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
  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.  

Reassure, resect or retreat?

What's the diagnosis and management of this nodule likely to be?

This video clip shows a nodule that was found on the greater curve of the stomach in a 35-year-old man referred for a gastroscopy because of symptoms of reflux oesophagitis.

You take a full set of samples and after the examination the patient asks what the management of the lesion is likely to be.

What do you tell the patient? a) This is probably a hyperplastic polyp and eradication of any Helicobacter pylori may well induce spontaneous regression. You tell the patient that he will most likely be offered another examination in a year to reassess the stomach after treatment to eradicate Helicobacter pylori. b) This is probably a gastrointestinal stromal tumour (GIST). You tell the patient that he is likely to be offered an assessment by endoscopic ultrasonography (EUS) and, as the lesion is small, it is likely that surveillance will be offered. c) This is probably a neuroendocrine tumour (NET). You tell the patient that it is likely to require surgical resection. d) This is probably an early gastric cancer. You tell the patient that he is likely to be offered an attempt at endoscopic resection. e) This is probably an advanced gastric cancer. You tell the patient that he is likely to be offered a gastrectomy. 

This was Basic Science Course 2015

41 young clinicians and scientists were in this year's Basic Science Course.

KRAS or BRAF—that is the question

What's causing the altered bowel habits in this elderly patient?

The photograph shows a lesion that was found in the ascending colon of a 75-year-old man who was undergoing colonoscopy because of a change in bowel habit.

a) Hyperplastic polyp
b) Sessile serrated polyp
c) Traditional serrated adenoma
d) Mixed hyperplastic polyp
e) Tubulovillous adenoma

Updated E-course - Irritable Bowel Syndrome

Irritable Bowel Syndrome

Improve your consultation skills and knowledge of the condition.

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NeuroGASTRO Meeting 2015

37 recorded lectures covering advances in neurogastroenterology .

Get access to 10 recorded lectures from recent Summer School

This intense clinical-based weekend course is perfect for trainees and early career medical professionals and can now be attended from home. 

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. 

9th EDS Postgraduate course

26 surgical lectures from the meeting in Riga are available free of charge. 

New E-course - Coeliac Disease

Coeliac disease

Based on the ESPGHAN guidelines this course was developed to assist medical professionals with correctly diagnosing the condition.

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.

Benign or malignant disease?

The photo shows the findings in a 65 year-old woman.

The photo shows the findings in a 65 year-old woman. The photograph shows the findings in a 65-year-old woman undergoing investigations for anaemia. Her only medications are ibuprofen for backache and tamoxifen, which was started 7 years previously. WHAT IS THE MOST LIKELY DIAGNOSIS?  a) NSAID-induced gastric ulceration b) CMV gastritis c) Gastric lymphoma d) Linitis plastica e) Gastric metastates

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).

A 30-year-old diagnosis.

An elderly patient being investigated for iron deficiency anaemia.

The photograph shows what was found in an elderly patient who was being investigated for iron deficiency anaemia.

WHAT IS THE MOST LIKELY DIAGNOSIS? a) Gastritis associated with Helicobacter pylori infection b) Gastric cytomegalovirus infection c) Cameron ulceration d) NSAID-induced ulceration e) Ulceration from a diffusely infiltrating gastric cancer


ESGE is combining forces with EASL and ESGAR for this symposium.

ESGE is combining forces with EASL and ESGAR for the Quality in Endoscopy symposium on ERCP & EUS. Don’t miss the perfect opportunity to increase your knowledge on ERCP & EUS and join the symposium on: November 13-14, 2015 in Budapest, Hungary. On Sunday, November 15, hands-on training will be offered to a limited number of participants. Early registration fee deadline September 13, 2015. Online registration closes November 8, 2015. Official website: www.quality-in-endoscopy.org


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.

Research Course - 29 young investigators gathered this weekend

29 young investigators gathered this weekend

Participants had a busy schedule with best practices in preparing scientific abstracts, presentation training and professional networking.

An easy diagnosis but difficult aetiology

Try your diagnostic skills!

The photograph shows the mucosal appearance throughout the colon in a 49-year-old woman undergoing investigations for abdominal pain and diarrhoea.

WHAT IS THE CAUSE OF THE MUCOSAL APPEARANCE? a) Melanin b) Lipofuscin c) Haemosidderin d) Food colourings e) Cyanosis