Early Detection of Pancreatic Cancer—How?
What's the outlook for the development of biomarkers?
World Pancreatic Cancer Day is being held on November 13. It is estimated that 367,000 new cases of pancreatic cancer will be diagnosed worldwide in 2015 and the dismal survival rate means that only 2–10% of patients will be alive 5 years after diagnosis.Globally, pancreatic cancer is the seventh most common cause of cancer-related death, and while death rates for many cancers are dropping, the death rate for pancreatic cancer is rising in Europe and the United States.1 The mortality of pancreatic cancer may, at least in part, be explained by the fact that early diagnosis is challenging. However, advances in the development of various biomarkers appear to hold promise for future screening of high-risk individuals, which—according to Cancer Research UK—includes patients with hereditary pancreatitis, a high incidence of pancreatic cancer in their family or a family history of at least one person with pancreatic cancer plus a linked cancer syndrome (e.g. a BRCA2 mutation).2 It has been reported that levels of serum cancer antigen 19-9 (CA19-9) are elevated in approximately 80% of patients with pancreatic cancer,3 and CA19-9 has been useful for therapeutic monitoring and early detection of recurrent disease after treatment in patients with known pancreatic cancer.4 However, CA19-9 is not a specific biomarker for pancreatic cancer. Moreover, patients who are negative for Lewis antigen a or b (approximately 10% of patients with pancreatic cancer) are unable to synthesize CA19-9. Although measurement of serum CA 19-9 levels is useful in patients with known pancreatic cancer, the use of this biomarker as a screening tool has yielded disappointing results.4 In addition to genetic alterations, dysregulation of specific epigenetic mechanisms is critical to tumour development. Comparing patients who have pancreatic cancer with healthy individuals and patients with chronic pancreatitis, Schultz et al. described differences in microRNA expression in whole blood with a view to identifying microRNA panels (classifiers) for diagnosing pancreatic cancer.3 microRNAs—non-coding 17–25-nucleotide-long RNAs that regulate gene expression—play important roles in tumour development and metastasis, and several have been described as specific to pancreatic cancer. Schultz and colleagues validated microRNA panels against CA19-9 sero-status and disease, and identified two panels for diagnosing pancreatic cancer using combinations of four and ten microRNAs in whole blood, respectively. The investigators call for further studies that could validate the use of these biomarkers as a screening tool for early-stage pancreatic cancer detection. More on the role of microRNAs in pancreatic tumour growth and progression can be found in a paper by Frampton and colleagues that was published in The Lancet in February 2015.5 Even more recently, in an article in Nature, Melo and colleagues6 suggested the use of a proteoglycan molecule (glypican-1 [GPC1]) anchored in the membrane of extracellular vesicles—exosomes—circulating in the bloodstream as a cancer biomarker. In particular, the team claimed that detection of GPC1+ exosomes in the blood could distinguish patients with early-stage and late-stage pancreatic cancer from patients with benign pancreatic disease and healthy individuals. The assay appeared more reliable than that based on CA19-9 detection. Compared with healthy donors, serum CA19-9 levels were increased in patients with cancer, but CA19-9 levels were also significantly increased in the serum of patients with benign pancreatic disease. Moreover, CA19-9 levels failed to distinguish patients with pancreatic cancer precursor lesions from healthy donors. An expanded interpretation of this important study, including a discussion of semantic issues, can be found in an accompanying News & Views article by Clotilde Théry.7 Apart from microRNAs, epigenetic features such as DNA methylation, satellite repeats and histone modifications might serve as biomarkers for early diagnosis of pancreatic cancer.8 Reviewing genes aberrantly methylated in pancreatic cancer, Henriksen and her team concluded that investigations into hypermethylated markers in cell-free DNA in plasma or serum are still limited by the availability of only a handful of small studies, which lack well-defined control groups, and that no single gene has been identified as a diagnostic marker.9 To read more about the many challenges related to identifying biomarkers for early diagnosis of pancreatic cancer, I recommend looking up a review by Jenkinson and colleagues.10 There are also a couple of interesting sessions from the recently concluded UEG Week 2015 in Barcelona that I’d like to highlight—all are available online. To learn more about ‘liquid biopsies’, including cell-free DNA, exosomes, and circulating tumour cells, you could look up the talk delivered by Aldo Scarpa, “Molecular diagnostics: From tissue biomarkers to liquid biopsies, single genes and panels”, which was part of the session “Pancreatic cancer: Where are we and what is the future?”11 There’s also an update session on therapy, including talks on chemotherapy, surgical resection, preoperative and palliative treatment, and neoadjuvant and adjuvant treatment.12 Finally, I would like to direct your attention to a talk that was given by Jean-Luc van Laethem, entitled “Pancreatic cancer in annual review”.13 Challenges aside, sensitive and specific biomarkers of early pancreatic cancer that can be obtained non-invasively appear critical to reducing the morbidity and mortality associated with pancreatic cancer. As we mark the 2015 World Pancreatic Cancer Day, we should set our hopes on it not being too long until one or more biomarkers prove valid for use in screening. References
- Schultz NA, Dehlendorff C, Jensen BV, et al. MicroRNA biomarkers in whole blood for detection of pancreatic cancer. JAMA 2015; 311: 392–404.
- Hidalgo M. Pancreatic cancer. N Eng J Med 2010; 362: 1605–1617.
- Frampton AE, Castellano L, Colombo T. Integrated molecular analysis to investigate the role of microRNAs in pancreatic tumour growth and progression. Lancet 2015; 385 Suppl 1: S37.
- Melo SA, Luecke LB, Kahlert C, et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 2015; 523: 177–182.
- Théry C. Cancer: Diagnosis by extracellular vesicles. Nature 2015; 523: 161–162.
- Fukushige S, Horii A. Road to early detection of pancreatic cancer: Attempts to utilize epigenetic biomarkers. Cancer Lett 2014; 342: 231–237.
- Henriksen SD, Madsen PH, Krarup H, et al. DNA hypermethylation as a blood-based marker for pancreatic cancer: A literature review. Pancreas 2015; 44: 1036–1045.
- Jenkinson C, Earl J, Ghaneh P, et al. Biomarkers for early diagnosis of pancreatic cancer. Expert Rev Gastroenterol Hepatol 2015; 9: 309—315.
- Pancreatic cancer: Where are we and what is the future? Session at UEG Week 2015.
- Therapy update: Pancreatic cancer Session at UEG Week 2015.
- Pancreatic cancer in annual review Presentation by Jean-Luc van Laetham in the Pancreas: What’s new in 2015? Session at UEG Week 2015.
A coeliac conundrum
What would you do next for this middle-aged woman previously diagnosed with coeliac disease?
A middle-aged woman presented with loose stool and weight loss. Initially, she refused an endoscopy and a diagnosis of coeliac disease was made on the basis of a high tissue transglutaminase (tTG) antibody titre. She was started on a gluten-free diet (GFD) but her symptoms remained despite adherence to the GFD. After several months she agreed to undergo an endoscopy. The images show the endoscopic view of the duodenal mucosa (figure 1) and the corresponding histology slide (figure 2) stained with haemotoxylin and eosin (H&E).WHAT WOULD YOU DO NEXT? a) Refer the patient for a dietary review b) Request a clonal analysis of the intraepithelial lymphocytes c) Refer for HLA DQ2/DQ8 testing d) Refer the patient for capsule endoscopy e) Add prednisolone to the dietary restrictions
An interesting ileal finding
What are the treatment options for this lesion discovered during colonoscopy?
A 50-year-old woman is undergoing a colonoscopy because of loose stool. When the tip of the endoscope enters the terminal ileum, the lesion in the photograph is found. The patient asks you if any treatment will be necessary.WHAT DO YOU TELL THE PATIENT? a) The lesion is likely to be a lipoma and can probably be ignored b) The lesion is likely to be adenomatous and should be removed by endoscopic mucosal resection (EMR) c) The lesion is likely to be a neuroendocrine tumour (NET) and should be removed surgically d) The lesion is likely to be a gastrointestinal stromal tumour (GIST), requiring annual surveillance e) None of the above
Small things, vast impact: gut microbiota in health & disease
All things microbiota related at UEG Week 2015!
The relevance of manipulating gut microbiota—that is using gut microbiota (e.g. faecal microbiota transplantation [FMT]), components thereof, or diet (including probiotics)—with a view to ameliorating or potentially treating diseases and syndromes is currently subject to intense scrutiny.The number of conditions that could potentially benefit from gut microbiota manipulation is vast, ranging from autoimmune diseases, such as inflammatory bowel disease (IBD) and multiple sclerosis, to functional bowel diseases (e.g. irritable bowel syndrome [IBS]), antibiotic-induced gut dysbiosis (e.g. recurrent Clostridium difficile infection) and metabolic syndrome. Others include mental health diseases/personality disorders, including anxiety, depression, autism, and schizophrenia. Through my own research, I have discovered that some intestinal microbes are much more common in healthy individuals than in patients with infectious diarrhoea, functional or inflammatory bowel diseases. Just to be clear, I’m not talking about Akkermansia muciniphila or Faecalibacterium prausnitzii, in fact, I’m not even talking about bacteria! I’m referring to a couple of intestinal protists (Blastocystis sp. and Dientamoeba fragilis) that once were thought by many to be gut pathogens. Well, a lot of recent data not only suggest that they are not gut pathogens, but that they also appear to be much more common than previously anticipated. At our lab, we have developed and are currently validating a gut microbiota profiling tool that enables unprecedented and exhaustive interrogation of ribosomal genes from bacteria, yeasts, moulds, and parasites (protists and helminths) in complex samples, such as stool samples. In other words, we will be able to identify all gut colonising/infecting organisms present in a stool sample to at least genus level, and very often to species level. Given my background and interests, I was very pleased to learn that UEG Week 2015 has a specific “Gut Microbiota” pathway. I’m going to adhere to it as much as I can! Not only am I interested in being able to pin down every single organism squatting our guts, I also want to know what they do! You’ll definitely find me in Room E2 at the “From omics to better understanding of pathogenesis” session, which is being chaired by my fellow Web Editor, Rui Castro. Here, Loris Lopetuso will present and compare data on gut microbiota composition (16S NGS data) in patients with IBD, IBS, diverticular disease and healthy controls. If you’re new to research into gut microbiota, you’d do well to attend the talk by Paul O’Toole on “Microbiota: What gastroenterologists should know.” This talk is part of the symposium “Microbiota: Evolving concepts in GI disorders” that takes place in Room F1 on Tuesday 27 October (14:00–15:30). Also in this session, you’ll be able to listen to Patricia Lepage discussing the fundamental issue of causation versus correlation in research into IBD-associated microbiota. Harry Sokol will reveal whether FMT for non-infectious GI diseases is “ready for prime time”, and Gerardo Nardone will deliver a talk with the title, “Microbiota and upper GI diseases: What is the clinical relevance?” “Brain–gut interactions in health and disease” is the title of a Round Table Discussion taking place in Room E4 on Tuesday 27 October (14:00–15:30). As Peter Andrey Smith says, referring to the gut-brain axis, “…the mechanisms by which gut microbes and the brain might communicate are unclear, but there are several tantalising leads for researchers to follow.” In a recent News Feature in Nature, he provides some examples as to how differences in gut microbiota may lead to differences in brain development and behaviour. Butyrate, one of the short-chain fatty acids apparently produced by gut bacteria in those of us who are not on the FODMAP diet (for more information, see my previous blog), fortifies the blood–brain barrier by tightening connections between cells, hence influencing the basic physiology of the blood–brain barrier. I’m also really looking forward to the “Abstracts on Fire: Gut microbiota in lower GI diseases” session, which will be chaired by Antonio Gasbarrini and Herbert Tilg, and takes place at the UEG Hotspot on Wednesday 28 October (8:30–10:30). This free paper session provides us with no less than 12 talks, focusing on topics such as recurrent C. difficile infection and FMT. Among these, we will be spoiled with two talks from Gianluca Ianiro, who is going to try to convince us that surgery is no longer required in patients with C. difficile infection after FMT performed in an academic tertiary care centre. If you’d like to come and talk to me about gut microbiota in health and disease in general, research communication, or about UEG E-learning, I’ll be at the Young GI Network “Let’s Meet” event on Sunday evening and at the UEG Booth on Monday (13:00–14:00) and Tuesday (15:30–15:45). See you there!
The hot PET
Hot spots in the descending colon. What would you do with the polyps found on subsequent colonoscopy?
A 72-year-old man previously presented with obstructive bowel symptoms. He was diagnosed with mantle cell lymphoma—a type of non-Hodgkin lymphoma—with involvement of the rectosigmoid junction and terminal ileum.He underwent a left hemicolectomy and resection of the terminal ileum followed by chemotherapy (fludarabine, mitoxantrone, dexamethasone and rituximab). After treatment he went into prolonged remission and follow-up colonoscopies 5 years and 7 years later were both unremarkable. The findings of a gastroscopy and capsule endoscopy were also normal 7 years after treatment, at which time the patient was asymptomatic with normal blood results. His haematologist requested a surveillance FDG PET-CT scan, which demonstrated a hot spot in the descending colon (figure 1). A further colonoscopy was carried out and showed 2 polyps in the descending colon (figure 2; DC1 [15mm] and DC2 [50 mm]). The ileocolonic anastomosis and neoterminal ileum were both unremarkable. WHAT WOULD YOU DO WITH THESE POLYPS? a) Ignore them, as they are inflammatory. b) Take biopsy samples only. c) Perform standard snare polypectomy. d) Organise an endoscopic mucosal resection (EMR). e) Organise an endoscopic submucosal dissection (ESD).
E-learning adventures at UEG Week 2015
Getting ready for a busy few days in Barcelona!
UEG Week 2015 is just around the corner and the UEG E-learning team is getting ready for a busy few days in Barcelona! As well as meeting to plan future UEG Education online courses and content, we’ll be spending time at the UEG Booth and the Young GI Lounge in Hall 8.0 during many of the session breaks on Monday, Tuesday and Wednesday. We’ll also be attending the “Young GI Network—Let’s Meet” reception on Sunday evening. If you’d like to meet the team to find out more about what we do, discuss how we can best serve you and how you might be able to get involved, then please do come and say hello!Tomer, Rui and Bjorn will also be chairing sessions and, as one of this year’s UEG Rising Stars, Rui will be presenting his work on microRNAs in NASH in Room E1 during the first session on Wednesday morning. The team will also be attending many of the sessions to get their annual updates across the breadth of the field, and below are a few highlights that everyone is looking forward to. Charlie’s choice: As usual there is so much excellent content that the problem will be fitting it all in. I'll certainly be attending the Rising Stars session, highlighting the best of our researchers from Europe and the USA—this is always an inspiring session. I'll also be playing close attention to the IBD free paper sessions. Like Rune, I'm looking forward to attending the microbiota-focused sessions. And for all the rest there is UEG Week Live! Bjorn’s choice: My pick of the sessions would be “Endoscopic management of benign oesophageal strictures.” I am convinced that in treatment-resistant cases a “stricturoplasty”—whereby the stricture is cut with an endoscopic knife—can turn failure into victory. I would like to discuss this option with the presenters! Tomer’s choice: There are many attractive learning options at the upcoming UEG Week, ranging from basic science to practical patient management. I am looking forward to “Introducing the omics: A guide for clinicians” on Monday morning, as part of the Today’s Science; Tomorrow’s Medicine lectures. This field has evolved greatly and I am looking to hear an update on the implications for clinicians. I am also glad the Postgraduate Teaching Programme has a session dedicated to lower GI bleeding, a topic that applies to our everyday practice. Rui’s choice: I am particularly interested in the hepatobiliary pathway, featuring different session formats on liver cirrhosis and cholestasis. And I always love the Today’s Science; Tomorrow’s Medicine sessions, showing just how much can be achieved from a well-sustained and rational basic-to-translational/clinical research plan. And speaking of research, I am also looking forward to a great panel discussion at the “How to do research?” Hotspot Symposia! Rune’s choice: The impact of the intestinal microbiota on human health and disease is something that never ceases to fascinate me, and of course, I’ll be giving priority to the gut microbiota pathway. I’m especially looking forward to the session chaired by my colleague Mirjana Rajilic-Stojanovic and Giovanni Barbara on evolving microbiota concepts in GI disorders on Tuesday. Here, Paul O'Toole will deliver a talk with the title “Microbiota: What gastroenterologists should know.” Natalie’s choice: I love a bit of controversy, so I’m really looking forward to visiting the UEG Week Hotspot to see some of the new session formats—Abstracts on Fire, Clinical Trials Revisited and Hotspot Symposia—in action! Coming from a basic research background, I’m also particularly interested in the sessions on the ‘omics’ and learning more about what difference they are making to practical patient care and what they might allow us to achieve in the future. Don’t forget to look out for tweets from all of the team (@CharlieMuz, @Bjorn_Rembacken, @Eukaryotes, @RuiCastroHD, @adartom and @nataliewood06) during UEG Week (#uegweek)! Why not join the dialogue and tell us what’s got your attention? And if you like twitter debates then make sure you’re online for the #WeekChat on Sunday with Mark Hull (@mark_tbh; Diet, microbiota and colonic disease) and on Tuesday with Chris Hawkey (@chrishawkey; Updates on stem cell research in gastroenterology). There will also be three Decide on the Spot cases published in the UEG Week News and online during UEG Week (on Saturday, Monday and Tuesday)—the answer and explanation for each case will be posted online the following day. Those of you who view the case online, sign in to myUEG and post a comment or answer in the comments section will qualify for a complimentary UEG Education Power Bank, which is perfect for charging your mobile devices on the go! To receive your UEG Education Power Bank, simply come and show us your post on the laptop at the UEG booth in Hall 8.0. Please note that comments on social media don’t count, participants are entitled to a maximum of one Power Bank and the number of Power Banks available each day is limited! Wishing you all an enjoyable and productive time in Barcelona!
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Quick or Quincke's thinking?
What next for a patient who's recently been feeling unwell & passing black stools?
A 40-year-old male patient went to his local A&E department with a short history of feeling unwell and passing black stools. He had a past history of chronic pancreatitis that was attributable to alcohol and a bleeding peptic ulcer some 15 years earlier. He was not taking any medication. On admission, the patient was pale with a heart rate of 75 BPM and his blood pressure was 125/80 mm Hg. The patient’s Hb level was 36 g/L, with a mean corpuscular volume of 8.93, iron 1.253 mmol/L and ferritin 0.27 pmol/L. On endoscopy, the oesophagus and stomach were unremarkable and the photographs show the appearance of the duodenal ampulla (figure 1a–c).WHAT WOULD YOU DO NEXT? a) Endoscopic retrograde cholangiopancreatography (ERCP) b) Percutaenous transhepatic cholangiogram c) Abdominal computed tomography (CT) d) Angiogram e) Abdominal ultrasound
Time to change a treatment paradigm
Models of care and malnourished patients
In the past 10 years we have seen the expansion of a cadre of gastroenterologists who have a sub-specialty interest in nutrition. As a result, we have seen nutrition rightfully taking centre stage in our hospitals. Indeed, in the UK hospital mealtimes are now ‘protected’ and malnourished patients have their food served on red trays.Our nutrition experts have more directly been involved in a transformation of the care of patients who have short bowels. This group of patients is a complex mix, in which every patient is different depending on how much small bowel is left, what type of anastomosis was constructed and the underlying disease. Such patients may suffer high morbidity and mortality because the malabsorption of macronutrients, micronutrients, electrolytes and water can result in impaired growth, premature aging, sudden hypotension, renal failure, arrhythmias, fits, infections, liver failure and impaired healing. The increased survival of these desperately ill patients has been achieved by meticulous attention to detail. A tiny shift in a patient’s serum magnesium level triggers an adjustment. As the 2003 AGA review put it: “Vitamin and mineral status should be monitored regularly, and supplementation should be customized for each patient.”1 Of course, it takes a particular type of meticulous doctor to tirelessly manage a patient’s micronutrient intake. I am not sure that I could manage to pay such careful daily attention to every patient’s zinc, copper, magnesium and selenium levels. Luckily, gastroenterologists with a specialist interest in nutrition are self-selected, thorough doctors and their patients with intestinal failure benefit greatly. Most UK hospitals now have a nutrition team, which is headed up by a gastroenterologist with a specialist interest in nutrition. Initially these teams only cared for patients with intestinal failure. Subsequently their remit enlarged to include patients with malabsorption and more recently came to include all those who are malnourished. The most severely malnourished patients in our hospitals are those with anorexia nervosa. The nutrition of these patients is now often looked after by gastroenterologists with an expertise in intestinal failure. Just as intestinal failure is at the sharp end of gastroenterology, anorexia nervosa is at the sharp end of psychiatry. Not only does the condition have the highest mortality rate of any mental illness,2 the management is complicated by a lack of reliably successful treatments. The National Institute for Health and Care Excellence (NICE) has reviewed the therapies available and awarded only “grade C level evidence” for 74 of the 75 therapies for eating disorders.3 As we start to see severely malnourished patients who have eating disorders on our gastroenterology wards, it is becoming apparent that simply focusing on a patient’s nutritional needs does not work. Care may be reduced to a battle of wills in which patients pull out their feeding tubes as quickly as doctors put them back down. Furthermore, in spite of opiates, botox injections, naso-gastric feeding, venting PEGs, gastric pacemakers and parenteral nutrition, many patients remain just as debilitated. Personally, I believe that the key to understanding why many patients with the most severe eating disorders do not seem to be greatly improved by pipes and pills is because we practise the “Medical Model” of care. This model focuses on ‘curing’ patients, whereby ‘cure’ is defined by the absence of symptoms and a return to normal, pre-morbid health.4 Of course, such a model is entirely appropriate for treating reflux oesophagitis, a peptic ulcer or an exacerbation of colitis. However, when managing patients who have functional bowel disease, alcohol addiction or eating disorders this model of care may be less helpful. In all areas of psychiatry, the Medical Model of care is being superseded by the “Recovery Model”. Indeed, the Recovery Model of care has been integrated into public mental health policy in many countries, including Australia, New Zealand, USA, Canada, Ireland and the UK.5 The Recovery Model emphasises the personal experience of recovery, involving hope, rebuilding connections with family, friends and supporting patients in rebuilding a fulfilling life in spite of ongoing illness. In contrast to the Medical Model, this model aims for ‘recovery’, defined as enabling a return of hope, personal responsibility, control and empowerment.6 Supporting patients with functional bowel disease, alcohol addiction and eating disorders on their journey towards recovery involves understanding their agenda, active listening, empathy and the setting of realistic goals in equal partnership with patients and their families. Unfortunately, this model of care is unfamiliar to many gastroenterologists, and perhaps particularly to those with a sub-speciality interest in intestinal failure. For this reason we may have to train a new cadre of gastroenterologists with particular expertise in functional disease. This new gastroenterological subspeciality would protect vulnerable patients against repeated cycles of inappropriate investigations and increasingly invasive interventions and instead focus on supporting them on a road towards recovery and a living a fulfilling life. References
- Buchman AL, Scolapio J and Fryer J. AGA technical review on short bowel syndrome and intestinal transplantation. Gastroenterology 2003; 124: 1111–1134.
- Beumont PJ and Touyz SW. What kind of illness is anorexia nervosa? European Child and Adolescent Psychiatry 2003; 12: i20–i24.
- National Institute for Health and Clinical Excellence. Eating disorders. NICE clinical guideline 9. January 2004.
- Roberts G and Wolfson P. The rediscovery of recovery: open to all. Advances in Psychiatric Treatment 2004; 10: 37–49.
- Andresen R, Oades LG and Caputi P. Psychological Recovery: Beyond Mental Illness. Chichester, UK: Wiley-Blackwell 2011
- Schrank B and Slade M. Recovery in psychiatry. Psychiatric Bulletin 2007; 31: 321–325.
Ruminations on gut fermentation—any link to IBS?
Diet, gut microbiota, fermentation and IBS
The aetiology of irritable bowel syndrome (IBS), a disease that may affect at least 10% of the general population, continues to puzzle gastroenterologists and other scientists. While there is some evidence of perturbed gut microbiota in patients with IBS, microbiota profiles reliably linked to IBS remain to be identified. Meanwhile, studies of intestinal fermentation might hold the key to expanding our knowledge on the aetiology and management of IBS.In a recent article in the American Journal of Gastroenterology, Rajilić-Stojanović et al. reviewed data on the impact of diet and the intestinal microbiota on IBS symptoms.1 One of their important conclusions was that powerful interactions between distinct dietary patterns and intestinal microbial communities may—at least in part—be responsible for the fact that IBS has not yet been shown to be defined by certain microbiota profiles. As a lot of data going into studies exploring associations between microbiota profiles and disease conditions are cross-sectional, what we need to know much more about is how, including how quickly, changes in diet influences our gut microbiota, and therefore how resilient gut microbiota are to dietary changes. A study that appeared in Gut earlier in 2015 was looking into just that issue. In their study, Halmos et al. considered whether differences in dietary FODMAP (fermentable oligo-, di-, monosaccharides and polyols) content reflect differences in the colonic luminal microenvironment.2 Study participants (IBS patients and healthy controls) consumed their habitual diets for 1 week, but were subsequently switched to one of two challenge diets for 3 weeks (i.e. either a diet low in FODMAPs or a typical Australian diet). They were then allowed a wash-out period of 5 days, during which they consumed their habitual diets, and then later allocated to the alternative challenge diet for a further 3 weeks. Halmos et al. found that the higher FODMAP content of the Australian diet compared with that of the low FODMAP or habitual diets was associated with specific stimulation of the growth of bacterial groups with putative health benefits, including butyrate-producers and mucus-associated Akkermansia muciniphila. This finding made the team speculate that long-term use of low-FODMAP diets should be used with caution, at least until the long-term effects of such diets on intestinal microbiota have been fully elucidated. To this end, a recent randomized controlled trial by Böhn et al. compared the effects of a diet low in FODMAPs with traditional dietary advice in patients with IBS. The findings of this study suggest that traditional IBS dietary advice is just as effective in terms of reducing IBS symptoms as adhering to a diet low in FODMAPs.3 In the study by Halmos et al., the concentration of short-chain fatty acids (SCFAs) in stool, which was used as a colonic health index, was independent of diet type.2 The SCFAs acetate, propionate, and butyrate are produced primarily by bacterial fermentation of undigested carbohydrates (primarily dietary fibre aka ‘resistant starch’). The relevance of using the faecal SCFA concentration as a biomarker has, however, been questioned. Ringel–Kulka et al. looked into altered intestinal bacterial fermentation in the setting of IBS with regard to bowel characteristics and gastrointestinal symptoms.4 In their study, the primary aim was not merely to look at the distribution and composition of the microbiota, but to look at what the bacteria were actually doing. For this purpose, they looked at surrogate markers of gut bacterial fermentation, namely intestinal intraluminal pH and faecal SCFAs. Faecal SCFAs are naturally acidic and therefore cause a drop in the pH of the intestinal lumen. Compared with healthy controls, patients with IBS—independent of subtype—exhibited a significantly lower mean total colonic pH level, which could indicate higher intraluminal bacterial fermentation in this cohort. Of note, small-intestine pH levels did not differ between IBS patients and healthy controls, which suggests that bacterial fermentation is not increased in the small intestine of IBS patients. This finding may have important implications for understanding the contribution of small intestinal bacterial overgrowth (SIBO) in the pathophysiology of IBS. The SCFA levels in stool from IBS patients and healthy controls did not differ. Although this could be due to a number of circumstances, including differences in the absorption of SCFAs and colonic transit time, the authors do not recommend using faecal SCFAs as a marker for estimating intraluminal bacterial fermentation. There seems to be an emerging focus on the role of SCFAs in intestinal health and disease. While the low-FODMAP diet used by some IBS patients is associated with reduced SCFA production, these fermented substances appear to have a central role in the prevention of colon cancer and possibly other diseases. The use of surrogate markers of fermentation may have taken us some way already in our search for aetiological factors, but we need to know more about the direct impact of changes in intestinal fermentation and the various molecules generated by these processes on the development and course of IBS. I look forward to discussing the impact on SCFAs on intestinal homeostasis specifically and public health in general in one or more future blog posts. References
- Rajilić-Stojanović M, Jonkers DM, Salonen A, et al. Intestinal microbiota and diet in IBS: causes, consequences, or epiphenomena? Am J Gastroenterol 2015; 110: 278–287.
- Halmos EP, Christophersen CT, Bird AR, et al. Diets that differ in their FODMAP content alter the colonic lumincal microenvironment. Gut Epub ahead of print 12 July 2015 doi: 10.1136/gutjnl-2014-307264.
- Böhn L, Störsrud S, Liljebo T, et al. Diet low in FODMAPs reduces symptoms of irritable bowel syndrome as well as traditional dietary advice: A randomized controlled trial. Gastroenterology Epub ahead of print 5 August 2015. DOI: 10.1053/j.gastro.2015.07.054.
- Ringel-Kulka T, Choi CH, Temas D, et al. Altered colonic bacterial fermentation as a potential pathophysiological factor in irritable bowel syndrome. Am J Gastroenterol 2015; 110: 1339–1346.
A curious case of colitis
What type of colitis would you diagnose?
A 45-year-old Chinese woman presented with a 2-year history of intermittent loose stools, occasional PR bleeding and abdominal pain. The mucosal patches seen on the photograph were found in the left side of the colon. A full set of mucosal biopsy samples were taken and a representative histology slide, stained with H&E, is also shown.WHAT IS THE MOST LIKELY DIAGNOSIS? a) Schistosomal colitis b) Crohn’s colitis c) Ulcerative colitis d) Ischaemic colitis e) Amoebic colitis
On gut microbiota profiles and obesity
Can we prevent obesity by controlling our intestinal flora?
- OECD. Obesity update. June 2014.
- Hu H-J, Park S-G, Jang HB, et al. Obesity alters the microbial community profile in Korean adolescents. PLoS ONE 2015 10: e0134333.
Gastric balloons join the fight against obesity
How can we tackle obesity?
Obesity is one of today’s most worrying public health problems; it strongly correlates with cardiovascular disease, diabetes, cancer and non-alcoholic fatty liver disease, among other pathologies associated with metabolic syndrome.According to the World Health Organization (WHO),1 the worldwide prevalence of obesity has more than doubled since 1980; in 2014, a whopping 39% of adults aged 18 years and older were overweight and 13% were obese. The culprits? Ever-increasing sedentary lifestyles and overconsumption of high-fat/high-sugar foods. Which means that the solution should be very easy—to move more and eat less of the wrong foods—right? Unfortunately, there is no simple solution/easy answer. Obesity encompasses many social and psychological layers, which are difficult to get past. Children and adults are constantly exposed to advertisements on how tasty and delicious sugary drinks or high-fat/high-sugar foods are, not to mention the fun and approval associated with sharing them with friends. At the same time, kids will play on their videogame consoles or chat with friends online, rather than going outside and doing the exact same things… for real. Not that I am against any of those things, but a knowledge-based balance is essential. Healthy lifestyles are now being heavily promoted at the societal level, starting from a very early age; as an example, the WHO has created a commission on ending childhood obesity, taking into account the different economic and cultural contexts of each region of the world. The medical community itself has been changing gears in the fight against obesity. Several recent clinical guidelines advise doctors to think of obesity as a disease and to have a more active role in treating obese patients to help them achieve weight loss.2 As a result, most medical practitioners now require that their patients engage in healthy lifestyles before any medical or surgical procedure is considered. In particular, gastroenterologists are stepping up their game. As stated by Professor Mathus-Vliegen, Gastroenterologist and Professor in Clinical Nutrition at the Academic Medical Centre, University of Amsterdam, there are several natural reasons why gastroenterologists should take care of obese patients: many obesity-associated diseases develop in the gastrointestinal tract; patients with complications arising from bariatric surgery can be managed using minimally invasive endoscopic techniques; and the gastrointestinal tract is also the target for other forms of treatment, like endoscopic therapy.3 Indeed, endoscopic bariatric treatment of obesity has recently jumped into the spotlight since the US Food and Drug Administration (FDA) approved the use of two different inflatable medical devices, which are delivered to the stomach via a quick and minimally invasive endoscopic procedure and that trigger a feeling of fullness to help with weight loss. The ReShape™ Integrated Dual Balloon System consists of two attached balloons that are filled and sealed separately in the stomach of the patient during an endoscopic procedure. 326 obese patients (BMI 30–40 kg/m2), who had at least one obesity-related health condition, participated in the clinical study that led to the FDA approval.4 Individuals who received the device lost an average of 6.8% of their total body weight at the time of removal (6 months after placement) compared with an average of 3.3% in the control group. The ORBERA™ Intragastric Balloon System uses a single balloon that can be filled with different amounts of saline. In the pivotal ORBERA™ clinical trial in the US, 255 obese patients (BMI 30–40 kg/m2) were randomly allocated to the treatment and control groups.5 The treatment group lost 3.1 times as much weight as the control group at 6 months. Gastric balloons have been around for years outside the US and are not without controversy. Both of the obesity devices approved by the FDA are temporary and should be removed after 6 months. As such, are they effective in the long term? The clinical trials showed that patients were able to keep off most of the weight they had lost 6 months after removal of the device. But whether the same is true for longer periods of time is not clear. It is also important to note that both trials used obesity devices as adjuncts to lifestyle modification and it would be interesting to see their effect in isolation, for patients unable to diet and exercise. Whatever the case might be, it is clear that gastroenterologists are on the look out for obesity, which is also reflected by the increasing discussion of this topic at speciality meetings. At UEG Week 2015, for instance, you can expect to hear all about potential novel solutions for obesity, new developments in our knowledge on the gut-brain axis and cancer as they relate to obesity, as well as a dedicated symposium on its epidemiology, treatment and management. I am curious to see what gastroenterologists will bring to the table this time around! References
- World Health Organization. Obesity and overweight. Fact Sheet No 311 (January 2015) http://www.who.int/mediacentre/factsheets/fs311/en/.
- Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol 2014; 63: 2985–3023.
- Mathus-Vliegen EM. Endoscopic treatment: the past, the present and the future. Best Pract Res Clin Gastroenterol 2014; 28: 685–702.
- Ponce J, Woodman G, Swain J, et al. The REDUCE pivotal trial: a prospective, randomized controlled pivotal trial of a dual intragastric balloon for the treatment of obesity. Surg Obes Relat Dis 2015; 11: 874–881.
- Abu Dayyeh BK, Eaton LL, Woodman G, et al. 444. A randomized, multi-center study to evaluate the safety and effectiveness of an intragastric balloon as an adjunct to a behavioral modification program, in comparison with a behavioral modification program alone in the weight management of obese subjects. Gastrointest Endosc 2015; 81: Supplement, Page AB147.
An incidental gastric finding
What would you diagnose in this elderly, overweight man with diabetes and iron deficiency anaemia?
The lesion in the photographs was noted in the stomach of an overweight 70-year-old man with diabetes who was undergoing gastroscopy because of iron deficiency anaemia.WHAT IS YOUR ENDOSCOPIC DIAGNOSIS? a) Lymphangiectatic cyst b) Small gastrointestinal stromal tumour (GIST) c) Small leiomyoma d) Xanthelasma e) Small signet ring cell carcinoma
Summer School on Nutrition
Get practical, up-to-date information on the management of healthy children or those with specific illnesses.
A scary looking polyp
What would you do if you found this polyp in the high rectum of an elderly patient?
These four photographs show a polyp that was found in the high rectum of an elderly patient.WHAT WOULD YOU DO NEXT? a) Take a full set of samples and wait for histology findings b) Take samples and request an endoscopic ultrasound (EUS) c) Take samples and request staging X-rays d) Resect the polyp endoscopically e) Refer the polyp for transanal resection
Endoscopy Symposium 2015
16 recordings cover recent advances and new endoscopic techniques presented at this symposium.