Flaminia Cavallaro

Microscopic Colitis and Colorectal Neoplastic Lesion Rate in Chronic Nonbloody Diarrhea: A Prospective, Multicenter Study

Background:Lymphocytic and collagenous colitis are emerging as common findings in subjects undergoing colonoscopy for chronic non-bloody diarrhea (CNBD). Data concerning microscopic colitis (MC) are still limited and affected by controversial epidemiological evidences. Recent converging lines of evidence suggest that MC correlates a lower risk of colorectal neoplasia. Accordingly, we prospectively assessed MC prevalence in a multicenter cohort of subjects submitted to colonoscopy for CNBD, thereby defining whether MC influences the risk of colorectal neoplasia. Methods:Consecutive patients with CNBD of unknown origin underwent pan-colonoscopy with multiple biopsies. The prevalence of neoplastic patients in MC was compared with that observed in negative CNBD subjects. Results:Among 8006 colonoscopy, 305 subjects were enrolled for CNBD. Patients with CNBD were more likely to be women than men (odds ratio = 1.5; P = 0.001). Histopathology detected high prevalence of MC (16%) with a clear predominance of collagenous colitis (70%). A striking age-dependent rise in MC-associated risk was observed, depicting outstanding differences among varying age groups, as in the number needed to screen 1 new case. Gender distribution was balanced within MC patients (Female/Male = 1.5/1), especially among lymphocytic colitis (Female/Male = 1.2/1). MC patients were negatively associated with the risk of neoplastic polyps compared with negative CNBD subjects (odds ratio = 0.22; P = 0.035). Conclusions:MC is the first cause of CNBD in subjects submitted to colonoscopy. Multiple biopsies are strongly recommended, even in the case of uneventful endoscopic inspection, especially for age ≥40 years. MC has a reduced risk of colorectal neoplasia, suggesting that this model of chronic inflammation plays a protective effect against colorectal carcinogenesis.

Resistance to thrombomodulin is associated with de novo portal vein thrombosis and low survival in patients with cirrhosis

Portal vein thrombosis (PVT) is frequently observed in cirrhosis and may be a clinically important complication. In vitro assays for endogenous thrombin potential (ETP) demonstrated that in cirrhosis plasma has intrinsic resistance to the anticoagulant action of thrombomodulin (TM‐R). This study retrospectively explores the association of TM‐R with de novo PVT and its clinical impact on cirrhosis.

Butyric acid: pharmacological aspects and routes of administration

Abstract Butyric acid is an organic acid containing 4 carbon atoms and is produced in the large intestine through fermentation by the intestinal bacterial flora of undigested sugars and dietary fibre. It is considered the most important source of energy for colonic cells; in addition, it exerts numerous anti-inflammatory effects while regulating proliferation of colonocytes and absorption of water and electrolytes. Many intestinal diseases are characterised by reduced concentrations of butyric acid in the colon and drugs that successfully prevent oxidation have been shown to be effective in the treatment of chronic inflammatory intestinal diseases.

Extensive small-bowel Crohn’s disease detected by the newly introduced 360° panoramic viewing capsule endoscopy system

Chronic, nonbloody diarrhea may represent a diagnostic challenge in patients with inconclusive findings after standard clinical work-up [1]. In this setting, smallbowel capsule endoscopy (SBCE) has high sensitivity and a favorable clinical impact in assessing the presence of small-bowel mucosal lesions in patients with suspected Crohn’s disease and no obstructive symptoms [1–3]. Very recently, the CapsoCam SV-1 (CapsoVision, Inc. Saratoga, California, USA) has been introduced as a new standard in SBCE. The system allows lateral panoramic 360° viewing with wire-free technology, longlasting battery life, and 12–20 frames per second captured by four highresolution cameras located on the capsule sides and facing the four quadrants of the digestive wall [4,5]. To the best of our knowledge, there is no published report on the use of this new technique in patients with suspected small-bowel Crohn’s disease. Here, the case of a 51year-old woman with a 2-year history of chronic, nonbloody diarrhea is presented. Physical examination was unremarkable and laboratory parameters were within the reference ranges, with the exception

Do antibodies have a role in IBD pathogenesis

The presence of several types of antibodies in the sera of inflammatory bowel disease (IBD) patients is 1 of several findings suggesting the immune-mediated nature of both Crohn’s disease (CD) and ulcerative colitis (UC). The first detection of such a reactivity emerged in the late 1950s with the report of autoantibodies against colonic epithelial cells in UC patients.1 Since then, several types of antibodies have been shown to react with a vast array of antigens, including microbial as well as autoantigens from intestinal or extraintestinal structures. Many studies have been performed that were mainly aimed at evaluating the possible use of these antibodies as a noninvasive diagnostic tool or as a means to detect distinct clinical subsets of patients with particular phenotypic or prognostic profiles. Fewer efforts have been devoted to understanding the possible role of such antibodies in the pathogenesis of IBD. Among the circulating antibodies detected in IBD, the most studied are those directed toward some specific intestinal epithelial antigens (ECAC and TM-5), a yet undefined nuclear antigen of neutrophils (p-ANCA), and mannose residues from the cell wall mannans of Saccharomyces cerevisiae (ASCA). More recently, circulating antibodies reacting with different glycans and other microbial antigens have also been reported. ECAC are intestinal goblet cell glycoproteins recognized by both circulating antibodies and mononuclear cells from IBD patients, suggesting autosensitization to these potential autoantigens. Mucosal CD3 lymphocytes inducing antibody-mediated cytotoxicity against ECAC have also been reported.2 However, further characterization of this reactivity has not been carried out, so its importance in IBD pathogenesis remains undefined. TM-5 is a colonic isoform of the cytoskeletal protein tropomyosin. Circulating and lamina propria mononuclear cell-secreted antibodies against this protein have been reported in UC but not in CD subjects. An intriguing finding related to this antigen is the observation that similar epitopes are present in skin, eye, joint, and bile ducts, all common sites of extraintestinal complications of IBD.3 This finding suggests that a crossreactive antigenic recognition might play a role in the pathogenesis of the disease and its complications. Although the observation of an activated complement and of IgG1 deposits colocalized with anti-TM-5 monoclonal antibody in intestinal epithelium would suggest a direct pathogenic role of this autoantigen–antibody reaction, its relevance in the pathogenesis of IBD is still undefined. p-ANCA (perinuclear antineutrophil cytoplasmic antibodies) are directed toward a yet undefined nuclear lamina antigen(s) of human neutrophils, different from the antigens recognized by sera of patients with vasculitis or nephritis.4 Several studies have shown that this antibody is associated with UC, where it is detected in 40%–80% of the patients,5 whereas in CD it is observed in a smaller proportion of patients (5%–15%), particularly those with a UC-like disease pattern. However, very few studies have addressed their possible pathogenic role, and most have produced negative results. In particular, contrary to what is observed with vasculitis associated p-ANCA, IgG from p-ANCA-positive UC patients were not able to activate neutrophil respiratory burst.6 This, together with the observation that 20%–50% of UC patients develop in the absence of the antibody, suggests that p-ANCA does not play a prominent role in the pathogenesis of the disease. Anti-Saccharomyces cerevisiae antibodies (ASCA) are associated with CD, where they are observed in up to 68% of the patients.5 Since they are directed against the cell wall mannan of S. cerevisiae, they cannot be considered a true autoantigen. Although they may be observed in association with increased intestinal permeability, a putative pathogenetic mechanism of CD, their direct role in the mechanism of disease appears unlikely. The sensitivity of this antibody is quite poor, in fact, 30%–50% of CD patients do not have ASCA. Thus, despite both pANCA and ASCA being specific markers of UC and CD, respectively,5 and seemingly predicting the development of the disease years before the onset, as shown in a Jewish cohort of patients,7 their low prevalence in affected subjects does not support the hypothesis of their primary involvement in IBD pathogenesis. Interestingly, the seroreactivity against oligosaccharides appears to be a preeminent feature of CD. In fact, recently each component of a wide panel of anti-glycan antibodies has been tested for its association with IBD; among these, antibodies anti-laminaribioside (ALCA), antichitobioside (ACCA), anti-mannobioside (AMCA) and against a mannan epitope of S. cerevisiae (gASCA) displayed a high specificity for CD; furthermore, some data suggest that From the IRCCS Policlinico San Donato Hospital & University of Milan, Milan, Italy. Copyright

Thulium laser in interventional endoscopy: animal and human studies

Background and study aims The thulium laser system (TLS) is an emerging surgical tool. The 2-μm wavelength provides a confined coagulation depth (0.2 - 0.4 mm) to reduce the potential for inadvertent injuries. For the first time ever, we assessed TLS feasibility for endoscopic hemostasis ex vivo in pigs. In addition, we performed the first in vivo hemostatic treatments in humans. Patients and methods Tissue damage induced by TLS using different settings and optical fibers was compared to that from argon plasma coagulation (APC) in established ex vivo animal models. Three consecutive patients with complex nonvariceal upper gastrointestinal bleedings were treated and followed up. Results No deep submucosal injury was observed in animal models. The TLS showed a progressive penetration depth with increased power outputs and tissue exposures but very limited vertical tissue injury (0.1 - 2.0 mm) and lateral spreading damage (0.1 - 0.3 mm and 0.2 - 0.7 mm using the 365-µm and 550-µm fibers, respectively). In vivo, endoscopic hemostasis with TLS was always successful without complications. Conclusions The TLS has proven to be very precise and easy to use. This novel technique appears to be a promising tool for advanced interventional endoscopy.

Anti-TNF-Mediated Modulation of Prohepcidin Improves Iron Availability in Inflammatory Bowel Disease, in an IL-6-Mediated Fashion

Background. Anaemia is common in inflammatory bowel disease (IBD), frequently resulting from a combination of iron deficiency and of anaemia of chronic disease (ACD). ACD is characterized by macrophage iron retention induced by proinflammatory cytokines. Hepcidin is the master inducer of iron accumulation during ACD, and its production is mainly regulated by IL-6 and the novel erythroid hormone erythroferrone (ERFE). This study evaluates whether anti-TNF monoclonal antibodies therapy modurates hepcidin production and the levels of its main regulators, leading to a restoration of iron homeostasis. Methods. Sera were collected from 21 IBD patients, before each anti-TNF administration, for the first 6 weeks of therapy. Prohepcidin, erythropoietin, erythroferrone, C reactive protein, interleukin-6, iron markers, and haemoglobin levels were measured and clinical activity indexes were evaluated. Results. Serum prohepcidin, IL-6, CRP, and ferritin were significantly reduced after 6-week treatment; an increase in serum iron and total transferrin was observed. No changes in the EPO-ERFE axis were found. Remarkably, haemoglobin was significantly increased. Conclusions. Anti-TNF therapy improves iron metabolism and, subsequently, anaemia in IBD. This effect appears to be related to the modulation of the cytokine network and specifically IL-6 leading to a relevant decrease of hepcidin, a master regulator of ACD.

Predictors of Psychopathological Outcome During Peg-Interferon and Ribavirin Therapy in Patients with Chronic HCV-Correlated Hepatitis

Peg-interferon (Peg-IFN) and ribavirin (RBV) therapy is reported to induce psychiatric symptoms and syndromes in 20% of patients treated for Hepatitis C Virus (HCV) infection. Present study was aimed to quantify the phenomenon and assess the influence of psychiatric counseling over antiviral completion rate and the use of psychometric tools, in terms of prediction of psychopathological outcome. Ninety-six HCV patients were assessed, before antiviral treatment, by means of the Sheehan Disability Scale (SDS), Mood Disorder Questionnaire (MDQ), Symptom Checklist-90, and Internal State Scale (ISS). Sociodemographic and clinical variables and completion rate were collected. Binary logistic regression was performed to evaluate whether scores were predictive of psychiatric visit, development of psychiatric disorders, and need for treatment. Ninety-five patients (99%) completed antiviral treatment; 27 subjects (29%) needed psychiatric visit: among them, mood disorder was diagnosed in 15 (16%) and were pharmacologically treated. Baseline SDS and MDQ higher scores were found to be predictive of psychiatric visit [odds ratio (OR)=1.258, P<0.001 and OR=1.425, P=0.05, respectively]. Furthermore, higher MDQ score (P=0.017) and ISS hostility scores (OR=1.048, P=0.014) at baseline predicted the subsequent development of mood episodes, while ISS activation correlated negatively (OR=0.948, P=0.009). Finally, the need for treatment was predicted by higher scores at the MDQ and ISS activation items (OR=2.467, P=0.030; OR=0.970, P=0.038). Present findings suggest that psychiatric counseling may be needed in almost 30% of HCV patients on antiviral treatment, with positive influence over the completion rate. Baseline higher scores at psychometric questionnaires-MDQ-in particular, predictors of psychopathological outcome during Peg-IFN and RBV therapy in patients with chronic HCV-correlated hepatitis reflecting individual functioning before starting antiviral therapy and positive history for mood disorders, seem to predict psychiatric visit, onset of mood episodes, and need for psychopharmacological treatment. Further investigation is warranted to confirm results.

The role of wireless capsule endoscopy (WCE) in the detection of occult primary neuroendocrine tumors

BACKGROUND AND AIMS Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms with unclear etiology that may show functioning or non-functioning features. Primary tumor localization often requires integrated imaging. The European Neuroendocrine Tumors Society (ENETS) guidelines proposed wireless-capsule endoscopy (WCE) as a possible diagnostic tool for NETs, if intestinal origin is suspected. However, its impact on therapeutic management is debated. We aimed to evaluate the yield of WCE in detecting intestinal primary tumors in patients showing liver NET metastases when first-line investigations are inconclusive. METHOD Twenty-four patients with a histological diagnosis of metastatic NET from liver biopsy and no evidence of primary lesions at first-line investigations were prospectively studied in an ENETS-certified tertiary care center. Wireless-capsule endoscopy was requested before explorative laparotomy and intra-operative ultrasound. The diagnostic yield of WCE was compared to the surgical exploration. RESULTS Sixteen subjects underwent surgery; 11/16 had positive WCE identifying 16 bulging lesions. Mini-laparotomy found 13 NETs in 11/16 patients (9 small bowel, 3 pancreas, 1 bile ducts). Agreement between WCE and laparotomy was recorded in 9 patients (Sensitivity=75%; Specificity=37.5%; PPV=55%; NPV=60%). Correspondence assessed per-lesions produced similar results (Sensitivity=70%; Specificity=25%; PPV=44%; NPV=50%). No capsule retentions were recorded. CONCLUSIONS Wireless-capsule endoscopy is not indicated as second-line investigation for patients with gastro-entero-pancreatic NETs. In the setting of a referral center, it might provide additional information when conventional investigations are inconclusive about the primary site.

Feasibility, Safety and Diagnostic Yield of Omom Ce, a New Capsule Endoscopy System: The First Experience in Caucasian Patients

Small bowel evaluation has been considered for a long time technically challenging because of its length, location and tortuosity. But in 2001, with the FDA approval of capsule endoscopy started a revolution in the study of small bowel that, in the last years, has progressively and rapidly expanded [1-5]. Nevertheless, one of the main limitations to the spread of capsule endoscopy is the high cost and therefore a questionable cost-effectiveness when used in clinical practice. Lately the picture could change to the introduction in the European of a new video capsule system (OMOM CE) produced by Jinshan Science & Technology Company (Chongqing, China) [6, 7]; this device has and obtained the CE mark for marketing in Europe. Indeed, this device costs approximately half the other capsule systems. However, to date only few studies have been performed on the use in clinical practice of this new video capsule system, and none of them was carried out in the western world.