Treatment failure in patients with chronic hepatitis E

Are we a step forward?

Ribavirin (RBV) is used for the treatment of patients with chronic hepatitis E, but RBV is associated with treatment failure and associated mortality. A new in vitro study identifies a virulence mutation in the hepatitis E virus (HEV) genome that may explain why treatment failures occur.

Awareness and detection of acute HEV infection is increasing, including in some regions where the infection was hitherto thought to be rare.1 Indeed, HEV is now thought to be most common cause of acute viral hepatitis. Most infected individuals remain asymptomatic and in most symptomatic patients the infection clears spontaneously; however, patients with chronic liver disease or haematological malignancies, solid organ recipients and other immunocompromised patients are at risk of developing a chronic HEV infection. Debing et al. studied the blood samples of 15 solid organ recipients with a chronic HEV infection who were treated with RBV, which is generally the treatment of choice.2 Two patients did not respond to treatment and one of them died. In both nonresponders, a nucleotide substitution was detected that resulted in a G1634R mutation in the C-terminal region of the HEV polymerase. To further assess the significance of this mutation, the 1634R mutation was introduced into a HEV genotype 3 replicon. RBV sensitivity did not differ between the 1634R construct and the wild-type replicon, but the luminescence signals yielded by the 1634R construct were consistently higher than those yielded by the wild-type replicon, suggesting that viral replication was increased. Similar observations were made when two hepatoma cell lines were transfected with 1634R, 1634K (the predominant amino acid at this position in genotype 1 HEV) or wild-type replicons. Quantification of viral RNA released from transfected Huh7 cells showed that 1634R and 1634K variants replicated to higher titres than the wild type at every time point. Finally, the fitness of G1634 and 1634R variants was assessed using direct competition assays. This demonstrated a relative fitness gain for 1634R of 7–9%. This study provides the first evidence of a viral polymerase mutation that contributes to increased HEV replication. Although there was no difference in RBV sensitivity, the authors suggest that it is the increased viral replication that leads to treatment failure. This is not entirely unexpected. In an abstract presented at UEG Week 2012, viral load was linked with the risk of acute liver failure.3 Another area of the HEV genome under scrutiny in relation to acute liver failure is the region encoding capsid proteins; the occurrence of nucleotide substitutions in this region was studied in another abstract presented at UEG Week 2013.4 The study by Debing et al. raises further questions. Could mutations at the 1634 locus help predict the outcomes of patients with a chronic HEV infection? Would combination antiviral therapy benefit these patients or should they be offered one of the newer antivirals? The current study is probably one of the first steps in the quest to find the answers.    References
  1. Salunke SS, Hunt AC, Laing RB, et al. Hepatitis E: An emerging infection in North of Scotland? Gut 2013;62:A186.
  2. Debing Y, Gisa A, Dalleier K, et al. A mutation in the hepatitis E virus RNA polymerase promotes its replication and associates with Ribavirin treatment failure in organ transplant recipients. Gastroenterology 2014; 147:1008–1011.e7. 
  3. Borkakoti J, Hazam RK, Kar P, et al. Viral load of hepatitis E virus: a key agent in acute liver failure during pregnancy. Gut 2012;61 (Suppl 3):A36.
  4. Borkakoti J, Ahmed G and Kar P. Nucleotide substitutions in the hepatitis E virus genome: a prime agent in acute liver failure. United European Gastroenterology Journal 2013;1 (Suppl 1):A299.
Further UEG Education resources
  1. Hepatitis E: Who, when and how to treat? Presentation by Robert A De Man at UEG Week Vienna 2014
  2. Hepatitis E. Presentation by Rakesh Aggarwal at UEG Week Berlin 2013

Finding the right level

Infliximab levels antibodies to infliximab and disease activity in Crohn's disease.

With the widespread use of biologics such as Infliximab (IFX) for the treatment of IBD, research has focused on why some individuals respond well to their use, whilst others lose response over time or don't respond at all. Attention has focused on the role of antibodies to IFX (ATI) and whether they are responsible, at least in part, for this phenomenon, and whether monitoring and measuring ATI is useful for frontline clinicians treating patients.

The development of anti-TNF drugs (biologics) to treat chronic inflammatory conditions such as Crohn's disease has brought about dramatic changes in disease management. However, over the past 10 years there has been growing recognition that disease activity may be inversely related to the circulating drug levels. In patients with Crohn's disease, low or undetectable serum trough levels of IFX are associated with worse clinical outcomes. ATI are thought to increase the clearance of IFX, resulting in low serum trough levels. As part of a multinational research group, Vande Casteele et al. investigated the clinical relevance of ATI in patients who had adequate IFX concentrations.1 In this observational study, 1,487 trough serum samples from 483 patients with Crohn's disease were analysed using a fluid phase mobility shift assay, which is sensitive for the identification of ATI in the presence of IFX. They found that IFX trough concentrations >2.79 mg/mL during maintenance therapy were associated with remission, as measured by a C-reactive protein concentration of <5mg/L.  In addition, an ATI concentration level <3.15 U/mL was also associated with remission. Multivariate analysis showed that both the IFX trough concentration and ATI concentration were independent predictors of remission. The authors concluded that any detectable concentration of ATI was associated with greater disease activity, even in the presence of an adequate IFX trough concentration. They also postulated that ATI impair the effect of IFX via an alternative mechanism than by simply increasing its clearance. This suggestion is in keeping with the conclusion of Van Moerkecke et al. reporting on IFX levels and primary non-response at UEG Week 2009.2 These results support the role of therapeutic drug monitoring in patients with Crohn's disease who are receiving IFX. The results also provide justification for dose intensification with IFX in those patients without ATI but with a low IFX trough level and evidence of ongoing disease activity.  Patients with both low IFX trough levels and high ATI levels may benefit from conversion to a different TNF antagonist or 'class' of biologic agent. In an era of personalised medicine, adjusting medications according to the particular pharmacokinetics and immune adaptations of the individual receiving the medication may become the future gold standard. References 
  1. Vande Casteele N, Khanna R, Levesque BG, et al. The relationship between infliximab concentrations, antibodies to infliximab and disease activity in Crohn's disease. Gut Epub ahead of print 21 October 2014. DOI: 10.1136/gutjnl-2014-307883. 
  2. Van Moerkecke W, Cleynen I, Compernolle G, et al. Trough levels of infliximab in a cohort of primary non-responders. Gut 2009; 58 (Suppl II): A70.

Endoscopic happenings at UEG Week 2014

I am limbering up for a dose of endoscopy at UEG Week. The ESGE has already sent me free complimentary access to their eLearning unit "Colonoscopy – the Basics". Clearly they are trying to tell me something.

Hopefully you have now downloaded the UEG Week 2014 App, which allows you to choose between 20 different pathways. The UEG Week Vienna Pathways Tool can also be downloaded. I am particularly looking forward to the endoscopy pathway. On Saturday during the postgraduate teaching programme there will be two live endoscopy sessions in the afternoon. The live endoscopists can then relax until Tuesday morning when there will be wall-to-wall live endoscopy in Hall A. These Live sessions do not always go to plan and they are a great opportunity to see experts get into and out of difficulties. Alex Meining is in charge and has told me that he has a record 36 cases lined up. He promises "polyps, polyps, polyps (small ones, ugly ones, polyps in the ileum, polyps in the rectum, polyps in Barrett's, polyps in the stomach), several IBD patients with strictures, new endoscopes (a new gastroscope and the three-lens screening colonoscope from FUSE, Olympus brand new extra-wide-angle scope, etc.). (Only) one ESD, a POEM, pancreatic cysts (with drainage, inspection of IPMN with Spy and confocal). In addition, there are pancreatic and biliary strictures of various types, contrast-enhanced EUS and various EUS-FNAs using various needles". Sounds like the kind of real-life stuff that is always interesting to see how other approach. Don't forget UEG Week Live and UEG 24/7—streaming many sessions as they happen and then making them available later on. Note, however, that none of the live endoscopy sessions are live streamed. On Monday, I'm looking forward to the acute upper GI bleeding therapy update in Hall D. I've got high hopes for the Hemospray device, which I hope will allow me to stay in bed when injection and thermal therapy has failed. In my mind the only outstanding question is "Do we need to organise an early re-check the next morning?" My guess is yes, that white powder will not stay on forever! We have two free paper sessions on new imaging and diagnostic modalities in upper and lower GI endoscopy on Monday afternoon. Not sure why the organisers haven't put the two sessions in the same hall though? Nevertheless, it's great to see that technology arms race is still in place. Sadly, there is a clash between the upper GI update and the update on gastro and duodenal endotherapy. I have the greatest respect for duodenal endotherapy, which is Tiger country indeed. It would be great if there were something that reduces the risk of late bleeding! For a large mucosal defect I spray thrombin, but this stuff is ridiculously expensive. On Tuesday morning Lars Aabakken and I will be hosting a session dedicated to the future of colorectal cancer screening. We'll give you an update on what to do with sessile serrated lesions, and presentations on the thorny issue of how to prevent and deal with local recurrences. Hopefully we can get a consensus on how many times we should try to get rid of a local recurrence before we give up. These are just some of the endoscopic happenings at UEG Week 2014. There are lots more to choose from including updates on Barrett's, EUS, ERCP, capsule and small bowel disease. Endoscopy continues to develop in numerous simultaneous directions driven by new technologies. I think that it has overtaken radiology in complexity, variety and colour! Please give us some feedback on which endoscopy sessions you're enjoying throughout the meeting. The easiest way may be to tweet using any of the hashtags: #UEGWeek #endoscopy #UEGEducation. Alternatively, just grab me for a chat!

Moving through the oesophagus at UEG Week 2014

If this is not your first time at UEG Week, you will already know that coffee breaks and lunch are on us! Just don’t spend too much time on them, as we have an extensive programme on the oesophagus and all things related waiting for you as well!

The postgraduate teaching programme on Sunday is your entrée. It starts with novel approaches and views on dysphagia and eosinophilic oesophagitis in patients with normal endoscopy, followed by a case presentation session on new options in gastro-oesophageal reflux disease (GORD). In the afternoon, you will be served an update on the management and outcomes of upper gastrointestinal bleeding (UGIB). Starting Monday, the oesophagus offering becomes truly 'buffet style' and you may want to take a look at the UEG Week Vienna Pathways Tool to help tailor your schedule to your appetite. For instance, this might be a good opportunity to get a therapy update on acute upper GI bleeding, starting at 11:00 in Hall D. Alternatively, you may walk into Hall B for views on the optimal management of patients with belching, aerophagia, rumination and hiccups. Can't decide? Here's a tip. Look for sessions with a 'Live' symbol. These will be streaming live on the UEG website and made available after the meeting via UEG 24/7. This is also a good day for you to grab your congress lunch and join Professor Mark Fox and colleagues in a round table discussion on dysphagia, based on a case presentation. Please come early though, as seats are limited. During the afternoon, there are two free paper sessions that might interest you: "Clinical and molecular factors in oesophago-gastric cancer outcomes", starting at 14:00 in Lounge 5, and "New diagnostic modalities in upper GI endoscopy", starting at 15:45 in Hall G/H. Continuing with your oesophageal main course, Tuesday kicks off with a therapy update on GORD, the implications of molecular pathogenesis on endoscopic therapy for Barrett's oesophagus, and a session on the risk factors and management of upper GI bleeding. If you are interested in novel endoscopic interventions in the oesophagus, please be sure to attend a free paper session on this topic at 11:00 in Hall O. Right after lunch at 14:00, you might want to join the discussion on whether function tests for the upper GI tract are indeed necessary or not (Hall B) or perhaps you might rather attend a free paper session on risk stratification and ablation in Barrett's oesophagus (Hall O). Moving towards the end of the day, a symposium on evidence-based treatment of achalasia takes place. No meal is complete without dessert! On Wednesday, the oesophagus pathway wraps up, starting with fresh and innovative views on the challenges and new frontiers in GORD and Barrett's oesophagus. You are also in for an integrated pathologist's versus endoscopist's view on oesophageal squamous cell carcinoma, early Barrett's neoplasia and early gastric carcinoma in the 11:00 symposium in Hall I/K. To return home with a sweet taste in your mouth, UEG Week 2014 ends with three cherries on top of the cake: a symposium on adenocarcinomas of the oesophago-gastric junction, another on endoscopic resection of upper GI tumours, and a free paper session on eosinophilic oesophagitis and other immune-mediated upper GI diseases.      We hope you enjoy the oesophagus 'course' at this year's UEG Week and look forward to your comments and tweets! (#UEGWeek #oesophagus #UEGEducation).

Spotlight on cancer—covering all bases at UEG Week 2014

Time is ticking away to UEG Week 2014 and if fighting cancer makes you tick, you are about to enjoy a full-course week, with servings from a cutting-edge research programme on cancer screening, diagnosis and prevention, and treatment.

If you're an early bird, you might decide to start your UEG Week 2014 experience on Saturday by attending the postgraduate teaching programme, with a mid-morning session dedicated to pancreatic adenocarcinoma, which covers endoscopic ultrasound, radiology and pathology for differential diagnosis, resectability and novel systemic treatment options. Sunday is a busy day and kicks off early morning with a session on colorectal cancer (CRC), focusing on early detection and local treatment, with talks on colonoscopy and non-invasive tests in population screening, and on recognition and diagnosis of early (T1) cancer: endoscopy, histopathological diagnosis and the use of ESD or TEM. This session is followed by one on terminal GI cancer, focused on symptom management and patient care (including case presentations). If you are only arriving on Monday, no worries! You are just in time to get in gear for the opening plenary session, which includes a talk on advances in the management of CRC, and is followed later in the morning by a free paper session focusing on the clinico-pathological features of GI cancer. During the lunch break you may want to electronically browse through the posters at the E-poster exhibition, and attend the new 'Poster Champ' sessions (from Monday to Wednesday), to select and award the best posters in each category. The afternoon programme includes plenty of sessions for you to choose from, starting with a free paper session on imaging techniques in colonoscopy, followed by another on new diagnostic modalities in upper GI endoscopy. In parallel, from a cancer treatment perspective, the session on late breaking digestive oncology abstracts is very appealing, and just prior to a session on the current and future perspectives in pancreatic cancer. Tuesday begins with a session on funding available for research under the EU research framework programme (H2020), followed by a 'Posters in the Spotlight' session on "Mechanisms underlying the development of GI cancer". This format is new for UEG Week 2014, in which hot topic research E-posters are presented on stage, and an oral free paper prize will be presented to the best poster. The afternoon kicks off with a free paper session on novel mechanisms and targets in CRC, followed by two sessions focusing on endoscopic management of early colorectal neoplasia and treatment of liver metastases. Wednesday wraps up this year's exciting and vibrant UEG Week, starting with novel approaches to rectal cancer from the viewpoint of the pathologist and the endoscopist. The final afternoon starts off with a round table discussion on molecular guided therapy for GI cancer, and ends with a session on the pancreas, in which an annual review of pancreatic cancer will be presented from basic and clinic viewpoints.  To make sure you're not missing out, please do complement this brief by browsing the complete programme online or by viewing the cancer pathway, which can be accessed online or via the UEG Week App.  We'd also love to hear what cancer content you find appealing throughout the meeting. Tweet to let us know! #UEGWeek #GIcancer #UEGEducation. On a footnote, since you can't physically be in two places at once (yet!), UEG will be livestreaming many of the sessions as they happen via UEG Week Live and all recorded talks will be made available via UEG 24/7.

Hepatobiliary highlights at UEG Week 2014

There is no doubt that 2014 is witnessing a revolution in the treatment of hepatitis C. You can find out all the latest information at this year's UEG Week, starting with a dedicated session during the postgraduate teaching programme on Saturday morning (Viral hepatitis: Cure by modern regimens?). The course will further offer you the opportunity to get an update on non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease, as well as on the endoscopic management of malignant biliary obstruction challenges, and will also feature a clinical case-based session on liver function assessments.

For further insights into hepatitis C management, be sure to attend the opening plenary session on Monday morning, which includes a talk by Professor Michael Manns, followed by an overview by Professor Heiner Wedermeyer of what's new in hepatology in clinical practice in 2014. After lunch, there will be a special free paper session on the lingering clinical challenges for hepatitis C therapy, followed by an update symposium on viral hepatitis therapies. Hepatitis C may be a lead actor in this year's UEG Week liver 'play', but much more besides is being covered. For example, why not join a round table discussion on non-obstructive jaundice on Monday lunchtime (please note that numbers are limited for these sessions)? Updates on NAFLD and liver cirrhosis (in the format of a free paper session and posters in the spotlight) are also featured in the afternoon, in parallel with a session on the immunopathogenesis of pancreatitis and hepatitis, as part of UEG’s two day "Today's Science; Tomorrow's Medicine" initiative. On Tuesday morning you might find yourself undecided on which session to attend. Will it be 'Clinical management of liver cirrhosis' or 'The liver as a central regulator of inflammation'? Shortly after, there's an update on alcoholic liver disease and novel aspects of biliary tract cancer to choose between. Finally, the afternoon has new concepts in management of biliary diseases and a free paper session on biliary tract cancer occurring simultaneously. Lucky for you, UEG has your back; all recorded sessions will be made available via UEG 24/7, with many of the sessions being made available as they happen, via UEG Week Live. For the final day of the meeting, there will still be plenty to learn about cholangiocellularcarcinoma (and neuroendocrine tumours), as well as diagnosis and management of both non-cirrhotic and cirrhotic liver nodules. And you may want to return home with some new insights on biliary stenting or on the interconnecting pathways linking viral hepatitis, cytokines and liver regeneration, which you can learn all about in the last two free paper sessions of the day. And don't forget there are poster sessions running throughout the whole meeting! Last but not least, we invite to visit the online program and search for your specific topic of interest—the word 'liver’ alone returns 355 matches! Or you might want to make use of the UEG Week Vienna Pathways Tool to make sure you’re not missing out! You can also download the UEG Week App for your mobile device and have all this information and more at your fingertips. We hope you enjoy the hepatobiliary pathway and would love to hear what you find interesting at this year's meeting! Please do comment or tweet to let us know by including one or more of the following hashtags: #UEGWeek #Hepatobiliary #UEGEducation. You can also visit the UEG Education Lounge located in Hall Z and talk to us personally. Have a great meeting!

UEG Week 2014 in transit: A view from the intestine

With UEG Week 2014 just around the corner, we have forged a brief summary for your perusal that might be of interest if you're into inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) or other issues related to functional and organic bowel diseases.

Unsurprisingly, IBD is one of the major topics at UEG Week 2014. If IBD is your thing, then you should kick things off with the postgraduate teaching programme on Saturday and Sunday, when you can learn more about what's important for diagnosis, the challenges of refractory IBD and also skin lesions in IBD. And do make sure you're ready for Monday because it's jam-packed! The opening plenary session includes no fewer than two talks on 'How to translate basic immunology findings into clinical reality in IBD'. You may then want to stay put in Hall A to get updates on 'What's new in 2014' and to receive highlights from Digestive Disease Week 2014. However, you might prefer to stretch your legs and explore the convention centre. Why not look up environmental factors and IBD (Hall F2), conventional therapy for IBD (Hall I/K) or the free paper session on small bowel imaging and endoscopic interventions (Lounge 6), where you can get updates on everything from the diagnostic value of faecal calprotectin to the clinical usefulness of virtual enteroscopy for Crohn’s Disease. At lunchtime there's a round table discussion on treating IBD in patients with cancer and early in the afternoon there are parallel sessions on pathophysiology and new imaging tools. After all that, move to Hall E to be updated on the new European guidelines for diagnosing IBD or to Hall L/M to find out about new therapeutics for specific targets. Tuesday and Wednesday continue in the same vein, with more than ten other IBD sessions on offer—from management of complicated Crohn's disease to the best use of biologics, new biomarkers, new drugs, epidemiology and outcomes, targeting new pathways and what's new in 2014. In order to bone up on coeliac disease and wheat allergy, you should look up the postgraduate teaching programme session in Hall E on Sunday morning. Monday sees an afternoon session on 'New Challenges in Gluten Sensitivity: From Bench to Bedside', and includes a talk on triggers and drivers of autoimmunity. Look up 'Posters in the Spotlight' on Tuesday afternoon to learn about the applicability of serological tests for the diagnosis of coeliac disease in asymptomatic children. Speaking of those who are asymptomatic—should they be put on a gluten-free diet? Find out at the round table discussion on Wednesday lunchtime! To learn more about diet, food intolerance, and nutrition you'll probably want to secure a seat in Hall G/H Wednesday from 11:00am. Diet appears to be a major modulator of gut microbiota and this is one of the topics covered in the 'Today's Science Tomorrow's Medicine' session on 'Diet, immunity and systemic disease' in Hall R late on Monday morning. Moving on to bacteria, blooming blasters of bad bugs probably don't want to miss out on the postgraduate training programme on Saturday afternoon, which covers diagnosis, management and prevention of Clostridium difficile infections. Obviously, faecal microbial transplantation is bound to attract a lot of attention—make sure you secure your seat in Hall C on Tuesday afternoon! To learn more about the gut microbiota in health and disease, the symposium on altered intestinal microbiota composition in IBS on Monday morning in Hall G/H is an absolute must. Participate in the debate on whether gut microbiota alterations in patients with IBS are a cause or a consequence. To be updated on FODMAP and gluten-free diets for IBS patients you just have to look up Hall I/K and Hall Q on Monday afternoon, and if this is not enough, a panoply of talks on restrictive diets is in store for you in Hall E just before lunch on Tuesday. Next, hurry to Hall G/H to participate in the round table discussion on how to manage the difficult IBS patient, and then, immediately after this, Hall D is certainly the place to be on Tuesday afternoon if you want to continue learning how to manage IBS patients successfully. Please, however, be aware that there is also a Translational/Basic Science pathway session on normal and abnormal cross-talk at the mucosal border and the relevance of this for GI function and dysfunction taking place on Tuesday afternoon (Hall L/M). Faecal incontinence gets attention in the postgraduate teaching programme on Sunday, while constipation takes the stage on Tuesday afternoon—these two topics are also the focus of a free paper session in Hall R on Wednesday morning. Finally, don't forget the 'Neurogastroenterology and Motility: What’s new in 2014?' symposium in Hall 2 at 11:00–12:30 on Wednesday! With so much on offer, don't forget that there are plenty of tools available to help you make the most of UEG Week 2014. Downloading the UEG Week Vienna Pathways Tool is one way of getting acquainted with the entire conference programme. Or maybe you prefer to download the UEG Week App instead? The App includes the 'Pathways' feature that enables you to identify exactly which sessions might be of particular interest for your specialty. Many of the talks will be made available as they happen via UEG Week Live, which is great if you can't make the meeting in person. All recorded sessions will also be made available via UEG 24/7—perfect if you can't decide between parallel sessions!   We'd love to hear what intestine and motility content you find interesting throughout the meeting, so please do tweet to let us know by including the hashtag #UEGEducation and one or more of the following: #Intestine #IBS #IBD #motility #microbiota #FMT (faecal microbial transplantation) #Cdiff   Happy ruminating!

Translating the basics at UEG Week 2014

If you're a GI researcher interested in basic and translational science, you could be forgiven for not registering for the postgraduate teaching programme at UEG Week 2014. Well, if you happen to be arriving in Vienna this weekend, I invite you to give it a try—you might leave with your next big grant project idea on your hands!

The postgraduate teaching programme on Saturday and Sunday will focus on the most recent and urgent clinical needs in how to better diagnose, manage and treat GI diseases, with basic and translational science having an increasing role in providing answers. For more information, please have a look at the postgraduate teaching programme online.  If you prefer to enjoy the city sights during the weekend and start fresh on Monday morning, there will be plenty of opportunity to learn and interact. Indeed, UEG has increased the number of translational/basic science symposia available during this year's core meeting. The first symposium takes place on Monday morning, with a session on nuclear receptors and the molecular pathways governing insulin resistance and lipotoxicity in non-alcoholic steatohepatitis. In the afternoon, you can learn about novel regulatory mechanisms involving cytokines and intestinal inflammation in inflammatory bowel disease. Four (!) additional translational/basic science sessions take place on Tuesday, with topics ranging from the implications of molecular pathogenesis on endoscopic therapy for Barrett's oesophagus to the development of cystic pancreatic lesions, dysbiosis and intestinal barrier defects, and bile acids and nuclear receptors. The final day of the meeting will feature the latest on genetics and upper GI cancer, focusing on its clinical relevance, as well as the emerging role of microbiota in non-alcoholic fatty liver disease. This also seems like the perfect opportunity to draw your attention to the Young GI Network activities taking place during UEG Week 2014, where delegates below the age of 40 will have the unique opportunity to talk with and receive guidance from experienced scientists and physicians. To make these interactions easier and more casual, UEG has prepared a dedicated lounge at the venue where you can network with peers from around the world and form new collaborations over a smooth cup of coffee. For more information please check out the plans for the Young GI Network at UEG Week 2104. We would love to hear your thoughts on the translational/basic science content at this year’s meeting! Please feel free to comment here or tweet with one or more of the following hashtags: #UEGWeek #Science #UEGEducation. Alternatively, why not come and talk to us in person at the UEG Education Lounge, which is located in Hall Z. As a final reminder, and in case you won't be able to join us in person this year, UEG will be live streaming a significant amount of sessions through UEG Week Live. As an alternative, or if you cannot decide on which parallel session to attend, we also have things covered; all recorded presentations will be made available via UEG 24/7.

How to stomach H. pylori during UEG Week 2014

UEG Week 2014 is now just a few days away, and if your research or specialty involves upper GI diseases, such as gastric ulcers or gastric cancer, you're sure to get your fill at this year’s meeting.

With more than 35 sessions of relevance to choose from, we've selected a few that you might find interesting and informative, but do consider downloading the UEG Week Vienna Pathways Tool to make sure you're not missing out! The postgraduate teaching programme on Sunday has a lot in store for you. In the morning, there is a session on advanced endoscopic techniques, including gastrointestinal imaging and submucosal endoscopy. Around noon, you'll need to choose between three practical sessions that are supported by case presentations: learn more about managing and caring for patients with terminal GI cancer, progress in dysphagia and gastroparesis or whether we've solved all the problems associated with H. pylori infection. The afternoon is completed by a session on management and outcomes of upper GI bleeding, including endoscopic management, blood transfusion, pharmacological strategies for improving outcomes in acute upper GI bleeding, and information on the impact of novel oral anticoagulants on the gastroenterologist's case load. How H. pylori alters stem cell homeostasis by direct colonization of the gastric glands is the subject of a talk by Michael Sigal in Monday morning's opening plenary session in Hall A. If you choose to stay put in Hall A, you will certainly be able to find something to your liking in the 'What's new in 2014' session. Alternatively, you may want to proceed to Hall D if you're particularly interested in issues related to acute upper GI bleeding, or to Hall B if you’re more into topics related to belching, aerophagia, hiccups, rumination or cyclic vomiting. Of course, functional dyspepsia is also on the menu. Talks on diagnostic criteria and therapeutic approaches will surely attract quite a few attendants in a symposium dedicated to new thoughts in functional dyspepsia. This symposium also includes a talk on the role of food allergy in dyspepsia, and data on the association of serum adipocytokines and gut hormone levels with gastric emptying and symptoms in patients with functional dyspepsia will be presented. Monday finishes with talks and a panel discussion on 'quality endoscopy', including upper GI diagnosis, and should give rise to some interesting discussions based on experience and data from around the world. By the way, don't forget to season your Monday with some of the 'Best of DDW' from 14.00—15.30 in Hall A. There are two free paper sessions on offer if you're up and about bright and early on Tuesday morning: one on upper GI bleeding (risk factors and management) and the other on gastric carcinogenesis (new insights into pathogenesis and management). Tuesday morning is also H. pylori galore and offers an entire symposium on H. pylori-associated gastric carcinogenesis, covering everything on how H. pylori is able to induce gastric cancer. Unsurprisingly, there will be presentations on H. pylori-induced epigenetic changes, H. pylori-mediated miRNA regulation, proteolytic activity, and how iron deficiency may be involved in H. pylori-associated carcinogenesis. Later in the day, Hall B will also host talks on function tests for the upper GI tract and this session is a must for those interested in lactose intolerance and for those who do not really know what to make of oesophageal high-resolution manometry. If you're not full by the end of Tuesday, there's still plenty on offer on the final day of the meeting. On Wednesday lunchtime there are limited spaces available at two Round Table Discussions: one on the impact of long-term PPI use and one on molecular guided therapy for GI cancer. You also have your pick of two Wednesday afternoon symposia. In case you want to update yourself on advances in obtaining a mechanistic understanding of dyspepsia, Hall B is the place to be. Here you will also get a general update on dyspepsia, including data on new drugs, psychological therapies, and diagnostic tools. If adenocarcinoma of the oesophago-gastric junction sounds more alluring, then you should proceed to Hall F1. Here, different aspects of diagnosis and treatment will be dealt with, and the session highlights the relevance of taking a multidisciplinary approach to this particular disease. Finally, don't forget to check out the poster sessions on Monday, Tuesday and Wednesday, with 'Posters in the Spotlight' available for viewing in the E-poster lounge on those days. We'd love to hear what stomach and H. pylori content you find interesting throughout the meeting, so please do tweet to let us know by including one or more of the following hashtags: #UEGWeek #Stomach #Hpylori #upperGI #UEGEducation. In case you're not attending UEG Week in person, please note that many of the talks will be made available as they happen via UEG Week Live – just follow the livestream on the UEG website (www.live.ueg.eu/week). If you can't catch every talk as it happens (in person or via the livestream), then you're in luck because all recorded sessions will be made available via UEG 24/7 (www.ueg.eu/week/24-7). Bon appétit!

Cap, hood, cuff, balloon

What is next for colonoscopy?

Balloon colonoscopy is yet another invention that aims to improve the adenoma detection rate (ADR) during colonoscopy. A recent pilot study evaluated the safety and efficacy of a novel colonoscope with an inflatable balloon at the distal end, reporting no serious adverse events among the study population. Quality indicators such as caecal intubation rate, ADR and polyp detection rate were reported, but future studies are awaited to compare the ADR of balloon colonoscopy with that of standard colonoscopy.

Endoscopy is a great specialty, in which opportunities for research and development are abundant for the enthusiasts, owing to a steady stream of technological developments. This technological arms race has resulted in the emergence of numerous optical enhancement methods. High-definition scopes, narrow-band imaging (NBI), autofluorescence imaging (AFI), Fuji Intelligent Chromoendoscopy (FICE), i-SCAN image enhancement technology, wide angle endoscopes, the Third Eye retroscope, caps and more recently Full Spectrum Endoscopy (FUSE) are aimed at improving the detection and recognition of pathology. It is the limited visibility behind colonic folds, particularly in the right hemi-colon, that these new technologies are trying to overcome. Gralnek et al. now describe the use of a novel colonoscope with an integrated inflatable balloon situated behind the distal end of the colonoscope.1 A standard adult colonoscope was modified and only white light examination was performed. Two expert endoscopists from a single centre took part in this pilot study. Upon reaching the caecum the balloon was inflated for controlled withdrawal, the idea being that when inflated the balloon would straighten out the colonic fold and improve visualisation. 47 patients were included in the final analysis and the authors report no major adverse events following use of the novel colonoscope. The reported average caecal intubation time, withdrawal time and total procedure time were 4.3 minutes, 7.4 minutes and 16.5 minutes, respectively. The polyp detection rate and adenoma detection rate were 53.2% and 44.7%, respectively.  Unfortunately, there was no control group, which raises the question of whether a comparable adenoma detection rate might have been achieved with the use of a conventional endoscope, particularly if withdrawn slowly over a 7–8 minute period. The participants in this study were recruited from colorectal cancer and polyp surveillance groups, along with others (no breakdown provided) in whom the polyp burden was expected to be greater than in 'all comers'. It was unclear as to why terminal ileal intubation was successful in only 5 of 47 colonoscopies and rectal retroversion in 31 of 47 colonoscopies. Whether the impregnated balloon impairs manoeuvrability of the tip is not known. I guess that the aim of the study was to look only at safety outcomes. Intermediate results from a randomised controlled tandem study comparing standard colonoscopy with balloon colonoscopy were presented at the UEG Week Berlin 2013.2 The results were impressive, with 100% additional detection of polyps with second-pass balloon colonoscopy and a 5.6 % polyp miss-rate on first-pass balloon colonoscopy. The final report is still awaited, however, future research into right-sided adenoma detection and tip control for difficult polypectomy using balloon colonoscopy would be interesting. References
  1. Gralnek IM, Suissa A and Domanov S. Safety and efficacy of a novel balloon colonoscope: a prospective cohort study. Endoscopy. 2014; 46: 883–887.
  2. Shpak B HZ, Kiesslich R, Moshkowitz M, et al. Novel balloon-colonoscope for increased polyp detection rate—intermediate results of a randomized tandem study. United European Gastroenterology Week (UEGW); Oct 12-16 2013, Berlin, Germany.

A pancreatic potpourri at UEG Week 2014

The countdown to UEG Week 2014 is on and for those of you interested in all things pancreatic, there are rich pickings at this year's meeting.

Saturday morning on the postgraduate teaching programme starts things off with a session dedicated to pancreatic adenocarcinoma, the eighth most common cancer in Europe. The mysteries of diagnosis, staging investigations and treatment options will all be dissected. In the afternoon the focus turns towards necrotizing pancreatitis, with presentations by both a gastroenterologist and a surgeon. Sunday moves onto the tricky issue of cystic pancreatic lesions, considering diagnostic evaluation, follow up and the role of observation or resection. If you're not arriving at UEG Week until Monday then don't despair! The opening plenary session includes a talk on the effect of lymphotoxin in KRAS-induced pancreatic tumorigenesis and is followed later on in the morning by a free paper session dedicated to cellular crosstalk in pancreatic cancer. There are plenty of sessions to choose from on Monday afternoon too. Straight after the lunch break, check out the symposium on therapeutic EUS or the free paper session on the challenges of imaging pancreatic cancer. There is even a session dedicated to the pancreatic highlights from this year's DDW. Later in the afternoon there are two symposia on offer—one on quality endoscopy (from East to West) that includes talks on pancreatobiliary disease and pancreatobiliary EUS and one on current and future standards in pancreatic cancer. Alternatively, you might be interested in going along to one of the free paper sessions—immunopathogenesis of pancreatitis and hepatitis (part of the Today's Science, Tomorrow's Medicine pathway) and minimally invasive interventions in the pancreas. If you get out of bed on time on Tuesday morning, you will be rewarded with an update on the management of acute pancreatitis and a free paper session on hot topics in cholestatic and pancreatic disease. This is followed by a translational session on cystic pancreatic lesions and the diagnostic and therapeutic challenge they pose. The diagnosis of cystic pancreatic lesions is also the focus of a round table discussion on Tuesday lunchtime (note that numbers are limited for this particular session). An early afternoon symposium considers what to do in the face of abnormal liver and pancreatic function tests, while a free paper session takes on the topic of challenges in the treatment of pancreatic and biliary cancer. Following the session on acute pancreatitis during the morning, the multidisciplinary management of chronic pancreatitis is the focus of a symposium late on Tuesday afternoon. In addition, the clinical dilemma posed by cystic pancreatic lesions is again under consideration, but this time in a free paper session. The final day of UEG Week 2014 begins with a free paper session on chronic pancreatitis, specifically the pathophysiology and management of pain and fibrosis. As a suitable finish to UEG Week there are sessions reviewing the most interesting developments of 2014, including one dedicated to the pancreas. Posters session are running throughout the meeting on Monday, Tuesday and Wednesday, so do seek them out too! We'd love to hear what pancreas content you find interesting throughout the meeting, so please do tweet to let us know by including one or more of the following hashtags: #UEGWeek #Pancreas #UEGEducation. And don't forget that if you're not able to make it to UEG Week in person that many of the talks will be made available as they happen via UEG Week Live – just follow the livestream on the UEG website. If you can't catch every talk as it happens (in person or via the livestream), then you're in luck because all recorded sessions will be made available via UEG 24/7. Enjoy!

Inflammatory Bowel Disease

When to screen for latent tuberculosis?

Current guidelines recommend using a sensitive interferon-gamma release assay (IGRA) to screen patients with IBD for latent tuberculosis prior to initiation of anti-TNF therapy. However, new findings suggest that such screening should be considered much earlier, before initiation of any immunosuppressive therapy.

In their study, Wong et al. considered the performance of an IGRA (QuantiFERON®-TB Gold; Cellestis) in a population at moderate-to-high risk of tuberculosis; 268 patients with IBD were compared with 234 healthy controls.1 Among the patients with IBD, half were taking at least one immunosuppressant, such as azathioprine. The authors found that patients who were taking an immunosuppressant were significantly less likely to have a positive test result than patients who were not taking any immunosuppressants (13% versus 29.6%, P=0.002), thereby possibly masking the true incidence of latent tuberculosis. This effect was most pronounced in patients taking azathioprine (11.8% versus 27.3%; P=0.006). A subsequent quantitative analysis confirmed that patients taking an immunosuppressant generated a significantly lower interferon-gamma response (0.45 IU/ml versus 1.27 IU/ml; P=0.005). Although this study was confined to a population at moderate-to-high risk of tuberculosis, similar findings were reported in a previous meta-analysis, which looked at 9 studies that included 1,309 patients from across Europe and the USA.2 Whilst IGRAs have been found to have a high specificity and negative predictive value in immunocompetent adults, an accurate result does depend on an intact cell-mediated immune response. The authors propose that screening patients with IBD for latent tuberculosis should be carried out prior to initiation of any immunosuppressive therapies. However, to screen all patients with IBD would have cost implications. In addition, despite finding the most pronounced negative impact among those on azathioprine, current evidence elsewhere does not clarify the impact of individual immunosuppressants on the outcome of IGRAs. Screening only those patients at moderate-to-high risk of tuberculosis or who have more severe IBD, prior to starting immunosuppressants, may therefore be more cost effective. References
  1. Wong SH, Ip M, Tang W, et al. Performance of interferon-gamma release assay for tuberculosis screening in inflammatory bowel disease patients. Inflamm Bowel Dis Epub ahead of print 26 August 2014. DOI 10.1097/MIB.0000000000000147.
  2. Shahidi N, Fu YT, Qian H, et al. Performance of interferon-gamma release assays in patients with inflammatory bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis 2012; 18: 2034–2042.

Barrett's high-grade dysplasia with oesophageal varices. A difficult case!

Cases of Barrett's high-grade dysplasia with underlying varices are extremely rare and there is very little published literature on how best to manage these patients. A new case report attempts to address this question by suggesting band ligation without resection, but is this the answer?

Barrett's high-grade dysplasia and intramucosal cancer are now usually managed endoscopically by endoscopic mucosal resection (EMR) of visible lesions and ablation of flat dysplasia. Patients who have portal hypertension and oesophageal varices pose a particular challenge as they are at increased risk of bleeding. The increased risk of bleeding is not only due to the presence of varices but also because these patients are often coagulapathic and thrombocytopenic. One way of managing such patients is by endoscopic eradication of the varices followed by confirmation of success by endoscopic ultrasound (EUS) before proceeding with EMR or ablation.1 Alternatively, portal pressure can be reduced by transjugular intrahepatic portosystemic shunt (TIPS) placement followed by endoscopic therapy.Band ligation without resection has also been reported as safe, effective and simple for curing patients with short-segment Barrett’s oesophagus.3 Now, a single case report with a video presents the attempt of Palmer et al. to use band ligation without resection to eradicate high-grade dysplasia with a focus of intramucosal carcinoma, as diagnosed via prior biopsy.4 Unfortunately, superficial mucosal biopsies underestimate the stage of disease. Decisions about 'endoscopic cure' of such lesions should be made after histological analysis of the resection specimen to determine the depth of invasion, degree of differentiation and exclude lymphovascular invasion. The authors attempted to address this shortcoming by taking samples from the pseudo polyps created by the band ligator, but this only showed low-grade dysplasia and the staging of the disease remained unclear. As such, the proposal to use band ligation without resection seems to be an unsatisfactory halfway house! References
  1. Aranda-Hernandez J, Cirocco M and Marcon N. Treatment of dysplasia in Barrett esophagus. Clin Endosc 2014; 47: 55–64. 
  2. NeSmith M, Jou J, Fennerty MB, et al. Transjugular intrahepatic portosystemic shunt prior to endoscopic mucosal resection for Barrett’s esophagus in the setting of varices. ACG Case Rep J 2014; 1: 189–192. 
  3. Diaz-Cervantes E, De-la-Torre-Bravo A, Spechler SJ, et al. Banding without resection (endoscopic mucosal ligation) as a novel approach for the ablation of short-segment Barrett's epithelium: results of a pilot study. Am J Gastroenterol 2007; 102:1640–1645. 
  4. Palmer WC, Di Leo M, Jovani M, et al. Endoscopic management of high-grade dysplastic Barrett’s oesophagus with oesophageal varices. Gastrointes Endosc Epub ahead of print 9 August 2014. DOI:10.1016/j.gie.2014.06.034

Polyp surveillance

New study from Norway published in the New England Journal of Medicine.

Evidence regarding surveillance post-adenoma resection and the risks of eventual colorectal cancer (CRC) incidence and mortality over time is limited. The findings of a recent study from Norway published in the New England Journal of Medicine show that high-risk adenoma patients have increased CRC-related mortality despite colonoscopy surveillance, and suggest that low-risk adenoma patients may not require this intervention.

A huge proportion of colonoscopy capacity is taken up by adenoma surveillance. Guidelines from the ESGE1 and IARC in Europe and the AGA2 in the USA broadly recommend a follow-up 5–10 years after resection for individuals with low-risk or intermediate-risk adenomas and ever 3 years for those with high-risk adenomas. By contrast, guidelines from the BSG3 recommend a first follow-up after 1 year for individuals with high-risk adenomas. The paper by Løberg et al. in the New England Journal of Medicine used Cancer Registry and Cause of Death Registry data from Norway to identify 40,826 patients who had colorectal adenomas resected between 1993 and 2007.4 The Norwegian surveillance guidelines are similar to the ESGE guidelines, with high-risk cases defined as those with 3 or more polyps. Such high-risk cases are offered their first surveillance colonoscopy after 3 years. Patients who had polyps harbouring high-grade dysplasia, with a villous morphology or those who had a polyp 10 mm or larger in size, were offered a follow-up surveillance colonoscopy after 5 years. Patients with any other finding were classified as low risk and were not offered any surveillance. CRC mortality was analysed for those in low-risk and high-risk adenoma groups, with standardised incidence-based mortality ratios (SMR) calculated in comparison to a matched Norwegian population cohort. The median follow-up period in the study was 7.7 years, with 1,273 patients given a diagnosis of CRC in this period. In spite of the index adenomas having been removed, the number of deaths seen due to CRC was found to be increased during follow-up in the high-risk adenoma group (expected deaths 209, observed deaths 242; SMR 1.16). In the low-risk adenoma group mortality from CRC was reduced (expected deaths 189, observed deaths 141; SMR 0.75). This study is reassuring in that those patients who had 1–2 small tubular adenomas removed had a below average risk of developing CRC later in life. For this reason, the authors propose that colonoscopic surveillance may not be indicated in the low-risk group of patients. It is intriguing that the risk of bowel cancer remained above average in patients with high-risk findings. Do we need to carry out more frequent surveillance in this group? British surveillance guidelines advise a first follow-up after 1 year in patients with 3 or more polyps. Might this interval be sufficient to reduce the risk of subsequent CRC to background risk? References
  1. Hassan C, Quintero E, Dumonceau J-M, et al. Post-polpyectomy colonoscopy surveillance: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy 2013; 45: 842–851
  2. Lieberman DA, Rex DK, Winawer SJ, et al. Guidelines for colonoscopy surveillance after screening and polypectomy: a consensus update by the US Multi-Society Task Force on colorectal cancer. Gastroenterology 2012; 143:844–857
  3. Atkin WS and Saunders BP. Surveillance guidelines after removal of colorectal adenomatous polyps. Gut 2002; 51 (Suppl V): v6–v9
  4. Løberg M, Kalager M, Holme O, et al. Long-term colorectal-cancer mortality after adenoma removal. New Engl J Med 2014; 371: 799–807

A perfect storm

A record number of patient complaints for the 12-month.

The English Health and Social Care Information Centre recently reported a record number of patient complaints for the 12-month period from 1 April 2013—31 March 2014. The total tally was 174,872 complaints and the largest single source was complaints about inpatient care. In a country where people apologise for getting their feet stepped on, most patients do not complain about poor medical care and this figure is likely to be the tip of the iceberg.

So who is to blame for this epidemic? The West in general and the English National Health Service (NHS) in particular is seeing the beginning of a perfect storm in which several forces are converging. The first component is our increased life expectancy (lifespan), which has not been mirrored by an increase in healthy life expectancy (health span). People are now living longer in spite of accumulating health problems. Patients survive heart attacks, only to require multiple vascular interventions. Patients live with cancer longer, at huge expense, requiring close monitoring and frequent imaging. The second component of the perfect storm is patient expectation. It is paradoxical that although we now live longer than at any time before in history, we worry more about our health than ever. People are no longer content to see if that stubborn cough or sore throat will settle in a few days. After all, it may well be the beginning of something serious! Furthermore, they would rather have someone else, a 'qualified person', telling them that they have nothing to worry about. If their insomnia then turns out to be the first sign of a brain tumour, at least there is someone to sue. Many of the major IT companies are also developing smart watches with the ability to monitor health parameters and turn healthy people into nervous patients concerned about extra heart beats or poor quality of their REM sleep. In the case of the English NHS, the third component is that politicians are unwilling to pour further money into a health service that they see as inefficient. I guess that by throttling funds, they are hoping that a more efficient service will emerge. Sadly they are mistaken and instead services are increasingly managed on a shoestring. Wards are kept open with the bare minimum of nursing staff. Support services such as audiology, speech therapy, physiotherapy and occupational health are told that they have to cut expenditure by up to 20% As the above three factors are beginning to exert an irresistible force on the English health care system, managers' and politicians' eyes are increasingly turning towards the Pandora's box that is 'the marketplace'. When I first arrived in England some 30 years ago, hearing aids, dental care, retirement homes and eyesight tests were all free. However, it was soon realised that these services could be taken care of by private providers. As our creaking NHS is finding itself subjected to the unyielding effect of the above three forces, it is inevitable that this Pandora's box will be opened. Naturally, the NHS could never stop providing free emergency care for patients with serious acute disease or cancer, but this leaves plenty of scope for private providers in the marketplace. Why not ask pharmacists to see patients who develop a sore throat, wake up with a headache or simply feel tired? Pharmacists could charge patients either directly for giving them advice or indirectly by incurring a fee for the medicines that they recommend. Parents who find that their children have wonky teeth, can’t sit still in the classroom or simply don't seem to develop as well as their siblings, will in the future have to pay to have their children seen to. But why stop there? Why should the NHS provide joint replacements for free when instead it could supply patients with walking sticks? Why should the NHS provide free cataract extractions in both eyes when operating on just one eye is enough to allow people to read a book? Osteoarthritis and cataracts are neither emergency care nor cancer! Furthermore, why shouldn't patients pay for more expensive medication themselves? If patients don't like their angiotensin receptor blocker, they may opt for an angiotensin-II receptor blocker that has a different side effect profile! If patients are prepared to pay an extra €30.000 for a cytotoxic agent that gives them hope of an extra few months' survival, why stop them? The marketization of our lives is becoming omnipresent. Soon it will be possible to purchase everything. I can see three reasons why the free rein of market forces will be bad. Firstly, there will obviously be people who cannot afford care. Parents who do not have the funds or knowledge of 'the system' will not be able to obtain medication for ADHD or pay a psychologist for cognitive behavioural therapy. I predict that we will in the future see more evidence of what can go wrong when children are left unsupervised on our streets. Secondly, I would miss the fact that when I recommend a treatment to a patient, both of us know that I do not stand to gain personally from the advice. In most parts of the world, patients do not have this reassurance and may be tempted to seek an alternative and perhaps cheaper opinion. Patients seeking multiple opinions and then choosing the one that suits their own ideas best will not necessarily lead to better health outcomes. Thirdly, the 'haves' and the 'have-nots' will live completely separate lives. They will live in different parts of the city, their children will go to different schools, they will travel to work by different means and their leisure time will be spent in different places. I don’t think that this is good for society. Democracy itself will be under direct attack as those who can afford to pay for political influence and lobbyists will seek to buy the policies that favour them. Why not—it's the marketplace! In the meantime, I keep staring at those X-ray machines in the knowledge that when my own cataracts have reached maturity, and I can no longer read a book, my optician will swiftly point me in the direction of a private ophthalmologist without any involvement of the NHS. 

UEG Member Societies EFISDS & EDS are now accepting registrations for their combined course on GI surgery, to be held in beautiful Cluj-Napoca in Romania on October 30-31, 2014.

The Lancet and World Hepatitis Day

HEV, HCV and even some IBD!

As a junior gastroenterologist, Mondays are typically spent running around like a headless chicken sorting out jobs from the weekend. Despite this, I did eventually notice that Monday, July 28 was ‘World Hepatitis Day’ (http://www.worldhepatitisday.org), with The Lancet publishing a fascinating paper on hepatitis E and blood transfusions to mark the event, in addition to papers on both hepatitis C and ulcerative colitis.

The papers that caught my attention on World Hepatitis Day were the fascinating article on the prevalence and transmission of hepatitis E in the UK, the phase III data on daclatasvir and asunaprevir and the phase II data on sofosbuvir and simeprevir for patients infected with hepatitis C virus (HCV) genotype 1.  For those of us interested in inflammatory bowel disease (IBD), there were data on Etrolizumab in moderate-to-severe ulcerative colitis to consider. Starting though with the thought-provoking paper on hepatitis E, lead by members of Public Health England (previously known as the Health Protection Agency). The authors provide an interesting historical overview of hepatitis E, which was first identified from an outbreak in Kashmir in 1978, before moving onto the eye-catching data showing that up to 25% of people in their sixth or seventh decade are seropositive for hepatitis E virus (HEV) in England and Wales!1  This would make HEV the most likely cause of acute enterally transmitted viral hepatitis in those individuals without a recent travel history.  I have noticed an increasing trickle of patients infected with HEV and listening to the podcast accompanying the paper, the author believes that the reason for this is the current fashion for consuming meat that is less well cooked and also processed meats (sausages?). Similar results have been published by groups in Sweden and Germany, which implies that cooking practices may have to change throughout Northern Europe. Blood donors in the UK are not currently screened for HEV. Analysis of 225,000 blood donations in the study from Public Heath England identified HEV RNA in 0.04% of blood donations. This prevalence could have led to an extra 80,000–100,000 acute HEV infections during the study period! The HEV transmission rate from infected donations was 42%, but on follow up most individuals (two-thirds) had spontaneously cleared the virus. Delayed or chronic infection was more common in the severely immunosuppressed. This finding creates some dilemmas regarding monitoring practices for transplant patients, and a recent article in The New England Journal of Medicine on the use of ribavirin in HEV-infected solid-organ transplant recipients may be a useful reference in this scenario. In their discussion, the authors stop short of mandating HEV blood-donor screening, rather they imply that the aim should be to improve our cooking and dietary habits.2 Moving from hepatitis E to hepatitis C, I’m sure we’ve all been in awe, but perhaps somewhat saturated, at the huge advances made in the treatment of HCV over the past year. The Lancet has now published the findings of the phase III international study of the NS5A inhibitor daclatasvir and the NS3 protease inhibitor asunaprevir as a IFN-free treatment option in patients chronically infected with HCV genotype 1b.3 A successful SVR 12 (sustained virological response at 12 weeks post-treatment) was seen in 91% of treatment-naive patients, in 82% of previous non-responders to Peg-IFN and ribavirin, and in 83% of treatment-intolerant patients. Overall the study medications were well tolerated. Although viral resistance has been seen in the treatment failure groups, these SVR rates seem encouraging. Phase II data on the NS3/4A protease inhibitor simeprevir and sofosbuvir with or without ribavirin for chronic HCV genotype 1 infection have also been published in The Lancet.4 Simeprevir (along with sofosbuvir) is already licensed in the US and Europe, and aims to provide improved tolerability and efficacy compared with the current NS3/4A protease inhibitors telaprevir and boceprevir.  The study looked at IFN-free treatment with sofosbuvir or simeprevir with or without ribavirin for 12 or 24 weeks in two cohort groups, divided based on the severity of liver fibrosis (METAVIR scores F0-F2 or F3-F4). Results presented on an intention-to-treat basis showed SVR 12 rates of 90% and 94% in the two treatment groups, respectively. None of the patients included in the study had decompensated liver disease, and side effects from a mild to severe grading were seen in both groups, with viral resistance to simeprevir, but not sofosbuvir, noted in a small number of patients. The addition of ribavirin and treatment duration (12 or 24 weeks) did not seem to significantly alter the noted SVR rates. Both sofosbuvir and simeprevir feature as a treatment option in the latest EASL recommendations; however, this is one of several recommended options, and only one of many options that should soon receive EMA (European Medicines Agency) authorisation. Aside from viral hepatitis, the week’s print issue of The Lancet also contained the phase II trial of ertolizumab in patients with ulcerative colitis.5 Ertolizumab is one of a new wave of monoclonal antibodies that target integrins (transmembrane receptors that are important in the extracellular matrix) and their interaction with the MAdCAM-1 adhesion molecule, which is known to play a key role in the direction of lymphocyte traffic from the circulation into intestinal tissue. Patients with ulcerative colitis were randomly allocated to two different subcutaneous doses of ertolizumab or matching placebo in this double-blind placebo-controlled study. 124 adult patients with moderate-to-severe ulcerative colitis unresponsive to standard therapy with prednisolone, immunomodulators (azathioprine, methotrexate etc.) or anti-TNF therapy were included, with just over 60% of the patients having failed to respond to anti-TNF agents. Statistically significant improvement in disease remission at 10 weeks was seen in both ertolizumab groups compared with placebo; no patients in the placebo group achieved disease remission at week 10. Adverse events were noted at a similar rate in all three groups. There were no cases of progressive multifocal leukoencephalopathy, a nasty condition that has been seen in patients with multiple sclerosis who were treated with natalizumab (a non-selective anti-integrin antibody). The authors say that they did not expect to see any cases as ertolizumab is more selective, but also acknowledge that there is as yet limited safety data and patient numbers involved with this agent. The accompanying comment article praises the study for its rigorous design using a double-blind placebo-controlled approach, as well as the use of the Mayo Clinic Score in the assessments.6 The Lancet of course also included robust comment articles—on the escalating Ebola outbreak in Western Africa, Polio eradication in conflict zones, gruesome food-safety concerns in China, an interesting piece on the possible role of neuraminidase inhibitors (e.g. oseltamivir and zanamivir) in influenza and the crisis in Gaza—reflecting bleak times globally. One hopes for brighter comment pieces in the future. References 1. Hewitt P, et al. Hepatitis E virus in blood components: a prevalence and transmission study in southeast England. Lancet online July 28, 2014 doi:10.1016/S0140-6736(14)61034-5  2. Kamar N, et al. Ribavirin for chronic hepatitis E virus infected transplant recipients. N Engl J Med 2014 vol. 370 no. 12 1111–1120  3. Manns M, et al. All-oral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study. Lancet online July 28, 2014 doi:10.1016/S0140-6736(14)61059-X  4. Lawitz E, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype I in non-responsders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet online July 28, 2014 doi:10.1016/S0140-6736(14)61036-9  5. Vermeire S, et al. Ertolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial. Lancet 2014 vol. 384 no. 9940 309–318  6. Armuzzi A and Felice C. Etrolizumab in moderate-to-severe ulcerative colitis. Lancet 2014 vol. 384 no. 9940 285–286 

Impact of day of admission on mortality in upper gastrointestinal haemorrhage

Evidence suggests that death is more likely to occur for some patients who are admitted to hospital on a weekend rather than on a weekday, but that evidence is not conclusive. New findings now indicate that mortality from upper gastrointestinal bleeding does not differ by day of admission.

There is evidence that some patients are more likely to die if admitted to hospital on weekends; however, the evidence is not equivocal. For example, Goldacre and Maisonneuve found that there was no evidence of excess deaths from meningococcal disease when patients were admitted at the weekend rather than on a weekday.1  Emergency gastrointestinal bleeding is associated with a mortality rate of around 10% in the UK, and a UK-wide audit in 2007 highlighted significant deficiencies in the care of patients presenting with upper gastrointestinal bleeding.2 In particular, outcomes were less good for patients attending hospitals in which there was a lack of on-call consultant-led endoscopy in the out-of-hours setting.  For this reason, I was interested to read an American nationwide analysis with huge patient numbers showing that there is no difference in the mortality rates between patients with upper gastrointestinal bleeding admitted on weekends versus weekdays.3 An earlier American database study from 2004 had found that the risk of death was greater for weekend admissions.4 However, the current study used stricter criteria for the diagnosis of an upper gastrointestinal bleed. We do know from a recently presented study5 that presentation with coffee ground vomiting is associated with a similar risk of mortality (but with a significantly lower endoscopic yield) as presentation with haematemesis and melaena.  This difference in diagnostic criteria may be one of the reasons why previously published studies comparing mortality in patients with upper gastrointestinal bleeding have given conflicting results. Nevertheless, the paper by Salzman and colleagues3 may not be the end of the matter. The group only looked at new admissions, whilst it is well recognised that inpatients who develop emergency gastrointestinal bleeding as a complication whilst recovering from another condition have a higher risk of mortality. Furthermore, the patients in the study seemed to be a surprisingly healthy bunch.  The mortality rate was only 2.2%, only 1.6% of patients were admitted with variceal bleeding (which is known to be associated with a higher mortality rate) and the patients only stayed an average of 3 days in hospital! Understandably, the study was unable to provide detailed information on the emergency endoscopies themselves and some questions linger.  Why were 13% of patients with non-variceal bleeding not offered endoscopy?  What was the level of experience of the endoscopists staffing the units during the weekdays versus the weekends?  Were current guidelines on “dual modality therapy” adhered to?  What were the rebleeding rates in patients admitted at weekdays versus weekends? But for now, the findings of the study support the idea that there is no difference in mortality from upper gastrointestinal bleeding regardless of the day of admission. References 1. Goldacre MJ and Maisonneuve JJ. Mortality from meningococcal disease by day of the week: English national linked database study. Journal of Public Health 2013 vol. 35 no. 3 413–421 2. Hearnshaw SA, et al. Acute upper gastrointestinal bleeding in the UK: patients characteristics, diagnoses and outcomes in the 2007 UK audit. Gut 2011 vol. 60 no. 10 1327–1335 3. Abougergi MS, et al. Impact of day of admission on mortality and other outcomes in upper GI hemorrhage: a nationwide analysis. Gastrointestinal Endoscopy 2014 vol. 80, no. 2 228–235.e1 4. Barkun AN. Do predictors of mortality in upper gastrointestinal bleeding include a weekend time of admission? Clinical Gastroenterology and Hepatology 2009 vol. 7 no. 3 257–258 5. Schneider JR, et al. Is coffee ground vomiting important? Findings from a large bleeding unit database with outcomes at 30 days. Gut, 2014 vol. 63 no. 6  suppl. 1 A6

The enemy within

Dysbiosis and ulcerative colitis.

In recent years, there has been a growing recognition that the gut microbiota and the development of a microbial imbalance within the gastrointestinal tract—termed ‘dysbiosis’—are important in the pathogenesis of inflammatory bowel diseases, especially Crohn’s disease.

However, studies demonstrating dysbiosis in ulcerative colitis have been conflicting. A study from a group based in Belgium now adds to the evidence that dysbiosis is also important in ulcerative colitis, but indicates that the microbial signature differs to that found in patients with Crohn’s disease.  The group found a reduction in the abundance of butyrate-producing ‘good’ species Roseburia hominis and Faecalibacterium prausnitzii in patients with ulcerative colitis.1 This study also demonstrated that the abundance of these ‘good’ bacteria, both of which belong to the phylum Firmicutes, was inversely correlated with disease activity. This is an interesting finding since short-chain fatty acids (SCFA) potentially produced by such organisms not only provide energy for the mucosa but also exert anti-inflammatory effects.  However, the relationship is probably more complex than anticipated. Although patients with ulcerative colitis had reduced levels of SCFA, there was no correlation between the levels of SCFA and the presence or absence of these bacteria. Nevertheless, the discovery is important as it may pave the way for trials of selective therapeutic agents, such as probiotics, prebiotics and/or synbiotics, to restore these species in the gut microbiota of patients with ulcerative colitis to reduce disease activity. If you would like to read more on dysbiosis in colitis, please click the following link:  https://www.ueg.eu/education/document-detail/?name=digestive_functions_and_gut_microbiota&file=97297

References

1. Machiels K, Joossens M, Sabino J, et al. A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut 2014; 63: 1275–1283.  

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