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ESPGHAN invites those who want to gain further experience of endoscopy and paediatric gastroenterology to participate in their Endoscopy Summer School

ESPGHAN invites those who want to gain further experience of endoscopy and paediatric gastroenterology to participate in their Endoscopy Summer School, taking place from: September 15–19, 2015 in Sheffield, UK The format of the programme will be hands on training interspersed with lectures, with an emphasis on skills acquisition. Official website: www.endo2015.org.uk

Visibility during endoscopy for upper GI bleeding: 

When to give erythromycin?

Visibility can be an issue during emergency endoscopy for upper GI bleeding, but it can be improved by nasogastric lavage or prokinetics such as erythromycin. Factors predicting poor endoscopic visibility—and therefore the potential need for erythromycin—have been highlighted in a new prospective study.

Acute GI bleeding is a common major medical emergency. In a 2007 UK-wide audit, the overall mortality of patients admitted to hospital with acute GI bleeding was 7%.1 By contrast, the mortality of patients who bled during admission to hospital for other reasons was 26%. Emergency upper GI endoscopy is indicated for patients with significant Rockall or Blatchford scores.2,3 However, the effectiveness of upper GI endoscopy as an emergency treatment for patients with significant GI bleeding can be limited by poor visibility due to the presence of luminal blood and other gastric contents. Nasogastric (NG) lavage and prokinetics such as erythromycin have been shown to improve visibility and decrease the need for a second-look endoscopy.4–7 Administering 3mg/kg erythromycin IV slowly over 30 minutes and then waiting up to 90 minutes for the infusion to take effect can, however, delay the emergency procedure. Furthermore, the risk of inadequate visibility is generally not high in this setting, so knowing who is most likely to benefit from IV erythromycin beforehand would be desirable. Jung et al. from Yonsei University College of Medicine, Seoul, South Korea, conducted a prospective observational study to identify factors affecting visibility during emergency endoscopy for upper GI bleeding (within 24 hours of presentation).8 The study authors also integrated these factors in a regression model that indicate the likelihood for poor visibility and this could have potential for predicting the need for erythromycin. The primary endpoint of this study was a ‘visibility score’ applied to four parts of the upper GI tract: the fundus, body, antrum, and duodenal bulb. A score from 0 to 2 was given to each part, depending on the degree of mucosal visibility (a score 0 was given for areas where less than 25% of the mucosa was visible), with a total score between 0 and 8. Good visibility was a score of 7 points or more. Multivariate logistic regression analysis was used to determine the factors independently associated with visibility, including age, sex, smoking, aspirin and anticoagulant use, rectal examination findings, blood pressure, heart rate and blood test results. The appearance of the NG tube aspirate (blood or coffee grounds), the emergency endoscopy being scheduled within 8.5 hours of presentation to hospital and blood urea levels were the variables that had a statistically significant association with endoscopic visibility. However, only the first two variables were incorporated in an algorithm that could predict visibility prior to endoscopy—the CART model. Using the CART model, good visibility was predicted when the NG aspirate was clear. If the NG aspirate was not clear, patients scheduled for an emergency endoscopy more than 8.5 hours after presentation were also likely to have good visibility The study does have some limitations: single centre, observational, small sample size (114 patients), and variability in calculating the visibility score amongst different endoscopists. Furthermore, the aim of the study was simply to score the visibility. The study did not address the real question of how many patients required a second endoscopy because the site of bleeding could not be identified at the index examination. This study confirms that IV erythromycin is most likely to be of benefit for those patients who have more severe bleeding. Paradoxically, these are the patients for whom we may feel the least confident delaying the emergency procedure whilst a nasogastric tube is passed and IV erythromycin is prescribed, administered and then allowed to take effect. It would be simple enough to incorporate erythromycin into our routine practice when it comes to the endoscopic treatment of acute upper GI bleeding, but randomised prospective studies are needed before we do! References 
  1. British Society of Gastroenterology. UK comparative audit of upper gastrointestinal bleeding and the use of blood (2007, accessed from http://www.bsg.org.uk/clinical/general/uk-upper-gi-bleeding-audit.html April 2015). 
  2. Blatchford O, Murray WR, Blatchford M. A risk score to predict need for treatment for upper-gastrointestinal haemorrhage. Lancet 2000; 356: 1318–1321. 
  3. Rockall TA, Logan RF, Devlin HB, et al. Risk assessment after acute upper gastrointestinal haemorrhage. Gut 1996; 38: 316–321. 
  4. Altraif I., Handoo FA, Aljumah A, et al. Effect of erythromycin before endoscopy in patients presenting with variceal bleeding: a prospective, randomized, double-blind, placebo-controlled trial. Gastrointest. Endosc. 2011; 73: 245–250. 
  5. Coffin B, Pocard M, Panis Y, et al. Erythromycin improves the quality of EGD in patients with acute upper GI bleeding: a randomized controlled study. Gastrointest. Endosc. 2002; 56: 174–179. 
  6. Carbonell, N., Pauwels, A., Serfaty, L. et al. Erythromycin infusion prior to endoscopy for acute upper gastrointestinal bleeding: a randomized, controlled, double-blind trial. Am. J. Gastroenterol. 2006; 101: 1211–1215. 
  7. Huang, E.S., Karsan, S., Kanwal, F. et al. Impact of nasogastric lavage on outcomes in acute GI bleeding. Gastrointest. Endosc. 2011; 74: 971–980. 
  8. Jung S, Kim E, Kim H, et al. Factors that affect visibility during endoscopic hemostasis for upper GI bleeding: a prospective study. Gastrointest Endosc Epub ahead of print 12 March 2015. DOI: 10.1016/j.gie.2014.12.024. 

47th Annual Meeting 2014

Focus of the meeting were recent advances in genetic, immunological, microbiological in the field of GI.

GI Bleeding, Berlin 2014

Recordings of this combined ESGE, ESGAR and EAES symposium are available online.

A classic colonic lesion.

These photographs show a lesion that was resected from the sigmoid colon.

These photographs show a lesion that was resected from the sigmoid colon.

WHAT IS YOUR ENDOSCOPIC DIAGNOSIS? a) Hyperplastic polyp b) Tubular adenoma c) Tubulovillous adenoma d) Villous adenoma e) Serrated adenoma

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.

EFISDS & EDS Postgraduate Course: “Challenges in Gastrointestinal Surgery”

Access is now available to the lectures recorded during the first combined EFISDS and EDS postgraduate course “Challenges in Gastrointestinal Surgery”. The meeting was held at the end of October 2014 in the Romanian city Cluj-Napoca and focused on the latest advances in GI surgery and its practical applications. Visit: EFISDS & EDS Postgraduate Course: "Challenges in GI Surgery"

A condition not associated with…?

The photograph shows what was found in a 55-year-old man who was undergoing upper digestive endoscopy because of iron deficiency anaemia.

WHICH OF THE FOLLOWING DOES NOT HAVE A RECOGNISED ASSOCIATION WITH THE CONDITION? a) Hypergastrinaemia b) Portal hypertension c) Liver disease without portal hypertension d) Systemic sclerosis e) Bile reflux

Registration now open for postgraduate course on Helicobacter Pylori

The EHMSG/ESPHGAN postgraduate course "An update on H.pylori infection" in conjunction with the XXVIIIth International Workshop on Helicobacter and Microbiota in Inflammation and Cancer will be held in Nicosia, Cyprus on September 23, 2015. The aim of this postgraduate course is to update current knowledge on this infection both in adulthood and childhood. Official website: www.helicobacter.org

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.

Endoscopic biopsy for coeliac disease diagnosis:

How many bites does it take?

A definitive diagnosis of coeliac disease is made based on the presence of characteristic histological changes in biopsy samples taken from the proximal small bowel in patients who have clinical features of gluten sensitivity. New findings suggest that the best biopsy samples for the diagnosis of coeliac disease are obtained using the single-biopsy technique.

Guidelines for the diagnosis and management of coeliac disease recommend that a minimum of four biopsy samples are taken from the second part of the duodenum and the bulb.1,2 A ‘well-oriented’ biopsy specimen is defined as a piece of intestinal mucosa that encompasses four consecutive, parallel, crypt-to-villous units that can be visualized along their entire length; however, the majority of specimens taken lack such quality, which decreases their diagnostic yield.3 In order to decrease procedural time, endoscopists usually take two bites per pass of the biopsy forceps (double-biopsy technique), as opposed to taking one bite per pass of the biopsy forceps (single-biopsy technique). Previous studies of the quality of biopsy specimens obtained by single versus multiple bites taken from both the upper4–6 and lower7 gastrointestinal tract have generated conflicting results. Melissa Lattore and colleagues from Columbia University, New York, USA, have now compared the double-biopsy and single-biopsy techniques in terms of the quality of biopsy samples obtained for the diagnosis of coeliac disease.In this study, four biopsy samples were taken from each patient: two were obtained using the double-biopsy technique and two were obtained using the single-biopsy technique. All specimens were obtained using the same equipment and the pathologist was blinded to the indication and biopsy technique. Duodenal bulb biopsies were excluded to eliminate any confounders. The authors determined that the single-biopsy technique was superior to the double-biopsy technique in yielding more well-oriented specimens and decreasing procedural specimen loss. Another relevant finding was the better sensitivity for detecting subtle mucosal changes indicating coeliac disease as intraepithelial lymphocytosis in samples obtained with the single-biopsy technique. They explain their findings by pointing out that the needle at the centre of the biopsy forceps—which is meant to help retain specimens—causes fragmentation and limits the capacity of the forceps to accommodate tissue once a second bite is taken. I also had this idea, but dismissed it, saying I was thinking too much, so I’m glad someone else did! So, what does this mean? The study was single centred and not randomized, but the change in practice proposed is easily applied. It is possible that limiting yourself to taking a single biopsy when using spiked forceps gives better histology throughout the gastrointestinal tract. Certainly for coeliac disease, where only 12–17% of patients currently get diagnosed,9,10 it is worth considering. References
  1. Ludvigsson JF, Bai JC, Biagi F, et al. Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology. Gut. Epub ahead of print 20 June 2014. DOI: 10:1136/gutjnl-2013-306578.
  2. Rubio-Tapia A, Hill ID, Kelly CP, et al. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol. 2013; 108: 656–676. 
  3. Gonzalez S, Gupta A, Cheng J, et al. Prospective study of the role of duodenal bulb biopsies in the diagnosis of celiac disease. Gastrointest Endosc. 2010; 72: 758–765. 
  4. Padda S, Shah I and Ramirez FC. Adequacy of mucosal sampling with the “two-bite” forceps technique: a prospective, randomized, blinded study. Gastrointest Endosc. 2003; 57: 170–173. 
  5. Fantin AC, Neuweiler J, Binek JS, et al. Diagnostic quality of biopsy specimens: comparison between a conventional biopsy forceps and Multibite forceps. Gastrointest Endosc. 2001; 54: 600–604.
  6. Chu KM, Yuen ST, Wong WM, et al. A prospective comparison of performance of biopsy forceps used in single passage with multiple bites during upper endoscopy. Endoscopy. 2003; 35: 338–342.
  7. Hookey LC, Hurlbut DJ, Day AG, et al. One bite or two? A prospective trial comparing colonoscopy biopsy technique in patients with chronic ulcerative colitis. Can J Gastroenterol. 2007; 21: 164–168.
  8. Latorre M, Lagana SM, Fredberg DE, et al. Endoscopic biopsy technique in the diagnosis of celiac disease: one bite or two?. Epub ahead of print 28 January 2015. Gastrointest Endosc. DOI: 10.1016/j.gie.2014.10.024.
  9. Association of European Coeliac Societies. Improving Diagnosis of Coeliac Disease (accessed 25 February 2015). 
  10. Rubio-Tapia A, Ludvigsson JF, Brantner TL, et al. The prevalence of celiac disease in the United States. Am J Gastroenterol. 2012; 107: 1538–1544.

A suspicious sigmoid stricture?

Watch the video & decide!

This patient is undergoing an emergency flexible sigmoidoscopy after admission with sudden onset of vomiting and abdominal distension.

Watch the video WHAT IS THE DIAGNOSIS? a) Ischaemic stricture b) Crohn’s stricture c) Malignant stricture d) Diverticular stricture e) None of the above This is a most peculiar sigmoidoscopy! There is a narrowing of the lumen in the mid-sigmoid that the endoscopist is able to traverse. On the other side of the stricture you find yourself looking at… small bowel mucosa! The patient has suffered a colonic perforation that has given rise to a fistula into the ileum, so option e is the correct answer. Diverticular disease used to be a condition that was firmly in the surgical camp. However, uncomplicated diverticulitis is increasingly managed with conservative therapy and it appears that we don’t even need to give antibiotics in all cases.1 Only about a quarter of patients develop complications requiring surgery. Remarkably, patients who are well but have free air in the abdomen that is visible on X-ray, may be treated with antibiotics and bowel rest2  and abscesses are usually drained radiologically. In a case such as this, with a combined small bowel and colonic obstruction, surgery is indicated. The traditional operation is the Hartmann procedure with a proximal colostomy. The drawback is that a proportion of patients who undergo this procedure will never have their bowel continuity restored. In view of this, many colorectal surgeons have advocated that a primary anastomosis can be an equally safe but a better alternative in selected cases. There is no evidence from clinical trials to inform us which is the better option. However, the construction of a primary anastomosis is more demanding and requires the sound clinical judgment of an experienced colorectal surgeon to decide when this option is likely to fail. The Postgraduate Course of the UEG Week 2013 dedicated a complete session to the topic of diverticular disease (Diverticular disease: Important, poorly understood and badly managed) and is well worth a look. Just sign in to myUEG, put ‘Diverticular disease’ into the UEG Education Library search box and hit enter! References
  1. Chabok A, et al. Randomized clinical trial of antibiotics in acute uncomplicated diverticulitis. Br J Surg 2012; 99: 532–539. 
  2. Costi R, et al. Challenging a classic myth: pneumoperitoneum associated with acute diverticulitis is not an indication for open or laparoscopic emergency surgery in hemodynamically stable patients. A 10-year experience with a nonoperative treatment. Surg Endosc 2012; 26: 2061–2071. 

Case 2

The photograph shows what was found in the rectum of a 65-year-old homosexual man who was complaining of bright red rectal bleeding. He admitted to drinking two to three whiskeys per day. He was not taking any medication and his only past history was of prostatic carcinoma, which was treated 2 years previously. There was no relevant family history.

How would you initially manage the patient? a) Rectal steroids b) Rectal aminosalicylates c) Cautery using a heater probe or argon coagulator d) Antibiotics e) Surgical resection

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.

The sessile serrated polyp

It is there if you look for it.

Until 1996, serrated polyps were all classified as ‘hyperplastic polyps’ and the larger ones simply as ‘giant hyperplastic polyps’ or ‘variant hyperplastic polyps’. More recently it became evident that serrated polyps do have malignant potential and may be why colonoscopy does not protect well against future right-sided cancer. Much research into their molecular characteristics, clinical features, and malignant potential followed.

Four types of serrated polyp are now recognized. Normal hyperplastic polyps (HPs) are usually small and left sided. Traditional serrated adenomas (TSAs) are also usually left sided, but they are larger than HPs, sometimes pedunculated and have a crypt pattern reminiscent of villous adenomas. Sessile serrated polyps (SSA/Ps) are usually right sided, ≥10mm in diameter and they are sometimes covered with particularly large crypt openings. There are also the unclassified serrated polyps, which tend to be left sided and ≥5mm in diameter.  According to the WHO classification, ‘cytological dysplasia’ may or may not be present in HPs and SSA/Ps, whereas ‘conventional dysplasia’ may or may not be present in TSAs.1 SSA/Ps are thought to be one of the main serrated precursors of right-sided adenocarcinomas. Some studies have suggested that the SSA/P to carcinoma progression takes longer than the conventional adenoma to carcinoma progression, while others suggest a more rapid progression once dysplasia is identified in the SSA/P.2,3 The prevalence of SSA/Ps has varied between several studies from 0.6% to 5.3%.4,5  This is most likely due to the variability in the pathological criteria used and the high variability in  detection rate amongst endoscopists. There is a great deal of interobserver variability in the distinction between SSA/Ps and normal HPs amongst pathologists.6–8 Abdeljawad et al. conducted a retrospective study using their database of all average-risk patients aged >50 years who underwent a screening colonoscopy between August 2005 and April 2012 by a colonscopist with high detection rates for adenomas and serrated polyps (of course, the colonoscopist was Douglas Rex!).9 The plan was to come to a realistic estimate of the true prevalence of SSA/Ps in an average-risk population by combining the expertise of an experienced colonscopist with that of an experienced GI pathologist who has an interest in serrated polyps, and the application of an agreed terminology (the WHO consensus guidelines on serrated polyps). 1,910 average-risk patients underwent screening colonoscopy. A total of 656 serrated polyps were identified in 389 patients. Of the 656 serrated lesions, 599 (91.3%) were HPs, 44 (6.7%) were SSA/Ps, and 13 (2%) were mixed tubular adenomas/hyperplastic polyps. The study excluded diminutive rectal and sigmoid hyperplastic polyps, so it is possible that some of these may also have been SSA/Ps. In addition, the SSA/P detection rate at colonoscopy increased in the final year of the study, presumably as a result of a learning curve. This means that the true prevalence of SSA/Ps may have been underestimated. In conclusion, SSA/Ps are there if you look for them and may be more common than we think! References
  1. Snover D, Ahnen DJ, Burt RW. Serrated polyps of the colon and rectum and serrated (“hyperplastic”) polyposis. In: Bozman FT, Carneiro F, Hruban RH et al. (eds.) WHO classification of tumours. Pathology and genetics. Tumours of the digestive system. 4th ed. Berlin: Springer-Verlag, 2010.
  2. Lash R, Genta R and Schuler C. Sessile serrated adenomas: prevalence of dysplasia and carcinoma in 2139 patients. J Clin Pathol 2010; 63: 681–686.
  3. Oono Y, Fu K, Nakamura H, et al. Progression of a sessile serrated adenoma to an early invasive cancer within 8 months. Dig Dis Sci 2009; 54: 906–909. 
  4. Hetzel J, Huang C, Coukos J, et al. Variation in the detection of serrated polyps in an average risk colorectal cancer screening cohort. Am J Gastroenterol 2010; 105: 2656–2664.
  5. Kumbhari V, Behary J and Hui J. Prevalence of adenomas and sessile serrated adenomas in Chinese compared with Caucasians. J Gastroenterol Hepatol 2013; 28: 608–612. 
  6. Khalid O, Radaideh S, Cummings O, et al. Reinterpretation of histology of proximal colon polyps called hyperplastic in 2001. World J Gastroenterol 2009; 15: 3767–3770. 
  7. Wong N, Hunt L, Novelli M, et al. Observer agreement in the diagnosis of serrated polyps of the large bowel. Histopathology 2009; 55: 63–66. 
  8. Sandmeier D, Seelentag W and Bouzourene H. Serrated polyps of the colorectum: Is sessile serrated adenoma distinguishable from hyperplastic polyp in a daily practice? Virchows Arch 2007; 450: 613–618. 
  9. Abdeljawad K, Vemulapali K, Kahi C, et al. Sessile serrated polyp prevalence determined by a colonoscopist with a high lesion detection rate and an experienced pathologist. Epub ahead of print 3 July 3 2014. Gastrointest Endosc DOI: http://dx.doi.org/10.1016/j.gie.2014.04.064.

Hepatobiliary, pancreatic and GI tract neoplasms

The course provides knowledge on an integrated approach of imaging in the diagnosis and treatment of cancer.

ESGE is joining forces with ESDO to present the Quality in Endoscopy symposium on Colonoscopy & Colonic Neoplasms.

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. 

Case 1

These photographs show the stomach (top) and second part of the duodenum (bottom) of a 55-year-old man undergoing gastroscopy to investigate iron deficiency anaemia.

What would you organise next? a)    Gastric biopsies with immunohistochemical staining for e-cadherin b)    Measurement of serum gastrin levels c)    An enteroscopy d)    A capsule endoscopy e)    A colonoscopy
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