaminase (tTG) levels, CD markers, and intercellular cell adhesion molecule-1, and human leukocyte antigens before and after the gluten challenge test were extracted. RESULTS: Overall, 15 studies were included in this meta-analysis. Pooled sensitivity %/specificity % was 84/99 for EMA after the challenge, 52/96 for EMA without the challenge, 95.5/98.3 for anti-tTG after the challenge, and 95.1/98.3 for anti-tTG without the challenge test. Sensitivity/specificity for immunological markers were 89/97 for the percentage of CD25⁺-lamina propria lymphocytes, 96/91 for the percentage of CD3⁺-lamina propria lymphocytes, and 96.1/85.7 for the percentage of intercellular cell adhesion molecule-1-lamina propria lymphocytes. The factors that increased the sensitivity of EMA were longer test duration, and the evaluation of patients on a gluten-containing diet or short-term gluten-free diet. CONCLUSIONS: The in vitro gluten challenge test can be a useful part of the diagnostic workup of CD, rather than only a model to evaluate its mechanisms.

Weaknesses of histological analysis in celiac disease diagnosis: new possible scenarios.

INTRODUCTION: Celiac disease (CD) is an autoimmune disorder triggered by the ingestion of gluten. Serology and organ culture system can support CD diagnosis, despite histology being the gold standard. AIM: We wanted to test the uniformity of application of Marsh-Oberhuber criteria by five different histologists. We also compared histological and serological data with cultural results to consider new possible strategies in CD diagnosis. METHODS: We studied 114 patients, who were divided in two groups. Group A was composed of 66 patients on a gluten-containing diet, with gluten-related signs and symptoms, showing positive serological anti-endomysial antibodies (EMA) and anti-tissue transglutaminase (anti- tTG). Group B was composed of 48 disease-control patients, presenting serological EMA and anti-tTG negative results. All patients studied underwent esophagogastroduodenoscopy with duodenal biopsy and duodenal mucosa organ culture. All histological samples were evaluated by five different histologists according to an appropriate questionnaire following Marsh-Oberhuber classification. Cohen κ inter-test was used for evaluating the agreement between histologists regarding group A. RESULTS: Strength of agreement was fair/moderate for villous:crypt ratio, moderate/good for villous height and crypt depth, and poor for intraepithelial lymphocytosis. Patients belonging to group A presented positive serological as well as cultural results in 100% of cases. None of the patients belonging to group B presented serological or cultural positive results. DISCUSSION: Our study stresses the limits of histological interpretation due to the lack of uniformity in the use of Marsh-Oberhuber classification. These findings could cast doubt on the role of histology as CD gold standard and could open a debate on the most appropriate CD diagnostic procedure.

Endoscopic features with associated histological and molecular alterations in serrated polyps with dysplasia: Retrospective analysis of a tertiary case series.

BACKGROUND: Serrated polyps are incompletely understood lesions and include serrated sessile lesion (SSL) without or with dysplasia and traditional serrated adenoma (TSA). AIMS: We investigated prevalence and characteristics of serrated lesions, especially SSL with dysplasia (mixed polyps). METHODS: This retrospective study analyzed data from consecutive patients referred for colonoscopy at a tertiary care center. Endoscopic and histopathological characteristics of identified lesions were studied. SSLs with dysplasia were molecularly analyzed for mutations and microsatellite instability. RESULTS: Among 1147 patients, a total of 436 polyps were found, including 288 adenomas (66.1 %) and 114 serrated lesions (SLDR 26.2 %). PDR was 34.5 % and ADR was of 30.2 %. Serrated lesions included 75 hyperplastic polyps (17.2 %), 24 SSLs without dysplasia (5.5 %), 6 SSLs with dysplasia (mixed polyps) (1.4 %) and 9 TSA (2.1 %). The mixed polyps were evaluated molecularly: these analyses found no KRAS mutation, a single NRAS mutation in one lesion, the Val600Glu BRAF mutation in four lesions in both their serrated non-dysplastic and dysplastic areas, and microsatellite instability in four lesions, limited to the dysplastic areas. CONCLUSION: Our single-center experience confirms the high prevalence of serrated lesions, a part of which are SSL with dysplasia. These lesions seem to carry specific molecular alterations.

Colonic involvement in celiac disease and possible implications of the sigmoid mucosa organ culture in its diagnosis.

PURPOSE: Celiac disease (CD), a systemic autoimmune disorder that typically involves duodenal mucosa, can also affect other intestinal areas. Duodenal and oral mucosa organ culture has already been demonstrated as a reliable procedure to identify CD. The present study investigated gluten-dependent immunological activation of colonic mucosa in CD patients. We took advantage of the numerous colonoscopies performed for various clinical conditions or only for defensive medicine. METHODS: Forty-four patients with gastrointestinal symptoms or in need of colorectal cancer screening were divided into patients with serum anti-endomysium (EMA) and anti-tissue transglutaminase (anti-tTG) antibody positive results (Group A), patients with serum antibody negative results (Group B), and patients with inflammatory bowel disease (IBD) (Group C). The autoantibodies EMA and anti-tTG were evaluated in supernatants of cultured sigmoid and duodenal biopsies from patients on a gluten-containing diet. RESULTS: In Group A, EMA and anti-tTG resulted positive in all duodenal culture supernatants. In sigmoid culture supernatants, EMA and anti-tTG were detected in 12/16 (75 %) and 13/16 (81.3 %) patients, respectively. In Group B, none of the 17 patients showed EMA and anti-tTG positive results in both duodenal and sigmoid cultures. In Group C, all 11 patients presented EMA negative results in sigmoid cultures. Only in one patient, anti-tTG were detectable in the sigmoid culture supernatant, as expected in cases of IBD. CONCLUSIONS: Data confirm that the gluten-dependent immunological activation affects more intestinal tracts with different degrees of involvement, suggesting that the organ culture of colonic biopsies could represent a new tool to opportunistically detect CD.

New Insights into Intestinal Permeability in Irritable Bowel Syndrome-Like Disorders: Histological and Ultrastructural Findings of Duodenal Biopsies.

BACKGROUND AND AIM: Diarrhea, abdominal pain, and bloating are frequent in irritable bowel syndrome (IBS)-like disorders, although little is known about their intestinal ultrastructural alterations. The aim of the present study was to study duodenal biopsies from IBS-like patients to find ultrastructural alterations. MATERIALS AND METHODS: Study design: descriptive comparative pilot study. Thirty outpatients (9 male and 21 female; median age 37.7 years; range, 20 to 65 years) complaining of IBS-like symptoms were enrolled between January 2015 to May 2019 and were divided into 6 groups, each equally consisting of 5 patients: (A) untreated celiac disease (uCD); (B) treated celiac disease (tCD); (C) wheat allergy (WA); (D) Non-celiac gluten sensitivity (NCGS); (E) Nickel allergic contact mucositis (Ni ACM); (F) controls affected by GERD. Transmission electron microscopy (TEM) morphological characteristics were: microvilli length, intermicrovillar distance, junctional complexes (JC) gap width, autophagic bodies, apoptosis, altered mitochondria, lipid/chylomicron droplets, and mast cells. Regarding JC, we focused on tight junctions (TJ), adherens junctions (AJ), and desmosomes. RESULTS: Major alterations in microvilli length and intermicrovillar distance have been observed in the subjects affected by uCD. Microvilli of tCD patients showed marked recovery after adequate GFD, although not comparable to controls. Intermediate microvillar alterations were instead observed in NCGS and Ni ACM, while characteristics of WA subjects appeared more similar to tCD. Regarding JC, TJ did not show significant differences between all groups studied, including controls. The AJ were significantly more dilated in all groups compared to controls, while no significant differences were found between the pathological groups. The distance between desmosomes was greater in uCD, NCGS, and Ni ACM than in tCD, WA, and controls. Finally, intracellular alterations have been detected in most of the groups studied although they seemed more unspecific. CONCLUSIONS: TEM analysis confirmed damages to the intestinal barrier and defense mechanisms by enterocytes in IBS-like patients, probably linked to low-grade inflammation or adverse reactions triggered by food allergens, heavy metals, or other unknown. On the other hand, our study needs confirmation and further investigations with larger populations to facilitate diagnosis, therapy, and prevention of IBS-like disorders in the future.

Beneficial Effects of a Low-Nickel Diet on Relapsing IBS-Like and Extraintestinal Symptoms of Celiac Patients during a Proper Gluten-Free Diet: Nickel Allergic Contact Mucositis in Suspected Non-Responsive Celiac Disease.

BACKGROUND AND AIM: Nickel (Ni)-rich foods can induce allergic contact mucositis (ACM) with irritable bowel syndrome (IBS)-like symptoms in predisposed subjects. Ni ACM has a high prevalence (>30%) in the general population and can be diagnosed by a Ni oral mucosa patch test (omPT). Many celiac disease (CD) patients on a gluten-free diet (GFD) often show a recrudescence of gastrointestinal and extraintestinal symptoms, although serological and histological remission has been achieved. Since a GFD often results in higher loads of ingested alimentary Ni (e.g., corn), we hypothesized that it would lead to a consequent intestinal sensitization to Ni in predisposed subjects. We wanted to (1) study Ni ACM prevalence in still symptomatic CD patients on a GFD and (2) study the effects of a low-Ni diet (LNiD) on their recurrent symptoms. MATERIAL AND METHODS: We recruited 102 consecutive CD patients (74 female, 28 male; age range 18-65 years, mean age 42.3 ± 7.4) on a GFD since at least 12 months, in current serological and histological remission (Marsh-Oberhuber type 0-I) who complained of relapsing gastrointestinal and/or extraintestinal symptoms. INCLUSION CRITERIA: presence of at least three gastrointestinal symptoms with a score ≥5 on the modified Gastrointestinal Symptom Rating Scale (GSRS) questionnaire. EXCLUSION CRITERIA: IgE-mediated food allergy; history of past or current cancer; inflammatory bowel diseases; infectious diseases including Helicobacter pylori; lactose intolerance. All patients enrolled underwent Ni omPT and followed a LNiD for 3 months. A 24 symptoms questionnaire (GSRS modified according to the Salerno Experts' Criteria, with 15 gastrointestinal and 9 extraintestinal symptoms) was administered at T0 (free diet), T1 (GFD, CD remission), T2 (recurrence of symptoms despite GFD), and T3 (GFD + LNiD) for comparisons. Comparisons were performed using Wilcoxon signed-rank test. RESULTS: Twenty patients (all female, age range 23-65 years, mean age 39.1 ± 2.9) out of 102 (19.6%) were finally included. All 20 patients enrolled (100%) showed positive Ni omPT, confirming an Ni ACM diagnosis. A correct GFD (T0 vs. T1) induced the improvement of 19 out of the total 24 (79.2%) symptoms, and 14 out of 24 (58.3%) were statistically significant (p-value < 0.0083 according to Bonferroni correction). Prolonged GFD (T1 vs. T2) revealed the worsening of 20 out of the total 24 (83.3%) symptoms, and 10 out of 24 (41.7%) were statistically significant. LNiD (T2 vs. T3) determined an improvement of 20 out of the total 24 (83.4%) symptoms, and in 10 out of 24 (41.7%) symptoms the improvement was statistically significant. CONCLUSIONS: Our data suggest that the recrudescence of gastrointestinal and extraintestinal symptoms observed in CD subjects during GFD may be due to the increase in alimentary Ni intake, once gluten contamination and persisting villous atrophy are excluded. Ni overload can induce Ni ACM, which can be diagnosed by a specific Ni omPT. Improvement of symptoms occurs after a proper LNiD. These encouraging data should be confirmed with larger studies.

Irritable Bowel Syndrome-Like Disorders in Endometriosis: Prevalence of Nickel Sensitivity and Effects of a Low-Nickel Diet. An Open-Label Pilot Study.

Alimentary nickel (Ni) may result in allergic contact mucositis (ACM), whose prevalence is >30% and may present with IBS-like and extra-intestinal symptoms. These symptoms are also frequent in endometriosis, and Ni allergic contact dermatitis has already been observed in endometriosis. Therefore, intestinal and extra-intestinal symptoms in endometriosis may depend on a Ni ACM, and a low-Ni diet could improve symptoms. We studied the prevalence of Ni ACM in endometriosis and focused on the effects of a low-Ni diet on gastrointestinal, extra-intestinal, and gynecological symptoms. We recruited 84 women with endometriosis, symptomatic for gastrointestinal disorders. Thirty-one out of 84 patients completed the study. They underwent Ni oral mucosa patch test (omPT), questionnaire for intestinal/extra-intestinal/gynecological symptoms, and a low-Ni diet. Clinical evaluation was performed at baseline (T0) and after three months (T1). Twenty-eight out 31 (90.3%) patients showed Ni omPT positive results, with Ni ACM diagnosis, whereas three out of 31 (9.7%) patients showed negative Ni omPT. After three months of low-Ni diet, all gastrointestinal, extra-intestinal and gynecological symptoms showed a statistically significant reduction. Ni ACM has a high prevalence in endometriosis and a low-Ni diet may be recommended in this condition to reduce gastrointestinal, extra-intestinal and gynecological symptoms.

In extremis diagnosis of celiac disease and concomitant wheat allergy.

Celiac disease (CD) and concomitant wheat allergy are not commonly described in the literature. Both can have almost the same treatment consisting of a gluten-free or wheat-free diet. On the other hand, they are based on totally different pathogenetic mechanisms and can be easily underdiagnosed, particularly CD. We describe a peculiar case of a young female patient affected by wheat allergy whose serological and histological data were not diagnostic for CD. Organ culture system successfully detected specific antibodies for CD in duodenal biopsy supernatant, supporting the diagnosis of CD.

New insights in IBS-like disorders: Pandora's box has been opened; a review.

The most complained gastrointestinal symptoms are chronic diarrhea, bloating and abdominal pain. Once malignancies and inflammatory bowel diseases are excluded, irritable bowel syndrome (IBS) and the so called "IBS-like disorders" should be taken into account. The relationship between IBS as defined by Rome IV criteria and these clinical conditions is sometimes obscure, since many IBS patients identify food as a possible trigger for their symptoms. Here, we discuss IBS and the most common IBS-like disorders (celiac disease, non-celiac gluten sensitivity, fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs), lactose intolerance, small intestinal bacterial overgrowth (SIBO), α-amylase/trypsin inhibitor (ATIs), nickel allergic contact mucositis), focusing on epidemiologic, clinical, diagnostic and therapeutic aspects. Given the lack of specificity of symptoms, clinical investigation will be facilitated by awareness of these disorders as well as new specific diagnostic tools.

The effects of modified versus unmodified wheat gluten administration in patients with celiac disease.

Celiac disease (CD) treatment requires a gluten-free diet (GFD), although alternative approaches have been proposed. Modification of gliadin peptides using microbial transglutaminase (mTG) inhibits their ability to induce immune response in vitro. Our aim was to evaluate the safety of mTG-modified wheat flour ingestion in CD patients. Twenty-one CD patients in remission were randomized to receive mTG-modified (n=11) or unmodified (n=10) wheat flour rusks, in double-blind fashion. Monthly, patients completed a symptom questionnaire. Serum anti-tTG, EMA and creatinine levels were monitored. At baseline and after 90days, serum anti-actin antibodies (AAA) were measured and upper endoscopy was performed. Data were analyzed by non-parametric tests. 7/11 patients eating modified rusks and 7/10 patients receiving unmodified rusks completed the study. At baseline, all patients showed negative serum anti-tTG and EMA results. At the end, 2/7 (28.6%) patients ingesting modified and 4/7 (57.1%) patients taking unmodified rusks presented positive serum anti-tTG and EMA results. Creatinine results were unmodified. Moreover, 1/7 (14.3%) patients ingesting modified and 4/7 (57.1%) patients taking unmodified rusks presented villous atrophy. In patients who received unmodified rusks, the AAA levels increased significantly and duodenal anti-tTG levels appeared higher than those measured in patients who ate modified rusks. Abdominal swelling, bloating and nausea were more severe in patients ingesting unmodified rusks than those taking modified rusks. Our results may support larger clinical trials to confirm the enzymatic treatment of wheat flour as an alternative to GFD. Clinicaltrials.gov registration no: NCT02472119.