A unicentric cross-sectional observational study on chronic intestinal inflammation in total colonic aganglionosis: beware of an underestimated condition.

BACKGROUND: Inflammatory Bowel Diseases (IBD) are known to occur in association with Hirschsprung disease (HSCR). Most of cases are represented by Crohn Disease (CD) occurring in patients with Total Colonic Aganglionosis (TCSA) with an estimated prevalence of around 2%. Based on these considerations and on a number of provisional data belonging to our Center for Digestive Diseases, we developed a unicentric cross-sectional observational study aimed at describing phenotype, genotype, pathology and metagenomics of all patients with TCSA and Crohn-like lesions. RESULTS: Out of a series of 62 eligible TCSA patients, 48 fulfilled inclusion criteria and were enrolled in the study. Ten patients did not complete the study due to non-compliance or withdrawal of consent and were subsequently dropped out. A total of 38 patients completed the study. All patients were tested for chronic intestinal inflammation by a combination of fecal calprotectine (FC) or occult fecal blood (OFB) and underwent fecal metagenomics. Nineteen (50%) tested positive for FC, OFB, or both and subsequently underwent retrograde ileoscopy. Fourteen patients (36.8%) presented Crohn-like lesions, occurring after a median of 11.5 years after surgery (range 8 months - 21.5 years). No statistically significant differences regarding demographic, phenotype and genotype were observed comparing patients with and without lesions, except for need for blood transfusion that was more frequent in those with lesions. Faecal microbiome of patients with lesions (not that of caregivers) was less biodiverse and characterized by a reduction of Bacteroidetes, and an overabundance of Proteobacteria. FC tested negative in 3/14 patients with lesions (21%). CONCLUSIONS: Our study demonstrated an impressive 10-folds higher incidence of chronic inflammation in TCSA. Up to 50% of patients may develop IBD-like lesions postoperatively. Nonetheless, we failed in identifying specific risk factors to be used to implement prevention strategies. Based on the results of our study, we suggest screening all TCSA patients with retrograde ileoscopy regardless of FC/OFB values. The frequency of endoscopic assessments and the role of FC/OFB screening in prompting endoscopy is yet to be determined.

Simplified Histologic Mucosal Healing Scheme (SHMHS) for inflammatory bowel disease: a nationwide multicenter study of performance and applicability.

BACKGROUND: Assessment of mucosal healing is important for the management of patients with inflammatory bowel disease (IBD), but endoscopy can miss microscopic disease areas that may relapse. Histological assessment is informative, but no single scoring system is widely adopted. We previously proposed an eight-item histological scheme for the easy, fast reporting of disease activity in the intestine. The aim of the present study was to evaluate the performance of our Simplified Histologic Mucosal Healing Scheme (SHMHS). METHODS: Between April and May 2021 pathologists and gastroenterologists in Italy were invited to contribute to this multicenter study by providing data on single endoscopic-histological examinations for their IBD patients undergoing treatment. Disease activity was expressed using SHMHS (maximum score, 8) and either Simple Endoscopic Score for Crohn's Disease (categorized into grades 0-3) or Mayo Endoscopic Subscore (range 0-3). RESULTS: Thirty hospitals provided data on 597 patients (291 Crohn's disease; 306 ulcerative colitis). The mean SHMHS score was 2.96 (SD = 2.42) and 66.8% of cases had active disease (score ≥ 2). The mean endoscopic score was 1.23 (SD = 1.05), with 67.8% having active disease (score ≥ 1). Histologic and endoscopic scores correlated (Spearman's ρ = 0.76), and scores for individual SHMHS items associated directly with endoscopic scores (chi-square p < 0.001, all comparisons). Between IBD types, scores for SHMHS items reflected differences in presentation, with cryptitis more common and erosions/ulcerations less common in Crohn's disease, and the distal colon more affected in ulcerative colitis. CONCLUSIONS: SHMHS captures the main histological features of IBD. Routine adoption may simplify pathologist workload while ensuring accurate reporting for clinical decision making.

Diagnostic interobserver variability in Crohn's disease- and ulcerative colitis-associated dysplasia: a multicenter digital survey from the IG-IBD Pathologists Group.

BACKGROUND: Crohn's disease (CD) and ulcerative colitis, two forms of inflammatory bowel disease (IBD), are chronic and relapsing conditions of the gastrointestinal tract both characterized by long lasting chronic inflammation and increased risk of dysplasia and colorectal cancer (CRC). The aim of our study was to evaluate the interobserver agreement about IBD-associated dysplasia among pathologists belonging to the Italian Group for Inflammatory Bowel Diseases (IG-IBD P). METHODS: The present multicenter survey was performed using telepathology, supported by an open source E-learning platform. Biopsy specimens from 30 colonoscopies and from 20 patients were included. The glass slides of any case, including clinical and endoscopic data, were digitalized and uploaded on the E-learning platform. All the digital slides were grouped in 54 diagnostic "blocks". Blinded histopathological evaluation on all the digital slides was performed by 20 gastrointestinal pathologists. Closed-ended questions about (1) the occurrence of IBD; (2) the classification of IBD (as UC or CD); (3) the presence of active versus quiescent disease; (4) the presence of dysplasia; (5) the possible association of dysplasia with the sites of disease (dysplasia-associated lesion or mass-DALM vs adenoma-like mass-ALM); (6) the grading of dysplasia according to the ECCO guidelines (negative, indefinite, low grade, high grade categories) and (7) the presence of associated serrated features, were proposed in each case. Inter-observer agreement was evaluated by mean agreement percentage and kappa statistic, when suitable. RESULTS: The diagnosis of IBD was confirmed in 19 of 20 patients, 17 of 19 being classified as UC, 2 as CD. The mean interobserver agreement percentages about (1) the evidence of IBD, (2) the presence of either UC or CD and (3) the activity grading resulted to be 80%, 69% and 86%, respectively. Dysplasia was detected in 8/20 patients, with moderate agreement between pathologists (mean 72%, k 0.48). Particularly, low grade dysplasia was found in 13 biopsies (combined k 0.38), whereas high grade dysplasia in 8 (combined k 0.47). When the endoscopic and histopathological data were combined, features consistent with DALM were found in 6 of 20 patients with low grade dysplasia and those consistent with ALM in 2 patients with low grade dysplasia in a single biopsy (mean agreement: 86%). An associated serrated pattern was discovered in 4 patients (7 biopsies). CONCLUSIONS: Our study showed moderate interobserver agreement about the histopathological detection and classification of IBD-associated dysplasia. Further efforts should be undertaken to integrate the histopathological data with both the ancillary tests and molecular investigations.

Correction to: Inflammatory bowel disease (IBD) position statement of the Italian Society of Colorectal Surgery (SICCR): general principles of IBD management.

The affiliation of the author Silvio Danese has been incorrectly published in the original publication. The complete correct affiliation should read as follows.

Abnormal gut motility in inflammatory bowel disease: an update.

BACKGROUND: There is substantial evidence linking disturbed gastrointestinal motility to inflammation. Thus, it is not surprising that abnormalities of gastrointestinal motility play a role in inflammatory bowel disease (IBD), affecting patient outcomes. We performed a review of the literature to investigate the relationship between abnormal gut motility and IBD. METHODS: With an extensive literature search, we retrieved the pertinent articles linking disturbed gut motility to IBD in various anatomical districts. RESULTS: The evidence in the literature suggests that abnormal gastrointestinal motility plays a role in the clinical setting of IBD and may confuse the clinical picture. CONCLUSIONS: Abnormal gut motility may be important in the clinical setting of IBD. However, additional data obtained with modern techniques (e.g., magnetic resonance imaging) are needed to individuate in a more precise manner gastrointestinal motor dysfunctions, to understand the nature of clinical manifestations and properly tailor the treatment of patients.

Inflammatory bowel disease (IBD) position statement of the Italian Society of Colorectal Surgery (SICCR): general principles of IBD management.

The Italian Society of Colorectal Surgery (SICCR) promoted the project reported here, which consists of a Position Statement of Italian colorectal surgeons to address the surgical aspects of inflammatory bowel disease management. Members of the society were invited to express their opinions on several items proposed by the writing committee, based on evidence available in the literature. The results are presented, focusing on relevant points. The present paper is not an alternative to available guidelines; rather, it offers a snapshot of the attitudes of SICCR surgeons about the general principles of surgical treatment of inflammatory bowel disease. The committee was able to identify some points of major disagreement and suggested strategies to improve quality of available data and acceptance of guidelines.

Histopathology of Celiac Disease. Position Statements of the Italian Group of Gastrointestinal Pathologists (GIPAD-SIAPEC).

Celiac Disease (CeD) is an immune-mediated inflammatory disorder of the small intestine, affecting genetically susceptible individuals when exposed to gluten. Small intestinal biopsy interpretation has been the "gold standard" for celiac disease (CeD) for over 50 years. Despite today's availability of sensitive and specific serological tests, the histopathological features from mucosal biopsy play a key role in diagnosing when CeD is suspected. Such a diagnostic approach requires a multidisciplinary team to optimize both tissue sampling and interpretation via the interaction between the pathologist and the gastroenterologist. Pathologists of the Italian Group of Gastrointestinal Pathology (GIPAD-SIAPEC), together with a member (TR) of the Italian Society of Technicians (AITIC) and an expert gastroenterologist (CC), provide position statements as a practical tool for reading and interpreting the report. Moreover, a position statement was formulated about the recently described condition known as Non-Celiac Gluten Sensitivity (NCGS). Within such a diagnostic setting, both the architectural abnormalities of the duodenal mucosa, namely glandular hyperplasia, and villous atrophy and the number of intraepithelial T-lymphocytes should be well highlighted. Ancillary tests such as anti-CD3 stain are useful for an accurate count of the intraepithelial T lymphocytes when CeD or NCGS is suspected. Moreover, anti-CD3 and anti-CD8 stains are recommended in patients not responding to the gluten-free diet (GFD) to confirm a diagnosis of Refractory Celiac Disease (RCeD). Diagnostic clues about the differential diagnosis of both CeD and RCeD have also been rendered.

Optimal processing of ESD specimens to avoid pathological artifacts.

BACKGROUND: En bloc endoscopic submucosal dissection (ESD) has been recently introduced as a treatment for precancerous/neoplastic gastrointestinal conditions. The aim of the present study was histological assessment of en bloc ESD specimens. METHODS: Fifty-three ESD specimens were positioned over a cellulose acetate support (40 specimens; 12 from the upper gastrointestinal tract and 28 from the lower gastrointestinal tract) or pinned with nails on polystyrene or cork (13 specimens; 7 from the upper gastrointestinal tract and 6 from the lower gastrointestinal tract). We cut consecutive 2 mm-thick sections stained with hematoxylin and eosin. From the first and the last sections, we obtained a second slide, after a 180° rotation and re-embedding. The quality of ESD samples was scored as inadequate, suboptimal and adequate, based on the amount of crushing, shearing and stretching artifacts that were scored from 0 (absent) to 2 (diffuse or maximum). From the sum of these we obtained a global artifact score (GAS). RESULTS: Removed lesions were: adenocarcinoma (5 cases), neuroendocrine tumor (NET) G1 (1 case), premalignant conditions, including adenomatous polyps (41 cases) and hyperplastic lesions (6 cases). A positive deep surgical margin was found in 8/53 cases (15%): high- and low-grade dysplastic glands were detected in 5 cases, low-grade adenocarcinoma in 2, and NET cells in 1. Dysplastic glands were detected in the lateral surgical margins of 12 ESD specimens (23%). Among the ESD specimens positioned on the cellulose acetate support, apart from the modifications due to electrocoagulation, 2 (5%) showed shearing modifications. In the group of ESD specimens fixed with nails, 5 (38%) showed shearing, 10 (77%) crushing artifacts, 11 (85%) stretching and 11 (85%) multiple holes caused by the nails. On the basis of these data all histological specimens from ESD on cellulose acetate were adequate (GAS 0-1).However, in the group of ESD fixed with nails, 1 was adequate (GAS 0), 11 suboptimal (GAS 2-5) and 1 inadequate (GAS 6). CONCLUSIONS: Specific devices including cellulose support and adequate sampling blocks can be helpful to perform accurate histological assessment of ESD specimens after en bloc ESD for precancerous/neoplastic gastrointestinal lesions, with complete analysis of the status of the margins and the entirely en bloc evaluation of the lesion.

Simultaneous Diagnosis of Acute Crohn's Disease and Endometriosis in a Patient Affects HIV.

This is the case report of a 45-year-old woman affected by HIV, who was hospitalized for diffuse abdominal pain, constipation, and weight loss present for over one month. A colonoscopy showed the presence of a nontransitable stenosis of the ascending colon. A right hemicolectomy was performed. The histological examination reports CD with outbreaks of endometriosis. CD and the HIV infection may coexist in the same individual and it seems that HIV reduces the relapse rate in IBD patients. CD and intestinal endometriosis can also occur simultaneously. The diagnosis is often only made after surgical resection of the diseased segment. These patients were more likely to have stricturing CD but endometriosis does not seem to impact the natural history of CD.

Gastric GISTs: Analysis of c-Kit, PDGFRA and BRAF mutations in relation to prognosis and clinical pathological characteristics of patients - A GIRCG study.

BACKGROUND: Gastric gastrointestinal stromal tumors (GISTs) represent a subgroup of GISTs with a better prognosis than those located in other areas. In this retrospective study we performed a molecular characterization of a large series of patients with gastric GISTs in relation to clinical-pathological characteristics and prognosis. METHODS: DNA was extracted from paraffin-embedded sections from 221 gastric GIST patients submitted to surgery. Exons 9, 11, 13 and 17 of KIT, exons 12 and 18 of PDGFRA and exons 11 and 15 of BRAF were analyzed by direct sequencing. Cox regression analysis adjusted for clinical-pathological factors was performed to evaluate KIT and PDGFRA mutations in relation to the composite endpoint of relapse or death. RESULTS: KIT and PDGFRA mutations were observed in 119 (53.8%) and 56 (25.3%) patients, respectively, whereas 46 (20.8%) patients had wild type (wt) disease. Univariable analyses showed that a high Miettinen risk category and the presence of ulceration and KIT deletions were associated with increased risk of relapse or death (p < 0.001; p = 0.0389 and p = 0.002, respectively). After adjusting for Miettinen risk score, KIT deletions remained an independent prognostic factor (HRadj = 2.65, 95% CI [1.15-6.13], p = 0.023). Moreover, KIT deletions in exon 11 codons 557, 558 or 559 were associated with a higher risk of relapse or death than wt tumors (HRadj = 3.29 95% CI [1.64-6.64], p = 0.001). CONCLUSIONS: KIT deletions in exon 11, especially those involving codons 557, 558 or 559, were correlated with a more aggressive gastric GIST phenotype and increased risk of relapse or death.

The aged gut in inflammatory bowel diseases.

Senescence is accompanied by various anatomical and functional alterations starting from mastication and deglutition and consequent modifications of nutrition. In addition, the widespread use of proton pump inhibitors and non-steroidal anti-inflammatory drugs in aged subjects weakens the gastric barrier, thus contributing to easier entry of microbes into the gastrointestinal tract. The microbiota of the elderly is less stable than that of younger adults, therefore, gut dysbiosis is more frequent. Dysbiosis represents a key factor for infections, e.g. Clostridium difficile, especially after antibiotic treatment, but also represents an important step for the development of inflammatory bowel diseases (IBD). IBD onset in the elderly needs careful evaluation in order to distinguish this entity from other pathologies that may affect the gut in senescence. Colitis associated with diverticula, drug-induced, ischemic, and microscopic colitides are among the possible diseases and, therefore, a careful macroscopic and histologic evaluation is mandatory. Finally, late onset IBD represents an important challenge for physicians since it occurs in subjects with frequent comorbidities and relative concomitant treatments. Although there is some evidence that disease course of elderly-onset IBD follows a milder course, overall morbidity, hospitalization rates and even mortality, the latter mostly due to comorbidities, are increased, especially in emergency settings.

Randomised clinical study: gluten challenge induces symptom recurrence in only a minority of patients who meet clinical criteria for non-coeliac gluten sensitivity.

BACKGROUND: It is unknown whether symptoms in non-coeliac patients (non-CD) meeting clinical diagnostic criteria for noncoeliac gluten sensitivity (NCGS) are specifically triggered by gluten. AIM: To assess gluten sensitivity in patients diagnosed with NCGS. METHODS: We studied 35 non-CD subjects (31 females) that were on a gluten-free diet (GFD), in a double-blind challenge study. Participants were randomised to receive either gluten-containing flour or gluten-free flour for 10 days, followed by a 2-week washout period and were then crossed over. The main outcome measure was their ability to identify which flour contained gluten. Secondary outcome measures were based upon Gastrointestinal Symptoms Rating Scale (GSRS) scores. RESULTS: The gluten-containing flour was correctly identified by 12 participants (34%), who were classified as having NCGS. Their mean GSRS dimension scores were significantly higher following gluten challenge compared to baseline. The scores were: pain, 1.7 ± 0.8 vs. 2.6 ± 1.0; reflux, 1.6 ± 0.5 vs. 2.2 ± 0.9; indigestion, 1.9 ± 0.7 vs. 3.2 ± 1.1; diarrhoea, 1.6 ± 0.7 vs. 2.9 ± 1.5 and constipation, 1.9 ± 0.9 vs. 2.9 ± 1.3. Seventeen participants (49%) erroneously considered the gluten-free flour to contain gluten. Their mean GSRS dimension scores were significantly higher following gluten-free flour challenge compared to baseline. The scores were: pain, 1.6 ± 0.9 vs. 3.0 ± 0.9; reflux, 1.4 ± 0.5 vs. 2.3 ± 1.1; indigestion, 2.0 ± 1.1 vs. 3.7 ± 1.1; diarrhoea, 1.6 ± 0.7 vs. 3.0 ± 1.2 and constipation, 1.6 ± 0.9 vs. 2.6 ± 1.3. The other six participants (17%) were unable to distinguish between the flours. CONCLUSION: Double-blind gluten challenge induces symptom recurrence in just one-third of patients fulfilling the clinical diagnostic criteria for non-coeliac gluten sensitivity.

Symptomatic sensorineural hearing loss in patients with ulcerative colitis.

BACKGROUND: Sensorineural hearing loss has been reported as an extraintestinal manifestation of inflammatory bowel disease, especially in adult patients with ulcerative colitis. However, to date only a few series have been reported in the literature, and none from Italy. The aim of the present investigation was to assess the prevalence of symptomatic sensorineural hearing loss in Italian patients with ulcerative colitis. METHODS: We retrospectively assessed the charts of all patients with ulcerative colitis who underwent otolaryngologic investigation in a 10-year period. RESULTS: Complete charts of 57 patients were available for the observation period. Reasons for head and neck investigation were transient, mild hearing loss and sporadic vertigo. Clinical and instrumental head and neck examination was unremarkable in all but one woman who complained of mild hearing loss without vertigo or tinnitus, in whom sensorineural hearing loss was diagnosed. CONCLUSIONS: In our series, sensorineural hearing loss was found in less than 2 % of adult patients with ulcerative colitis evaluated in a department of otolaryngology. Systematic evaluation for this extraintestinal manifestation should not be carried out unless hearing loss is present.

Celiac disease, non-celiac gluten sensitivity and inflammatory bowel disease.

Celiac disease (CD) and inflammatory bowel disease (IBD), such as Crohn's disease (CrD) and ulcerative colitis (UC), are chronic inflammatory condition of the gastro-intestinal tract. The prevalence of IBD in celiac patients has been reported as 5-10 times higher than in the general population. The possibility of the presence of CD in IBD should be considered in IBD patients with long-term iron deficiency anemia (IDA) not responsive to iron supplementation. Non-celiac gluten sensitivity (NCGS) is characterized by intestinal and extra intestinal symptoms due to the ingestion of gluten-containing food in subject without CD and/or wheat allergy. Patients with Crohn's disease and SR-NCGS were more significantly affected by joint pains compared to UC patients (50% versus 11.1%). In Crohn's patients, a higher percentage of fatigue (50% versus 38.9%) and headache (27.3% versus 22.2%) was evident. For the association between NCGS and IBD new studies are warranted and, at this moment, a gluten free diet (GFD) may be useful more in CrD than in UC.