Nurse endoscopists

How have nurse endoscopists benefitted endoscopy services?

I remember the incredulity on the faces on my European colleagues 20 years ago when I told them that the UK was to start training nurse endoscopists. They doubted that it was desirable (or even possible!) to train nurses. Of course, by then the American Society for Gastrointestinal Endoscopy (ASGE) had for many years endorsed flexible sigmoidoscopy by ‘nonspecialists,’1,2 but little evidence of their effectiveness had been published.3

Unsurprisingly, it was the relentlessly increasing demand for endoscopy that made the introduction of nurse endoscopists necessary in the UK.  Some 20 years ago, the demand for gastroscopy approached 10 per 1,000 population per year and the demand for colonoscopy was expected to increase from an average of 2.5 to 10 colonoscopies per 1,000 population per year.4 In addition, the implementation of the NHS National Bowel Cancer Screening programme would further inflate the demand for endoscopy. For this reason, a British Society of Gastroenterology (BSG) Working Party5 gave the green light for nurse endoscopy, together with the United Kingdom Central Council (UKCC)6 and the General Medical Council (GMC). However, it was a cautious start because endoscopy was seen as a risky procedure that was associated with a 1:2,000 risk of death.7 The BSG, GMC and UKCC all agreed that nurse endoscopists were only to act as “technicians”. The responsibility for the patient’s management remained with “the supervising doctor” who had to be “immediately available within the hospital” (an oxymoron of course) in the event of complications or to give advice. Now we know that they were wrong and that the “interpretation of findings does not rely on the experience and training of an appropriately qualified doctor.”5 Endoscopy can be taught! Indeed, throughout the UK, nurse endoscopists now work independently, interpreting findings without the immediate supervision of a clinician. The uptake of nurse endoscopy has been steady in the past 20 years. In Leeds we have seven nurse endoscopists who undertake about 22% of our gastroscopies, 27% of our colonoscopies and all of our flexible sigmoidoscopies. ERCP, enteroscopy, EUS and most therapeutic endoscopy procedures that pose a significant risk of complications are carried out by consultants who are increasingly dedicating their time purely to endoscopy. Now we know more about the performance of nurse endoscopists. There is irrefutable evidence that the caecal intubation rate, adenoma detection rate, complication rate and patient satisfaction scores are comparable among nurses and doctors.8–10 In Leeds, the ‘raw’ caecal intubation rate for both our nurse endoscopists and consultants is 92% and the average polyp detection index (total number of polyps found/total number of patients) is also virtually identical (34.5 for nurses and 33.5 for consultants). In view of the reassuring published literature that has become available over the years, I was bemused to read a recent survey from New Zealand in which only 30% of doctors welcomed the introduction of nurse endoscopists.11 A huge majority believed that doctors would always deliver a better quality of endoscopy and that overall costs would spiral out of control if nurses were to be trained in endoscopy. Of course, endoscopy is a valued source of extra income for gastroenterologists in New Zealand, which makes me wonder if this may have had an influence on the outcome of the survey. Nevertheless, the statistics, reassuring as the may be, do not do nurse endoscopists justice. As a lead endoscopist, it is a relief to have a stable workforce that is fully committed to endoscopy. Most of my gastroenterology colleagues rush between ward rounds and outpatient clinics, phoning patients and their relatives in between. They have little time and energy to invest in endoscopy. By contrast, if an endoscopy list needs back filling, one of our nurse endoscopists will take it on. If an endoscopy audit is required, a nurse endoscopist can make the time. If there is an endoscopy-related problem, a nurse endoscopist will be willing to get involved. The truth is that without nurse endoscopists, endoscopy services will not be able to make the quantum leap from ‘Cinderella speciality’ to a core hospital service that is on an equal footing with radiology. My advice to any anxious colleagues who worry about the emergence of the nurse endoscopist is to welcome them, because with their help we can make endoscopy bloom! References 
  1. Maule WF. Screening for colorectal cancer by nurse endoscopist. NEJM 1994; 330(3):183–187. 
  2. DiSario JA and Sanowski RA. Sigmoidoscopy training for nurses and resident physicians. Gastrointest Endosc 1993; 39(1):29–32. 
  3. Committee on Training, Gross GWW, Bozymski EM, et al. Guidelines for training non-specialists in screening flexible sigmoidoscopy. Gastrointest Endosc 2000;51(6):783–785. 
  4. Barrison IG, Bramble MG, Wilkinson M, et al. Provision of endoscopy related services in district general hospitals: BSG Working Party Report 2001.
  5. British Society of Gastroenterology. Report of the British Society of Gastroenterology Working Party—The nurse endoscopist. 1994. 
  6. UKCC. The Scope Of Professional Practice. London UKCC 1992.
  7. Quine MA, Bell GD, McCloy RF, et al. Prospective audit of upper gastrointestinal endoscopy in two regions of England: safety, staffing, and sedation methods. Gut 1995; 36(3):462–467.
  8. Hui AJ, Lau JY, Lam PPY, et al. Comparison of colonoscopic performance between medical and nurse endoscopists: a non-inferiority randomised controlled study in Asia. Gut 2015; 64(7): 1058–1062. 
  9. Massl R, van Putten PG, Steyerberg EW, et al. Comparing quality, safety, and costs of colonoscopies performed by nurse vs physician trainees. Clin Gastroenterol Hepatol 2014; 12(3): 470–477. 
  10. Schoenfeld P; Lipscomb S; Crook J; et al. Accuracy of polyp detection by gastroenterologists and nurse endoscopists during flexible sigmoidoscopy: a randomized trial. Gastroenterology 1999; 117(2): 312–318. 
  11. Khan MI, Khan R and Owen W. Doctors and the nurse endoscopist issue in New Zealand. NZ Med J 2012; 125(1357): 88–97. 

Early Detection of Pancreatic Cancer—How?

What's the outlook for the development of biomarkers?

World Pancreatic Cancer Day is being held on November 13. It is estimated that 367,000 new cases of pancreatic cancer will be diagnosed worldwide in 2015 and the dismal survival rate means that only 2–10% of patients will be alive 5 years after diagnosis.

Globally, pancreatic cancer is the seventh most common cause of cancer-related death, and while death rates for many cancers are dropping, the death rate for pancreatic cancer is rising in Europe and the United States.1 The mortality of pancreatic cancer may, at least in part, be explained by the fact that early diagnosis is challenging. However, advances in the development of various biomarkers appear to hold promise for future screening of high-risk individuals, which—according to Cancer Research UK—includes patients with hereditary pancreatitis, a high incidence of pancreatic cancer in their family or a family history of at least one person with pancreatic cancer plus a linked cancer syndrome (e.g. a BRCA2 mutation).2 It has been reported that levels of serum cancer antigen 19-9 (CA19-9) are elevated in approximately 80% of patients with pancreatic cancer,3 and CA19-9 has been useful for therapeutic monitoring and early detection of recurrent disease after treatment in patients with known pancreatic cancer.4 However, CA19-9 is not a specific biomarker for pancreatic cancer. Moreover, patients who are negative for Lewis antigen a or b (approximately 10% of patients with pancreatic cancer) are unable to synthesize CA19-9. Although measurement of serum CA 19-9 levels is useful in patients with known pancreatic cancer, the use of this biomarker as a screening tool has yielded disappointing results.4 In addition to genetic alterations, dysregulation of specific epigenetic mechanisms is critical to tumour development. Comparing patients who have pancreatic cancer with healthy individuals and patients with chronic pancreatitis, Schultz et al. described differences in microRNA expression in whole blood with a view to identifying microRNA panels (classifiers) for diagnosing pancreatic cancer.3 microRNAs—non-coding 17–25-nucleotide-long RNAs that regulate gene expression—play important roles in tumour development and metastasis, and several have been described as specific to pancreatic cancer. Schultz and colleagues validated microRNA panels against CA19-9 sero-status and disease, and identified two panels for diagnosing pancreatic cancer using combinations of four and ten microRNAs in whole blood, respectively. The investigators call for further studies that could validate the use of these biomarkers as a screening tool for early-stage pancreatic cancer detection. More on the role of microRNAs in pancreatic tumour growth and progression can be found in a paper by Frampton and colleagues that was published in The Lancet in February 2015.5 Even more recently, in an article in Nature, Melo and colleagues6 suggested the use of a proteoglycan molecule (glypican-1 [GPC1]) anchored in the membrane of extracellular vesicles—exosomes—circulating in the bloodstream as a cancer biomarker. In particular, the team claimed that detection of GPC1+ exosomes in the blood could distinguish patients with early-stage and late-stage pancreatic cancer from patients with benign pancreatic disease and healthy individuals. The assay appeared more reliable than that based on CA19-9 detection. Compared with healthy donors, serum CA19-9 levels were increased in patients with cancer, but CA19-9 levels were also significantly increased in the serum of patients with benign pancreatic disease. Moreover, CA19-9 levels failed to distinguish patients with pancreatic cancer precursor lesions from healthy donors. An expanded interpretation of this important study, including a discussion of semantic issues, can be found in an accompanying News & Views article by Clotilde Théry.7 Apart from microRNAs, epigenetic features such as DNA methylation, satellite repeats and histone modifications might serve as biomarkers for early diagnosis of pancreatic cancer.8 Reviewing genes aberrantly methylated in pancreatic cancer, Henriksen and her team concluded that investigations into hypermethylated markers in cell-free DNA in plasma or serum are still limited by the availability of only a handful of small studies, which lack well-defined control groups, and that no single gene has been identified as a diagnostic marker.9 To read more about the many challenges related to identifying biomarkers for early diagnosis of pancreatic cancer, I recommend looking up a review by Jenkinson and colleagues.10 There are also a couple of interesting sessions from the recently concluded UEG Week 2015 in Barcelona that I’d like to highlight—all are available online. To learn more about ‘liquid biopsies’, including cell-free DNA, exosomes, and circulating tumour cells, you could look up the talk delivered by Aldo Scarpa, “Molecular diagnostics: From tissue biomarkers to liquid biopsies, single genes and panels”, which was part of the session “Pancreatic cancer: Where are we and what is the future?”11 There’s also an update session on therapy, including talks on chemotherapy, surgical resection, preoperative and palliative treatment, and neoadjuvant and adjuvant treatment.12 Finally, I would like to direct your attention to a talk that was given by Jean-Luc van Laethem, entitled “Pancreatic cancer in annual review”.13 Challenges aside, sensitive and specific biomarkers of early pancreatic cancer that can be obtained non-invasively appear critical to reducing the morbidity and mortality associated with pancreatic cancer. As we mark the 2015 World Pancreatic Cancer Day, we should set our hopes on it not being too long until one or more biomarkers prove valid for use in screening. References
  1. http://www.worldpancreaticcancerday.org/about/
  2. http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/pancreatic-cancer/risk-factors#heading-Eightteen
  3. Schultz NA, Dehlendorff C, Jensen BV, et al. MicroRNA biomarkers in whole blood for detection of pancreatic cancer. JAMA 2015; 311: 392–404.
  4. Hidalgo M. Pancreatic cancer. N Eng J Med 2010; 362: 1605–1617. 
  5. Frampton AE, Castellano L, Colombo T. Integrated molecular analysis to investigate the role of microRNAs in pancreatic tumour growth and progression. Lancet 2015; 385 Suppl 1: S37. 
  6. Melo SA, Luecke LB, Kahlert C, et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 2015; 523: 177–182. 
  7. Théry C. Cancer: Diagnosis by extracellular vesicles. Nature 2015; 523: 161–162. 
  8. Fukushige S, Horii A. Road to early detection of pancreatic cancer: Attempts to utilize epigenetic biomarkers. Cancer Lett 2014; 342: 231–237. 
  9. Henriksen SD, Madsen PH, Krarup H, et al. DNA hypermethylation as a blood-based marker for pancreatic cancer: A literature review. Pancreas 2015; 44: 1036–1045. 
  10. Jenkinson C, Earl J, Ghaneh P, et al. Biomarkers for early diagnosis of pancreatic cancer. Expert Rev Gastroenterol Hepatol 2015; 9: 309—315. 
  11. Pancreatic cancer: Where are we and what is the future? Session at UEG Week 2015. 
  12. Therapy update: Pancreatic cancer Session at UEG Week 2015.
  13. Pancreatic cancer in annual review Presentation by Jean-Luc van Laetham in the Pancreas: What’s new in 2015? Session at UEG Week 2015.

Small things, vast impact: gut microbiota in health & disease

All things microbiota related at UEG Week 2015!

The relevance of manipulating gut microbiota—that is using gut microbiota (e.g. faecal microbiota transplantation [FMT]), components thereof, or diet (including probiotics)—with a view to ameliorating or potentially treating diseases and syndromes is currently subject to intense scrutiny.

The number of conditions that could potentially benefit from gut microbiota manipulation is vast, ranging from autoimmune diseases, such as inflammatory bowel disease (IBD) and multiple sclerosis, to functional bowel diseases (e.g. irritable bowel syndrome [IBS]), antibiotic-induced gut dysbiosis (e.g. recurrent Clostridium difficile infection) and metabolic syndrome. Others include mental health diseases/personality disorders, including anxiety, depression, autism, and schizophrenia. Through my own research, I have discovered that some intestinal microbes are much more common in healthy individuals than in patients with infectious diarrhoea, functional or inflammatory bowel diseases. Just to be clear, I’m not talking about Akkermansia muciniphila or Faecalibacterium prausnitzii, in fact, I’m not even talking about bacteria! I’m referring to a couple of intestinal protists (Blastocystis sp. and Dientamoeba fragilis) that once were thought by many to be gut pathogens. Well, a lot of recent data not only suggest that they are not gut pathogens, but that they also appear to be much more common than previously anticipated. At our lab, we have developed and are currently validating a gut microbiota profiling tool that enables unprecedented and exhaustive interrogation of ribosomal genes from bacteria, yeasts, moulds, and parasites (protists and helminths) in complex samples, such as stool samples. In other words, we will be able to identify all gut colonising/infecting organisms present in a stool sample to at least genus level, and very often to species level. Given my background and interests, I was very pleased to learn that UEG Week 2015 has a specific “Gut Microbiota” pathway. I’m going to adhere to it as much as I can! Not only am I interested in being able to pin down every single organism squatting our guts, I also want to know what they do! You’ll definitely find me in Room E2 at the “From omics to better understanding of pathogenesis” session, which is being chaired by my fellow Web Editor, Rui Castro. Here, Loris Lopetuso will present and compare data on gut microbiota composition (16S NGS data) in patients with IBD, IBS, diverticular disease and healthy controls. If you’re new to research into gut microbiota, you’d do well to attend the talk by Paul O’Toole on “Microbiota: What gastroenterologists should know.” This talk is part of the symposium “Microbiota: Evolving concepts in GI disorders” that takes place in Room F1 on Tuesday 27 October (14:00–15:30). Also in this session, you’ll be able to listen to Patricia Lepage discussing the fundamental issue of causation versus correlation in research into IBD-associated microbiota. Harry Sokol will reveal whether FMT for non-infectious GI diseases is “ready for prime time”, and Gerardo Nardone will deliver a talk with the title, “Microbiota and upper GI diseases: What is the clinical relevance?”  “Brain–gut interactions in health and disease” is the title of a Round Table Discussion taking place in Room E4 on Tuesday 27 October (14:00–15:30). As Peter Andrey Smith says, referring to the gut-brain axis, “…the mechanisms by which gut microbes and the brain might communicate are unclear, but there are several tantalising leads for researchers to follow.” In a recent News Feature in Nature, he provides some examples as to how differences in gut microbiota may lead to differences in brain development and behaviour. Butyrate, one of the short-chain fatty acids apparently produced by gut bacteria in those of us who are not on the FODMAP diet (for more information, see my previous blog), fortifies the blood–brain barrier by tightening connections between cells, hence influencing the basic physiology of the blood–brain barrier. I’m also really looking forward to the “Abstracts on Fire: Gut microbiota in lower GI diseases” session, which will be chaired by Antonio Gasbarrini and Herbert Tilg, and takes place at the UEG Hotspot on Wednesday 28 October (8:30–10:30). This free paper session provides us with no less than 12 talks, focusing on topics such as recurrent C. difficile infection and FMT. Among these, we will be spoiled with two talks from Gianluca Ianiro, who is going to try to convince us that surgery is no longer required in patients with C. difficile infection after FMT performed in an academic tertiary care centre. If you’d like to come and talk to me about gut microbiota in health and disease in general, research communication, or about UEG E-learning, I’ll be at the Young GI Network “Let’s Meet” event on Sunday evening and at the UEG Booth on Monday (13:00–14:00) and Tuesday (15:30–15:45). See you there!

E-learning adventures at UEG Week 2015

Getting ready for a busy few days in Barcelona!

UEG Week 2015 is just around the corner and the UEG E-learning team is getting ready for a busy few days in Barcelona! As well as meeting to plan future UEG Education online courses and content, we’ll be spending time at the UEG Booth and the Young GI Lounge in Hall 8.0 during many of the session breaks on Monday, Tuesday and Wednesday. We’ll also be attending the “Young GI Network—Let’s Meet” reception on Sunday evening. If you’d like to meet the team to find out more about what we do, discuss how we can best serve you and how you might be able to get involved, then please do come and say hello!

Tomer, Rui and Bjorn will also be chairing sessions and, as one of this year’s UEG Rising Stars, Rui will be presenting his work on microRNAs in NASH in Room E1 during the first session on Wednesday morning. The team will also be attending many of the sessions to get their annual updates across the breadth of the field, and below are a few highlights that everyone is looking forward to. Charlie’s choice: As usual there is so much excellent content that the problem will be fitting it all in. I'll certainly be attending the Rising Stars session, highlighting the best of our researchers from Europe and the USA—this is always an inspiring session. I'll also be playing close attention to the IBD free paper sessions. Like Rune, I'm looking forward to attending the microbiota-focused sessions. And for all the rest there is UEG Week Live! Bjorn’s choice: My pick of the sessions would be “Endoscopic management of benign oesophageal strictures.” I am convinced that in treatment-resistant cases a “stricturoplasty”—whereby the stricture is cut with an endoscopic knife—can turn failure into victory. I would like to discuss this option with the presenters! Tomer’s choice: There are many attractive learning options at the upcoming UEG Week, ranging from basic science to practical patient management. I am looking forward to “Introducing the omics: A guide for clinicians” on Monday morning, as part of the Today’s Science; Tomorrow’s Medicine lectures. This field has evolved greatly and I am looking to hear an update on the implications for clinicians.  I am also glad the Postgraduate Teaching Programme has a session dedicated to lower GI bleeding, a topic that applies to our everyday practice. Rui’s choice: I am particularly interested in the hepatobiliary pathway, featuring different session formats on liver cirrhosis and cholestasis. And I always love the Today’s Science; Tomorrow’s Medicine sessions, showing just how much can be achieved from a well-sustained and rational basic-to-translational/clinical research plan. And speaking of research, I am also looking forward to a great panel discussion at the “How to do research?” Hotspot Symposia! Rune’s choice: The impact of the intestinal microbiota on human health and disease is something that never ceases to fascinate me, and of course, I’ll be giving priority to the gut microbiota pathway. I’m especially looking forward to the session chaired by my colleague Mirjana Rajilic-Stojanovic and Giovanni Barbara on evolving microbiota concepts in GI disorders on Tuesday. Here, Paul O'Toole will deliver a talk with the title “Microbiota: What gastroenterologists should know.” Natalie’s choice: I love a bit of controversy, so I’m really looking forward to visiting the UEG Week Hotspot to see some of the new session formats—Abstracts on Fire, Clinical Trials Revisited and Hotspot Symposia—in action! Coming from a basic research background, I’m also particularly interested in the sessions on the ‘omics’ and learning more about what difference they are making to practical patient care and what they might allow us to achieve in the future. Don’t forget to look out for tweets from all of the team (@CharlieMuz, @Bjorn_Rembacken, @Eukaryotes, @RuiCastroHD, @adartom and @nataliewood06) during UEG Week (#uegweek)! Why not join the dialogue and tell us what’s got your attention? And if you like twitter debates then make sure you’re online for the #WeekChat on Sunday with Mark Hull (@mark_tbh; Diet, microbiota and colonic disease) and on Tuesday with Chris Hawkey (@chrishawkey; Updates on stem cell research in gastroenterology). There will also be three Decide on the Spot cases published in the UEG Week News and online during UEG Week (on Saturday, Monday and Tuesday)—the answer and explanation for each case will be posted online the following day. Those of you who view the case online, sign in to myUEG and post a comment or answer in the comments section will qualify for a complimentary UEG Education Power Bank, which is perfect for charging your mobile devices on the go! To receive your UEG Education Power Bank, simply come and show us your post on the laptop at the UEG booth in Hall 8.0. Please note that comments on social media don’t count, participants are entitled to a maximum of one Power Bank and the number of Power Banks available each day is limited! Wishing you all an enjoyable and productive time in Barcelona! 

Time to change a treatment paradigm

Models of care and malnourished patients

In the past 10 years we have seen the expansion of a cadre of gastroenterologists who have a sub-specialty interest in nutrition. As a result, we have seen nutrition rightfully taking centre stage in our hospitals. Indeed, in the UK hospital mealtimes are now ‘protected’ and malnourished patients have their food served on red trays.

Our nutrition experts have more directly been involved in a transformation of the care of patients who have short bowels. This group of patients is a complex mix, in which every patient is different depending on how much small bowel is left, what type of anastomosis was constructed and the underlying disease. Such patients may suffer high morbidity and mortality because the malabsorption of macronutrients, micronutrients, electrolytes and water can result in impaired growth, premature aging, sudden hypotension, renal failure, arrhythmias, fits, infections, liver failure and impaired healing. The increased survival of these desperately ill patients has been achieved by meticulous attention to detail. A tiny shift in a patient’s serum magnesium level triggers an adjustment. As the 2003 AGA review put it: “Vitamin and mineral status should be monitored regularly, and supplementation should be customized for each patient.”1 Of course, it takes a particular type of meticulous doctor to tirelessly manage a patient’s micronutrient intake. I am not sure that I could manage to pay such careful daily attention to every patient’s zinc, copper, magnesium and selenium levels. Luckily, gastroenterologists with a specialist interest in nutrition are self-selected, thorough doctors and their patients with intestinal failure benefit greatly. Most UK hospitals now have a nutrition team, which is headed up by a gastroenterologist with a specialist interest in nutrition. Initially these teams only cared for patients with intestinal failure. Subsequently their remit enlarged to include patients with malabsorption and more recently came to include all those who are malnourished. The most severely malnourished patients in our hospitals are those with anorexia nervosa. The nutrition of these patients is now often looked after by gastroenterologists with an expertise in intestinal failure. Just as intestinal failure is at the sharp end of gastroenterology, anorexia nervosa is at the sharp end of psychiatry. Not only does the condition have the highest mortality rate of any mental illness,2 the management is complicated by a lack of reliably successful treatments. The National Institute for Health and Care Excellence (NICE) has reviewed the therapies available and awarded only “grade C level evidence” for 74 of the 75 therapies for eating disorders.3 As we start to see severely malnourished patients who have eating disorders on our gastroenterology wards, it is becoming apparent that simply focusing on a patient’s nutritional needs does not work. Care may be reduced to a battle of wills in which patients pull out their feeding tubes as quickly as doctors put them back down. Furthermore, in spite of opiates, botox injections, naso-gastric feeding, venting PEGs, gastric pacemakers and parenteral nutrition, many patients remain just as debilitated. Personally, I believe that the key to understanding why many patients with the most severe eating disorders do not seem to be greatly improved by pipes and pills is because we practise the “Medical Model” of care. This model focuses on ‘curing’ patients, whereby ‘cure’ is defined by the absence of symptoms and a return to normal, pre-morbid health.4 Of course, such a model is entirely appropriate for treating reflux oesophagitis, a peptic ulcer or an exacerbation of colitis. However, when managing patients who have functional bowel disease, alcohol addiction or eating disorders this model of care may be less helpful. In all areas of psychiatry, the Medical Model of care is being superseded by the “Recovery Model”. Indeed, the Recovery Model of care has been integrated into public mental health policy in many countries, including Australia, New Zealand, USA, Canada, Ireland and the UK.5 The Recovery Model emphasises the personal experience of recovery, involving hope, rebuilding connections with family, friends and supporting patients in rebuilding a fulfilling life in spite of ongoing illness. In contrast to the Medical Model, this model aims for ‘recovery’, defined as enabling a return of hope, personal responsibility, control and empowerment.6 Supporting patients with functional bowel disease, alcohol addiction and eating disorders on their journey towards recovery involves understanding their agenda, active listening, empathy and the setting of realistic goals in equal partnership with patients and their families. Unfortunately, this model of care is unfamiliar to many gastroenterologists, and perhaps particularly to those with a sub-speciality interest in intestinal failure. For this reason we may have to train a new cadre of gastroenterologists with particular expertise in functional disease. This new gastroenterological subspeciality would protect vulnerable patients against repeated cycles of inappropriate investigations and increasingly invasive interventions and instead focus on supporting them on a road towards recovery and a living a fulfilling life. References
  1. Buchman AL, Scolapio J and Fryer J. AGA technical review on short bowel syndrome and intestinal transplantation. Gastroenterology 2003; 124: 1111–1134. 
  2. Beumont PJ and Touyz SW. What kind of illness is anorexia nervosa? European Child and Adolescent Psychiatry 2003; 12: i20–i24. 
  3. National Institute for Health and Clinical Excellence. Eating disorders. NICE clinical guideline 9. January 2004.
  4. Roberts G and Wolfson P. The rediscovery of recovery: open to all. Advances in Psychiatric Treatment 2004; 10: 37–49.
  5. Andresen R, Oades LG and Caputi P. Psychological Recovery: Beyond Mental Illness. Chichester, UK: Wiley-Blackwell 2011 
  6. Schrank B and Slade M. Recovery in psychiatry. Psychiatric Bulletin 2007; 31: 321–325.

Ruminations on gut fermentation—any link to IBS?

Diet, gut microbiota, fermentation and IBS

The aetiology of irritable bowel syndrome (IBS), a disease that may affect at least 10% of the general population, continues to puzzle gastroenterologists and other scientists. While there is some evidence of perturbed gut microbiota in patients with IBS, microbiota profiles reliably linked to IBS remain to be identified. Meanwhile, studies of intestinal fermentation might hold the key to expanding our knowledge on the aetiology and management of IBS.

In a recent article in the American Journal of Gastroenterology, Rajilić-Stojanović et al. reviewed data on the impact of diet and the intestinal microbiota on IBS symptoms.1 One of their important conclusions was that powerful interactions between distinct dietary patterns and intestinal microbial communities may—at least in part—be responsible for the fact that IBS has not yet been shown to be defined by certain microbiota profiles. As a lot of data going into studies exploring associations between microbiota profiles and disease conditions are cross-sectional, what we need to know much more about is how, including how quickly, changes in diet influences our gut microbiota, and therefore how resilient gut microbiota are to dietary changes. A study that appeared in Gut earlier in 2015 was looking into just that issue. In their study, Halmos et al. considered whether differences in dietary FODMAP (fermentable oligo-, di-, monosaccharides and polyols) content reflect differences in the colonic luminal microenvironment.2 Study participants (IBS patients and healthy controls) consumed their habitual diets for 1 week, but were subsequently switched to one of two challenge diets for 3 weeks (i.e. either a diet low in FODMAPs or a typical Australian diet). They were then allowed a wash-out period of 5 days, during which they consumed their habitual diets, and then later allocated to the alternative challenge diet for a further 3 weeks. Halmos et al. found that the higher FODMAP content of the Australian diet compared with that of the low FODMAP or habitual diets was associated with specific stimulation of the growth of bacterial groups with putative health benefits, including butyrate-producers and mucus-associated Akkermansia muciniphila. This finding made the team speculate that long-term use of low-FODMAP diets should be used with caution, at least until the long-term effects of such diets on intestinal microbiota have been fully elucidated. To this end, a recent randomized controlled trial by Böhn et al. compared the effects of a diet low in FODMAPs with traditional dietary advice in patients with IBS. The findings of this study suggest that traditional IBS dietary advice is just as effective in terms of reducing IBS symptoms as adhering to a diet low in FODMAPs.3 In the study by Halmos et al., the concentration of short-chain fatty acids (SCFAs) in stool, which was used as a colonic health index, was independent of diet type.2 The SCFAs acetate, propionate, and butyrate are produced primarily by bacterial fermentation of undigested carbohydrates (primarily dietary fibre aka ‘resistant starch’). The relevance of using the faecal SCFA concentration as a biomarker has, however, been questioned. Ringel–Kulka et al. looked into altered intestinal bacterial fermentation in the setting of IBS with regard to bowel characteristics and gastrointestinal symptoms.4 In their study, the primary aim was not merely to look at the distribution and composition of the microbiota, but to look at what the bacteria were actually doing. For this purpose, they looked at surrogate markers of gut bacterial fermentation, namely intestinal intraluminal pH and faecal SCFAs. Faecal SCFAs are naturally acidic and therefore cause a drop in the pH of the intestinal lumen. Compared with healthy controls, patients with IBS—independent of subtype—exhibited a significantly lower mean total colonic pH level, which could indicate higher intraluminal bacterial fermentation in this cohort. Of note, small-intestine pH levels did not differ between IBS patients and healthy controls, which suggests that bacterial fermentation is not increased in the small intestine of IBS patients. This finding may have important implications for understanding the contribution of small intestinal bacterial overgrowth (SIBO) in the pathophysiology of IBS. The SCFA levels in stool from IBS patients and healthy controls did not differ. Although this could be due to a number of circumstances, including differences in the absorption of SCFAs and colonic transit time, the authors do not recommend using faecal SCFAs as a marker for estimating intraluminal bacterial fermentation. There seems to be an emerging focus on the role of SCFAs in intestinal health and disease. While the low-FODMAP diet used by some IBS patients is associated with reduced SCFA production, these fermented substances appear to have a central role in the prevention of colon cancer and possibly other diseases. The use of surrogate markers of fermentation may have taken us some way already in our search for aetiological factors, but we need to know more about the direct impact of changes in intestinal fermentation and the various molecules generated by these processes on the development and course of IBS. I look forward to discussing the impact on SCFAs on intestinal homeostasis specifically and public health in general in one or more future blog posts. References
  1. Rajilić-Stojanović M, Jonkers DM, Salonen A, et al. Intestinal microbiota and diet in IBS: causes, consequences, or epiphenomena? Am J Gastroenterol 2015; 110: 278–287. 
  2. Halmos EP, Christophersen CT, Bird AR, et al. Diets that differ in their FODMAP content alter the colonic lumincal microenvironment. Gut Epub ahead of print 12 July 2015 doi: 10.1136/gutjnl-2014-307264.
  3. Böhn L, Störsrud S, Liljebo T, et al. Diet low in FODMAPs reduces symptoms of irritable bowel syndrome as well as traditional dietary advice: A randomized controlled trial. Gastroenterology Epub ahead of print 5 August 2015. DOI: 10.1053/j.gastro.2015.07.054.
  4. Ringel-Kulka T, Choi CH, Temas D, et al. Altered colonic bacterial fermentation as a potential pathophysiological factor in irritable bowel syndrome. Am J Gastroenterol 2015; 110: 1339–1346. 

Gastric balloons join the fight against obesity 

How can we tackle obesity?

Obesity is one of today’s most worrying public health problems; it strongly correlates with cardiovascular disease, diabetes, cancer and non-alcoholic fatty liver disease, among other pathologies associated with metabolic syndrome.

According to the World Health Organization (WHO),1 the worldwide prevalence of obesity has more than doubled since 1980; in 2014, a whopping 39% of adults aged 18 years and older were overweight and 13% were obese. The culprits? Ever-increasing sedentary lifestyles and overconsumption of high-fat/high-sugar foods. Which means that the solution should be very easy—to move more and eat less of the wrong foods—right? Unfortunately, there is no simple solution/easy answer. Obesity encompasses many social and psychological layers, which are difficult to get past. Children and adults are constantly exposed to advertisements on how tasty and delicious sugary drinks or high-fat/high-sugar foods are, not to mention the fun and approval associated with sharing them with friends. At the same time, kids will play on their videogame consoles or chat with friends online, rather than going outside and doing the exact same things… for real. Not that I am against any of those things, but a knowledge-based balance is essential. Healthy lifestyles are now being heavily promoted at the societal level, starting from a very early age; as an example, the WHO has created a commission on ending childhood obesity, taking into account the different economic and cultural contexts of each region of the world. The medical community itself has been changing gears in the fight against obesity. Several recent clinical guidelines advise doctors to think of obesity as a disease and to have a more active role in treating obese patients to help them achieve weight loss.2 As a result, most medical practitioners now require that their patients engage in healthy lifestyles before any medical or surgical procedure is considered. In particular, gastroenterologists are stepping up their game. As stated by Professor Mathus-Vliegen, Gastroenterologist and Professor in Clinical Nutrition at the Academic Medical Centre, University of Amsterdam, there are several natural reasons why gastroenterologists should take care of obese patients: many obesity-associated diseases develop in the gastrointestinal tract; patients with complications arising from bariatric surgery can be managed using minimally invasive endoscopic techniques; and the gastrointestinal tract is also the target for other forms of treatment, like endoscopic therapy.3 Indeed, endoscopic bariatric treatment of obesity has recently jumped into the spotlight since the US Food and Drug Administration (FDA) approved the use of two different inflatable medical devices, which are delivered to the stomach via a quick and minimally invasive endoscopic procedure and that trigger a feeling of fullness to help with weight loss. The ReShape™ Integrated Dual Balloon System consists of two attached balloons that are filled and sealed separately in the stomach of the patient during an endoscopic procedure. 326 obese patients (BMI 30–40 kg/m2), who had at least one obesity-related health condition, participated in the clinical study that led to the FDA approval.4 Individuals who received the device lost an average of 6.8% of their total body weight at the time of removal (6 months after placement) compared with an average of 3.3% in the control group. The ORBERA™ Intragastric Balloon System uses a single balloon that can be filled with different amounts of saline. In the pivotal ORBERA™ clinical trial in the US, 255 obese patients (BMI 30–40 kg/m2) were randomly allocated to the treatment and control groups.5 The treatment group lost 3.1 times as much weight as the control group at 6 months. Gastric balloons have been around for years outside the US and are not without controversy. Both of the obesity devices approved by the FDA are temporary and should be removed after 6 months. As such, are they effective in the long term? The clinical trials showed that patients were able to keep off most of the weight they had lost 6 months after removal of the device. But whether the same is true for longer periods of time is not clear. It is also important to note that both trials used obesity devices as adjuncts to lifestyle modification and it would be interesting to see their effect in isolation, for patients unable to diet and exercise. Whatever the case might be, it is clear that gastroenterologists are on the look out for obesity, which is also reflected by the increasing discussion of this topic at speciality meetings. At UEG Week 2015, for instance, you can expect to hear all about potential novel solutions for obesity, new developments in our knowledge on the gut-brain axis and cancer as they relate to obesity, as well as a dedicated symposium on its epidemiology, treatment and management. I am curious to see what gastroenterologists will bring to the table this time around! References
  1. World Health Organization. Obesity and overweight. Fact Sheet No 311 (January 2015) http://www.who.int/mediacentre/factsheets/fs311/en/.
  2. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol 2014; 63: 2985–3023. 
  3. Mathus-Vliegen EM. Endoscopic treatment: the past, the present and the future. Best Pract Res Clin Gastroenterol 2014; 28: 685–702. 
  4. Ponce J, Woodman G, Swain J, et al. The REDUCE pivotal trial: a prospective, randomized controlled pivotal trial of a dual intragastric balloon for the treatment of obesity. Surg Obes Relat Dis 2015; 11: 874–881. 
  5. Abu Dayyeh BK, Eaton LL, Woodman G, et al. 444. A randomized, multi-center study to evaluate the safety and effectiveness of an intragastric balloon as an adjunct to a behavioral modification program, in comparison with a behavioral modification program alone in the weight management of obese subjects. Gastrointest Endosc 2015; 81: Supplement, Page AB147.
Further UEG Resources Invasive management of obesity Session at UEG Week 2014. Obesity and the digestive tract Session at EAGEN Obesity Conference 2013. Obesity: Causes and consequences for the digestive system Session at EAGEN Obesity Conference 2013.

IBD: Musings on models and methods

A snapshot of current developments!

From July 9–11, the UEG Basic Science Course 'IBD: Models and Methods' took place in the Netherlands. A total of 41 delegates had the opportunity to engage in lectures on models of inflammatory bowel disease (IBD)—mouse, rat and organoid cultures. Delegates also participated in hands-on training in the laboratory, which involved a 2D in vitro barrier function model and a 3D in vitro gut model amongst other things. Here, to follow this up, we highlight a newly published method for 3D-pattern profiling of mouse and human phenotypes of intestinal inflammation and give a snapshot of some of the current developments within gut experimental models.

IBD is a complex of diseases, mainly involving Crohn’s disease and ulcerative colitis, which differ in terms of intestinal involvement and other specific macroscopic and microscopic features. The distinction between macroscopic intestinal disease phenotypes has traditionally relied on macroscopic assessment of lesions by trained pathologists, along with histological characterisation of inflammatory processes using 2D sections from which inflammatory cell counts are calculated by analysis of a very limited amount of tissue. Rodriguez-Palacios et al. recently took a microscopic approach to comprehensively examining the integrity of the entire intestinal tract, with a view to characterising disease biology based on 3D-structural patterns.1 Realising that the different types of IBD are often histologically indistinguishable on the basis of mucosal biopsy samples and discovering that stereomicroscopy (SM) has great potential as a routine diagnostic tool for real-time topographical analysis of the gastrointestinal tract at the villous level, this team developed a method using SM to rapidly profile the entire intestinal topography (3D-structure patterns) in mouse models of colitis/ileitis and human IBD. After creating a comprehensive SM catalogue of histologically and scanning electron microscopy (SEM)-validated 3D-intestinal abnormalities (comprising 4,700 mice, 416 inbred strains, and various mouse models of acute/chronic intestinal inflammation and infection), they designed the ‘3D-SM Assessment and Pattern Profiling (3D-SMAPgut)’ system and a registration form to capture qualitative and quantitative data—cm by cm—in order to determine lesion co-occurrence and spatial distribution patterns. Introducing the concept of ‘stereroenterotypes’, which are subclusters of 3D-structure-patterns of IBD pathology that are histologically indistinguishable, the authors found that spontaneous ileitis led to the ‘cobblestone’ steroenterotype in some mouse lines, while the ‘villous mini-aggregation’ stereoenterotype was identified in others. This finding suggests that host genetics drive unique and divergent inflammatory 3D-structural patterns in the gut. To this end, on the basis of the 3D-stereoenterotype, SM correctly predicted with 100% accuracy whether a mouse ileum belonged to SAMP mice or TNFARE mice (strains that have different genetic backgrounds but that both develop spontaneous ileitis) or to a control (ileitis-free) strain. The authors believe that the use of SM will improve our understanding of human IBD by facilitating SM-target analysis of intestinal specimens from animals and IBD patients. This analysis is critical to intestinal phenotyping of genetically diverse mouse and human populations and for preclinical drug testing. The use of animal models has been indispensable in IBD research. These models can be chemically induced, genetically engineered, immunologically mediated or spontaneous. There are also other types of animal models, and the choice of which model to use relies on the specific hypothesis/question that is being addressed.2 The panel of mouse colitis models is vast;3 the oxazolone colitis model in particular appears relevant for studying human ulcerative colitis due to its close resemblance not only with respect to morphology, but also with respect to immunopathogenesis. Another model, the widely applied DSS colitis model, has proven useful for studies on innate immune mechanisms involved in the development of intestinal inflammation. This model has also been used to study the development of colon cancer in relation to colonic inflammation, such as that occurring in patients with long-standing ulcerative colitis. However, mouse models are intrinsically low throughput and sometimes do not adequately mimic human physiology.3,4 The development of ‘organoids’,4-6 including ‘enteroids’ and ‘colonoids’, by ex vivo culture of intestinal epithelial cells may soon enable a marked reduction in the animals used for experimental purposes and allow for more precise and targeted studies of human intestinal disease phenotypes. Indeed, it appears that there is immense potential for this culture system in gastrointestinal research, particularly to model diseases such as graft-versus-host-disease and IBD.7 As an example, Rodansky et al. have taken advantage of advances in stem-cell-derived human intestinal organoids by developing a new human model of fibrosis in Crohn’s disease.8 To find out more on the use of intestinal and hepatic organoids, please sign in to myUEG and search the UEG Education Library! To learn more about general advances in, and the outlook for, organoid technologies in terms of disease modelling, I’d suggest looking up the 2014 review by Lancaster and Knoblich.9
References
  1. Rodriguez-Palacios A, et al. Stereomicroscopic 3D-pattern profiling of murine and human intestinal inflammation reveals unique structural phenotypes. Nat Commun 2015; 6: 7577 doi: 10.1038/ncomms8577
  2. Pizarro T. Intestinal fibrosis (IBD) including models. Presentation in the "GI organ-specific fibrosis" session at UEGF Teaching Activity on Basic Science 2011. 
  3. Kiesler P, et al. Experimental models of inflammatory bowel diseases. Cell Mol Gastroenterol Hepatol 2015; 1: 154–170. 
  4. Wells JM, and Spence JR. How to make an intestine. Development 2014; 141: 752–760. 
  5. Sato T, et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Battett’s epithelium. Gastroenterology 2011; 141: 1762–1772. 
  6. Watson CL, et al. An in vivo model of human small intestine using pluripotent stem cells. Nat Med 2014; 20: 1310–1314. 
  7. Hartman KG, et al. Modeling inflammation and oxidative stress in gastrointestinal disease development using novel organotypic culture systems. Stem Cell Res Ther 2013; 4 Suppl. 1: S5. 
  8. Rodansky ES, et al. Intestinal organoids: a model of intestinal fibrosis for evaluating anti-fibrotic drugs. Exp Mol Pathol 2015; 98: 346–351. 
  9. Lancaster MA and Knoblich JA. Organogenesis in a dish: modelling development and disease using organoid technologies. Science 2014; 345: 1247125.  

Let’s get physical: Listen to your liver talk! 

Does exercise benefit NAFLD patients?

Summer is just around the corner and I’ve been hitting the gym more often to get ready for the beach (and by more often I mean I actually started going to the gym)! But there are many more important reasons why you should work out and your liver’s health is a major one, particularly concerning non-alcoholic fatty liver disease (NAFLD).

NAFLD consists of a spectrum of histopathological changes that range in severity from simple steatosis to non-alcoholic steatohepatitis (NASH). Although simple steatosis is characterized by a relatively favourable clinical outcome, NASH can progress to cirrhosis and hepatocellular carcinoma, leading to liver-related morbidity and mortality. Largely considered a manifestation of obesity and the metabolic syndrome, NAFLD is becoming the most common cause of chronic liver disease worldwide. Indeed, NAFLD is found in almost 70% of the adult obese population and in more than 90% of morbidly obese individuals.1 NAFLD is also highly prevalent in children and its incidence appears to be increasing in Europe, with 2–12.5% of children and early adolescents presenting with NAFLD, a number that rises to 36–44% in obese children.2 Of note, the risk factors for paediatric NAFLD mirror those for adult NAFLD and further correlate with an increasingly sedentary lifestyle, coupled with unbalanced dietary habits, where changes in macronutrients, increased calorie intake and decreased physical activity negatively influence NAFLD pathogenesis. There is no current pharmacological treatment for NAFLD, although several clinical trials are ongoing, with promising results reported so far. As a consequence, lifestyle interventions remain the cornerstone of NAFLD treatment; in parallel with healthier and smarter eating choices, the benefit of physical activity for NAFLD patients has recently been expounded. Originally thought to be effective only when combined with the introduction of a healthy diet in obese patients, it is now apparent that different exercise regimens can benefit NAFLD, even without dietary restriction and/or in the absence of significant weight loss. For instance, aerobic exercise alone has been shown to be able to decrease visceral adipose tissue volume and liver fat content in sedentary obese individuals by 12% and 21%, respectively.3 Similarly, Oh and co-workers showed that increased physical exercise with or without dieting significantly reduced hepatic inflammation and associated oxidative stress in obese men.4 More recently, Oh and colleagues have suggested that at least 250 minutes of moderate to vigorous intensity physical exercise per week was required to reduce liver fat in obese men as part of lifestyle management.5 In other words, this is more or less equivalent to 50 minutes of moderate (dancing, gardening, housework/domestic chores, walking domestic animals) to vigorous (walking, running, fast cycling/swimming, aerobics, competitive sports/games) intensity physical activity, 5 times per week. Not bad at all! But it gets even better. In April 2015, Keating et al. showed that inactive and overweight/obese adults placed under different aerobic exercise regimens reduce their liver fat and visceral adipose tissue, irrespective of exercise volume or intensity and in the absence of clinically significant weight loss!6 In my opinion, these findings suggest that regular exercise may also greatly benefit non-obese NAFLD patients, despite there being no expectation that these patients will lose a significant amount of weight (they are lean!). Although it might be surprising for some to learn that NAFLD is not solely a disease of the obese population, the prevalence of NAFLD in lean individuals is increasing. This increase in prevalence is particularly noticeable in the Asia-Pacific region, due to diverse environmental and genetic factors.7 As such, if you think you have ‘good genes’ because you look lean and healthy despite not working out much and/or eating junk food all the time, you might want to think twice, listen to your liver talk and get physical! If nothing else, individuals who exercise regularly might be, perhaps unknowingly, actively lowering their risk of developing fatty liver or even cardiometabolic disease, as the latter correlates with excess liver fat, even in the absence of NASH. However, the key word here is ‘regularly’; if you are a seasonal gym member like me, I would encourage you (and myself) to find other parallel and fun exercise activities and to stick to them. This might be difficult for some, but the sustainability of any intervention is the key to success. This is why—despite believing that specialized and personalized exercise prescription, in parallel with dietary advice, should continue to represent the main line of treatment for NAFLD patients—I think that the use of pharmacological agents on their own or as adjunctive therapies to lifestyle modification will remain desirable. When exercising, the old saying, “Feel good on the inside and look good on the outside,” usually crosses my mind. Now, I can also almost picture my liver shouting “I feel good, na na, na na, na na, na…” References: 
  1. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002; 346: 1221–12231.
  2. Durmaz O. Metabolic liver disease in the adolescent. Presentation in the Non-alcoholic fatty liver disease (NAFLD): any news? session at UEG Week 2014.
  3. Johnson NA, et al. Aerobic exercise training reduces hepatic and visceral lipids in obese individuals without weight loss. Hepatology 2009; 50: 1105–1112.
  4. Oh S, et al. Exercise reduces inflammation and oxidative stress in obesity-related liver diseases. Med Sci Sports Exerc 2013; 45: 2214–2222.
  5. Oh S, et al. Moderate to vigorous physical activity volume is an important factor for managing nonalcoholic fatty liver disease: a retrospective study. Hepatology 2015; 61: 1205–1215.
  6. Keating SE, et al. Effect of aerobic exercise training dose on liver fat and visceral adiposity. J Hepatol Epub ahead of print 1 April 2015. DOI: 10.1016/j.jhep.2015.02.022.
  7. Bugianesi E. Non-obese patients with NAFLD. Presentation in the Non-alcoholic fatty liver disease (NAFLD): any news? session at UEG Week 2014.
Further UEG Resources: Bellentani, S. How frequent is NAFLD in Europe and in the world? Presentation in the Update on non-alcoholic fatty liver disease session at UEG Week 2013 Dufour J-F. Impact of lifestyle and diet on disease progression. Presentation in the Non-alcoholic fatty liver  disease (NAFLD): any news? session at UEG Week 2014. Ratziu, V.  Medical treatment. Presentation in the Non-alcoholic fatty liver disease (NAFLD): any news? session at UEG Week 2014. Ratziu, V. Treatment modalities for non-alcoholic steatohepatitis. Presentation in the Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease in 2014 session at UEG Week 2014. 

Wake up Europe—it’s World IBD Day!

World IBD Day is observed on May 19.

World IBD Day (#worldIBDday) is observed on May 19 every year. This is the day for the millions of patients with IBD (inflammatory bowel disease), their supporters and IBD organizations worldwide to raise awareness, advance the understanding of the impact of IBD on human health and highlight the large number of people affected.

Ulcerative colitis and Crohn’s disease, the major types of IBD, are autoimmune diseases, the etiology of which appears multifactorial, involving both genetic and environmental factors. A study in the American Journal of Gastroenterology mapped the risk of acquiring IBD in relatives of patients with IBD.1 The study was based on data in the Danish National Patient Register, which included the 45,857 Danes who were diagnosed with IBD between 1977 and 2011. The team identified that the children, siblings or parents of individuals with IBD had an eightfold increased risk of developing IBD. For grandparents, uncles, aunts, nephews and nieces, the risk was increased by 2.5-fold. Among the younger siblings of patients with Crohn’s disease who were aged 20–25 years, the risk of developing IBD over the following 10 years was as high as 2%. First author on the paper, Frederik Trier Møller, says “Our results can be used in the counselling of relatives of IBD patients and maybe in the long run to identify persons, who could benefit from future available preventive measures.” Moving on to environmental factors, the intestinal microbiota is thought also to have a key role in the development of IBD. Books, such as ‘An Epidemic of Absence,’2 sum up some of the hypotheses on the etiology of allergic and autoimmune diseases. Intestinal parasites—protists and worms—are eukaryotic symbionts associated with the human intestine that have co-evolved with humans over thousands of years. These symbionts are still almost obligate findings in citizens in some regions of the world where IBD appears to be a very limited problem (e.g. Sub-Saharan Africa). Such organisms tend to establish stable communities in the human gut, but their role in human health and disease remains relatively unexplored. However, there is some evidence that the defaunation of the human gut seen in many countries with a Westernized lifestyle is associated with an increased incidence of immune-mediated and inflammatory diseases.2–5 Hence, while busy ridding ourselves of bugs, maybe particularly so those of our children, we may have inflicted new diseases on ourselves, including IBD. And so, in efforts to ‘dirty up’ our diets again, potential alleviation of IBD using concoctions of microscopic helminth eggs (Trichuris suis) is currently being investigated, the rationale being that helminth therapy will favorably modulate pro-inflammatory cytokine responses associated with intestinal inflammation. Indeed, IBD patients appear much less prone to being hosts of parasites than healthy individuals,6 but until now, only mere associations have been identified, not mechanistic understandings. Not only parasites—or the lack thereof—but also bacteria may have crucial roles in the etiology of IBD. It’s difficult not to think of peptic ulcers and gastric cancer when the word falls on Helicobacter pylori. Meanwhile, performing a meta-analysis of 33 available studies, comprising 4,400 IBD patients and 4,763 controls, to explore the association between H. pylori infection and IBD, Rokkas and colleagues7 found that 26.5% of IBD patients tested positive for H. pylori infection, compared with 44.7% of individuals in the control group. The significant negative association between H. pylori infection and IBD supports the hypothesis that H. pylori infection protects against the development of IBD. This conclusion is backed up by data in a recent study that was not included in the meta-analysis. Roka et al. found that the occurrence of H. pylori gastritis was less frequent in children with newly diagnosed IBD compared with controls.8 However, the team calls for studies that enable the distinction between a true protective role of H. pylori and a confounding effect due to, for instance, previous use of antibiotics in children with IBD. The fact that patients with IBD may have a slightly higher risk of developing small bowel cancer and colorectal cancer than individuals without the disease may now be quite well established, but how about the treatment offered to IBD patients? For example, what are the side effects of biologics and how severe are they? A study published in JAMA aimed to investigate whether patients with IBD who were exposed to TNF-α antagonists were at increased risk of developing cancer.9 Exposure to TNF-α antagonists (e.g. infliximab, adalimumab, and certolizumab pegol) among patients with IBD was not associated with an increased risk of cancer over a median follow-up of 3.7 years; an increased risk associated with longer-term accumulated doses and follow-up, however, could not be excluded. With regard to anti-TNF treatment and beyond, the ‘Therapy update: Best use of biologics in IBD in 2014’ session at UEG Week 2014 is available in the UEG Education Library. In the presentation, Professor Séverine Vermeire uses the ECCO guidelines and her experience to advise on when to use anti-TNF agents.10 Dr Silvio Danese then talks us through emerging therapeutic monoclonal antibodies, such as vedolizumab, golimumab, etrolizumab, tofacitinib, including their mechanisms of action.11 Dr Alessandro Armuzzi reviews the efficacy of drugs used for prevention of postoperative recurrence of Crohn’s disease recurrence, distinguishing between endoscopic and clinical recurrence, and highlights the importance of revisiting strategies to managing postoperative Crohn’s disease.12 In the final presentation from the session, Professor Gils highlights the importance of using pharmacokinetics to guide anti-TNF treatment in clinical practice.13 For more on the same topic, I guide your attention to the ‘How to manage IBD in 2014’ session from UEG Week 2014. Professor Maria Abreu brings you the best on IBD from Digestive Disease Week 201414 and also provides a strategy for how to make a confident diagnosis of IBD15 in the collection of presentations from the postgraduate course ‘What is important when diagnosing IBD?’ This collection also includes Dr Shomron Ben-Horin asking the question ‘Do characteristics at diagnosis predict disease outcome and complications?’,16 something which is also to some extent taken up by Dr Geert D’Haens in a very ‘good-for-teaching’ talk that aims to answer the question ‘Is differentiating ulcerative colitis from Crohn’s disease important?’17 The IBD material available in the UEG Education Library is vast, and I can only encourage you to mark #worldIBDday2015 by listening to some of these presentations. Also, if you want to know more about the activities related to World IBD Day, you may want to visit the World IBD events page. Finally, perhaps it is worth suggesting that World IBD Day should receive special attention on the Faroe Islands. This North-Atlantic archipelago has the highest incidence of IBD in the world, going from 8 per 100,000 person years in 1960–1979 to 75 per 100,000 person years in 2010–2014.18 Such a rapid change is most likely linked not only to increased diagnostic awareness but also to so-far-unidentified environmental factors. References
  1. Moller FT, et al. Familial risk of inflammatory bowel disease: a population-based cohort study 1977–2011. Am J Gastroenterol 2015; 110: 564–571.
  2. Velasquez-Manoff M. An Epidemic of Absence: A New Way of Understanding Allergies and Autoimmune Diseases. New York: Scribner, 2013.
  3. Elliot DE, and Weinstock JV. Where are we on worms? Curr Opin Gastroenterol 2012; 28: 551–556.
  4. Wiria AE, et al. Helminth infection in populations undergoing epidemiological transition: a friend or foe? Semin Immunopathol 2012; 34: 889–901.
  5. Rook GA, et al. Microbial ’Old Friends’, immunoregulation and stress resilience. Evol Med Public Health 2013; 2013: 46–64. 
  6. Petersen AM et al. Active ulcerative colitis associated with low prevalence of Blastocystis and Dientamoeba fragilis infection. Scand J Gastroenterol 2013; 48: 638–639. 
  7. Rokkas T, et al. The association between Helicobacter pylori infection and inflammatory bowel disease based on meta-analysis. United European Gastroenterology Journal Epub ahead of print April 9 2015. DOI:10.1177/2050640615580889. 
  8. Roka K, et al. The prevalence of Helicobacter pylori gastritis in newly diagnosed children with inflammatory bowel disease. Helicobacter 2014; 19: 400–405.
  9. Nyboe Andersen N, et al. Association between tumor necrosis factor-α antagonists and risk of cancer in patients with inflammatory bowel disease. JAMA 2014; 311: 2406–2413.
  10. Vermeire S. When should we start anti-TNF in IBD? Presentation in the “Therapy update: Best use of biologics in IBD in 2014” session at UEG Week 2014. 
  11. Danese S. Looking beyond anti-TNF in IBD: Vedolizumab, tofacitinib, etc. Presentation in the “Therapy update: Best use of biologics in IBD in 2014” session at UEG Week 2014. 
  12. Armuzzi A. Anti-TNF to prevent and treat postoperative recurrence of Crohn’s disease. Presentation in the “Therapy update: Best use of biologics in IBD in 2014” session at UEG Week 2014. 
  13. Gils A. Use of pharmacokinetics to guide anti-TNF treatment in clinical practice. Presentation in the “Therapy update: Best use of biologics in IBD in 2014” session at UEG Week 2014.
  14. Abreu MT. Inflammatory bowel disease. Presentation in the “Best of DDW” session at UEG Week 2014.
  15. Abreu MT. Diagnostic strategy to make a confident diagnosis of IBD. Presentation at UEG Week 2014. Presentation in the Postgraduate Teaching Programme at UEG Week 2014. 
  16. Ben-Horin S. Do characteristics at diagnosis predict disease outcome and complications? Presentation in the Postgraduate Teaching Programme at UEG Week 2014.
  17. d’Haens G. Is differentiating UC from CD important? Presentation in the Postgraduate Teaching Programme at UEG Week 2014.
  18. Hammer T et al. DOP010 Incidence of inflammatory bowel diseases in the Faroe Islands from 1960–2014: a 54-year overview from a population-based cohort. Presentation in “DOP Session 2 – Epidemiology of IBD" at ECCO Congress 2015.

The need for novel GORD diagnostic tools.

The need of noninvasive methods.

Gone are the days when a doctor would diagnose gastroesophageal reflux disease (GORD) simply by asking about symptoms and/or evaluating the response to acid suppression. Though this is still the case in many clinical practices, particularly for patients who have uncomplicated symptoms, a more accurate diagnosis usually involves undertaking invasive and expensive procedures that, nonetheless, are still claimed to have only moderate sensitivity and specificity. As such, more specific, noninvasive and cost-effective methods are needed for the diagnosis of GORD.

GORD is a common and chronic condition that has a significant impact on quality of life and confers a significant economic burden. It generally arises from the reflux of stomach contents into the oesophagus, thus leading to oesophageal injury and associated complications. The most common cause of GORD is the disrupted relaxation of the anti-reflux barrier, which is composed of the lower oesophageal sphincter and the diaphragmatic crura; when failing to respond to swallowing, these transient lower oesophageal relaxations result in reflux of gastric fluid through the oesophagogastric junction. Heartburn and acid regurgitation follow. Ultimately, in some patients acid reflux may damage the oesophageal squamous epithelium and lead to the development of Barrett oesophagus. Left untreated, Barret oesophagus can progress to oesophageal adenocarcinoma.1 The European Association of Endoscopic Surgery (EAES) states that the two main GORD diagnostic tools are upper endoscopy and long-term impedance esophageal pH monitoring. Indeed, the combined information obtained from clinical symptoms, endoscopy and pH testing is usually considered to be sufficient and specific for the diagnosis of GORD.  The EAES also highlight that “…further diagnostic investigations may be needed to verify functional abnormalities and establish the indication for surgery or other invasive therapies.”2 These additional diagnostic tools include high-resolution manometry (HRM), video-radiography and scintigraphy. For patients who have more severe symptoms, such as dysphagia and odynophagia, those who do not respond to acid suppression, or those in whom Barrett oesophagus is suspected, such additional diagnostic tools should be employed.3 Unfortunately, this comes at a sizeable financial cost. In Germany, the incidence of GORD is high and the associated healthcare costs have been estimated at €4.8 billion.4 In the United States, GORD represents the most common GI-related diagnosis; annually, GORD accounts for 8.9 million patient visits to the clinic and endoscopy exams cost $32.4 billion.5 These budgets emphasize the need for alternative, cheaper diagnostic methods for GORD and, ideally, noninvasive ones. Encouragingly, we might be on the right track with two recently published studies on novel GORD diagnostic tools, namely pepsin detection in saliva and minimally invasive oesophageal mucosal impedance testing. Several pathological settings may lead to pepsin being found in the laryngeal and paranasal sinus mucosa, saliva, middle ear effusion, tracheal secretions and bronchoalveolar lavage fluid. In their study, Hayat and co-workers sought to determine the value of salivary pepsin for discriminating patients with reflux-related symptoms from those with functional heartburn (FH).6 Pepsin was more likely to be detected in the saliva of patients with GORD and hypersensitive oesophagus (HO) and at higher concentrations than in the saliva of controls or FH patients. As such, the authors propose that salivary pepsin testing may complement GORD diagnosis.6 The fact that salivary pepsin can distinguish between GORD/HO and FH is extremely relevant, as most GORD patients benefit from pharmacological or surgical anti-reflux therapy, whereas FH patients do not. Interestingly, the detection of pepsin in saliva may also help in the diagnosis of laryngopharyngeal reflux (LPR).7 Despite the belief that LPR symptoms primarily result from GORD-related alterations of the laryngeal mucosa by gastric fluids, LPR differs from GORD in symptomatology and treatment modalities. A higher concentration of pepsin and bile acids has also been found in the saliva of patients with early laryngeal cancer than in the saliva of healthy volunteers, suggesting that LPR plays a role in the development of laryngeal carcinoma and might have utility as a disease biomarker.8 The question of how specific pepsin is for the diagnosis of GORD then arises. Indeed, is salivary pepsin diagnosing GORD, LPR or laryngeal carcinoma in development? As it currently stands, the measurement of salivary pepsin seems to represent a quick, cost-effective, noninvasive and simple 'office-based' method for GORD diagnosis, which I believe should be  followed or paralleled with other disease-specific methods. Nonetheless, it holds a great value on its own in pinpointing the next step; for instance, the absence of pepsin could be taken as a sign of null or low frequency reflux events. Ates and co-workers have developed a minimally invasive device to assess oesophageal mucosal impedance as a marker of chronic reflux in GORD, where impedance is measured close to the squamocolumnar junction.9 They found that the impedance values were significantly lower in patients with GORD, with mucosal impedance patterns being identified in patients with oesophagitis at higher levels of specificity and positive predictive values than wireless pH monitoring.9 Despite being a simple method that’s easy to use and provides immediate results, it is unlikely that mucosal impedance will fully replace current GORD diagnosis tools, as it is unable to distinguish between different GORD symptoms or even GORD-related disorders, which require different therapeutic approaches. Still, it represents an excellent strategy to differentiate between GORD and FH, much like salivary pepsin. Though measurement of mucosal impedance is still invasive, the procedure is quick, which makes it attractive for patients who cannot (or will not) tolerate a transnasal probe that must be in place for 24 hours.   Salivary pepsin levels and oesophageal mucosal impedance stand as two recent major breakthroughs in GORD diagnosis, but more are needed. I hope to see a lot of new and exciting discoveries on GORD diagnosis and management this October at UEG Week 2015! In the meantime, please feel free to browse the UEG Education Library for more resources. References:
  1. Subramanian CR and Triadafilopoulos G. Refractory gastroesophageal reflux disease. Gastroenterol Rep (Oxf) 2015; 3: 41–53.
  2. Fuchs KH, Babic B, Breithaupt W, et al. EAES recommendations for the management of gastroesophageal reflux disease. Surg Endosc 2014; 28: 1753–1773.
  3. Badillo R and Francis D. Diagnosis and treatment of gastroesophageal reflux disease. World J Gastrointest Pharmacol Ther 2014; 5: 105–112.
  4. UEG White Book Brochure [https://ueg.eu/epaper/WhiteBook.Brochure/index.html].
  5. Medical Economics. Treatment of GERD evolving [May 2013, accessed April 14, 2015].
  6. Hayat JO, Gabieta-Somnez S, Yazaki E, et al. Pepsin in saliva for the diagnosis of gastro-oesophageal reflux disease. Gut 2015; 64: 373–380.
  7. Ocak E, Kubat G and Yorulmaz I. Immunoserologic pepsin detection in the saliva as a non-invasive rapid diagnostic test for laryngopharyngeal reflux. Balkan Med J 2015; 32: 46–50.
  8. Sereg-Bahar M, Jerin A and Hocevar-Boltezar I. Higher levels of total pepsin and bile acids in the saliva as a possible risk factor for early laryngeal cancer. Radiol Oncol 2015; 49: 59–64.
  9. Ates F, Yuksel ES, Higginbotham T, et al. Mucosal impedance discriminates GERD from non-GERD conditions. Gastroenterology 2015; 148: 334–343.
Further UEG Resources “Challenges in GORD” Session at UEG Week 2014. “Therapy update: GORD” Session at UEG Week 2014. “New options in gastro-oesophageal reflux disease” Session at UEG Week 2014.

Is your ward happy?

All health services in Europe are under immense pressure …

I was woken up whilst on call recently by one of the staff nurses on our gastroenterology ward. It had been a busy day and, in addition to five new admissions, one patient—a withdrawing alcoholic—had become encephalopathic and was in the process of using a chair to try to smash through a window on the fifth floor. Earlier in the evening the same nurse had been hit in the mouth when she told another liver patient that he couldn’t go for a cigarette.

The 50 inpatient beds in our ward are always occupied by a mixture of patients who have alcoholic liver disease, inflammatory bowel disease, emergency GI bleeding, infective diarrhoea, GI cancer or eating disorders of such severity that they are unable to maintain their weight let alone their electrolyte balance. In my opinion, gastroenterology wards are undoubtedly the most challenging in any hospital. No other hospital ward hosts such a wide-ranging mixture of disease, affecting patients of any age and with such severity! In spite of the state-of-the-art care that we provide, we have more deaths on our ward than any other ward in our hospital. This is because our patients are the sickest. Of course all health services in Europe are under immense pressure. In the UK, the number of patients presenting to GPs and Accident & Emergency departments is increasing, as is the number of patients admitted to hospital.1 As the workload increases, hospital cost cutting has led to a reduction the number of nurses and an increasing pressure to squeeze as much work as possible out of the existing workforce. In the NHS, 12-hour shifts are now the norm. I am sceptical that a 12-hour working day is compatible with the provision of compassionate, expert care to a complex GI patient and would like to see the evidence that this is achievable. The “Registered Nurse Forecast Study”, published in the Lancet in February 2014, looked at the impact of nursing numbers on patient mortality in 300 hospitals across Norway, Ireland, Netherlands, Finland, Sweden, Switzerland, England, Belgium and Spain.2 The authors found that hospitals in which trained nurses cared for an average of 6 patients had almost 30% lower mortality than in hospitals where nurses cared for an average of 8 patients. Similarly, a study by Rafferty et al.3 showed that in the UK “Patients and nurses in the quartile of hospitals with the best staffing levels had consistently better outcomes.” Mortality was 31% worse in hospitals where a single nurse cared for 8 patients compared with those hospitals where a single nurse cared for only 4 patients. Naturally, morale drops as workloads and stress increase. A study by Aiken et al.4 looked at staffing levels at Canadian, American, English and Scottish sites. Higher staffing levels led to higher nurse reported satisfaction with care given, resulting in better nurse retention and reduced burn out. Similarly a study of the safety and quality of hospital care across 12 European countries and the US concluded that better ratios of patients to nurses were associated with increased care quality and patient satisfaction.5 The UK nursing trade union UNISON conduct an annual survey of workload. In 2014, 51% of nurses said that they did not have sufficient staff numbers to deliver dignified, compassionate care.6 Furthermore, an astonishing 48% of respondents described their organisation as being at risk of a similar situation to "the Staffordshire Hospital". The Francis report7 into the Staffordshire Hospital scandal concluded that quality of care had become a secondary priority to financial savings. As a result, the Staffordshire Hospital failed in its duty of care to hundreds of patients and families. Patients died needlessly and loved ones were left in the dark without adequate answers or explanations. There are no European guidelines on minimum nurse staffing levels. In every country, it remains up to each institution to decide how many nurses it should employ. Unfortunately, many hospital managers seem to have no idea of the challenges faced on gastroenterology wards, which have to accommodate the widest range of the most complex conditions in patients aged anywhere between 15 and 115 years old (our oldest ever patient). Next time you do your ward round, make a note of the patient-to-staff ratio and ask yourself whether it is good enough. References
  1. The King’s Fund. What’s going on in A&E? The key questions answered, http://www.kingsfund.org.uk/projects/urgent-emergency-care/urgent-and-emergency-care-mythbusters (14 January 2015, accessed 7 May 2015)
  2. Aiken LH, et.al. Nurse Staffing and education and hospital mortality in nine European countries; a retrospective observational study. Lancet 2014; 383:1824–1830.
  3. Rafferty AM, et al. Outcomes of variation in hospital nurse staffing in English hospitals: cross-sectional analysis of survey data and discharge records, Int J Nursing Studies 2007; 44: 175–182. 
  4. Aiken LH, Clarke SP and Sloane DM. Hospital staffing, organization, and quality of care: cross-national findings, Int J Quality in Health Care 2002; 14: 5–13. 
  5. Aiken LH, et al. Patient safety, satisfaction, and quality of hospital care: cross sectional surveys of nurses and patients in 12 countries in Europe and the United States. BMJ 2012;344:e1717. 
  6. UNISON. Running on Empty—NHS staff stretched to the limit: UNISON’s staffing levels survey 2014, https://www.unison.org.uk/upload/sharepoint/On%20line%20Catalogue/22245.pdf (14 May 2014, accessed 7 May 2015).
  7. Francis R. Report of the Mid Staffordshire NHS Foundation Trust Public Inquiry Executive Summary, http://www.midstaffspublicinquiry.com/sites/default/files/report/Executive%20summary.pdf (6 February 2013, accessed 7 May 2015).

MicrObesity

To what extent do gut microbes contribute to obesity?

Obesity—morbid overweight—is usually defined by a body mass index (BMI) >30. The condition can develop into metabolic syndrome, a rapidly emerging global epidemic that is associated with the development of multiple gastrointestinal (GI) disorders, including GI cancer.

In one of the presentations now available for viewing from the "EAGEN Obesity Course—metabolic and nutritional problems in Western and Eastern Europe", which was held in October 2014, Professor Peter Malfertheiner dishes out quite a few disturbing facts.1 In 2005, 1 billion people worldwide were overweight and 300 million were obese. Ten years on and the numbers have risen to 2.3 billion overweight people and 700 million obese. This means that 14% of the world’s population is now pre-obese (7%) or obese (7%). One of the main concerns regarding obesity is the level of co-morbidity and reduction in life expectancy that is associated with it. Indeed, at the age of 40, the life expectancy of obese individuals is reduced by 7 years compared with that of non-obese individuals. However, it is not the actual BMI level per se, but the number of years living with obesity that is the stronger predictor of mortality, which is why strategies to delay the onset of obesity should be developed and implemented. Distinctions are also made between ‘benign’ and ‘malign’ obesity, the latter being synonymous with ‘visceral obesity’ (or ‘central obesity’), which is linked to inflammatory processes and insulin resistance, and which is labelled metabolic syndrome. Professor Malfertheiner explains how an inappropriate diet may lead to dysbiosis, increased gut permeability and gut bacterial lipopolysaccharide-associated metabolic endotoxaemia, with deterioration in gut, liver and endocrine functions. Professor Malfertheiner also discusses how obesity-associated non-alcoholic fatty liver disease (NAFLD) may develop into hepatocellular cancer (HCC) and underlines the fact that patients receiving insulin have a much higher risk of developing colorectal cancer (CRC). In general, the role of metabolic syndrome in cancer development is currently under intense scrutiny. In his talk ‘The link between obesity and lower GI tract diseases’, Dr Lazlo Herzeny mentions that 15% and 20% of cancer deaths in men and women, respectively, can be attributed to visceral/central obesity.2 Allegedly, 40%, 30% and 10% cases of oesophageal carcinoma, HCC and CRC, respectively, are associated with this type of obesity. In their study, Kang et al.3 showed that visceral obesity and insulin resistance are risk factors of colorectal adenoma, and Rampal et al.4 found an association between metabolic syndrome and colorectal adenoma. Be sure to look up Dr Herzeny’s talk to learn more about the factors potentially involved in obesity-related tumour development and progression. Incidentally, the EAGEN meeting included a pro-con debate on the role of obesity in GI cancers. Citing a study by Danaei et al.,5 Professor Borut Stabuc argues that obesity is on its way to outcompeting tobacco as the number one preventable cause of cancer.6 He talks us through reviews and meta-analyses that provide data evidencing links between metabolic syndrome and various types of cancer. However, gender differences are seen, and the relative risks associating metabolic syndrome with cancer are generally quite modest. As Professor Jaroslaw Regula points out in his talk,7 we are swamped with epidemiological data evidencing associations between metabolic syndrome and GI cancer, but these associations do not necessarily represent causal relationships. Professor Regula gives examples of some of the caveats when interpreting epidemiological data and calls into question the overall applicability of BMI in epidemiological studies, since BMI is not a direct indicator of visceral obesity. Moreover, there are few intervention studies and they do not necessarily show the same trends for men and women.8 The composition of the gut microbiota varies substantially among individuals, but within individuals it is also dynamic and susceptible to change by diet and administration of antimicrobial agents. The term ‘MicrObesity’ (microbes and obesity), coined by Drs Cani and Delzenne, is about deciphering the specific role of intestinal microbiota dysbiosis and its impact on host metabolism and energy storage.9 Microbes take up approximately 1 kg of our body weight, with most microbes being in the gut. Perturbations of the intestinal microbiota can have severe implications for our health, and several diseases appear to stem from intestinal dysbiosis. According to Lopez-Legarrea et al.,10 the majority of the bacterial phylotypes found in the intestine are members of two phyla: the Firmicutes (e.g. Clostridium, Enterococcus, Lactobacillus, Ruminococcus), which make up 60% of the gut microbiota, and the Bacteroidetes (e.g. Bacteroides, Prevotella), which account for about 15%. Other phyla include Actinobacteria (e.g. Bifidobacterium) and Proteobacteria (Helicobacter, Escherichia). In her talk, Dr Darij Vranesic Bender points out that a Mediterranean diet, which is high in polyphenols and polyunsaturated fatty acids, leads to increases in Prevotella, Enterococcus, Bifidobacteria, Latobacillus and Bacteroides, while a decrease in obesity-associated Clostridium is seen.11 Changes in the relative balance of bacterial groups may be directly associated with nutritional uptake, but the situation is complex and influenced by host factors such as genetics/co-evolution and physical activity. Also, one might ask how do changes in microbiota structure and function impact benign and malign (visceral/central) obesity? Data are still scarce, but a study recently published in Gut showed that cranberry extract administered to mice fed on a high-fat/high-sucrose (HFHS) diet reduced HFHS-induced weight gain and visceral obesity.12 Cranberry extract treatment markedly increased the proportion of the mucin-degrading bacterium Akkermansia muciniphila, which has previously been shown to be decreased in obese individuals, and which may be a bacterium actively fighting obesity and diabetes.13 As pointed out by Professor Krznaric in his talk “The role of microbiota in the pathophysiology of obesity”, imbalances in the relative proportion of Bacteroides to Firmicutes may lead to obesity.14 Of particular interest is the recognition of obesity-associated gut microbiomes with increased capacity for energy harvest, since the human microbiota—in this rising era of microbiota transplantation—can be remodelled in different cohorts (obese vs underweight) with a view to optimising nutritional intake. Part of the mechanism underlying this is the role of short-chain fatty acids that are not only a source of energy for the intestinal epithelium, but also act as signalling molecules with implications for fat metabolism. Professor Krznaric also underlines the possibility that long-term exposure to low-dose antibiotics, for instance through foods, may lead to intestinal dysbiosis and obesity. Moreover, as pointed out by Professor Malfertheiner, non-caloric artificial sweeteners—quite paradoxically—drive the development of glucose intolerance, which is associated with insulin resistance, due to alterations of the structure and function of the intestinal microbiota.2 Given this complex situation it will be challenging to come up with one-size-fits-all strategies for combatting obesity in the future. Nonetheless, Professors Petr Díte and Tomica Milosavljevic both attempt to do this. To learn about their thoughts and to update yourself with much more news in the field interfacing obesity and GI diseases, please do listen to their talks.15,16 Gut microbiota manipulation appears to be critical to future advances in preventing and treating obesity, and the effect of diet on gut microbiota structure and function is probably one of today’s hottest research areas. The collection of talks from the EAGEN meeting includes a variety of other obesity-associated topics, including endoscopic approaches to obesity, an update on bariatric surgery and epidemiology, clinical presentation and management of non-alcoholic steatohepatitis (NASH), to mention just some. Why not sit down with a nice cup of coffee and have a browse yourself, though you may want to try the coffee without the sugar or sweetener … and skip the biscuits! References
  1. Malfertheiner, P. Epidemiological trends of metabolic syndrome affecting GI diseases. Presentation at EAGEN Obesity Course - metabolic & nutritional problems in Western and Eastern Europe.
  2. Herzeny, L. The link between obesity and lower GI tract diseases. Presentation at EAGEN Obesity Course - metabolic & nutritional problems in Western and Eastern Europe.
  3. Kang HW, et al. Visceral Obesity and Insulin Resistance as Risk Factors for Colorectal Adenoma: A Cross-Sectional, Case–Control Study. Am J Gastroenterol 2010; 105: 178–187. 
  4. Rampal S, et al. Association Between Markers of Glucose Metabolism and Risk of Colorectal Adenoma. Gastroenterology 2014; 147: 78–87.
  5. Danaei G, et al. Causes of cancer in the world: comparative risk assessment of nine behavioural and environmental risk factors. Lancet 2005; 366: 1784–1793.
  6. Stabuc  B. Debate: Obesity and the risk of GI cancer – PRO. Presentation at EAGEN Obesity Course - metabolic & nutritional problems in Western and Eastern Europe.
  7. Regula J. Debate: Obesity and the risk of GI cancer – CONTRA. Presentation at EAGEN Obesity Course - metabolic & nutritional problems in Western and Eastern Europe. 
  8. Sjöström L. Review of the key results from the Swedish Obese Subjects (SOS) trial - a prospective controlled intervention study of bariatric surgery. J Intern Med 2013; 273: 219–234.
  9. Cani PD and Delzenne NM. The gut microbiome as therapeutic target. Pharmacol Ther 2011; 130: 202–212. 
  10. Lopez-Legarrea P, et al. The influence of Mediterranean, carbohydrate and high protein diets on gut microbiota composition in the treatment of obesity and associated inflammatory state. Asia Pac J Clin Nutr 2014; 23: 360–368. 
  11. Bender DV.  Protein, carbs and fats in personalised weight control - efficacy and safety. Presentation at EAGEN Obesity Course - metabolic & nutritional problems in Western and Eastern Europe. 
  12. Anhê FF et al. A polyphenol-rich cranberry extract protects from diet-induced obesity, insulin resistance and intestinal inflammation in association with increased Akkermansia spp. population in the gut microbiota of mice. Gut (Epub ahead of print 30 July 2014) doi:10.1136/gutjnl-2014-307142.
  13. Everarda, A et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci 2013; 110: 9066–9071. 
  14. Krznarik Z. The role of microbiota in the pathophysiology of obesity. Presentation at EAGEN Obesity Course - metabolic & nutritional problems in Western and Eastern Europe. 
  15. Díte P. Health strategies to manage the epidemics of metabolic syndrome. Presentation at EAGEN Obesity Course - metabolic & nutritional problems in Western and Eastern Europe. 
  16. Milosavljevic T. Health strategies to manage the epidemics of metabolic syndrome. Presentation at EAGEN Obesity Course - metabolic & nutritional problems in Western and Eastern Europe.  
Further UEG Education Resources EAGEN Obesity Course—metabolic and nutritional problems in Western and Eastern Europe. Acknowledgements "Overweight and obesity tape measure" image: http://www.canstockphoto.com © Can Stock Photo / alexskopje.

Managing coeliac disease:

separating the wheat from the chaff

A few decades ago, you wouldn’t see any. Today, however, you won’t leave the supermarket without finding gluten-free labels on all sorts of foods, ranging from the usual suspects (grains, cereals, bread) to the lesser-known ones (beer, candies, French fries, gravy, processed meats, salad dressings and sauces, seasoned snack foods, and others).

Don’t get me wrong; we’ve come a long way! A gluten-free diet (GFD) remains the only treatment for coeliac disease. Still, I wonder whether most people are actually aware of this? A GFD is quickly becoming one of the trendiest alimentary diets. If you search the Internet, you will find claims of how GFD can increase your health and life span, and help you lose weight or rejuvenate your skin (ok, I didn’t actually find the last one!). My point is, a GFD has a point. In fact, a GFD may occasionally lead to vitamin and mineral deficiencies if not properly monitored by a physician or a nutritionist. Nonetheless, with reports of non-coeliac gluten sensitivity (NCGS) increasing,1 the long-term effects of a GFD on non-coeliac individuals do deserve further exploration. In addition, a significant number of patients with coeliac disease are nonresponsive to gluten withdrawal (nonresponsive celiac disease; NRCD), with unintentional gluten intake accounting for >50% of these cases.2 Alternatively, patients may develop refractory coeliac disease (RCD) despite strict adherence to a GFD for at least 6–12 months, in the absence of other causes of NRCD and overt malignancy. Both of these patient populations exhibit persistent or recurrent malabsorptive symptoms and intestinal injury. As such, the development of novel nondietary therapies for coeliac disease is of utmost importance. In recent years, a large number of targets likely to halt the process of immunological injury in coeliac disease have been explored. These include prolylendopeptidases to assist intraluminal digestion of gluten, zonulin antagonists to prevent the passage of immunogenic peptides through tight junctions (TJs) and blocking of HLA-DQ2 to prevent binding of immunogenic peptides.3 Of note, some of the targets have already reached phase II clinical trials.4 At the moment, however, they will probably not be able to fully replace a GFD regime, but rather be used as adjunctive therapies. Indeed, this might be the case for larazotide acetate, for which the phase IIb clinical trial results have just been published.5 Larazotide acetate is an 8-mer peptide that regulates intestinal TJs. In turn, TJs control the paracellular permeability and apical–basolateral polarity of intestinal cells, and deregulated permeability of intestinal cells is associated with coeliac disease. Proof-of-concept studies have shown that larazotide acetate inhibits gliadin translocation across cells, as well as gliadin-induced macrophage recruitment to the small intestine, both of which are events critical to the development of coeliac disease.6,7 By further promoting actin rearrangement, larazotide acetate stabilizes and preserves TJ structure, thus preventing gluten from reaching the intestinal submucosa and triggering an inflammatory response. Prior phase II clinical trials suggested larazotide acetate to be safe, well tolerated and effective in reducing gastrointestinal symptoms after a gluten challenge.8,9 Still, these studies were somewhat criticized for not meeting one of their primary endpoints, namely the lactulose-to-mannitol ratio, which is an experimental biomarker of intestinal permeability. In this most recent phase IIb trial,5 the primary endpoint was set as the difference, on average, in the on-treatment ‘Celiac Disease Gastrointestinal Symptom Rating Scale’ (CeD-GSRS) score. Larazotide acetate was shown to improve both gastrointestinal and nongastrointestinal symptoms of coeliac disease, resulting in fewer gastrointestinal symptomatic days in patients who have persistent symptoms despite a GFD. Not without its limitations, as acknowledged by the study authors, larazotide acetate may embody a future therapeutic option for coeliac disease patients who have persistent symptoms. Perhaps equally important, this study illustrates how the design of clinical trials for coeliac disease should be constantly improved, with surrogate endpoints specifically tailored to the drug, disease and target patient population. It may be some years before a GFD replacement is available. Thankfully, however, in parallel with all the current clinical research into coeliac disease, the food industry also has their brightest minds working in the laboratory to develop new gluten-free products. It shouldn’t be long before you go to the supermarket and find that guilty pleasure you’ve been craving for years … now gluten-free!       When it comes to separating the wheat from the chaff, there were three specific sessions at UEG Week 2014 on the lingering challenges for distinguishing and managing coeliac disease, NCGS, RCD and NRCD, as well as establishing the need for diagnostic biopsies and novel therapeutics (see Further UEG Resources below). Simply sign in to myUEG to watch the recorded sessions! You can also expect a full update on coeliac disease at UEG Week 2015 and, as always, don’t forget to browse through the UEG Education Library for more resources. References:
  1. Fasano A, Sapone A, Zevallos V, et al. Non-celiac gluten sensitivity. Gastroenterology Epub ahead of print 14 March 2015. DOI: http://dx.doi.org/10.1053/j.gastro.2014.12.049 
  2. Leffler DA, Dennis M, Hyett B, et al. Etiologies and predictors of diagnosis in nonresponsive celiac disease. Clin Gastroenterol Hepatol 2007; 5: 445-450.
  3. Makharia GK. Current and emerging therapy for celiac disease. Front Med 2014; 1: 6. 
  4. Gottlieb K, Dawson J, Hussain F, et al. Development of drugs for celiac disease: review of endpoints for Phase 2 and 3 trials. Gastroenterol Rep Epub ahead of print 26 February 2015. DOI: 10.1093/gastro/gov006
  5. Leffler DA, Kelly CP, Green PH, et al. Larazotide acetate for persistent symptoms of celiac disease despite a gluten-free diet: a randomized controlled trial. Gastroenterology Epub ahead of print 12 February 2015. DOI: http://dx.doi.org/10.1053/j.gastro.2015.02.008
  6. Gopalakrishnan S, Durai M, Kitchens K, et al. Larazotide acetate regulates epithelial tight junctions in vitro and in vivo. Peptides 2012; 35: 86–94.
  7. Gopalakrishnan S, Tripathi A, Tamiz AP, et al. Larazotide acetate promotes tight junction assembly in epithelial cells. Peptides 2012; 35: 95–101.
  8. Leffler DA, Kelly CP, Abdallah HZ, et al. A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge. Am J Gastroenterol 2012; 107: 1554–1562.
  9. Kelly CP, Green PH, Murray JA, et al. Larazotide acetate in patients with coeliac disease undergoing a gluten challenge: a randomised placebo-controlled study. Aliment Pharmacol Ther 2013; 37: 252-262.
Further UEG Resources “Coeliac disease, wheat allergy and wheat sensitivity: Still the tip of the iceberg” Session at UEG Week 2014. “New challenges in gluten sensitivity: From bench to bedside” Session at UEG Week 2014. "Challenges in coeliac disease and gluten-related disorders” Session at UEG Week 2014.

Are we finally saluting the fungal kingdom as a co-ruler of GI health and disease?

The human body is host to myriads of fungal species—typically yeasts, moulds and dermatophytes. It has also long been known that Candida spp. present on the skin or mucosal surfaces can end up causing invasive mycotic disease in immunocompromised individuals, critical care patients and in those undergoing abdominal surgery, resulting in candidaemia or deep-seated candidiasis. Meanwhile, the impact of intestinal fungal colonisation and infection on gastrointestinal health and disease remains elusive. Thanks to advances in DNA detection technologies and mass spectrometry, the role of fungi in human gastrointestinal pathology, immunology and ecology is now finally—though slowly—being unravelled.

Over the past few years, communities of intestinal bacteria have been scrutinized meticulously in order to identify their role in human health and disease. This discipline is now commonly referred to as ‘gut microbiome research’, involving analysis of the structure and function of bacteria. Meanwhile, kingdoms of ubiquitous organisms in and on the human body have been more or less ignored;1,2 these kingdoms include fungi and parasitic protists. If we acknowledge the fact that such organisms are common denizens of our gastrointestinal canal,3 why have they failed to catch our attention? Firstly, it’s not unusual to hear people saying that bacteria outnumber microbial eukaryotic organisms a zillion times or so, and that bacteria are therefore seemingly much more important to study. However, while the crude number of colonising eukaryote organisms may be several orders of magnitudes lower than the number of bacteria, we should remember that the genomes of such organisms are typically larger, and the expressed gene repertoire may be much more comprehensive and refined. Secondly, problems related to detection and identification are almost certainly one of the main reasons why we have failed to include eukaryotes in gut microbiome research. Finally, the potentially ‘bittersweet’ nature of fungal colonisation may blur the pathway to knowledge. The bittersweet nature of fungal colonisation is highlighted in a talk given by Dr Gianluca Ianiro at EAGEN Gut Microbiota 2014: EAGAN Advances in Gut Microbiota and Fecal Microbiota Transplantation.4 Dr Ianiro also addresses the fundamental question of why we should bother about the fungal microbiome (the mycobiome) at all. He puts emphasis on the fact that a yeast such as Saccharomoyces cerevisiae var. boullardi is widely used as a probiotic (and possibly the only commercialised probiotic yeast), but that Saccharomyces is also a potential cause of fungaemia, suggesting that the virulence and/or host response to the yeast may vary dramatically. “Nobody is fungus-free,” Huffnagle and Noverr claim in an article published in 2013.5 They go on, “Every individual’s microbiome contains thousands of different species of microbes, of which 99.9% of the total number of microbial cells belong to only a few species. The less abundant (< 0.1%), but more diverse, component of the microbiome has been termed the ‘rare biosphere’. The impact of this rare biosphere on human health is significant because it can act as a reservoir for blooms of pathogenic microbes when the host is compromised.”  Asymptomatic yeast colonisation of mucosal surfaces may develop into a yeast infection in cases where the microbial ecology is skewed, for example during and/or after the use of antibiotics. Although research into the gut mycobiome is still in its infancy, it is clear that species of Candida can coexist with the intestinal bacterial microbiome, bloom during dysbiosis due to use of antibiotics and colonise inflamed intestinal mucosal surfaces. Very recently, Luan and colleagues6 analysed the fungal microbiota by deep sequencing the internal transcribed spacer 1 region (the marker commonly used for DNA-based fungal identification) of fungal DNA extracted directly from rinsed tissue biopsy samples from early-stage and advanced-stage colorectal adenomas as well as from adjacent (normal) tissue. The authors identified that core operational taxonomic units (OTU; taxonomic level of sampling when only DNA data are available) formed separate clusters for advanced and nonadvanced adenomas, for which the abundance of four OTU differed significantly. Both adenoma size and disease stage were associated with changes in the fungal microbiota. With no control material from healthy individuals available for analysis, the most important take-home message here may not be so much the findings, but the technical approach and the recognition that—similar to bacteria—intestinal eukaryotic communities may be significantly linked to disease processes, including that of colorectal cancer (CRC), in which case the microbiota represents not only a potential means of CRC detection (screening by biomarkers) but also intervention (microbiota manipulation). In a very recent review, Mukherjee and co-workers conclude that fungi may contribute to aggravating inflammatory responses, leading to increased disease severity.7 This process may involve multiple steps and components, including interactions between host immune cells with specific pattern-recognition receptors (e.g. dectin-1—a natural-killer-cell-receptor-like C-type lectin possibly involved in innate immune responses to fungal pathogens through recognition of β-glucan8) and pathogen-associated molecular patterns, including fungal cell wall moieties, such as mannan, glucan and chitin. Intriguing observations published in 2012 in Science by Iliev and co-workers9 suggest that certain polymorphisms in CLEC7A, the gene encoding dectin-1, are associated with medically refractory ulcerative colitis. The presence of live fungi in stools is also interesting from the faecal microbiota transplantation (FMT) perspective. Which organisms—which potential pathogens—are screened for when manufacturing FMT products? This is one of several topics that will be addressed at the UEG-endorsed practice course ‘The Fecal Microbiota Transplantation’, which is taking place in Rome in April.  And while we’re at it, how should we screen for fungi in stool samples? There are probably many opinions on that! Gouba and Drancourt have suggested the use of ‘culturomics’, which involves the use of several different culture media and incubation conditions to increase the efficiency of detection of organisms by culture, later identified by MALDI-TOF-MS to expand the repertoire of species and safeguard comprehensive detection.10 Whether this approach has advantages over metagenomics remains to be revealed. Novel technologies and increased availability of genome data enable precise and sensitive detection and identification of fungal and other microeukaryotic organisms in the gastrointestinal tract and how they interact with each other and the host. Efforts to map differences in fungal diversity in various cohorts are essential to generating hypotheses on the role of fungi in disease. Such studies are often cross-sectional; however, longitudinal studies of the intestinal mycobiota and mycobiome in healthy and diseased cohorts are critical if we are to obtain a more detailed and accurate understanding of exactly how fungi govern our health.
References
  1. Anderson LO, Nielsen HV and Stensvold CR. Waiting for the human intestinal Eukaryotome. ISME J 2013; 7: 1253–1255.
  2. Norman JM, Handley SA and Virgin HW. Kingdom-agnostic metagenomics and the importance of complete characterization of enteric microbial communities. Gastroenterology 2014; 146: 1459–1469. 
  3. Scanlan PD and Marchesi JR. Micro-eukaryotic diversity of the human distal gut microbiota: qualitative assessment using culture-dependent and -independent analysis of faeces. ISME J 2008: 2: 1183–1193.
  4. Ianiro G. Gut Mycome. Presentation at the EAGEN Gut Microbiota 2014: EAGEN Advances on Gut Microbiota and Fecal Microbiota Transplantation. 
  5. Huffnagle GB and Noverr MC. The emerging world of the fungal microbiome. Trends Microbiol 2013; 21: 334–341. 
  6. Luan C, Xie L, Yang X, et al. Dysbiosis of fungal microbiota in the intestinal mucosa of patients with colorectal adenomas. Sci Rep 2015; 5:7980. doi: 10.1038/srep07980.
  7. Mukherjee PK, Sendid B, Hoarau G, et al. Mycobiota in gastrointestinal disease. Nat Rev Gastroenterol Hepatol 2015; 12: 77–87.
  8. Brown GD. Dectin-1: a signaling non-TLR pattern-recognition receptor. Nat Reviews Immunol 2006; 6: 33–43. 
  9. Iliev ID, Funari VA, Taylor KD, et al. Interactions between commensal fungi and the C-type lectin receptor Dectin-1 influence colitis. Science 2012; 336: 1314–1317.
  10. Gouba N and Drancourt M. Digestive tract mycobiota: A source of infection. Med Mal Infect 2015; 45: 9–16. 
Additional Information  The photograph of Candida albicans grown on CHROM agar, in which a few hyphae are visible at 40x magnification, is provided courtesy of Rasmus Hare Jensen.

Chasing up colorectal cancer

CRC claims more than 200,000 lives in Europe alone.

Each year, Europe’s second biggest cancer killer—colorectal cancer (CRC)—claims more than 200,000 lives in Europe alone; yet, early detection may result in a 90–95% survival rate. Implementation of CRC screening programmes across Europe is booming, but what are the nuts and bolts of a good CRC screening programme?

A press release issued by UEG in March 2014 warned that the annual incidence of CRC is predicted to have risen 12% by 2020, at which time it will potentially affect about half a million Europeans.1 CRC is currently the second and third most common cancer in European women and men, respectively, and accounts for 13% of all cancer-related deaths in Europe, resulting in one fatality every 3 minutes. Screening programmes have been implemented in several countries with a view to reducing morbidity and mortality by identifying and treating cases of early-stage CRC. It’s almost a year since a nationwide CRC screening programme was launched in Denmark, with an annual budget of approximately €50M. Starting in March 2014, all Danish citizens aged 50–74 years old are invited to participate in biannual screening.2 Those individuals who are willing to participate receive a screening kit by regular mail, and the test is free and voluntary to complete. The CRC screening programme uses a faecal occult blood (FOB) test (FOBT), and individuals with a positive FOBT are offered a colonoscopy. The Danish screening programme was implemented on the basis of a feasibility study carried out in 2005–2006, in which 2–3% of those screened tested positive for the presence of FOB; of these, 8% and 40% were found to have cancer and polyps, respectively, as demonstrated by colonoscopy.3 In the feasibility study, a chemical test with a sensitivity of only 60% was used. In the ongoing screening programme, however, the faecal immunochemical test (FIT; also known as an immunochemical FOBT) is being used, which is expected to increase sensitivity. Meanwhile, high FIT sensitivity and specificity may be difficult to achieve given the fact that not all CRCs bleed and there are causes of FOB other than cancer and polyps; hence, quite a few false-negatives and false-positives may still be expected with the FIT. Of course, there’s more to achieving a successful screening programme than safeguarding best possible intervention options and optimizing diagnostic performance parameters, such as test cut-off and predictive values. The very nature of the test itself, how the screening programme is presented to the public and overall public health awareness are all factors potentially influencing the success of a screening programme. In the case of CRC, the mere thought of having a colonoscopy may scare people off, and public health awareness may differ substantially between countries, both of which are factors that may significantly affect uptake and thereby overall success rates. Sometimes there are differences in the willingness to participate within the same country that have no obvious explanation. For example, as pointed out by Björn Rembacken in his talk on CRC screening strategies in the West, a striking difference in the uptake rate has been observed in Belgium, where the Flemish appear much more keen on participating than the Walloons.4 In the Danish feasibility study, women were more likely to participate, as were those with higher education and higher income.5 Moreover, a study carried out by The Danish Cancer Society suggests that it takes time for a population to adjust to thinking and speaking of CRC.6 In this study, the most common barriers to accepting screening invitations included:
  • Not wanting to know whether they have CRC
  • Thinking that the test is too awkward to do
  • The need for more information
  • Developing a sense of being ill merely by being offered the test
  • Feeling too old for the test to be relevant
Apart from mitigating issues that have to do with culture and tradition, by removing stigma and taboos through campaigns and the provision of information, what diagnostic tools can be developed to minimize the number of cases with a positive result for FOB but negative findings on colonoscopy? How far are we in terms of developing other non-invasive biomarkers, such as those based on microbiota signatures7 or DNA methylation, for the detection of both CRC and critical precursor lesions? To which extent may individual risk assessment replace invasive and semi-invasive diagnostic methods in terms of identifying patients with early CRC? The UEG Education Library boasts a large catalogue of presentations, abstracts and syllabi focusing on early detection of CRC as a means of improving patient survival and widening the window of therapeutic intervention. For instance, if you want to familiarise yourself with the current status of CRC screening programmes throughout Europe, simply sign in to myUEG, go the Library and search for “CRC AND screening”. I also recommend listening to the presentations included in the session on “Colorectal cancer screening: the future” from UEG Week 2014 (see Further UEG Resources below). References
  1. UEG Press Release. Europe is falling behind America in the fight against colorectal cancer due to low screening uptake. (March 2014, accessed February 2015).
  2. Danish Cancer Society. Screening for colon cancer. (2014, accessed February 2015)
  3. Research Centre for Prevention and Health—The Capital Region of Denmark. Screening for colorectal cancer in the counties of Vejle and Copenhagen—cross evaluation of pilot studies. [Article in Danish]
  4. Rembacken B. CRC screening strategies. Presentation in the East meets West: CRC Screening Strategies session at UEG Week 2013 
  5. Frederiksen BL, Jørgensen T, Brasso K, et al. Socioeconomic position and participation in colorectal cancer screening. Br J Cancer 2010; 103: 1496—1501.
  6. Meyer M. Department of Prevention and Documentation. The Danish Cancer Society. What were the barriers for participating in colorectal cancer screening? A qualitative and quantitative analysis of non-participant barriers to participating in a pilot colorectal cancer screening programme in Vejle and Copenhagen in 2005 and 2006. (April 2007) [Article in Danish].
  7. National Cancer Institute. Analyzing the gut microbiome to help detect colorectal cancer. (January 2015, accessed February 2015)
Further UEG resources “Colorectal cancer screening: The future” session at UEG Week 2014. Fight against colorectal cancer.  Colorectal cancer in Europe. Colorectal cancer incidence and mortality in Europe.  Colorectal cancer – how to spot the symptoms.

Hepatologists jump on screening bandwagon

In the UK, endoscopy is riding a wave of investment generated by population-level colorectal cancer screening. Now, it seems that hepatology is also planning to jump on the screening bandwagon.

In 2012 the US Centers for Disease Control and Prevention gave the go-ahead for population-level screening for chronic HCV infection.1 Then, in 2014, the World Health Organisation also recommended an expansion of the current screening strategy beyond those at high risk of HCV infection2. Screening for HCV infection is a sizeable undertaking as up to 150 million people worldwide are thought to have the disease. Although most are asymptomatic, all studies have found that patients infected with HCV have a reduced life expectancy. Understandably, in those countries where most HCV infections result from intravenous drug use, there is not only an increased risk of liver disease, but also an increased risk of death from alcohol, HIV infection, smoking or drug-related events such as overdose, suicide, homicide and trauma.3 In patients with iatrogenic HCV infections, an excess mortality from nonhepatic causes such as renal and heart disease and cancer has also been described.4 What do people with HCV infection usually die from? I must admit that I find it difficult to understand research papers reporting on standardised mortality rates (SMR). It seems counterintuitive that patients who have an SMR of 16.8 of dying from a liver-related cause are still far more likely to die from heart disease (SMR of 1.25).5,6 However, a slightly increased risk of dying from something that is already a frequent cause of death will obviously have a great impact on the total number of deaths. I was surprised to find that up to 85% of patients with chronic HCV infections die from nonhepatic causes.7–14 Is there anything we can do to reduce the risk of progression to liver fibrosis, cirrhosis, liver failure or hepatoma? Yes! Beneficial lifestyle interventions could include attempts to reduce intravenous drug taking, tackle alcohol dependency, help with weight reduction in the obese and treat HIV co-infection aggressively, all of which may reduce the risk of progression.15 In fact, all of the above interventions would be beneficial for patients regardless of infection status. The reason that hepatologists are so enthusiastic about screening for HCV infection is the fantastic sustained virologic response (SVR) rates achieved with the latest antiviral agents, which is now approaching 90%.16 However, it is worth pointing out that the SVR is a surrogate endpoint and sadly we don’t know if this translates into long-term clinical benefit. I find it surprising that this fundamental issue has not yet been clarified. However, I do understand that the issues surrounding antiviral therapy are complex! For example, the patients who are the most likely to achieve an SVR are those who are least likely to have risk factors for progressive disease.17–19 In other words, those who do well on treatment would probably also do well even without treatment. In addition, a proportion of patients who achieve an SVR, nevertheless develop and die from liver-related causes. In one of the largest studies with the longest follow up (8 years), patients with severe hepatic fibrosis but with an SVR, were found to have annual risk of developing hepatocellular carcinoma of 1%.20 This sounded like a good result until I realised that the background incidence of hepatocellular carcinoma in patients with HCV cirrhosis is very similar (1.4–3.3%).21 Once population-level screening for chronic HCV infection has been rolled out there will be some difficult consultations during which unsuspecting people are told that they are now patients with a chronic disease, requiring lifelong monitoring and treatment. Although the long-term clinical benefit of antiviral therapy is uncertain, I would nevertheless expect these difficult conversations to be easier if a safe and well-tolerated treatment was on offer. Sadly this is not the case. The adverse effects of interferon are well known and it is associated with a 4% increase in all-cause mortality.22 Both the guanosine analogues and the protease inhibitors may cause bone marrow suppression, skin reactions, gastrointestinal upset and insomnia in a large proportion of patients.23.24 In 2012, the US Food and Drug Administration reported that telaprevir was the most common reported cause of severe and fatal skin reactions of any drug.25 In one trial, 3% of patients randomly allocated to receive sofosbuvir experienced serious adverse events, with 1% occurring in the peginterferon plus ribavirin arm.26 In a more recent study, combination therapy with sofosbuvir plus ledipasvir was associated with a 0.5–2% rate of serious adverse events.27 As up to 85% of HCV-infected people in the population will die from nonhepatic causes, the newer antiviral therapies must be safer and better tolerated; otherwise, people will conclude that such a government screening programme turns well people into poorly patients. As an endoscopist, I find it reassuring to know that the benefit of colorectal cancer screening has been proven in several large, prospective studies. In view of the uncertainties surrounding population-level screening for HCV infection, I am not alone in wanting to see plans for large, prospective randomised controlled trials to prove it’s worthwhile.28 As a taxpayer, I would also like to be reassured that such screening would be money well spent. References
  1. Smith BD, Morgan RL, Beckett GA, et al. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945–1965. MMWR Recomm Rep 2012; 61(RR-4): 1–32 
  2. WHO. Guidelines for the screening, care and treatment of persons with hepatitis C infection. www.who.int/hiv/pub/hepatitis/hepatitis-c-guidelines/en/ (2014, accessed 28 January 2015)
  3. Grebely J and Dore GJ. What is killing people with hepatitis C virus infection? Semin Liver Dis 2011; 31: 331–333.
  4. Lee MH, Yang HI, Lu SN, et al. Chronic hepatitis C virus infection increases mortality from hepatic and extrahepatic diseases: a community-based long-term prospective study. J Infect Dis 2012; 206: 469–477.
  5. Amin J, Law MG, Bartlett M, et al. Causes of death after diagnosis of hepatitis B or hepatitis C infection: a large community-based linkage study. Lancet 2006; 368: 938–945.
  6. Butt AA, Xiaogiang W, Budoff M, et al. Hepatitis C virus infection and the risk of coronary disease. Clin Infect Dis 2009; 49: 225–232.
  7. Wiese M, Fischer J, Lobermann M, et al. Evaluation of liver disease progression in the German hepatitis C virus (1b)-contaminated anti-D cohort at 35 years after infection. Hepatology 2014; 59: 49–57. 
  8. Seeff LB, Hollinger FB, Alter HJ, et al. Long-term mortality and morbidity of transfusion-associated non-A, non-B, and type C hepatitis: a National Heart, Lung, and Blood Institute collaborative study. Hepatology 2001; 33: 455–463. 
  9. Vogt M, Lang T, Frosner G, et al. Prevalence and clinical outcome of hepatitis C infection in children who underwent cardiac surgery before the implementation of blood-donor screening. N Engl J Med 1999; 341: 866–870.
  10. Barrett S, Goh J, Coughlan B, et al. The natural course of hepatitis C virus infection after 22 years in a unique homogenous cohort: spontaneous viral clearance and chronic HCV infection. Gut 2001; 49: 423–430. 
  11. Casiraghi MA, De Paschale M, Romano L, et al. Long-term outcome (35 years) of hepatitis C after acquisition of infection through mini transfusions of blood given at birth. Hepatology 2004; 39: 90–96. 
  12. Seeff LB, Miller RN, Rabkin CS, et al. 45-year follow-up of hepatitis C virus infection in healthy young adults. Ann Intern Med 2000; 132: 105–111. 
  13. Locasciulli A, Testa M, Pontisso P, et al. Prevalence and natural history of hepatitis C infection in patients cured of childhood leukemia. Blood 1997; 90: 4628–4633. 
  14. Lai ME, Origa R, Danjou F, et al. Natural history of hepatitis C in thalassemia major: a long-term prospective study. Eur J Haematol 2013; 90: 501–507 
  15. Missiha SB, Ostrowski M and Heathcote EJ. Disease progression in chronic hepatitis C: modifiable and nonmodifiable factors. Gastroenterology 2008; 134: 1699–1714.
  16. Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 2014; 370: 1483–1493.
  17. Stattermayer AF, Scherzer T, Beinhardt S, et al. Review article: genetic factors that modify the outcome of viral hepatitis. Aliment Pharmacol Ther 2014; 39: 1059–1070. 
  18. Zeuzem S, Feinman SV, Rasenack J, et al. Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med 2000; 343: 1666–1672. 
  19. Koretz R. Chronic hepatitis: more quotes and misquotes. In: Gitnick G (ed) Current Hepatology. Vol 15. St. Louis: Mosby-Year Book Inc., 1995, pp.49–84.
  20. Van der Meer A, Feld J, Hofer H, et al. The risk for hepatocellular carcinoma among patients with chronic HCV infection and advanced hepatic fibrosis following sustained virological response. In: 64th Annual Meeting of the American Association for the Study of Liver Diseases, Washington, DC, USA, 1 November–5 November 2013. Abstract 143. 
  21. Everson GT. Management of cirrhosis due to chronic hepatitis C. J Hepatol 2005; 42 (suppl1): S65–S74. 
  22. Di Bisceglie AM, Stoddard AM, Dienstag JL, et al. Excess mortality in patients with advanced chronic hepatitis C treated with long-term peginterferon. Hepatology 2011; 53: 1100–1108. 
  23. Brok J, Gluud LL and Gluud C. Ribavirin plus interferon versus interferon for chronic hepatitis C. Cochrane Database Syst Rev 2010; 1: CD005445. 
  24. Casey LC and Lee WM. Hepatitis C virus therapy update 2013. Curr Opin Gastroenterol 2013; 29: 243–249. 
  25. Institute for Safe Medication Practices. Perspective on drug hypersensitivity. QuarterWatch 2013 Q1, www.ismp.org/quarterwatch/pdfs/2013Q1.pdf (2014, accessed 28 January 2015) 
  26. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013; 368: 1878–1887. 
  27. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014; 370: 1879–1888. 
  28. Koretz RL, Lin KW, Loannidis JPA, et al. Is widespread screening for hepatitis C justified? BMJ 2015; 350: g7809. 

The Intestinal Microbiome—Rosetta Stone or Tower of Babel?

One of the hot topics in modern-day research is the mapping and understanding of the human intestinal microbiome and its role in health and disease. Studies have suggested that the development of several diseases and conditions depends on how our microbiomes are influenced and shaped, but interpreting the data generated by such studies may not be that simple. Are we holding the key to understanding metabolic, immunological and pathological processes, or do the data produced so far preclude any type of generalization? Are we unraveling the code necessary to develop obesity, irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD), or are we looking at a chaos of data, different terminologies and methodologies?

UEG Week 2014 was the first UEG event that I’ve attended in person, and the meeting was so packed with interesting sessions, I felt like cloning myself and deploying my clones to follow the many parallel tracks on offer. But alas, like all my fellow attendees, I had to choose, and rarely have I felt so spoiled for choice! Luckily, accessing the UEG Education Library has allowed me to look up a lot of the material that I was unable to see in person. Of the 52 ‘microbiota’ files available from UEG Week 2014 that can be discovered in the library, 10 are video-recorded presentations. As I take a huge interest in the role of the gut microbiota in health and disease, I've been indulging in these to update myself with some of the most recent advances in the field. In one of his presentations at UEG Week 2014, Professor Antonio Gasbarrini starts out by asking several questions about the gut microbiota in relation to coeliac disease, an autoimmune enteropahty triggered by gluten proteins. Do patients with coeliac disease have a different gut microbiota to healthy people? Does the microbiota have a role in the pathogenesis of coeliac disease? Can a gluten-free diet (GFD) alter the composition of gut microbiota? He stresses that a GFD does alter the microbiota and that, in healthy individuals, just a few weeks on a GFD may in fact lead to a decrease in beneficial bacteria such as Bifidobacteria/Lactobacilli and an increase in Enterobacteriaceae, thus affecting immune-metabolic responses. Moreover, a decrease in short-chain fatty acids is seen, possibly conferring a decrease in the immunomodulatory role of the microbiota. It appears that an altered microbiota is a characteristic feature of coeliac disease, that Bifidobacteria is decreased, at least in children, along with upregulation of other bacterial species, while any causal link between microbiota composition and disease development remains to be established. At least one HLA genotype is known to select for early microbiota composition, so it is possible that this is in fact one of the mechanisms underlying the genetic component of the disease. As do so many other scientists nowadays, Professor Gasbarrini stresses that while it may be important to know the structure of the microbiome, it is probably more important to know about the function of the microbiome. He also stresses the importance of sampling by highlighting the fact that identification of microbial communities may differ in the same individual depending on whether analysis of faecal or bioptic samples (mucosal biopsies, for instance) has been performed. Regarding the function of the microbiome, there are two talks on the microbiota in the context of IBD by Professor Joël Doré, who expands on the existence of Crohn’s disease-specific signature genes that are much less abundant in Crohn’s disease patients than in healthy controls. However, single genes not being very informative, scientists of the MetaHIT Consortium recently took to ‘binning’ genes identified by metagenomic analysis of roughly 400 faecal samples into co-abundance gene groups (CAGs), enabling a comprehensive discovery of new microbial organisms, viruses and co-inherited genetic entities, and facilitating assembly of microbial genomes without the need for reference sequences.1 From these CAGs, a total of 741 metagenomic ‘units’ or ‘species’ could be derived, four of which have been identified as highly discriminatory identifiers of ulcerative colitis when compared with healthy individuals. In our lab, we have also been analysing these data, only with a view to identifying parasitic protist signatures rather than bacterial signatures in these CAGs, and we have just submitted our results for publication. Once the results are out, I’ll be back with more on this; it is safe to say already that we have found some very striking associations, with colonisation by certain parasitic protists being significantly linked to certain microbiota profiles and clinical phenotypes of study individuals. However, just like Professor Doré points out, in most cases we do not know whether such observations reflect causality or mere consequence; this is mostly due to the cross-sectional nature of such studies, but the prognostic/diagnostic value of such findings should, or course, be subject to scrutiny. Being one of the heavy mantras of recent years, Faecalibacterium prausnitzii has been shown to be a direct predictor of Crohn’s disease relapse following infliximab withdrawal. In one study, Crohn’s disease patients with F. prausnitzii levels above the median were less prone to relapse than those with F. prausnitzii levels below the median, indicating that F. prausnitzii may represent a predictive factor for relapse.2 Professor Doré highlights that this is a trend not only in Crohn’s disease but also in ulcerative colitis. In the second talk by Professor Doré, you can learn more about the anti-inflammatory properties conferred by F. prausnitzii and its potential applicability as a diagnostic/prognostic marker. Professor Doré also gave a presentation on diet as a major modulator of the gut microbiota. He included a very educational slide on the functions of the human intestinal microbiota that are essential to health and wellbeing, and a slide summarising the diseases conferred by low gut species richness/gene count, such as Crohn’s disease, ulcerative colitis, IBS, obesity, Type-1 diabetes, Type-2 diabetes, coeliac disease, allergy and autism, etc., although the situation might not be entirely clear for coeliac disease, for example, as demonstrated by the talk by Professor Gasbarrini. In this talk, you can learn more about the so-called ‘enterotypes’, and you will find a few take-home messages regarding the impact of diet on microbiota development. Four of the video-recorded presentations are from the session “The role of microbiota in non-alcoholic fatty liver disease”. If terms such as ‘microbiota’, ‘microbiome’ and ‘metagenome’, scare you off, you are offered a useful introduction from Dr Alexander Moschen. And in case these conspicuous accomplishments have slipped your attention, in this talk you are also introduced to the famous and heavily cited mouse studies by Bäckhed and colleagues3 and Turnbaugh and colleagues4 on the influence of gut microbiota on energy uptake. For me, Dr Moschen delivers one of the big take-home messages in this series of presentations, which again relates to microbiota structure and function: just because different people have different microbiota, this may not mean that these microbiota do different things. Rather, different species assemblages appear to lead to similar functional profiles (i.e. the metabolic properties of a given microbiota can be more or less identical to those metabolic properties characteristic of a microbiota of a different composition). Focusing mainly on IBS, Dr Purna Kashyap presents studies showing that the gut microbiota can influence mechanisms characteristic of IBS, including gastrointestinal motility and secretion, visceral hypersensitivity and intestinal permeability, and that the microbiota influences entero-endocrine cells, stimulates the release of neurotransmitters like GABA, and mediates activation of immune cells, all affecting CNS function. Giving a thorough account of some of his own work too, Dr Kashyap shows that the effect of the gut microbiota on intestinal motility may in part be due to the effect on the host serotonergic system and that diet-related changes in microbiota fermentation products may alter host serotonergic pathways and gastrointestinal function. Finally, I would like to recommend the presentation “Probiotics and antibiotics in IBS: Do they work?”, which was delivered by Dr Viola Andresen. Dr Andresen summarizes data from randomized controlled trials on the effect of rifaximin on non-constipated IBS patients, which includes a significant improvement of particularly (refractory) bloating, but also stool consistency and global symptoms. There may be some uncertainty as to whether the effect of rifaximin in IBS patients is due to alleviation related to unidentified small intestinal bacterial overgrowth (SIBO), and in general, the link between IBS and SIBO remains obscure, primarily due to a paucity of data. However, a study using animal experimental models that appeared in Gastroenterology almost a year ago proposed that rifaximin modulates the ileal bacterial community (leading to a relative abundance of Lactobacillus), reduces subclinical inflammation of the intestinal mucosa and improves gut barrier function to reduce visceral hypersensitivity.5 Although expensive, among its many advantages, rifaximin has few side effects, if any, and more studies on the use of this antibiotic in the management of functional bowel diseases are anticipated. The language of the intestinal microbiome is being developed. Deciphering its many signs and symbols requires patience, but hopefully, this will eventually provide us with the tools and knowledge necessary to manipulate the gut microbiota to prevent, alleviate and cure a variety of diseases and promote health. Presentations on the microbiota at UEG Week 2014 Gasbarrini A. Microbiota in coeliac disease. From New challenges in gluten sensitivity: From bench to bedside.  Dore J. Microbiota signatures in IBD. From IBD: What's new in 2014?  Dore J. Microbiota: The key player in IBD? From New insights into the pathophysiology of inflammatory bowel diseases.  Dore J. Diet: Major modulators of gut microbiota. From Diet, immunity and systemic disease.  Moschen AR. Microbiota composition in obesity and related disorders. From The role of microbiota in non-alcoholic fatty liver disease (NAFLD).  Gasbarrini A. Antibiotics, pre- and probiotics in NAFLD. From The role of microbiota in non-alcoholic fatty liver disease (NAFLD).  Tilg H. Innate immunity in NAFLD. From The role of microbiota in non-alcoholic fatty liver disease (NAFLD).  Serino M. Metabolic infection. From The role of microbiota in non-alcoholic fatty liver disease (NAFLD).  Kashyap P. Impact of gut microbiota on gut function and dysfunction. From Normal and abnormal cross-talk at the mucosal border: Relevance for GI function and dysfunction.  Andresen V. Probiotics and antibiotics in IBS: Do they work? From Altered intestinal microbiota composition in IBS: Does it affect clinical practice?  References
  1. Nielsen HB, Almeida M, Juncker AS, et al. Identification and assembly of genomes and genetic elements in complex metagenomic samples without using reference genomes. Nat Biotechnol 2014; 32: 822–828. 
  2. Rajca S, Grondin V, Louis E, et al. Alterations in the intestinal microbiome (dysbiosis) as a predictor of relapse after infliximab withdrawal in Crohn's disease. Inflamm Bowel Dis 2014; 20: 978-986. 
  3. Bäckhed F, Ding H, Wang T, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA 2004; 101: 15718–15723.
  4. Turnbaugh PJ, Ley RE, Mahowald MA, et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006; 444: 1027–1031. 
  5. Xu D, Gao J, Gillilland M 3rd, et al. Rifaximin alters intestinal bacteria and prevents stress-induced gut inflammation and visceral hyperalgesia in rats. Gastroenterology 2014; 146: 484–496. 

Postgraduate Course on the road from inflammation to cancer in the upper GI tract

During the Polish Society of Gastroenterology Congress in September 2014, EAGEN and EHMSG (formerly known as EHSG) held the joint Postgraduate Course "The road from inflammation to cancer in the upper GI tract." The aim of the course was to share knowledge and experience in this increasingly relevant field, with the participation of speakers from high-end specialty European centres, EAGEN and EHMSG. Recordings from each individual session of the course can now be found in the UEG Education library.

The Postgraduate Course was opened by Professor Jaroslaw Regula and was interactive in nature, including discussion time after the sessions and voting on questions posed by the speakers regarding the clinical cases presented.1 The relevance of inflammation leading to cancer was reinforced by Professor Peter Malfertheiner, who reported that infections leading to cancer are responsible for one out of every five cancer deaths worldwide.1 Session 1 began with an introductory lecture from Professor Tomica Milosavljević, who provided a general perspective on the inflammation and cancer axis.2 He started with the history of the field, addressing the two paradigms of the link between inflammation and cancer—chronic inflammation (extrinsic) and intratumoural inflammation (intrinsic)—as well as the molecular events and pathways regulating this axis. Professor Colm O’Morain delivered a case-based lecture, discussing therapeutic strategies to eradicate Helicobacter pylori and raising awareness of eosinophilic oesophagitis.3 Professor Lars Lundell adressed GORD, considering management and risk factors for progression, presenting and discussing two clinical cases.4 Next, Professor Heinz Hammer delivered a talk on food impaction.5 He guided the audience through the possible causes, criteria for endoscopic intervention and methods for removing impacted food. Eosinophilic oesophagitis and oesophageal eosinophilia were also discussed and an overview of treatment options provided. Dr. Jochen Weigt, presenting a case of Barrett’s esophageal cancer and dysplasia, initiated session 2.6 His presentation addressed the rationale for staging, problems with staging procedures, and treatment options, raising the discussion of the true value of chromoendoscopy (acetic acid staining) versus dedicated white-light high-definition endoscopy. Next, Professor Juan Malagelada presented two cases of dyspepsia, addressing diagnostic approaches, prevalence and also the pathophysiology of functional dyspepsia.7 He also covered the associated abdominal manifestations and putative influencing factors, as well as therapy for functional dyspepsia. Dr. Tamara Matysiak-Budnik completed session 2, by presenting three clinical cases of gastric malignancy, underscoring the relevance of early detection and the importance of multimodality treatment.8 The Healthy Stomach Initiative, which is striving to spread preventive measures for greater stomach health throughout the world, was also promoted. Session 3, the final session of the course, started with a lecture by Dr. Gunther Krejs on the topic of familial gastric cancer, providing clinical and practical advice.9 Next, Professor Malfertheiner delivered a lecture on “Helicobacter pylori and cancer: what studies are needed?”10 He indicated that we are currently still challenged by H. pylori and its consequences, highlighting the need for further studies. Professor Malfertheiner stressed that in both less developed and also in more developed regions of the world, H. pylori is the most frequent infectious agent ultimately leading to cancer, and remains as the most important risk factor for gastric cancer. The lecture also covered the general pathophysiology of gastric adenocarcinoma, atrophic gastritis and the assessment of risk of gastric cancer development, and the pathways from H. pylori infection to gastric cancer. Importantly, Professor Malfertheiner proposed several basic and clinical studies needed in this context, concluding with the message being promoted by the Healthy Stomach Initiative that what is needed is a healthy stomach that is H. pylori free. Presentations at "The road from inflammation to cancer in the upper GI tract" EAGEN and EHMSG Postgraduate Course
  1. Malfertheiner P and Regula J. Welcome. 
  2. Milosavljević T. Introductory lecture: the road from inflammation to cancer. 
  3. O’Morain C. Case based lecture: patient with heartburn: history, endoscopy, medical/interventional therapy. 
  4. Lundell L. Case based lecture: patient with severe reflux: history, diagnostic work-up, therapy. 
  5. Hammer H. Case based lecture: patient with oesophageal food impaction. 
  6. Weigt J. Case based lecture: Patient with Barrett oesophagus and cancer – history, endoscopy, medical/interventional therapy. 
  7. Malagelada J. Case based lecture: Patient with dyspeptic symptoms – how does the stomach signal discomfort and disease. History, diagnosis, endoscopy, medical/interventional therapy. 
  8. Matysiak-Budnik T. Case based lecture: Patients with gastric malignancies: history, diagnosis, endoscopy, medical/interventional therapy. 
  9. Krejs G. Case based lecture: Familial gastric cancer – clinical and practical advices. 
  10. Malfertheiner P. Helicobacter pylori and cancer: what studies are needed? 
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