Guanylate cyclase-C as a therapeutic target in gastrointestinal disorders Gut (IF 16.658) Pub Date : 2018-03-21 Scott A Waldman, Michael Camilleri
Functional gastrointestinal disorders (FGIDs) and IBDs are two of the most prevalent disorders of the GI tract and consume a significant proportion of healthcare resources. Recent studies have shown that membrane-bound guanylate cyclase-C (GC-C) receptors lining the GI tract may serve as novel therapeutic targets in the treatment of FGIDs and IBDs. GC-C receptor activation by its endogenous paracrine hormones uroguanylin and guanylin, and the resulting intracellular production of its downstream effector cyclic GMP, occurs in a pH-dependent manner and modulates key physiological functions. These include fluid and electrolyte homeostasis, maintenance of the intestinal barrier, anti-inflammatory activity and regulation of epithelial regeneration. Studies of the GC-C paracrine signalling axis have revealed the therapeutic potential of these receptors in treating GI disorders, including chronic idiopathic constipation and irritable bowel syndrome–constipation. This review focuses on the evolving understanding of GC-C function in health and disease, and strategies for translating these principles into new treatments for FGIDs and IBDs.
Endoscopic submucosal dissection or endoscopic mucosal resection for large colorectal laterally spreading lesions? Scientific and economic data are still lacking Gut (IF 16.658) Pub Date : 2018-03-21 Jérémie Jacques, Stanislas Chaussade, Thierry Ponchon, Emmanuel Coron, Vincent Lepilliez, Martin Dahan, Jeremie Albouys, Denis Sautereau, Sarah Leblanc, Gabriel Rahmi, Romain Legros, Mathieu Pioche
We read with great interest the paper of Bahin et al comparing piecemeal endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) for large colorectal laterally spreading lesions (LSLs) from a medico-economic point of view.1 Since the expanded use of ESDs in Japan that began in the early 2000s, a debate still persists in Western countries about the absolute need for en bloc resection of large colorectal lesions with a low risk of submucosal cancer.2 3 ESDs are associated with a high en bloc resection rate, low risk of recurrence and perfect pathological analysis.4 Defenders of piecemeal EMR point out the higher risk of ESD, the long duration of procedures, the discrepancies between Eastern and Western series, and the low proportion of lesions with superficial submucosal cancer.5 They also point out the good results of wide-field (WF)-EMR for complete eradication even when several sessions are needed.6 Economic reasons are not often mentioned, although they could be considered …
Markers of non-coeliac wheat sensitivity in patients with myalgic encephalomyelitis/chronic fatigue syndrome Gut (IF 16.658) Pub Date : 2018-03-17 Melanie Uhde, Alyssa C Indart, Xuechen B Yu, Sophie S Jang, Roberto De Giorgio, Peter H R Green, Umberto Volta, Suzanne D Vernon, Armin Alaedini
We recently reported in Gut that non-coeliac wheat sensitivity (NCWS) is associated with a state of systemic immune activation in conjunction with a compromised intestinal epithelium.1 Patients with NCWS experience GI symptoms, most commonly including abdominal pain and bloating, as well as extraintestinal symptoms, among which fatigue, headache and cognitive difficulties feature prominently.1 2 A principal component analysis of the generated data from our study, including markers of antibody reactivity to wheat gluten, intestinal cell damage and systemic innate and adaptive immune responses to microbial components, found clustering of the patients and controls into discernible groups and demonstrated the potential utility of the identified biomarkers for identifying patients with NCWS.1 Extreme fatigue, in particular one that does not improve with rest, is a hallmark of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).3 Immune system abnormalities have been found to be associated with symptoms in a substantial number of patients with ME/CFS.4 5 Furthermore, many patients complain of GI symptoms of unknown aetiology. …
Hypertriglyceridaemia delays pancreatic regeneration after acute pancreatitis in mice and patients Gut (IF 16.658) Pub Date : 2018-03-16 Na Yang, Baiqiang Li, Yiyuan Pan, Jianfeng Tu, George Liu, Guotao Lu, Weiqin Li
We read with great interest the recent publication by Barlass et al in which morphine was demonstrated to aggravate the severity of acute pancreatitis (AP) and delay pancreatic regeneration. These results indicated the risk of morphine use in AP-associated pain treatment.1 Similar to their observation, we found another interesting phenomenon that hypertriglyceridaemia (HTG), a prevalent metabolic disorder, delayed pancreatic regeneration after AP in mice and patients. Moreover, the delayed regeneration process could be ameliorated by lipid-lowering therapy. Two models of HTG (drug induced: poloxamer 407 (P407) and gene modified: glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) deficiency) were employed to explore the effect of HTG on AP repair. AP induced by caerulein infusion in both normal triglyceride (NTG) mice and HTG mice caused pancreatic acinar cell necrosis. The injured pancreas was reconstructed in 3 days and recovered its normal architecture in 7 days in the NTG mice (figure 1A–C). However, we observed reduced morphological recovery in the HTG mice, especially in the severe HTG mice that presented with prolonged necrosis until 7 days (figure 1A–C, online supplementary figures 1–3). Furthermore, the key cellular responses involved in AP repair, including the fibroinflammatory response and acinar cell proliferation,2 were significantly delayed in the HTG mice (online supplementary figures 4–6). The above results …
Diagnosis of hepatocellular carcinoma with MRI Gut (IF 16.658) Pub Date : 2018-03-16 Martin H Maurer
In most cases, hepatocellular carcinoma (HCC) is associated with a known underlying risk factor like chronic viral hepatitis type B and C or alcoholic cirrhosis.1 Patients with chronic liver disease that are at risk for HCC should undergo surveillance ultrasound examinations every 6 months and dynamic cross-sectional imaging like CT and MRI if a detected hepatic nodule exceeds 1 cm in size.2 The established radiological hallmarks for diagnosing HCC non-invasively by imaging—strong contrast uptake in the arterial phase in conjunction with washout in the venous or later phases of dynamic contrast-enhanced studies—as proposed in practice guidelines of different specialised societies (eg, American Association for the Study of the Liver (AASLD) and European Association for the Study of the Liver (EASL) have not been changed for many years.3 Although these imaging features have proven to be very robust with specificities close to 100% even in detecting HCC lesions as small as 1–2 cm in size, their sensitivities continue to be unsatisfactorily low at around 70%.2 4 In this context, comparison of the two cross-sectional imaging modalities MRI and multidetector CT has shown MRI to have a better diagnostic accuracy than CT for detecting HCC.5 An extensive meta-analysis comparing the two imaging modalities on a per-lesion basis showed the sensitivity of MRI for detecting …
Lipid-rich environment: a key role promoting carcinogenesis in obesity-related non-alcoholic fatty liver disease Gut (IF 16.658) Pub Date : 2018-03-14 Patricia Aspichueta
The epidemic of obesity has led to increased risk of many types of cancer including hepatocellular carcinoma (HCC).1 HCC is the most frequent presentation of liver cancer, the fifth most common cancer in men worldwide and the seventh in women.2 Even though viral and alcohol-related liver diseases are main causes of HCC, non-alcoholic fatty liver disease (NAFLD) has become the most rapidly increasing cause during the last decade.1 Even more, HCC may also develop in the absence of liver cirrhosis, and the incidence in livers without fibrosis is higher in the metabolic syndrome and NAFLD.1 According to data from the Surveillance, Epidemiology and End Results registries (2004–2009), in the USA, NAFLD-driven HCC is associated with shorter survival time and more advanced tumour stage.3 Besides, although numerous drugs have been proposed, there is still no available treatment for most patients with HCC.4 Thus, there is a need to understand the mechanism involved in NAFLD-driven HCC to provide new targets of treatment. A hallmark of NAFLD and HCC is the disrupted lipid metabolism. Fujiwara et al 5 provide a new mechanism that links lipid accumulation with carcinogenesis in …
Re: Cumulative burden of inflammation predicts colorectal neoplasia risk in ulcerative colitis: a large single-centre study Gut (IF 16.658) Pub Date : 2018-03-13 Yoshinaga Okugawa, Yuji Toiyama, Masato Kusunoki, Ajay Goel
In a recent issue of the journal, Choi1 and colleagues have assessed cumulative inflammatory burden (CIB) using endoscopic and histological findings from surveillance colonoscopy, and for the first time have revealed that CIB was significantly associated with the development of colorectal neoplasia (CRN) in patients with UC. This study is an elegant article and very meaningful from a clinical standpoint because the mean severity of microscopic inflammation derived from all surveillance procedures performed in the last decade has suggested it to be an important predictive biomarker for risk stratification of CRN in patients with UC. However, we would like to draw attention to a few important issues related to this very interesting article. First, the authors evaluated endoscopic and histological inflammatory scores from the most extreme degree …
Novel device for measuring polyp size: an ex vivo animal study Gut (IF 16.658) Pub Date : 2018-03-13 Omer Goldstein, Ori Segol, Seth A Gross, Harold Jacob, Peter D Siersema
In situ assessment of polyp size during colonoscopy is of clinical importance for optimal treatment and follow-up. In this initial study, we evaluated the accuracy and usability of a virtual tape measure, a novel device providing quantitative measurements, as compared with current practice of unassisted assessment and using biopsy forceps as scale. The virtual tape-measure prototype was shown to provide submillimetre accuracy, almost an order of magnitude better than current practice. It has the potential of becoming the standard for quantitative in situ polyp size measurement; however, further studies in a clinical setting are needed. In colonoscopy, there is clinical importance for in situ assessment of polyp size.1 To date, no commercially available medical endoscope has the capability of performing measurements. There are several mechanical devices designed to perform these measurements, such as a calibrated hood2 and a ruler snare,3 but these are mainly used in research, as they are limited in their capacity and are difficult to operate. Therefore, in current practice, endoscopist estimates are based on acquired expertise and/or an approximate scale (eg, using biopsy forceps), leading to a large …
Providing safe, efficient and affordable sedation in endoscopy Gut (IF 16.658) Pub Date : 2018-03-09 Barbara Braden, Alissa Walsh
We compliment the authors of the ProSed 2 Study1 for their large-scale analysis on the safety of sedation in endoscopic procedures. The vast majority of the over 300 000 endoscopies in this study have been performed under propofol sedation administered by the endoscopic team and only 0.2% were supported by an anaesthetist. In Germany and many other European countries, propofol is routinely administered by the endoscopist or trained endoscopy nurse according to clearly defined standards as set out in the European or German guidelines.2 3 Propofol sedation administered by non-anaesthetists is even practised widely in doctors’ surgeries with endoscopy facilities. Currently, according to recommendations of a working party of the Royal College of Anaesthetists …
Whole grain-rich diet reduces body weight and systemic low-grade inflammation without inducing major changes of the gut microbiome: a randomised cross-over trial Gut (IF 16.658) Pub Date : 2018-03-09 Henrik Munch Roager, Josef K Vogt, Mette Kristensen, Lea Benedicte S Hansen, Sabine Ibrügger, Rasmus B Mærkedahl, Martin Iain Bahl, Mads Vendelbo Lind, Rikke L Nielsen, Hanne Frøkiær, Rikke Juul Gøbel, Rikard Landberg, Alastair B Ross, Susanne Brix, Jesper Holck, Anne S Meyer, Morten H Sparholt, Anders F Christensen, Vera Carvalho, Bolette Hartmann, Jens Juul Holst, Jüri Johannes Rumessen, Allan Linneberg, Thomas Sicheritz-Pontén, Marlene D Dalgaard, Andreas Blennow, Henrik Lauritz Frandsen, Silas Villas-Bôas, Karsten Kristiansen, Henrik Vestergaard, Torben Hansen, Claus T Ekstrøm, Christian Ritz, Henrik Bjørn Nielsen, Oluf Borbye Pedersen, Ramneek Gupta, Lotte Lauritzen, Tine Rask Licht
Objective To investigate whether a whole grain diet alters the gut microbiome and insulin sensitivity, as well as biomarkers of metabolic health and gut functionality. Design 60 Danish adults at risk of developing metabolic syndrome were included in a randomised cross-over trial with two 8-week dietary intervention periods comprising whole grain diet and refined grain diet, separated by a washout period of ≥6 weeks. The response to the interventions on the gut microbiome composition and insulin sensitivity as well on measures of glucose and lipid metabolism, gut functionality, inflammatory markers, anthropometry and urine metabolomics were assessed. Results 50 participants completed both periods with a whole grain intake of 179±50 g/day and 13±10 g/day in the whole grain and refined grain period, respectively. Compliance was confirmed by a difference in plasma alkylresorcinols (p<0.0001). Compared with refined grain, whole grain did not significantly alter glucose homeostasis and did not induce major changes in the faecal microbiome. Also, breath hydrogen levels, plasma short-chain fatty acids, intestinal integrity and intestinal transit time were not affected. The whole grain diet did, however, compared with the refined grain diet, decrease body weight (p<0.0001), serum inflammatory markers, interleukin (IL)-6 (p=0.009) and C-reactive protein (p=0.003). The reduction in body weight was consistent with a reduction in energy intake, and IL-6 reduction was associated with the amount of whole grain consumed, in particular with intake of rye. Conclusion Compared with refined grain diet, whole grain diet did not alter insulin sensitivity and gut microbiome but reduced body weight and systemic low-grade inflammation. Trial registration number [NCT01731366]; Results. : /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01731366&atom=%2Fgutjnl%2Fearly%2F2018%2F03%2F08%2Fgutjnl-2017-314786.atom
Global elimination of viral hepatitis and hepatocellular carcinoma: opportunities and challenges Gut (IF 16.658) Pub Date : 2018-04-01 Chien-Jen Chen
The most common causes of hepatitis worldwide is a group of viruses known as hepatitis A, B, C, D and E virus. Most deaths from viral hepatitis are due to hepatitis B and hepatitis C. Globally, an estimated 257 million people were living with HBV and 71 million people were living with HCV, which caused 1.34 million deaths in 2015 comparable with deaths from tuberculosis and exceeding deaths from HIV.1 Both liver cancer, mostly hepatocellular carcinoma (HCC), and cirrhosis are end-stage clinical outcomes of chronic hepatitis B (CHB) and chronic hepatitis C (CHC).2 HBV and HCV are the main causes of liver cancer worldwide, and liver cancer was the seventh commonly diagnosed cancer and the second common cause of cancer death as reported in GLOBOCAN 2012.3 There was a significant increase in global deaths from liver cancer and cirrhosis from 1990 to 2013 with a 60% increase for liver cancer and a 45% increase for cirrhosis. Such increases are mostly attributable to the increase in infection of HBV and HCV.4 The incidence of liver cancer and the prevalence of HBV and HCV infection are high in the East, Southeast and Central Asia and the sub-Saharan Africa.1–4 However, the aetiological proportion of liver cancer varies in different countries and regions. HCV is more prevalent in patients with HCC in Japan, North America and Europe, and HBV is more prevalent in patients with HCC in Taiwan, Southeast Asia and China.1 2 Around 75% of global liver cancer cases are caused by chronic HBV and HCV infection,4 and control of viral hepatitis may thus significantly reduce the burden of HCC globally. The causality of chronic HBV infection to induce HCC was reported in several cross-sectional case-control studies2 and first confirmed by the GECC cohort study in Taiwan,5 …
Minimal access necrosectomy: the newest advance of many in the treatment of necrotising pancreatitis Gut (IF 16.658) Pub Date : 2018-04-01 Michael G Sarr
This study by van Brunschott and international colleagues1 has shown that when possible in high-risk patients with severe acute necrotising pancreatitis, a minimal access approach for drainage combined with a necrosectomy, either via an operative (ie, laparoscopic like) or an endoscopic transgastric or transduodenal approach, decreases mortality of this horrible disease when compared with the classic open operation (laparotomy). These data are convincing and support the use of such minimal access approaches whenever feasible. This study reviews the data on another huge advance in our treatment and understanding of this horrific disease. In this commentary, I want to use this study as an example of the marked changes in our thinking of pancreatitis over the last 40 years. Our current approach to the treatment of necrotising pancreatitis really had its origin in the 1970s with the introduction of the new concept of an operative ‘necrosectomy’ rather than just peripancreatic drainage which at that time was designed to remove the bad humours believed to be the cause of the systemic aspects of the disease. Through the pioneering work of Beger and colleagues2 in Ulm, Germany and that of Bradley (and Stone) in Atlanta, Georgia, USA,3 a new era emerged with our thinking of this systemic inflammatory disease originating from endogenous pancreatic parenchymal necrosis and later, its superinfection. Indeed, the introduction of the importance of removing the infected necrotic tissues (necrosectomy) combined with drainage of the peripancreatic region immediately decreased the mortality of this disease …
High on drugs: lessons from opiates in pancreatitis Gut (IF 16.658) Pub Date : 2018-04-01 Vijay P Singh
The current opiate epidemic, the widespread clinical utilisation of opiates, along with the controversies that revolve around their use, mandate that we take a fresh look at the risks and benefits of this invaluable yet potentially hazardous class of drugs. Pancreatitis is a common illness in which opiates are used extensively for pain control. With the well-known overlap between the complications of acute pancreatitis and opiate use, that is, ileus and bacterial translocation, and the difficulty in identifying the underlying causality in a clinical scenario, it is appropriate that this dilemma be approached using animal models. Additionally, the recent paradigm1 that chronic pancreatitis (for which opioids may be used for long periods) evolves from recurrent acute attacks reinforces the need to weigh the risks this usage may create apart from opiate abuse. In the study entitled ‘Morphine worsens the severity and prevents pancreatic regeneration in mouse models of acute pancreatitis’, Balrass et al 2 present a clinically relevant argument of the multiple ways in which opiates may be worsening the outcomes of acute pancreatitis (AP). They postulate three mechanisms: (1) increased bacterial translocation, (2) a temporal delay in the reparative inflammatory response and (3) a delay in the regenerative response. Additionally, they note that morphine worsens pancreatic necrosis and acute inflammation in mechanistically distinct models. These effects of morphine are prevented in μ-opioid receptor knockout mice. The influence …
Deciphering the biology of IgG4-related disease: specific antigens and disease? Gut (IF 16.658) Pub Date : 2018-04-01 Debashis Haldar, Gideon M Hirschfield
Immunoglobulin G4-related disease (IgG4-RD) is the name applied to a corticosteroid and/or B-cell depletion responsive illness, in which patients present with the consequences of usually multiorgan, relapsing and remitting, fibroinflammation.1 The disease is histologically characterised by obliterative phlebitis, storiform fibrosis and a dense lymphoplasmacytic infiltrate.2 IgG4-RD is not a new disease, but is benefiting from the application of new technologies in the pursuit of better biological understanding. The histologic enrichment of IgG4-expressing plasma cells is a diagnostic hallmark of disease that additionally serves as a biological phenomenon driving scientific evaluation.3 Key disease themes have evolved to include a large clonal expansion of activated plasmablasts and CD4+ cytotoxic, inflammatory and profibrotic lymphocytes. Therapeutically, a reduced frequency of CD4+ cytotoxic lymphocytes are seen after B-cell depletion; such therapy may consequently impact on antigen presentation.4–6 To date, the activity of IgG4-RD is not readily tracked by disease biomarkers with even serum IgG4 concentration remaining an imperfect diagnostic and prognostic tool for many patients.7 IgG4 molecules have structural and functional characteristics suggesting anti-inflammatory and tolerance-inducing effects,8 9 and in IgG4-RD a reported oligoclonal reactivity to multiple antigens.4 10 In Gut , Hubers et al describe a body of work that identifies the first IgG4 autoantibody against an antigen which appears to be specific to IgG4-RD (IgG4-associated cholangitis (IAC) and autoimmune pancreatitis (AIP)), at the exclusion of its major differential diagnoses: primary sclerosing cholangitis and cholangiocarcinoma.11 The authors demonstrate that patients with IgG4-RD raise IgG1 and IgG4 in their sera that recognise a 56 kDa cytosolic protein in an immortalised cell line lysate (H69 cholangiocytes) and in human liver lysate. Both IgG1 and IgG4 antibodies recognise the same 56 kDa protein, and subsequent label-free quantitative liquid chromatography-tandem mass spectrometry analysis and immunoprecipitation identifies the cytosolic protein, Annexin A11, as the target. Annexin A11 IgG4 …
Aspirin prevents NF-κB activation and CDX2 expression stimulated by acid and bile salts in oesophageal squamous cells of patients with Barrett's oesophagus Gut (IF 16.658) Pub Date : 2018-04-01 Xiaofang Huo, Xi Zhang, Chunhua Yu, Edaire Cheng, Qiuyang Zhang, Kerry B Dunbar, Thai H Pham, John P Lynch, David H Wang, Robert S Bresalier, Stuart J Spechler, Rhonda F Souza
Objective In previous studies using oesophageal squamous cells from patients with Barrett's oesophagus (normal oesophageal squamous (NES)-B cells) and from patients without Barrett's oesophagus (NES-G cells), we showed that acid and bile salts induced caudal-related homeobox transcription factor 2 (CDX2) expression only in NES-B cells. CDX2, a transcription factor required to form intestinal epithelium, is a target of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling, which can be inhibited by aspirin. We explored mechanisms underlying differences between NES-B and NES-G cells in CDX2 expression and effects of aspirin on that CDX2 expression. Design We exposed NES-B and NES-G cells to acid and bile salts, with and without aspirin, and evaluated effects on IκB-NF-κB-PKAc complex activation, p65 NF-κB subunit function, and CDX2 expression. Results In both NES-B and NES-G cells, acid and bile salts activated nicotinamide adenine dinucleotide phosphate oxidase to generate H2O2, which activated the IκB-NF-κB-PKAc complex. NES-B cells exhibited higher levels of phosphorylated IκB and p65 and greater NF-κB transcriptional activity than NES-G cells, indicating greater IκB-NF-κB-PKAc complex activation by acid and bile salts in NES-B cells, and p65 siRNA prevented their increased expression of CDX2. Aspirin blocked IκB phosphorylation, p65 nuclear translocation, CDX2 promoter activation and CDX2 expression induced by acid and bile salts in NES-B cells. Conclusions Differences between NES-B and NES-G cells in NF-κB activation by acid and bile salts can account for their differences in CDX2 expression, and their CDX2 expression can be blocked by aspirin. These findings might explain why some patients with GORD develop Barrett's oesophagus while others do not, and why aspirin might protect against development of Barrett's oesophagus.
Are random biopsies still useful for the detection of neoplasia in patients with IBD undergoing surveillance colonoscopy with chromoendoscopy? Gut (IF 16.658) Pub Date : 2018-04-01 Driffa Moussata, Matthieu Allez, Dominique Cazals-Hatem, Xavier Treton, David Laharie, Jean-Marie Reimund, Philippe Bertheau, Arnaud Bourreille, Anne Lavergne-Slove, Hedia Brixi, Julien Branche, Jean-Marc Gornet, Carmen Stefanescu, Jacques Moreau, Philippe Marteau, Anne-Laure Pelletier, Franck Carbonnel, Philippe Seksik, Marion Simon, Jean-François Fléjou, Jean-Fréderic Colombel, Anne-Laure Charlois, Xavier Roblin, Stéphane Nancey, Yoram Bouhnik, Françoise Berger, Bernard Flourié
Background Colonoscopy with pan-chromoendoscopy (CE) is superior to standard colonoscopy in detecting neoplasia in patients with IBD. Performing random biopsies in unsuspicious mucosa after CE remains controversial. Methods Consecutive patients with IBD who underwent surveillance colonoscopy using CE were prospectively included. The standardised procedure used CE, performed targeted biopsies or endoscopic resection on suspicious lesions and then quadrant random biopsies every 10 cm. A panel of five expert pathologists reviewed histological slides with dysplasia. Logistic regression model was used to evidence the factors associated with neoplasia in any or in random biopsies. Results 1000 colonoscopes were performed in 1000 patients (495 UC, 505 Crohn's colitis). In 82 patients, neoplasia was detected from targeted biopsies or removed lesions, and among them dysplasia was detected also by random biopsies in 7 patients. Importantly, in 12 additional patients dysplasia was only detected by random biopsies. Overall, 140 neoplastic sites were found in 94 patients, 112 (80%) from targeted biopsies or removed lesions and 28 (20%) by random biopsies. The yield of neoplasia by random biopsies only was 0.2% per-biopsy (68/31 865), 1.2% per-colonoscopy (12/1000) but 12.8% per-patient with neoplasia (12/94). Dysplasia detected by random biopsies was associated with a personal history of neoplasia, a tubular appearing colon and the presence of primary sclerosing cholangitis (PSC). Conclusions Despite their low yield, random biopsies should be performed in association with CE in patients with IBD with a personal history of neoplasia, concomitant PSC or a tubular colon during colonoscopy. Trial registration number IRB 001508, Paris 7 University.
The microbiome of professional athletes differs from that of more sedentary subjects in composition and particularly at the functional metabolic level Gut (IF 16.658) Pub Date : 2018-04-01 Wiley Barton, Nicholas C Penney, Owen Cronin, Isabel Garcia-Perez, Michael G Molloy, Elaine Holmes, Fergus Shanahan, Paul D Cotter, Orla O'Sullivan
Objective It is evident that the gut microbiota and factors that influence its composition and activity effect human metabolic, immunological and developmental processes. We previously reported that extreme physical activity with associated dietary adaptations, such as that pursued by professional athletes, is associated with changes in faecal microbial diversity and composition relative to that of individuals with a more sedentary lifestyle. Here we address the impact of these factors on the functionality/metabolic activity of the microbiota which reveals even greater separation between exercise and a more sedentary state. Design Metabolic phenotyping and functional metagenomic analysis of the gut microbiome of professional international rugby union players (n=40) and controls (n=46) was carried out and results were correlated with lifestyle parameters and clinical measurements (eg, dietary habit and serum creatine kinase, respectively). Results Athletes had relative increases in pathways (eg, amino acid and antibiotic biosynthesis and carbohydrate metabolism) and faecal metabolites (eg, microbial produced short-chain fatty acids (SCFAs) acetate, propionate and butyrate) associated with enhanced muscle turnover (fitness) and overall health when compared with control groups. Conclusions Differences in faecal microbiota between athletes and sedentary controls show even greater separation at the metagenomic and metabolomic than at compositional levels and provide added insight into the diet–exercise–gut microbiota paradigm.
Bacteriophage transfer during faecal microbiota transplantation in Clostridium difficile infection is associated with treatment outcome Gut (IF 16.658) Pub Date : 2018-04-01 Tao Zuo, Sunny H Wong, Kelvin Lam, Rashid Lui, Kitty Cheung, Whitney Tang, Jessica Y L Ching, Paul K S Chan, Martin C W Chan, Justin C Y Wu, Francis K L Chan, Jun Yu, Joseph J Y Sung, Siew C Ng
Objective Faecal microbiota transplantation (FMT) is effective for the treatment of recurrent Clostridium difficile infection (CDI). Studies have shown bacterial colonisation after FMT, but data on viral alterations in CDI are scarce. We investigated enteric virome alterations in CDI and the association between viral transfer and clinical outcome in patients with CDI. Design Ultra-deep metagenomic sequencing of virus-like particle preparations and bacterial 16S rRNA sequencing were performed on stool samples from 24 subjects with CDI and 20 healthy controls. We longitudinally assessed the virome and bacterial microbiome changes in nine CDI subjects treated with FMT and five treated with vancomycin. Enteric virome alterations were assessed in association with treatment response. Results Subjects with CDI demonstrated a significantly higher abundance of bacteriophage Caudovirales and a lower Caudovirales diversity, richness and evenness compared with healthy household controls. Significant correlations were observed between bacterial families Proteobacteria , Actinobacteria and Caudovirales taxa in CDI. FMT treatment resulted in a significant decrease in the abundance of Caudovirales in CDI. Cure after FMT was observed when donor-derived Caudovirales contigs occupied a larger fraction of the enteric virome in the recipients (p=0.024). In treatment responders, FMT was associated with alterations in the virome and the bacterial microbiome, while vancomycin treatment led to alterations in the bacterial community alone. Conclusions In a preliminary study, CDI is characterised by enteric virome dysbiosis. Treatment response in FMT was associated with a high colonisation level of donor-derived Caudovirales taxa in the recipient. Caudovirales bacteriophages may play a role in the efficacy of FMT in CDI. Trial registration number [NCT02570477] : https://clinicaltrials.gov/ct2/show/NCT02570477?term=NCT02570477&rank=1
T-cell repertoires in refractory coeliac disease Gut (IF 16.658) Pub Date : 2018-04-01 Julia Ritter, Karin Zimmermann, Korinna Jöhrens, Stefanie Mende, Anke Seegebarth, Britta Siegmund, Steffen Hennig, Kremena Todorova, Andreas Rosenwald, Severin Daum, Michael Hummel, Michael Schumann
Objective Refractory coeliac disease (RCD) is a potentially hazardous complication of coeliac disease (CD). In contrast to RCD type I, RCD type II is a precursor entity of enteropathy-associated T-cell lymphoma (EATL), which is associated with clonally expanding T-cells that are also found in the sequentially developing EATL. Using high-throughput sequencing (HTS), we aimed to establish the small-intestinal T-cell repertoire (TCR) in CD and RCD to unravel the role of distinct T-cell clonotypes in RCD pathogenesis. Design DNA extracted from duodenal mucosa specimens of controls (n=9), active coeliacs (n=10), coeliacs on a gluten-free diet (n=9), RCD type I (n=8), RCD type II (n=8) and unclassified Marsh I cases (n=3) collected from 2002 to 2013 was examined by TCRβ-complementarity-determining regions 3 (CDR3) multiplex PCR followed by HTS of the amplicons. Results On average, 106 sequence reads per sample were generated consisting of up to 900 individual TCRβ rearrangements. In RCD type II, the most frequent clonotypes (ie, sequence reads with identical CDR3) represent in average 42.6% of all TCRβ rearrangements, which was significantly higher than in controls (6.8%; p<0.01) or RCD type I (6.7%; p<0.01). Repeat endoscopies in individual patients revealed stability of clonotypes for up to several years without clinical symptoms of EATL. Dominant clonotypes identified in individual patients with RCD type II were unique and not related between patients. CD-associated, gliadin-dependent CDR3 motifs were only detectable at low frequencies. Conclusions TCRβ-HTS analysis unravels the TCR in CD and allows detailed analysis of individual TCRβ rearrangements. Dominant TCRβ sequences identified in patients with RCD type II are unique and not homologous to known gliadin-specific TCR sequences, supporting the assumption that these clonal T-cells expand independent of gluten stimulation.
Acute lower GI bleeding in the UK: patient characteristics, interventions and outcomes in the first nationwide audit Gut (IF 16.658) Pub Date : 2018-04-01 Kathryn Oakland, Richard Guy, Raman Uberoi, Rachel Hogg, Neil Mortensen, Michael F Murphy, Vipul Jairath
Objective Lower GI bleeding (LGIB) is a common reason for emergency hospital admission, although there is paucity of data on presentations, interventions and outcomes. In this nationwide UK audit, we describe patient characteristics, interventions including endoscopy, radiology and surgery as well as clinical outcomes. Design Multicentre audit of adults presenting with LGIB to UK hospitals over 2 months in 2015. Consecutive cases were prospectively enrolled by clinical teams and followed for 28 days. Results Data on 2528 cases of LGIB were provided by 143 hospitals. Most were elderly (median age 74 years) with major comorbidities, 29.4% taking antiplatelets and 15.9% anticoagulants. Shock was uncommon (58/2528, 2.3%), but 666 (26.3%) received a red cell transfusion. Flexible sigmoidoscopy was the most common investigation (21.5%) but only 2.1% received endoscopic haemostasis. Use of embolisation or surgery was rare, used in 19 (0.8%) and 6 (0.2%) cases, respectively. 48% patients underwent no inpatient investigations. The most common diagnoses were diverticular bleeding (26.4%) and benign anorectal conditions (16.7%). Median length of stay was 3 days, 13.6% patients rebled during admission and 4.4% were readmitted with bleeding within 28 days. In-hospital mortality was 85/2528 (3.4%) and was highest in established inpatients (17.8%, p<0.0001) and in patients experiencing rebleeding (7.1%, p<0.0001). Conclusions Patients with LGIB have a high burden of comorbidity and frequent antiplatelet or anticoagulant use. Red cell transfusion was common but most patients were not shocked and required no endoscopic, radiological or surgical treatment. Nearly half were not investigated. In-hospital mortality was related to comorbidity, not severe haemorrhage.
MED12 is recurrently mutated in Middle Eastern colorectal cancer Gut (IF 16.658) Pub Date : 2018-04-01 Abdul K Siraj, Tariq Masoodi, Rong Bu, Poyil Pratheeshkumar, Nasser Al-Sanea, Luai H Ashari, Alaa Abduljabbar, Samar Alhomoud, Fouad Al-Dayel, Fowzan S Alkuraya, Khawla S Al-Kuraya
Objective Colorectal cancer (CRC) is a common cancer and a leading cause of cancer deaths. Previous studies have identified a number of key steps in the evolution of CRC but our knowledge of driver mutations in CRC remains incomplete. Recognising the potential of studying different human populations to reveal novel insights in disease pathogenesis, we conducted genomic analysis of CRC in Saudi patients. Design In the discovery phase of the study, we conducted whole genome sequencing of tumour and corresponding germline DNA in 27 patients with CRC. In addition to known driver mutations, we identified three MED12 somatic mutations. In the replication phase, we employed a next-generation sequencing approach to capture and sequence MED12 and other candidate genes in a larger sample of 400 patients with CRC and confirmed the enrichment for recurrent MED12 mutations. Results In order to gain insight into a plausible biological mechanism for the potential role of MED12 mutations in CRC, we studied CRC cell lines that differ substantially in the expression level of MED12 , and found the latter to be correlated inversely with transforming growth factor (TGF)-β signalling and directly with apoptosis in response to chemotherapeutic agents. Importantly, these correlations were replicated when MED12 expression was experimentally manipulated. Conclusions Our data expand the recently described role of MED12 as a tumour suppressor in other cancers to include CRC, and suggest TGF-β signalling as a potential mediator of this effect.
Long-term use of antibiotics and risk of colorectal adenoma Gut (IF 16.658) Pub Date : 2018-04-01 Yin Cao, Kana Wu, Raaj Mehta, David A Drew, Mingyang Song, Paul Lochhead, Long H Nguyen, Jacques Izard, Charles S Fuchs, Wendy S Garrett, Curtis Huttenhower, Shuji Ogino, Edward L Giovannucci, Andrew T Chan
Objective Recent evidence suggests that antibiotic use, which alters the gut microbiome, is associated with an increased risk of colorectal cancer. However, the association between antibiotic use and risk of colorectal adenoma, the precursor for the majority of colorectal cancers, has not been investigated. Design We prospectively evaluated the association between antibiotic use at age 20–39 and 40–59 (assessed in 2004) and recent antibiotic use (assessed in 2008) with risk of subsequent colorectal adenoma among 16 642 women aged ≥60 enrolled in the Nurses' Health Study who underwent at least one colonoscopy through 2010. We used multivariate logistic regression to calculate ORs and 95% CIs. Results We documented 1195 cases of adenoma. Increasing duration of antibiotic use at age 20–39 (ptrend=0.002) and 40–59 (ptrend=0.001) was significantly associated with an increased risk of colorectal adenoma. Compared with non-users, women who used antibiotics for ≥2 months between age 20 and 39 had a multivariable OR of 1.36 (95% CI 1.03 to 1.79). Women who used ≥2 months of antibiotics between age 40 and 59 had a multivariable OR of 1.69 (95% CI 1.24 to 2.31). The associations were similar for low-risk versus high-risk adenomas (size ≥1 cm, or with tubulovillous/villous histology, or ≥3 detected lesions), but appeared modestly stronger for proximal compared with distal adenomas. In contrast, recent antibiotic use within the past four years was not associated with risk of adenoma (ptrend=0.44). Conclusions Long-term antibiotic use in early-to-middle adulthood was associated with increased risk of colorectal adenoma.
Socioeconomic and ethnic inequities within organised colorectal cancer screening programmes worldwide Gut (IF 16.658) Pub Date : 2018-04-01 CM de Klerk, S Gupta, E Dekker, ML Essink-Bot
Objective Colorectal cancer (CRC) screening programmes can reduce CRC mortality. However, the implementation of a screening programme may create or exacerbate socioeconomic and ethnic health inequities if participation varies by subgroup. We determined which organised programmes characterise participation inequities by socioeconomic and ethnic subgroups, and assessed the variation in subgroup participation among programmes collecting group-specific data. Design Employing a literature review and survey among leaders of national or regional screening programmes, this study identified published and unpublished data on participation by socioeconomic status and ethnicity. We assessed programmes offering faecal occult blood tests (FOBT) for screening. Primary outcome was screening participation rate. Results Across 24 organised FOBT-screening programmes meeting the inclusion criteria, participation rates ranged from 21% to 73%. Most programmes (13/24, 54%) did not collect data on participation by socioeconomic status and ethnicity. Among the 11 programmes with data on participation by socioeconomic status, 90% (28/31 publications) reported lower participation among lower socioeconomic groups. Differences across socioeconomic gradients were moderate (66% vs 71%) to severe (35% vs 61%). Only six programmes reported participation results by ethnicity. Ethnic differences were moderate, though only limited data were available for evaluation. Conclusions Across organised CRC screening programmes worldwide, variation in participation by socioeconomic status and ethnicity is often not assessed. However, when measured, marked disparities in participation by socioeconomic status have been observed. Limited data were available to assess inequities by ethnicity. To avoid exacerbating health inequities, screening programmes should systematically monitor participation by socioeconomic status and ethnicity, and investigate and address determinants of low participation.
Development and external validation of a nomogram and online tool to predict bowel dysfunction following restorative rectal cancer resection: the POLARS score Gut (IF 16.658) Pub Date : 2018-04-01 Nick J Battersby, George Bouliotis, Katrine J Emmertsen, Therese Juul, Rob Glynne-Jones, Graham Branagan, Peter Christensen, Søren Laurberg, Brendan J Moran
Objective Bowel dysfunction is common following a restorative rectal cancer resection, but symptom severity and the degree of quality of life impairment is highly variable. An internationally validated patient-reported outcome measure, Low Anterior Resection Syndrome (LARS) score, now enables these symptoms to be measured. The study purpose was: (1) to develop a model that predicts postoperative bowel function; (2) externally validate the model and (3) incorporate these findings into a nomogram and online tool in order to individualise patient counselling and aid preoperative consent. Design Patients more than 1 year after curative restorative anterior resection (UK, median 54 months; Denmark (DK), 56 months since surgery) were invited to complete The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 version3 (EORTC QLQ-C30 v3), LARS and Wexner incontinence scores. Demographics, tumour characteristics, preoperative/postoperative treatment and surgical procedures were recorded. Using transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD) guidelines, risk factors for bowel dysfunction were independently assessed by advanced linear regression shrinkage techniques for each dataset (UK:DK). Results Patients in the development (UK, n=463) and validation (DK, n=938) datasets reported mean (SD) LARS scores of 26 (11) and 24 (11), respectively. Key predictive factors for LARS were: age (at surgery); tumour height, total versus partial mesorectal excision, stoma and preoperative radiotherapy, with satisfactory model calibration and a Mallow's Cp of 7.5 and 5.5, respectively. Conclusions The Pre-Operative LARS score (POLARS) is the first nomogram and online tool to predict bowel dysfunction severity prior to anterior resection. Colorectal surgeons, gastroenterologist and nurse specialists may use POLARS to help patients understand their risk of bowel dysfunction and to preoperatively highlight patients who may require additional postoperative support.
Minimally invasive and endoscopic versus open necrosectomy for necrotising pancreatitis: a pooled analysis of individual data for 1980 patients Gut (IF 16.658) Pub Date : 2018-04-01 Sandra van Brunschot, Robbert A Hollemans, Olaf J Bakker, Marc G Besselink, Todd H Baron, Hans G Beger, Marja A Boermeester, Thomas L Bollen, Marco J Bruno, Ross Carter, Jeremy J French, Djalma Coelho, Björn Dahl, Marcel G Dijkgraaf, Nilesh Doctor, Peter J Fagenholz, Gyula Farkas, Carlos Fernandez del Castillo, Paul Fockens, Martin L Freeman, Timothy B Gardner, Harry van Goor, Hein G Gooszen, Gerjon Hannink, Rajiv Lochan, Colin J McKay, John P Neoptolemos, Atilla Oláh, Rowan W Parks, Miroslav P Peev, Michael Raraty, Bettina Rau, Thomas Rösch, Maroeska Rovers, Hans Seifert, Ajith K Siriwardena, Karen D Horvath, Hjalmar C van Santvoort
Objective Minimally invasive surgical necrosectomy and endoscopic necrosectomy, compared with open necrosectomy, might improve outcomes in necrotising pancreatitis, especially in critically ill patients. Evidence from large comparative studies is lacking. Design We combined original and newly collected data from 15 published and unpublished patient cohorts (51 hospitals; 8 countries) on pancreatic necrosectomy for necrotising pancreatitis. Death rates were compared in patients undergoing open necrosectomy versus minimally invasive surgical or endoscopic necrosectomy. To adjust for confounding and to study effect modification by clinical severity, we performed two types of analyses: logistic multivariable regression and propensity score matching with stratification according to predicted risk of death at baseline (low: <5%; intermediate: ≥5% to <15%; high: ≥15% to <35%; and very high: ≥35%). Results Among 1980 patients with necrotising pancreatitis, 1167 underwent open necrosectomy and 813 underwent minimally invasive surgical (n=467) or endoscopic (n=346) necrosectomy. There was a lower risk of death for minimally invasive surgical necrosectomy (OR, 0.53; 95% CI 0.34 to 0.84; p=0.006) and endoscopic necrosectomy (OR, 0.20; 95% CI 0.06 to 0.63; p=0.006). After propensity score matching with risk stratification, minimally invasive surgical necrosectomy remained associated with a lower risk of death than open necrosectomy in the very high-risk group (42/111 vs 59/111; risk ratio, 0.70; 95% CI 0.52 to 0.95; p=0.02). Endoscopic necrosectomy was associated with a lower risk of death than open necrosectomy in the high-risk group (3/40 vs 12/40; risk ratio, 0.27; 95% CI 0.08 to 0.88; p=0.03) and in the very high-risk group (12/57 vs 28/57; risk ratio, 0.43; 95% CI 0.24 to 0.77; p=0.005). Conclusion In high-risk patients with necrotising pancreatitis, minimally invasive surgical and endoscopic necrosectomy are associated with reduced death rates compared with open necrosectomy.
c-Myc downregulation is required for preacinar to acinar maturation and pancreatic homeostasis Gut (IF 16.658) Pub Date : 2018-04-01 Victor J Sánchez-Arévalo Lobo, Luis César Fernández, Enrique Carrillo-de-Santa-Pau, Laia Richart, Isidoro Cobo, Jaroslaw Cendrowski, Ulisses Moreno, Natalia del Pozo, Diego Megías, Bernardette Bréant, Christopher V Wright, Mark Magnuson, Francisco X Real
Background and aims c-Myc is highly expressed in pancreatic multipotent progenitor cells (MPC) and in pancreatic cancer. The transition from MPC to unipotent acinar progenitors is associated with c-Myc downregulation; a role for c-Myc in this process, and its possible relationship to a role in cancer, has not been established. Design Using coimmunoprecipitation assays, we demonstrate that c-Myc and Ptf1a interact. Using reverse transcriptase qPCR, western blot and immunofluorescence, we show the erosion of the acinar programme. To analyse the genomic distribution of c-Myc and Ptf1a and the global transcriptomic profile, we used ChIP-seq and RNA-seq, respectively; validation was performed with ChIP-qPCR and RT-qPCR. Lineage-tracing experiments were used to follow the effect of c-Myc overexpression in preacinar cells on acinar differentiation. Results c-Myc binds and represses the transcriptional activity of Ptf1a . c-Myc overexpression in preacinar cells leads to a massive erosion of differentiation. In adult Ela1-Myc mice: (1) c-Myc binds to Ptf1a, and Tcf3 is downregulated; (2) Ptf1a and c-Myc display partially overlapping chromatin occupancy but do not bind the same E-boxes; (3) at the proximal promoter of genes coding for digestive enzymes, we find reduced PTF1 binding and increased levels of repressive chromatin marks and PRC2 complex components. Lineage tracing of committed acinar precursors reveals that c-Myc overexpression does not restore multipotency but allows the persistence of a preacinar-like cell population. In addition, mutant KRas can lead to c-Myc overexpression and acinar dysregulation. Conclusions c-Myc repression during development is crucial for the maturation of preacinar cells, and c-Myc overexpression can contribute to pancreatic carcinogenesis through the induction of a dedifferentiated state.
Morphine worsens the severity and prevents pancreatic regeneration in mouse models of acute pancreatitis Gut (IF 16.658) Pub Date : 2018-04-01 Usman Barlass, Raini Dutta, Hassam Cheema, John George, Archana Sareen, Ajay Dixit, Zuobiao Yuan, Bhuwan Giri, Jingjing Meng, Santanu Banerjee, Sulagna Banerjee, Vikas Dudeja, Rajinder K Dawra, Sabita Roy, Ashok K Saluja
Background Opioids such as morphine are widely used for the management of pain associated with acute pancreatitis. Interestingly, opioids are also known to affect the immune system and modulate inflammatory pathways in non-pancreatic diseases. However, the impact of morphine on the progression of acute pancreatitis has never been evaluated. In the current study, we evaluated the impact of morphine on the progression and severity of acute pancreatitis. Methods Effect of morphine treatment on acute pancreatitis in caerulein, L-arginine and ethanol–palmitoleic acid models was evaluated after induction of the disease. Inflammatory response, gut permeability and bacterial translocation were compared. Experiments were repeated in mu (µ) opioid receptor knockout mice (MORKO) and in wild-type mice in the presence of opioid receptor antagonist naltrexone to evaluate the role of µ-opioid receptors in morphine’s effect on acute pancreatitis. Effect of morphine treatment on pathways activated during pancreatic regeneration like sonic Hedgehog and activation of embryonic transcription factors like pdx-1 and ptf-1 were measured by immunofluorescence and quantitative PCR. Results Histological data show that treatment with morphine after induction of acute pancreatitis exacerbates the disease with increased pancreatic neutrophilic infiltration and necrosis in all three models of acute pancreatitis. Morphine also exacerbated acute pancreatitis-induced gut permeabilisation and bacteraemia. These effects were antagonised in the MORKO mice or in the presence of naltrexone suggesting that morphine’s effect on severity of acute pancreatitis are mediated through the µ-opioid receptors. Morphine treatment delayed macrophage infiltration, sonic Hedgehog pathway activation and expression of pdx-1 and ptf-1. Conclusion Morphine treatment worsens the severity of acute pancreatitis and delays resolution and regeneration. Considering our results, the safety of morphine for analgesia during acute pancreatitis should be re-evaluated in future human studies.
Annexin A11 is targeted by IgG4 and IgG1 autoantibodies in IgG4-related disease Gut (IF 16.658) Pub Date : 2018-04-01 Lowiek M Hubers, Harmjan Vos, Alex R Schuurman, Robin Erken, Ronald P Oude Elferink, Boudewijn Burgering, Stan F J van de Graaf, Ulrich Beuers
Objective Immunoglobulin G4-related disease (IgG4-RD) is a multiorgan immune-mediated disease that predominantly affects the biliary tract (IgG4-associated cholangitis, IAC) and pancreas (autoimmune pancreatitis, AIP). We recently identified highly expanded IgG4+ B-cell receptor clones in blood and affected tissues of patients with IAC/AIP suggestive of specific (auto)antigenic stimuli involved in initiating and/or maintaining the inflammatory response. This study aimed to identify (auto)antigen(s) that are responsible for the clonal expansion of IgG4+ B cells in IgG4-RD. Design We screened sera of patients with IAC/AIP (n=50), in comparison to control sera of patients with primary sclerosing cholangitis (PSC) and pancreatobiliary malignancies (n=47), for reactivity against human H69 cholangiocyte lysates on immunoblot. Subsequently, target antigens were immunoprecipitated and analysed by mass spectrometry. Results Prominent reactivity against a 56 kDa protein was detected in human H69 cholangiocyte lysates exposed to sera of nine patients with IAC/AIP. Affinity purification and mass spectrometry analysis identified annexin A11, a calcium-dependent phospholipid-binding protein. Annexin A11-specific IgG4 and IgG1 antibodies were only detected in serum of patients with IgG4-RD of the biliary tract/pancreas/salivary glands and not in disease mimickers with PSC and pancreatobiliary malignancies. Epitope analysis showed that two annexin A11 epitopes targeted by IgG1 and IgG4 autoantibodies were shared between patients with IAC/AIP and IgG4 antibodies blocked binding of IgG1 antibodies to the shared annexin A11 epitopes. Conclusion Our data suggest that IgG1-mediated pro-inflammatory autoreactivity against annexin A11 in patients with IgG4-RD may be attenuated by formation of annexin A11-specific IgG4 antibodies supporting an anti-inflammatory role of IgG4 in IgG4-RD.
Humanisation of a claudin-1-specific monoclonal antibody for clinical prevention and cure of HCV infection without escape Gut (IF 16.658) Pub Date : 2018-04-01 Che C Colpitts, Rajiv G Tawar, Laurent Mailly, Christine Thumann, Laura Heydmann, Sarah C Durand, Fei Xiao, Eric Robinet, Patrick Pessaux, Mirjam B Zeisel, Thomas F Baumert
Objective HCV infection is a leading cause of chronic liver disease and a major indication for liver transplantation. Although direct-acting antivirals (DAAs) have much improved the treatment of chronic HCV infection, alternative strategies are needed for patients with treatment failure. As an essential HCV entry factor, the tight junction protein claudin-1 (CLDN1) is a promising antiviral target. However, genotype-dependent escape via CLDN6 and CLDN9 has been described in some cell lines as a possible limitation facing CLDN1-targeted therapies. Here, we evaluated the clinical potential of therapeutic strategies targeting CLDN1. Design We generated a humanised anti-CLDN1 monoclonal antibody (mAb) (H3L3) suitable for clinical development and characterised its anti-HCV activity using cell culture models, a large panel of primary human hepatocytes (PHH) from 12 different donors, and human liver chimeric mice. Results H3L3 pan-genotypically inhibited HCV pseudoparticle entry into PHH, irrespective of donor. Escape was likely precluded by low surface expression of CLDN6 and CLDN9 on PHH. Co-treatment of a panel of PHH with a CLDN6-specific mAb did not enhance the antiviral effect of H3L3, confirming that CLDN6 does not function as an entry factor in PHH from multiple donors. H3L3 also inhibited DAA-resistant strains of HCV and synergised with current DAAs. Finally, H3L3 cured persistent HCV infection in human-liver chimeric uPA-SCID mice in monotherapy. Conclusions Overall, these findings underscore the clinical potential of CLDN1-targeted therapies and describe the functional characterisation of a humanised anti-CLDN1 antibody suitable for further clinical development to complement existing therapeutic strategies for HCV.
ERK activation and autophagy impairment are central mediators of irinotecan-induced steatohepatitis Gut (IF 16.658) Pub Date : 2018-04-01 Abdo Mahli, Michael Saugspier, Andreas Koch, Judith Sommer, Peter Dietrich, Seren Lee, Reinhard Thasler, Jan Schulze-Luehrmann, Anja Luehrmann, Wolfgang Erwin Thasler, Martina Müller, Anja Bosserhoff, Claus Hellerbrand
Objective Preoperative chemotherapy with irinotecan is associated with the development of steatohepatitis, which increases the risk of perioperative morbidity and mortality for liver surgery. The molecular mechanisms of this chemotherapeutic complication are widely unknown. Design Mechanisms of irinotecan-induced steatohepatitis were studied in primary human hepatocytes in vitro, in mice treated with irinotecan and in liver specimens from irinotecan-treated compared with control patients. Results Irinotecan dose-dependently induced lipid accumulation and pro-inflammatory gene expression in hepatocytes. This was accompanied by an impairment of mitochondrial function with reduced expression of carnitine palmitoyltransferase I and an induction of acyl-coenzyme A oxidase-1 (ACOX1), oxidative stress and extracellular signal-regulated kinase (ERK) activation. ERK inhibition prevented irinotecan-induced pro-inflammatory gene expression but had only a slight effect on lipid accumulation. However, irinotecan also induced an impairment of the autophagic flux mediated by alkalisation of lysosomal pH. Re-acidification of lysosomal pH abolished irinotecan-induced autophagy impairment and lipid accumulation. Also in mice, irinotecan treatment induced hepatic ACOX1 expression, ERK phosphorylation and inflammation, as well as impairment of autophagy and significant steatosis. Furthermore, irinotecan-treated patients revealed higher hepatic ERK activity, expression of pro-inflammatory genes and markers indicative for a shift to peroxisomal fatty acid oxidation and an impaired autophagic flux. Pretreatment with the multityrosine kinase inhibitor sorafenib did not affect autophagy impairment and steatosis but significantly reduced ERK phosphorylation and inflammatory response in irinotecan-treated hepatocytes and murine livers. Conclusions Irinotecan induces hepatic steatosis via autophagy impairment and inflammation via ERK activation. Sorafenib appears as a novel therapeutic option for the prevention and treatment of irinotecan-induced inflammation.
Genome-wide association study identiﬁes HLA-DR variants conferring risk of HBV-related acute-on-chronic liver failure Gut (IF 16.658) Pub Date : 2018-04-01 Wenting Tan, Jie Xia, Yunjie Dan, Mengying Li, Shide Lin, Xingnan Pan, Huifen Wang, Yingzi Tang, Nana Liu, Shun Tan, Ming Liu, Weiwei He, Weihua Zhang, Qing Mao, Yuming Wang, Guohong Deng
Objective Acute-on-chronic liver failure (ACLF) is an extreme condition after severe acute exacerbation of chronic hepatitis B; however, the underlying genetic factors involved in its onset and progression are currently unclear. Design We carried out a genome-wide association study among 399 HBV-related ACLFs (cases) and 401 asymptomatic HBV carriers (AsCs, as controls) without antiviral treatment. The initial findings were replicated in four independent case–control sets (a total of 901 ACLFs and 1686 AsCs). The roles of risk variants on clinical traits of ACLF were also analysed. Results Among 1300 ACLFs and 2087 AsCs, we identified rs3129859 at human leucocyte antigen (HLA) class II region (chromosome 6p21.32) associated with HBV-related ACLF (combined P dominant =2.64×10−20, OR=1.83). Analysis identiﬁed HLA-DRB1*12:02 as the top susceptible HLA allele associated with ACLF (p=3.94×10−6, OR=2.05). The association of rs3129859 was robust in ACLF subgroups (ACLFs with liver cirrhosis, p=1.36×10−16; ACLFs without liver cirrhosis, p=1.52×10−7), and patients at low-replicative phase (p=6.36×10−11, OR=2.29) or HBV e antigen-negative chronic hepatitis B phase (p=1.51×10−14, OR=1.86). Clinical traits analysis in patients with ACLF showed that the risky rs3129859*C allele was also associated with prolonged prothrombin time, faster progression to ascites development and higher 28-day mortality. Conclusions Our genome-wide association study identified HLA-DR as the major locus for susceptibility to HBV-related ACLF. Our findings highlight the importance of HLA class II restricted CD4+ T-cell pathway on the immunopathogenesis of HBV-related ACLF.
Liver sampling: a vital window into HBV pathogenesis on the path to functional cure Gut (IF 16.658) Pub Date : 2018-04-01 Upkar S Gill, Laura J Pallett, Patrick T F Kennedy, Mala K Maini
In order to optimally refine the multiple emerging drug targets for hepatitis B virus (HBV), it is vital to evaluate virological and immunological changes at the site of infection. Traditionally liver biopsy has been the mainstay of HBV disease assessment, but with the emergence of non-invasive markers of liver fibrosis, there has been a move away from tissue sampling. Here we argue that liver biopsy remains an important tool, not only for the clinical assessment of HBV but also for research progress and evaluation of novel agents. The importance of liver sampling has been underscored by recent findings of specialised subsets of tissue-resident immune subsets capable of efficient pathogen surveillance, compartmentalised in the liver and not sampled in the blood. Importantly, the assessment of virological parameters, such as cccDNA quantitation, also requires access to liver tissue. We discuss strategies to maximise information obtained from the site of infection and disease pathology. Fine needle aspirates of the liver may allow longitudinal sampling of the local virus/host landscape. The careful utilisation of liver tissue and aspirates in conjunction with blood will provide critical information in the assessment of new therapeutics for the functional cure of HBV.
GI highlights from the literature Gut (IF 16.658) Pub Date : 2018-04-01 Mairi H McLean
### The role of the microbiota in hypertension: take it with a pinch of salt? Wilck N, Matus MG, Kearney SM et al . Salt-responsive commensal modulates TH17 axis and disease. Nature 2017;551:585–589. A high salt diet predisposes to hypertension and cardiovascular disease. This paper proposes that the microbiome and immune system bring about these effects of a high salt diet. High salt intake induces proinflammatory Th17 cells, which have been linked to hypertension and autoimmune disease. To find a link between salt intake and microbiota, mice were fed a high-salt diet made up of 4% salt, as compared with a normal-salt diet of 0.5% salt. After 2 weeks, faecal pellets were sequenced to reveal microbiota populations. There were clear differences between the two groups, but the most marked change was a reduction in Lactobacillus murinus in the high-salt group. L. murinus was cultured in the lab and growth was salt sensitive. It is known that a high salt diet exacerbates experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Daily gavage of L. murinus ameliorated salt-induced EAE. Likewise, a 3-week high salt diet caused hypertension in mice, but L. murinus treatment ameliorated salt-sensitive hypertension and reduced Th17 cells. In a small human trial, 12 volunteers were given double their usual salt intake with 6 g of extra salt for a fortnight. Participants’ blood pressure increased, there was reduced survival of Lactobacillus species and a significant increase in Th17 cells. Interestingly, Lactobacillus is less abundant in microbiomes in the West and may be related to higher salt intake from an early age. Manipulating the microbiota, for example, with probiotics could be a therapy in salt-sensitive conditions. ### Hepatic expression of the deubiqitination enzyme cylindromatosis inhibits NASH Ji Y-X, Huang Z, Yang X, et al. The deubiquitinating enzyme cylindromatosis mitigates nonalcoholic steatohepatitis. Nat Med 2018 Jan 1. doi: 10.1038/nm.4461. [Epub ahead of print]. Cellular ubiquitination controls the activation and degradation of intracellular proteins. Ubiquitination has been suggested …
Faecal microbiota composition associates with abdominal pain in the general population Gut (IF 16.658) Pub Date : 2018-04-01 Fatemeh Hadizadeh, Ferdinando Bonfiglio, Meriem Belheouane, Marie Vallier, Sascha Sauer, Corinna Bang, Luis Bujanda, Anna Andreasson, Lars Agreus, Lars Engstrand, Nicholas J Talley, Joseph Rafter, John F Baines, Susanna Walter, Andre Franke, Mauro D’Amato
We read with great interest the recent communication by Simrén et al ,1 reporting a correlation between visceral hypersensitivity and GI symptom severity in functional GI disorders (FGID). Previously, it has been shown that visceral hypersensitivity can be modulated or even induced in animal models, by altering the composition of their gut microbiota with antibiotics or faecal transplantation from IBS donors.2 3 Hence, while a direct link between gut microbiota composition and visceral pain may need to be conclusively established, this holds great potential for translational exploitation in the treatment of IBS and other FGID. Thus far, the potential association between microbiota and abdominal pain in humans has only been investigated in one study that included 15 individuals.4 For this purpose, we studied 159 individuals (average age 59.1, 39.6% men) from the Swedish Population-based Colonoscopy (PopCol) cohort, previously described and with faecal microbiota 16S sequencing data and daily recordings of abdominal pain (number of episodes, duration and intensity) collected over the same period (7.41±7.91 days).5–7 Among these, 52 individuals (assigned to the case group) reported at least one episode …
Germline variation of circadian pathway genes and prognosis of gastric cancer patients Gut (IF 16.658) Pub Date : 2018-04-01 Senthilkumar Rajendran, Clara Benna, Halenya Monticelli, Giovanna Spiro, Chiara Menin, Simone Mocellin
As we have summarised in this journal,1 germline DNA variation has been long recognised as a key component of the risk to develop to gastric carcinoma, the discovery pace being greatly accelerated by genome-wide association studies.2 More recently, growing evidence is accumulating also on the association between genetic variation and prognosis of patients with gastric cancer.3 4 Furthermore, investigators have demonstrated that alterations of the circadian rhythm can predispose to a variety of illnesses, including different types of malignancies and gastrointestinal diseases.5 6 Putting together these observations, we studied the relationship between circadian genes germline variation and the overall survival of 460 patients with TNM stage I to IV gastric carcinoma. We considered 21 single nucleotide polymorphisms (SNPs) of 14 circadian pathway genes. Genotyping was performed with real-time quantitative PCR using patient peripheral blood samples. Expression quantitative trait locus (eQTL) analysis was employed to …
Combined effect of anti-BAG3 and anti-PD-1 treatment on macrophage infiltrate, CD8+ T cell number and tumour growth in pancreatic cancer Gut (IF 16.658) Pub Date : 2018-04-01 Vittoria Iorio, Alessandra Rosati, Raffaella D’Auria, Margot De Marco, Liberato Marzullo, Anna Basile, Michelina Festa, Maria Pascale, Paolo Remondelli, Mario Capunzo, Gianluca Sala, Verena Damiani, Giuseppina Amodio, Marta Di Nicola, Rossano Lattanzio, Maria Caterina Turco, Vincenzo De Laurenzi
We read with great interest the article by Zhang et al 1 showing that CD8+ cell infiltration in pancreatic tumours can be enhanced by depletion of myeloid cells (CD11b+ macrophages and myeloid-derived suppressor cells) and that the depletion of CD11b+ cells resulted in decreased PD-L1 expression on cancer cells thus impairing the triggering of the inhibitory receptor PD-1 on T cells.1 Recruitment and activation of CD8+ lymphocytes in tumours are suppressed by mechanisms only partially understood and rescuing CD8+ cell infiltrate in tumours is one of the objectives of immunotherapies.1 2 Tumour-associated macrophages (TAMs) play a crucial role in the relation between tumour cells and their environment.3 Here, we confirm the interplay between macrophages and CD8+ cells in pancreatic cancer and identify a potential way to exploit this enhancing effect of anti-PD-1 treatment. Indeed, we show that reduction of macrophage infiltrate, through treatment with an anti-Bcl-2-Associated athanoGene 3 (BAG3) antibody,4 results in increased number of CD8+ cells in pancreatic tumours in a murine model. BAG3 is a co-chaperone of …
Correction: Discoidin domain receptor 2 deficiency predisposes hepatic tissue to colon carcinoma metastasis Gut (IF 16.658) Pub Date : 2018-04-01 BMJ Publishing Group Ltd and British Society of Gastroenterology
Badiola I, Olaso E, Crende O , et al. Discoidin …
Tears of colonoscopy Gut (IF 16.658) Pub Date : 2018-04-01 Michael McFarlane, Ben Disney, Jayne Eaden
A 72-year-old woman was referred to the gastroenterology outpatient clinic reporting an 18-month history of loose and watery stools up to 10 times per day with nocturnal episodes. She also presented with urgency, occasional faecal incontinence, excessive bloating and flatulence. She had lost 14 kg in weight over the same period. There was no blood or mucus in her stools. Her symptoms began after she underwent an emergency appendicectomy for suspected appendicitis. The histology revealed a carcinoid tumour, but with clear resection margins and a subsequent CT scan showed no …
Large and middle hepatitis B surface antigen: the lower the better? Gut (IF 16.658) Pub Date : 2018-03-07 Hsuan-Ho Lin, Tai-Chung Tseng, Jia-Horng Kao
We read with great interest the article entitled ‘Quantification of large and middle proteins of hepatitis B virus surface antigen (HBsAg) as a novel tool for the identification of inactive HBV carriers’ by Pfefferkorn et al .1 Serum hepatitis B surface antigen (HBsAg) level has been shown to complement HBV DNA level in predicting clinical outcomes of patients with chronic HBV infection.2 3 In Asian patients, mostly genotype B and C infection, with a low viral load (HBV DNA ≤2000 IU/mL), HBsAg level >1000 IU/mL indicates …
IPMNs with co-occurring invasive cancers: neighbours but not always relatives Gut (IF 16.658) Pub Date : 2018-03-02 Matthäus Felsenstein, Michaël Noë, David L Masica, Waki Hosoda, Peter Chianchiano, Catherine G Fischer, Gemma Lionheart, Lodewijk A A Brosens, Antonio Pea, Jun Yu, Georgios Gemenetzis, Vincent P Groot, Martin A Makary, Jin He, Matthew J Weiss, John L Cameron, Christopher L Wolfgang, Ralph H Hruban, Nicholas J Roberts, Rachel Karchin, Michael G Goggins, Laura D Wood
Objective Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions that can give rise to invasive pancreatic carcinoma. Although approximately 8% of patients with resected pancreatic ductal adenocarcinoma have a co-occurring IPMN, the precise genetic relationship between these two lesions has not been systematically investigated. Design We analysed all available patients with co-occurring IPMN and invasive intrapancreatic carcinoma over a 10-year period at a single institution. For each patient, we separately isolated DNA from the carcinoma, adjacent IPMN and distant IPMN and performed targeted next generation sequencing of a panel of pancreatic cancer driver genes. We then used the identified mutations to infer the relatedness of the IPMN and co-occurring invasive carcinoma in each patient. Results We analysed co-occurring IPMN and invasive carcinoma from 61 patients with IPMN/ductal adenocarcinoma as well as 13 patients with IPMN/colloid carcinoma and 7 patients with IPMN/carcinoma of the ampullary region. Of the patients with co-occurring IPMN and ductal adenocarcinoma, 51% were likely related. Surprisingly, 18% of co-occurring IPMN and ductal adenocarcinomas were likely independent, suggesting that the carcinoma arose from an independent precursor. By contrast, all colloid carcinomas were likely related to their associated IPMNs. In addition, these analyses showed striking genetic heterogeneity in IPMNs, even with respect to well-characterised driver genes. Conclusion This study demonstrates a higher prevalence of likely independent co-occurring IPMN and ductal adenocarcinoma than previously appreciated. These findings have important implications for molecular risk stratification of patients with IPMN.
Calcium and vitamin D supplementation and increased risk of serrated polyps: results from a randomised clinical trial Gut (IF 16.658) Pub Date : 2018-03-01 Seth D Crockett, Elizabeth L Barry, Leila A Mott, Dennis J Ahnen, Douglas J Robertson, Joseph C Anderson, Kristen Wallace, Carol A Burke, Robert S Bresalier, Jane C Figueiredo, Dale C Snover, John A Baron
Objective Serrated lesions such as sessile serrated adenomas or polyps (SSA/Ps) are important colorectal cancer precursors, but aetiological factors for these lesions are largely unknown. We aimed to determine the effects of calcium and vitamin D supplementation on the incidence of serrated polyps (SPs) in general and hyperplastic polyps and SSA/Ps specifically. Design Participants with one or more adenoma at baseline were randomised to receive 1200 mg/day of elemental calcium, 1000 IU/day of vitamin D3, both or neither agent. Treatment continued for 3 or 5 years, when risk of polyps was determined from surveillance colonoscopy (treatment phase). Outcomes after treatment ceased were also assessed (observational phase). Adjusted risk ratios (aRRs) of SPs were determined via multivariable generalised linear models. Results SPs were diagnosed in 565 of 2058 (27.5%) participants during the treatment phase and 329/1108 (29.7%) during the observational phase. In total, 211 SSA/Ps were identified during follow-up. In the treatment phase, there was no effect of either calcium or vitamin D on incidence of SSA/Ps. However, during the later observational phase, we observed elevated risks of SSA/Ps associated with calcium alone and calcium+vitamin D treatment (aRR (95% CI): 2.65 (1.43 to 4.91) and 3.81 (1.25 to 11.64), respectively). Conclusion In a large multicentre chemoprevention study, we found evidence that calcium and vitamin D supplementation increased the risk of SSA/Ps. This appeared to be a late effect: 6–10 years after supplementation began. These possible risks must be weighed against the benefits of calcium and vitamin D supplementation. Trial registration number [NCT00153816; Results.] : http://NCT00153816
Plasma ghrelin is probably not a useful biomarker for risk prediction or early detection of colorectal cancer Gut (IF 16.658) Pub Date : 2018-02-28 Anneli Sundkvist, Robin Myte, Richard Palmqvist, Sophia Harlid, Bethany Van Guelpen
A recent study by Murphy et al reported an intriguing, time-dependent relationship between ghrelin, an appetite-stimulating hormone, and colorectal cancer (CRC).1 In the 10 years prior to diagnosis, but not earlier, low serum ghrelin concentrations were associated with a dramatic increase in CRC risk (OR=10.86). This raises the question of whether ghrelin might be a candidate biomarker for clinical use. However, whether ghrelin levels actually go down during the period approaching diagnosis is challenging to assess, requiring repeated prediagnostic blood samples from patients. We conducted a validation of the study by Murphy et al 1 using fasting plasma samples from the Västerbotten Intervention Programme, collected from CRC cases and matched controls within the 5 years preceding diagnosis of the cases. All participants had provided an additional blood sample 10 years earlier. This unique study design, described in detail elsewhere,2 allowed us to investigate potential changes in ghrelin levels over a long prediagnostic time period, from a generally tumour-free phase of 10–15 years prior to diagnosis to the window of opportunity for early detection. Repeated plasma samples were available for 60 …
Single-cell RNAseq reveals seven classes of colonic sensory neuron Gut (IF 16.658) Pub Date : 2018-02-26 James R F Hockley, Toni S Taylor, Gerard Callejo, Anna L Wilbrey, Alex Gutteridge, Karsten Bach, Wendy J Winchester, David C Bulmer, Gordon McMurray, Ewan St John Smith
Objective Integration of nutritional, microbial and inflammatory events along the gut-brain axis can alter bowel physiology and organism behaviour. Colonic sensory neurons activate reflex pathways and give rise to conscious sensation, but the diversity and division of function within these neurons is poorly understood. The identification of signalling pathways contributing to visceral sensation is constrained by a paucity of molecular markers. Here we address this by comprehensive transcriptomic profiling and unsupervised clustering of individual mouse colonic sensory neurons. Design Unbiased single-cell RNA-sequencing was performed on retrogradely traced mouse colonic sensory neurons isolated from both thoracolumbar (TL) and lumbosacral (LS) dorsal root ganglia associated with lumbar splanchnic and pelvic spinal pathways, respectively. Identified neuronal subtypes were validated by single-cell qRT-PCR, immunohistochemistry (IHC) and Ca2+-imaging. Results Transcriptomic profiling and unsupervised clustering of 314 colonic sensory neurons revealed seven neuronal subtypes. Of these, five neuronal subtypes accounted for 99% of TL neurons, with LS neurons almost exclusively populating the remaining two subtypes. We identify and classify neurons based on novel subtype-specific marker genes using single-cell qRT-PCR and IHC to validate subtypes derived from RNA-sequencing. Lastly, functional Ca2+-imaging was conducted on colonic sensory neurons to demonstrate subtype-selective differential agonist activation. Conclusions We identify seven subtypes of colonic sensory neurons using unbiased single-cell RNA-sequencing and confirm translation of patterning to protein expression, describing sensory diversity encompassing all modalities of colonic neuronal sensitivity. These results provide a pathway to molecular interrogation of colonic sensory innervation in health and disease, together with identifying novel targets for drug development.
Quantification of large and middle proteins of hepatitis B virus surface antigen (HBsAg) as a novel tool for the identification of inactive HBV carriers Gut (IF 16.658) Pub Date : 2018-02-26 Maria Pfefferkorn, Stephan Böhm, Tina Schott, Danilo Deichsel, Corinna M Bremer, Kathrin Schröder, Wolfram H Gerlich, Dieter Glebe, Thomas Berg, Florian van Bömmel
Objective Among individuals with chronic hepatitis B, those with hepatitis B e-antigen (HBeAg)-negative chronic hepatitis (CHB) can be difficult to distinguish from those with HBeAg-negative chronic HBV infection, also referred to as inactive HBV carriers (ICs), but both require different medical management. The level of HBV surface antigen (HBsAg) has been proposed as a marker to discriminate between chronic infection and hepatitis stages. HBsAg consists of large, middle and small HBs. The aim of this study was to determine whether the composition of HBsAg improved the identification of ICs among HBsAg-positive subjects with different phases of HBV infections. Design HBV large surface proteins (LHBs) and HBV middle surface proteins (MHBs) were quantified in serum samples from 183 clinically well-characterised untreated patients with acute (n=14) HBV infection, ICs (n=44), CHBs (n=46), chronic HBeAg-positive phase (n=68) and hepatitis delta coinfection (n=11) using an ELISA, with well-defined monoclonal antibodies against the preS1 domain (LHBs) and the preS2-domain (MHBs). A Western blot analysis was used to verify the quantitation of the components of HBsAg. Total HBsAg was quantified using a modified commercially available assay (HBsAg V.6.0, Enzygnost, Siemens, Erlangen). Results The composition of HBsAg showed specific patterns across different phases of hepatitis B. Individuals in the IC phase had significantly lower proportions of LHBs and MHBs than patients in acute or chronic phases irrespective of their HBV e-antigen status (p<0.0001) or HBsAg level. Both LHBs and MHBs ratios better predicted the IC phase than total HBsAg levels. Conclusion Quantification of MHBs, particularly LHBs represents a novel tool for the identification of the IC stage.
UK guidelines on oesophageal dilatation in clinical practice Gut (IF 16.658) Pub Date : 2018-02-24 Sarmed S Sami, Hasan, N Haboubi, Yeng Ang, Philip Boger, Pradeep Bhandari, John de Caestecker, Helen Griffiths, Rehan Haidry, Hans-Ulrich Laasch, Praful Patel, Stuart Paterson, Krish Ragunath, Peter Watson, Peter D Siersema, Stephen E Attwood
These are updated guidelines which supersede the original version published in 2004. This work has been endorsed by the Clinical Services and Standards Committee of the British Society of Gastroenterology (BSG) under the auspices of the oesophageal section of the BSG. The original guidelines have undergone extensive revision by the 16 members of the Guideline Development Group with representation from individuals across all relevant disciplines, including the Heartburn Cancer UK charity, a nursing representative and a patient representative. The methodological rigour and transparency of the guideline development processes were appraised using the revised Appraisal of Guidelines for Research and Evaluation (AGREE II) tool. Dilatation of the oesophagus is a relatively high-risk intervention, and is required by an increasing range of disease states. Moreover, there is scarcity of evidence in the literature to guide clinicians on how to safely perform this procedure. These guidelines deal specifically with the dilatation procedure using balloon or bougie devices as a primary treatment strategy for non-malignant narrowing of the oesophagus. The use of stents is outside the remit of this paper; however, for cases of dilatation failure, alternative techniques—including stents—will be listed. The guideline is divided into the following subheadings: (1) patient preparation; (2) the dilatation procedure; (3) aftercare and (4) disease-specific considerations. A systematic literature search was performed. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool was used to evaluate the quality of evidence and decide on the strength of recommendations made.
Alcohol dysregulates miR-148a in hepatocytes through FoxO1, facilitating pyroptosis via TXNIP overexpression Gut (IF 16.658) Pub Date : 2018-02-23 Mi Jeong Heo, Tae Hyun Kim, Jueng Soo You, Delia Blaya, Pau Sancho-Bru, Sang Geon Kim
Objective Alcoholic liver disease (ALD) is a leading cause of death among chronic liver diseases. However, its pathogenesis has not been completely established. MicroRNAs (miRNAs) are key contributors to liver diseases progression. This study investigated hepatocyte-abundant miRNAs dysregulated by ALD, its impact on hepatocyte injury and the underlying basis. Design Alcoholic hepatitis (AH) human and animal liver samples and hepatocytes were used to assess miR-148a levels. Pre-miR-148a was delivered specifically to hepatocytes in vivo using lentivirus. Immunoblottings, luciferase reporter assays, chromatin immunoprecipitation and immunofluorescence assays were carried out in cell models. Results The miRNA profile and PCR analyses enabled us to find substantial decrease of miR-148a in the liver of patients with AH. In mice subjected to Lieber-DeCarli alcohol diet or binge alcohol drinking, miR-148a levels were also markedly reduced. In cultured hepatocytes and mouse livers, alcohol exposure inhibited forkhead box protein O1 (FoxO1) expression, which correlated with miR-148a levels and significantly decreased in human AH specimens. FoxO1 was identified as a transcription factor for MIR148A transactivation. MiR-148a directly inhibited thioredoxin-interacting protein (TXNIP) expression. Consequently, treatment of hepatocytes with ethanol resulted in TXNIP overexpression, activating NLRP3 inflammasome and caspase-1-mediated pyroptosis. These events were reversed by miR-148a mimic or TXNIP small-interfering RNA transfection. Hepatocyte-specific delivery of miR-148a to mice abrogated alcohol-induced TXNIP overexpression and inflammasome activation, attenuating liver injury. Conclusion Alcohol decreases miR-148a expression in hepatocytes through FoxO1, facilitating TXNIP overexpression and NLRP3 inflammasome activation, which induces hepatocyte pyroptosis. Our findings provide information on novel targets for reducing incidence and progression of ALD.
Association between proton pump inhibitors use and risk of gastric cancer in patients with GERD Gut (IF 16.658) Pub Date : 2018-02-22 Yen-Chun Peng, Lam-Ru Huang, Cheng-Li Lin, Wan-Yun Hsu, Chi-Sen Chang, Hong-Zen Yeh, Chia-Hung Kao
We read with interest the study by Cheung et al confirming the risk of proton pump inhibitors (PPIs) for gastric cancer regarding the patients after Helicobacter pylori (H. pylori) eradication with long-term PPIs use.1 Most concerns about the safety of PPIs pertain to the increased risk for enteric infections, fractures and nutritional deficiencies.2 To date, the association of PPIs use and risk of gastric cancer is still controversial in patients with gastro-oesophageal reflux diseases (GERD). For GERD, PPIs are the mainstay of treatment in the management of patients with acid-related disorders.3 Thus, patients with GERD usually take long-term PPIs,and possibly carry the risk of gastric cancer. In the present study, we performed a case–control study to investigate the association of PPIs use and risk of gastric cancer using data from a nationwide population database, the National Health Insurance Research Database (NHIRD) in Taiwan.4 This study also used a subdataset of the NHIRD, which comprises one million randomly sampled beneficiaries enrolled in the NHI programme in 2000 (Longitudinal Health Insurance Database …
Polarised epithelial monolayers of the gastric mucosa reveal insights into mucosal homeostasis and defence against infection Gut (IF 16.658) Pub Date : 2018-02-21 Francesco Boccellato, Sarah Woelffling, Aki Imai-Matsushima, Gabriela Sanchez, Christian Goosmann, Monika Schmid, Hilmar Berger, Pau Morey, Christian Denecke, Juergen Ordemann, Thomas F Meyer
Objective Helicobacter pylori causes life-long colonisation of the gastric mucosa, leading to chronic inflammation with increased risk of gastric cancer. Research on the pathogenesis of this infection would strongly benefit from an authentic human in vitro model. Design Antrum-derived gastric glands from surgery specimens served to establish polarised epithelial monolayers via a transient air–liquid interface culture stage to study cross-talk with H. pylori and the adjacent stroma. Results The resulting ‘mucosoid cultures’, so named because they recapitulate key characteristics of the gastric mucosa, represent normal stem cell-driven cultures that can be passaged for months. These highly polarised columnar epithelial layers encompass the various gastric antral cell types and secrete mucus at the apical surface. By default, they differentiate towards a foveolar, MUC5AC-producing phenotype, whereas Wnt signalling stimulates proliferation of MUC6-producing cells and preserves stemness—reminiscent of the gland base. Stromal cells from the lamina propria secrete Wnt inhibitors, antagonising stem-cell niche signalling and inducing differentiation. On infection with H. pylori , a strong inflammatory response is induced preferentially in the undifferentiated basal cell phenotype. Infection of cultures for several weeks produces foci of viable bacteria and a persistent inflammatory condition, while the secreted mucus establishes a barrier that only few bacteria manage to overcome. Conclusion Gastric mucosoid cultures faithfully reproduce the features of normal human gastric epithelium, enabling new approaches for investigating the interaction of H. pylori with the epithelial surface and the cross-talk with the basolateral stromal compartment. Our observations provide striking insights in the regulatory circuits of inflammation and defence.
Adipose tissue macrophages induce hepatic neutrophil recruitment and macrophage accumulation in mice Gut (IF 16.658) Pub Date : 2018-02-20 Mitchell Bijnen, Tatjana Josefs, Ilona Cuijpers, Constantijn J Maalsen, José van de Gaar, Maria Vroomen, Erwin Wijnands, Sander S Rensen, Jan Willem M Greve, Marten H Hofker, Erik A L Biessen, Coen D A Stehouwer, Casper G Schalkwijk, Kristiaan Wouters
Objective Obesity is a risk factor for non-alcoholic steatohepatitis (NASH). This risk has been attributed to visceral adipose tissue (vAT) expansion associated with increased proinflammatory mediators. Accumulation of CD11c+ proinflammatory adipose tissue macrophages (ATM) is an important driver of vAT inflammation. We investigated the role of ATMs in hepatic inflammation during NASH development. Design vAT isolated from lean, obese or ATM-depleted (using clodronate liposomes) obese mice was transplanted to lean ldlr-/- acceptor mice. Systemic and hepatic inflammation was assessed either after 2 weeks on standard chow or after 8 weeks on high cholesterol diet (HCD) to induce NASH. Results Transplanting donor vAT from obese mice increased HCD-induced hepatic macrophage content compared with lean-transplanted mice, worsening liver damage. ATM depletion prior to vAT transplantation reduced this increased hepatic macrophage accumulation. On chow, vAT transplantation induced a more pronounced increase in circulating and hepatic neutrophil numbers in obese-transplanted than lean-transplanted mice, while ATM depletion prior to vAT transplantation reversed this effect. Microarray analysis of fluorescence-activated cell sorting of CD11c+ and CD11c− macrophages isolated from donor adipose tissue showed that obesity resulted in enhanced expression of neutrophil chemotaxis genes specifically in CD11c+ ATMs. Involvement of the neutrophil chemotaxis proteins, CXCL14 and CXCL16, was confirmed by culturing vAT. In humans, CD11c expression in vAT of obese individuals correlated with vAT expression of neutrophil chemotactic genes and with hepatic expression of neutrophil and macrophage marker genes. Conclusion ATMs from obese vAT induce hepatic macrophage accumulation during NASH development, possibly by enhancing neutrophil recruitment.
Consensus guidelines on the optimal management in interventional EUS procedures: results from the Asian EUS group RAND/UCLA expert panel Gut (IF 16.658) Pub Date : 2018-02-20 Anthony Y B Teoh, Vinay Dhir, Mitsuhiro Kida, Ichiro Yasuda, Zhen Dong Jin, Dong Wan Seo, Majid Almadi, Tiing Leong Ang, Kazuo Hara, Ida Hilmi, Takao Itoi, Sundeep Lakhtakia, Koji Matsuda, Nonthalee Pausawasdi, Rajesh Puri, Raymond S Tang, Hsiu-Po Wang, Ai Ming Yang, Robert Hawes, Shyam Varadarajulu, Kenjiro Yasuda, Lawrence Khek Yu Ho
Objectives Interventional endoscopic ultrasonography (EUS) procedures are gaining popularity and the most commonly performed procedures include EUS-guided drainage of pancreatic pseudocyst, EUS-guided biliary drainage, EUS-guided pancreatic duct drainage and EUS-guided celiac plexus ablation. The aim of this paper is to formulate a set of practice guidelines addressing various aspects of the above procedures. Methods Formulation of the guidelines was based on the best scientific evidence available. The RAND/UCLA appropriateness methodology (RAM) was used. Panellists recruited comprised experts in surgery, interventional EUS, interventional radiology and oncology from 11 countries. Between June 2014 and October 2016, the panellists met in meetings to discuss and vote on the clinical scenarios for each of the interventional EUS procedures in question. Results A total of 15 statements on EUS-guided drainage of pancreatic pseudocyst, 15 statements on EUS-guided biliary drainage, 12 statements on EUS-guided pancreatic duct drainage and 14 statements on EUS-guided celiac plexus ablation were formulated. The statements addressed the indications for the procedures, technical aspects, pre- and post-procedural management, management of complications, and competency and training in the procedures. All statements except one were found to be appropriate. Randomised studies to address clinical questions in a number of aspects of the procedures are urgently required. Conclusions The current guidelines on interventional EUS procedures are the first published by an endoscopic society. These guidelines provide an in-depth review of the current evidence and standardise the management of the procedures.
Gastrointestinal ultrasound in inflammatory bowel disease: an underused resource with potential paradigm-changing application Gut (IF 16.658) Pub Date : 2018-02-14 Robert Venning Bryant, Antony B Friedman, Emily Kate Wright, Kirstin M Taylor, Jakob Begun, Giovanni Maconi, Christian Maaser, Kerri L Novak, Torsten Kucharzik, Nathan S S Atkinson, Anil Asthana, Peter R Gibson
Evolution of treatment targets in IBD has increased the need for objective monitoring of disease activity to guide therapeutic strategy. Although mucosal healing is the current target of therapy in IBD, endoscopy is invasive, expensive and unappealing to patients. GI ultrasound (GIUS) represents a non-invasive modality to assess disease activity in IBD. It is accurate, cost-effective and reproducible. GIUS can be performed at the point of care without specific patient preparation so as to facilitate clinical decision-making. As compared with ileocolonoscopy and other imaging modalities (CT and MRI), GIUS is accurate in diagnosing IBD, detecting complications of disease including fistulae, strictures and abscesses, monitoring disease activity and detecting postoperative disease recurrence. International groups increasingly recognise GIUS as a valuable tool with paradigm-changing application in the management of IBD; however, uptake outside parts of continental Europe has been slow and GIUS is underused in many countries. The aim of this review is to present a pragmatic guide to the positioning of GIUS in IBD clinical practice, providing evidence for use, algorithms for integration into practice, training pathways and a strategic implementation framework.
Outcome measures in coeliac disease trials: the Tampere recommendations Gut (IF 16.658) Pub Date : 2018-02-13 Jonas F Ludvigsson, Carolina Ciacci, Peter HR Green, Katri Kaukinen, Ilma R Korponay-Szabo, Kalle Kurppa, Joseph A Murray, Knut Erik Aslaksen Lundin, Markku J Maki, Alina Popp, Norelle R Reilly, Alfonso Rodriguez-Herrera, David S Sanders, Detlef Schuppan, Sarah Sleet, Juha Taavela, Kristin Voorhees, Marjorie M Walker, Daniel A Leffler
Objective A gluten-free diet is the only treatment option of coeliac disease, but recently an increasing number of trials have begun to explore alternative treatment strategies. We aimed to review the literature on coeliac disease therapeutic trials and issue recommendations for outcome measures. Design Based on a literature review of 10 062 references, we (17 researchers and 2 patient representatives from 10 countries) reviewed the use and suitability of both clinical and non-clinical outcome measures. We then made expert-based recommendations for use of these outcomes in coeliac disease trials and identified areas where research is needed. Results We comment on the use of histology, serology, clinical outcome assessment (including patient-reported outcomes), quality of life and immunological tools including gluten immunogenic peptides for trials in coeliac disease. Conclusion Careful evaluation and reporting of outcome measures will increase transparency and comparability of coeliac disease therapeutic trials, and will benefit patients, healthcare and the pharmaceutical industry.
Immune activation underlies a sustained clinical response to Yttrium-90 radioembolisation in hepatocellular carcinoma Gut (IF 16.658) Pub Date : 2018-02-13 Valerie Chew, Yun Hua Lee, Lu Pan, Nurul J M Nasir, Chun Jye Lim, Camillus Chua, Liyun Lai, Sharifah Nur Hazirah, Tony Kiat Hon Lim, Brian K P Goh, Alexander Chung, Richard H G Lo, David Ng, Rene L F Filarca, Salvatore Albani, Pierce K H Chow
Objectives Yttrium-90 (Y90)-radioembolisation (RE) significantly regresses locally advanced hepatocellular carcinoma and delays disease progression. The current study is designed to deeply interrogate the immunological impact of Y90-RE, which elicits a sustained therapeutic response. Design Time-of-flight mass cytometry and next-generation sequencing (NGS) were used to analyse the immune landscapes of tumour-infiltrating leucocytes (TILs), tumour tissues and peripheral blood mononuclear cells (PBMCs) at different time points before and after Y90-RE. Results TILs isolated after Y90-RE exhibited signs of local immune activation: higher expression of granzyme B (GB) and infiltration of CD8+ T cells, CD56+ NK cells and CD8+ CD56+ NKT cells. NGS confirmed the upregulation of genes involved in innate and adaptive immune activation in Y90-RE-treated tumours. Chemotactic pathways involving CCL5 and CXCL16 correlated with the recruitment of activated GB+CD8+ T cells to the Y90-RE-treated tumours. When comparing PBMCs before and after Y90-RE, we observed an increase in tumour necrosis factor-α on both the CD8+ and CD4+ T cells as well as an increase in percentage of antigen-presenting cells after Y90-RE, implying a systemic immune activation. Interestingly, a high percentage of PD-1+/Tim-3+CD8+ T cells coexpressing the homing receptors CCR5 and CXCR6 denoted Y90-RE responders. A prediction model was also built to identify sustained responders to Y90-RE based on the immune profiles from pretreatment PBMCs. Conclusion High-dimensional analysis of tumour and systemic immune landscapes identified local and systemic immune activation that corresponded to the sustained response to Y90-RE. Potential biomarkers associated with a positive clinical response were identified and a prediction model was built to identify sustained responders prior to treatment.
Does Akkermansia muciniphila play a role in type 1 diabetes? Gut (IF 16.658) Pub Date : 2018-02-10 Gilles Mithieux
A field currently attracting increasing interest concerns the possible role that the intestinal microbiota might play in human health and disease. The fact that novel sequencing approaches applied to the microbiota genome are available has definitely favoured the rapid development of this field. The recent re-emergence in this area began with studies on obesity and metabolic diseases. Various associations between microbiota composition and metabolic diseases such as obesity and type 2 diabetes have been reported, in both rodents and humans, emphasising the key role of dietary habits in the composition of the bacterial population.1–3 However, experiments aimed at changing microbiota composition and transferring/exchanging the intestinal microbiota to alter the metabolism of the host have proved somewhat controversial and failed to unequivocally establish a causal role for the gut microbiota in metabolic diseases.4 Whatever the case, it is noteworthy that a specific bacterium, Akkermansia muciniphila , an abundant constituent of the gut microbiota in healthy humans, has been demonstrated to correct host metabolic disorders when given by gavage as a probiotic in obese insulin-resistant mice.2 Nowadays, interest in the role of intestinal microbiota in …
Comprehensive characterisation of compartment-specific long non-coding RNAs associated with pancreatic ductal adenocarcinoma Gut (IF 16.658) Pub Date : 2018-02-10 Luis Arnes, Zhaoqi Liu, Jiguang Wang, Hans Carlo Maurer, Irina Sagalovskiy, Marta Sanchez-Martin, Nikhil Bommakanti, Diana C Garofalo, Dina A Balderes, Lori Sussel, Kenneth P Olive, Raul Rabadan
Objective Pancreatic ductal adenocarcinoma (PDA) is a highly metastatic disease with limited therapeutic options. Genome and transcriptome analyses have identified signalling pathways and cancer driver genes with implications in patient stratification and targeted therapy. However, these analyses were performed in bulk samples and focused on coding genes, which represent a small fraction of the genome. Design We developed a computational framework to reconstruct the non-coding transcriptome from cross-sectional RNA-Seq, integrating somatic copy number alterations (SCNA), common germline variants associated to PDA risk and clinical outcome. We validated the results in an independent cohort of paired epithelial and stromal RNA-Seq derived from laser capture microdissected human pancreatic tumours, allowing us to annotate the compartment specificity of their expression. We employed systems and experimental biology approaches to interrogate the function of epithelial long non-coding RNAs (lncRNAs) associated with genetic traits and clinical outcome in PDA. Results We generated a catalogue of PDA-associated lncRNAs. We showed that lncRNAs define molecular subtypes with biological and clinical significance. We identified lncRNAs in genomic regions with SCNA and single nucleotide polymorphisms associated with lifetime risk of PDA and associated with clinical outcome using genomic and clinical data in PDA. Systems biology and experimental functional analysis of two epithelial lncRNAs ( LINC00673 and FAM83H-AS1 ) suggest they regulate the transcriptional profile of pancreatic tumour samples and PDA cell lines. Conclusions Our findings indicate that lncRNAs are associated with genetic marks of pancreatic cancer risk, contribute to the transcriptional regulation of neoplastic cells and provide an important resource to design functional studies of lncRNAs in PDA.
Modern diagnosis of GERD: the Lyon Consensus Gut (IF 16.658) Pub Date : 2018-02-09 C Prakash Gyawali, Peter J Kahrilas, Edoardo Savarino, Frank Zerbib, Francois Mion, André J P M Smout, Michael Vaezi, Daniel Sifrim, Mark R Fox, Marcelo F Vela, Radu Tutuian, Jan Tack, Albert J Bredenoord, John Pandolfino, Sabine Roman
Clinical history, questionnaire data and response to antisecretory therapy are insufficient to make a conclusive diagnosis of GERD in isolation, but are of value in determining need for further investigation. Conclusive evidence for reflux on oesophageal testing include advanced grade erosive oesophagitis (LA grades C and D), long-segment Barrett’s mucosa or peptic strictures on endoscopy or distal oesophageal acid exposure time (AET) >6% on ambulatory pH or pH-impedance monitoring. A normal endoscopy does not exclude GERD, but provides supportive evidence refuting GERD in conjunction with distal AET <4% and <40 reflux episodes on pH-impedance monitoring off proton pump inhibitors. Reflux-symptom association on ambulatory reflux monitoring provides supportive evidence for reflux triggered symptoms, and may predict a better treatment outcome when present. When endoscopy and pH or pH-impedance monitoring are inconclusive, adjunctive evidence from biopsy findings (histopathology scores, dilated intercellular spaces), motor evaluation (hypotensive lower oesophageal sphincter, hiatus hernia and oesophageal body hypomotility on high-resolution manometry) and novel impedance metrics (baseline impedance, postreflux swallow-induced peristaltic wave index) can add confidence for a GERD diagnosis; however, diagnosis cannot be based on these findings alone. An assessment of anatomy, motor function, reflux burden and symptomatic phenotype will therefore help direct management. Future GERD management strategies should focus on defining individual patient phenotypes based on the level of refluxate exposure, mechanism of reflux, efficacy of clearance, underlying anatomy of the oesophagogastric junction and psychometrics defining symptomatic presentations.
Non-coding regulatory variations: the dark matter of pancreatic cancer genomics Gut (IF 16.658) Pub Date : 2018-03-01 Aldo Scarpa, Andrea Mafficini
Pancreatic ductal adenocarcinoma (PDAC) is the seventh cause of death for cancer worldwide and the third in the USA, where it is expected to become the second by year 2030. Unlike other cancers, little progress has been made when it comes to therapeutic options other than surgery, which is possible only for a small fraction (~20%) of patients presenting with localised disease.1 2 For the above reasons, large efforts have been undertaken to get a deeper understanding of the molecular alterations and their effects on cancer cells and tumour microenvironment, by exploiting both innovative disease models and high-throughput studies for genomic and transcriptomic profiling of PDAC.3 4 In the meanwhile, genome-wide association studies, and the study of familial pancreatic cancer, have been looking for and found genetic variations associated to PDAC onset and outcome.5 6 At the genomic level, mutations in the coding region of several genes have been consistently identified, together with disruptive structural alterations whose effect has been linked to the altered functionality (eg, KRAS, TP53 ) or loss (eg, CDNK2A , SMAD4, ARID1A, ROBO2, BRCA1/2 ) of the respective gene products. Frequent and rare alterations identified converge in specific pathways, such as Wnt/Notch, Hedgehog, axon guidance, transforming growth factor beta, SWI/SNF (SWItch/sucrose non-fermentable) and DNA damage repair.3 RNA expression profiles, on the other …
Chronic hepatitis B: divide and conquer? Gut (IF 16.658) Pub Date : 2018-03-01 Michael Nassal
Chronic hepatitis B (CHB) puts 250 million people or more at a greatly increased risk to develop terminal liver disease.1 The causative agent, hepatitis B virus (HBV), is a small hepatotropic DNA virus that replicates via reverse transcription.2 Persistence of infection is the combined result of an inadequate host immune response3 and the stability of a special episomal form of the virus genome termed covalently closed circular (ccc) DNA.4 5 Associating with host and viral proteins into a minichromosome, cccDNA serves as template for all viral RNAs and thus progeny virions (figure 1). A true cure of CHB would thus require elimination of cccDNA from a patient’s liver; this is rarely achieved by current CHB therapies with type I interferon or nucleos(t)ide analogues (NAs) which inhibit HBV reverse transcription. Also, none of the new anti-HBV drugs in clinical development,6 including entry inhibitors such as Myrcludex-B (Myr-B)7 which block the interaction between HBV and its receptor Na+-taurocholate cotransporting polypeptide (NTCP; figure 1), directly target cccDNA. Not even recovery from acute self-limited hepatitis B appears to eradicate all cccDNA molecules although their number (corresponding to at least the ~1010 infected hepatocytes at the peak of infection) is massively reduced by the immune system within a few weeks,3 mostly with fully maintained liver function. Figure 1 Hepatitis B virus (HBV) covalently closed circular (ccc) DNA synthesis and immune-mediated loss. (A) HBV cccDNA synthesis and amplification from relaxed circular (rc) DNA. Hepatitis B virions exploit the bile acid transporter Na+-taurocholate cotransporting polypeptide (NTCP) as entry receptor into human hepatocytes. After the envelope is stripped off, the nucleocapsids (NC) transport the rcDNA genome to the nucleus where conversion into cccDNA takes place. cccDNA associates with host and viral factors into a minichromosome (not shown) that serves as transcription template for the viral RNA; …
Can we prevent and modify cardiometabolic disorders by controlling HCV infection? Gut (IF 16.658) Pub Date : 2018-03-01 Salvatore Petta, Antonio Craxi
HCV infection has an estimated global prevalence of 1.0%, corresponding to roughly 71.1 million of infected individuals in 2015, with major geographical heterogeneity.1 Due to the large burden of infected individuals in the general population, the likelihood of co-occurrence of chronic HCV infection and common comorbidities is substantial regardless of causal linkages. Population-based studies show a higher overall mortality, both for liver-related and unrelated causes in HCV infected subjects compared with those uninfected, and cross-sectional and cohort studies identify HCV as an independent risk factor for extrahepatic manifestations.2 These issues are summarised in two meta-analyses reporting that HCV-infected patients are at higher risk of mixed cryoglobulinaemia, lymphoma, lichen planus, Sjögren’s syndrome, porphyria cutanea tarda, rheumatoid-like arthritis, depression, chronic kidney or end-stage renal disease, type 2 diabetes and cardiovascular disorders/mortality.3 4 While the link between HCV and some of these comorbidities—mixed cryoglobulinaemia, lymphoma and glomerulonephritis—is well established and driven by recognised pathophysiological mechanisms, the nature of the association between the infection and other common extrahepatic comorbidities is less clear. Clinical and experimental evidences suggest an intrinsic link between HCV infection and insulin-resistance/diabetes driven by the ability of the virus to interfere with insulin signalling, even if the strength of this association is not always confirmed. Emerging data also support a link between HCV infection and cardiovascular alterations. However, relative to this topic, contrasting data exist and the basis of this association stems on associative data, theoretical speculations and inconclusive experimental evidence.5 This mass of data and the recent availability of highly effective antiviral regimens, able …
Management of patients on antithrombotic agents undergoing emergency and elective endoscopy: joint Asian Pacific Association of Gastroenterology (APAGE) and Asian Pacific Society for Digestive Endoscopy (APSDE) practice guidelines Gut (IF 16.658) Pub Date : 2018-03-01 Francis K L Chan, Khean-Lee Goh, Nageshwar Reddy, Kazuma Fujimoto, Khek Yu Ho, Seiji Hokimoto, Young-Hoon Jeong, Takanari Kitazono, Hong Sik Lee, Varocha Mahachai, Kelvin K F Tsoi, Ming-Shiang Wu, Bryan P Yan, Kentaro Sugano
This Guideline is a joint official statement of the Asian Pacific Association of Gastroenterology (APAGE) and the Asian Pacific Society for Digestive Endoscopy (APSDE). It was developed in response to the increasing use of antithrombotic agents (antiplatelet agents and anticoagulants) in patients undergoing gastrointestinal (GI) endoscopy in Asia. After reviewing current practice guidelines in Europe and the USA, the joint committee identified unmet needs, noticed inconsistencies, raised doubts about certain recommendations and recognised significant discrepancies in clinical practice between different regions. We developed this joint official statement based on a systematic review of the literature, critical appraisal of existing guidelines and expert consensus using a two-stage modified Delphi process. This joint APAGE-APSDE Practice Guideline is intended to be an educational tool that assists clinicians in improving care for patients on antithrombotics who require emergency or elective GI endoscopy in the Asian Pacific region.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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