The need for novel GORD diagnostic tools.
The need of noninvasive methods.
Gone are the days when a doctor would diagnose gastroesophageal reflux disease (GORD) simply by asking about symptoms and/or evaluating the response to acid suppression. Though this is still the case in many clinical practices, particularly for patients who have uncomplicated symptoms, a more accurate diagnosis usually involves undertaking invasive and expensive procedures that, nonetheless, are still claimed to have only moderate sensitivity and specificity. As such, more specific, noninvasive and cost-effective methods are needed for the diagnosis of GORD.GORD is a common and chronic condition that has a significant impact on quality of life and confers a significant economic burden. It generally arises from the reflux of stomach contents into the oesophagus, thus leading to oesophageal injury and associated complications. The most common cause of GORD is the disrupted relaxation of the anti-reflux barrier, which is composed of the lower oesophageal sphincter and the diaphragmatic crura; when failing to respond to swallowing, these transient lower oesophageal relaxations result in reflux of gastric fluid through the oesophagogastric junction. Heartburn and acid regurgitation follow. Ultimately, in some patients acid reflux may damage the oesophageal squamous epithelium and lead to the development of Barrett oesophagus. Left untreated, Barret oesophagus can progress to oesophageal adenocarcinoma.1 The European Association of Endoscopic Surgery (EAES) states that the two main GORD diagnostic tools are upper endoscopy and long-term impedance esophageal pH monitoring. Indeed, the combined information obtained from clinical symptoms, endoscopy and pH testing is usually considered to be sufficient and specific for the diagnosis of GORD. The EAES also highlight that “…further diagnostic investigations may be needed to verify functional abnormalities and establish the indication for surgery or other invasive therapies.”2 These additional diagnostic tools include high-resolution manometry (HRM), video-radiography and scintigraphy. For patients who have more severe symptoms, such as dysphagia and odynophagia, those who do not respond to acid suppression, or those in whom Barrett oesophagus is suspected, such additional diagnostic tools should be employed.3 Unfortunately, this comes at a sizeable financial cost. In Germany, the incidence of GORD is high and the associated healthcare costs have been estimated at €4.8 billion.4 In the United States, GORD represents the most common GI-related diagnosis; annually, GORD accounts for 8.9 million patient visits to the clinic and endoscopy exams cost $32.4 billion.5 These budgets emphasize the need for alternative, cheaper diagnostic methods for GORD and, ideally, noninvasive ones. Encouragingly, we might be on the right track with two recently published studies on novel GORD diagnostic tools, namely pepsin detection in saliva and minimally invasive oesophageal mucosal impedance testing. Several pathological settings may lead to pepsin being found in the laryngeal and paranasal sinus mucosa, saliva, middle ear effusion, tracheal secretions and bronchoalveolar lavage fluid. In their study, Hayat and co-workers sought to determine the value of salivary pepsin for discriminating patients with reflux-related symptoms from those with functional heartburn (FH).6 Pepsin was more likely to be detected in the saliva of patients with GORD and hypersensitive oesophagus (HO) and at higher concentrations than in the saliva of controls or FH patients. As such, the authors propose that salivary pepsin testing may complement GORD diagnosis.6 The fact that salivary pepsin can distinguish between GORD/HO and FH is extremely relevant, as most GORD patients benefit from pharmacological or surgical anti-reflux therapy, whereas FH patients do not. Interestingly, the detection of pepsin in saliva may also help in the diagnosis of laryngopharyngeal reflux (LPR).7 Despite the belief that LPR symptoms primarily result from GORD-related alterations of the laryngeal mucosa by gastric fluids, LPR differs from GORD in symptomatology and treatment modalities. A higher concentration of pepsin and bile acids has also been found in the saliva of patients with early laryngeal cancer than in the saliva of healthy volunteers, suggesting that LPR plays a role in the development of laryngeal carcinoma and might have utility as a disease biomarker.8 The question of how specific pepsin is for the diagnosis of GORD then arises. Indeed, is salivary pepsin diagnosing GORD, LPR or laryngeal carcinoma in development? As it currently stands, the measurement of salivary pepsin seems to represent a quick, cost-effective, noninvasive and simple 'office-based' method for GORD diagnosis, which I believe should be followed or paralleled with other disease-specific methods. Nonetheless, it holds a great value on its own in pinpointing the next step; for instance, the absence of pepsin could be taken as a sign of null or low frequency reflux events. Ates and co-workers have developed a minimally invasive device to assess oesophageal mucosal impedance as a marker of chronic reflux in GORD, where impedance is measured close to the squamocolumnar junction.9 They found that the impedance values were significantly lower in patients with GORD, with mucosal impedance patterns being identified in patients with oesophagitis at higher levels of specificity and positive predictive values than wireless pH monitoring.9 Despite being a simple method that’s easy to use and provides immediate results, it is unlikely that mucosal impedance will fully replace current GORD diagnosis tools, as it is unable to distinguish between different GORD symptoms or even GORD-related disorders, which require different therapeutic approaches. Still, it represents an excellent strategy to differentiate between GORD and FH, much like salivary pepsin. Though measurement of mucosal impedance is still invasive, the procedure is quick, which makes it attractive for patients who cannot (or will not) tolerate a transnasal probe that must be in place for 24 hours. Salivary pepsin levels and oesophageal mucosal impedance stand as two recent major breakthroughs in GORD diagnosis, but more are needed. I hope to see a lot of new and exciting discoveries on GORD diagnosis and management this October at UEG Week 2015! In the meantime, please feel free to browse the UEG Education Library for more resources. References:
- Subramanian CR and Triadafilopoulos G. Refractory gastroesophageal reflux disease. Gastroenterol Rep (Oxf) 2015; 3: 41–53.
- Fuchs KH, Babic B, Breithaupt W, et al. EAES recommendations for the management of gastroesophageal reflux disease. Surg Endosc 2014; 28: 1753–1773.
- Badillo R and Francis D. Diagnosis and treatment of gastroesophageal reflux disease. World J Gastrointest Pharmacol Ther 2014; 5: 105–112.
- UEG White Book Brochure [https://ueg.eu/epaper/WhiteBook.Brochure/index.html].
- Medical Economics. Treatment of GERD evolving [May 2013, accessed April 14, 2015].
- Hayat JO, Gabieta-Somnez S, Yazaki E, et al. Pepsin in saliva for the diagnosis of gastro-oesophageal reflux disease. Gut 2015; 64: 373–380.
- Ocak E, Kubat G and Yorulmaz I. Immunoserologic pepsin detection in the saliva as a non-invasive rapid diagnostic test for laryngopharyngeal reflux. Balkan Med J 2015; 32: 46–50.
- Sereg-Bahar M, Jerin A and Hocevar-Boltezar I. Higher levels of total pepsin and bile acids in the saliva as a possible risk factor for early laryngeal cancer. Radiol Oncol 2015; 49: 59–64.
- Ates F, Yuksel ES, Higginbotham T, et al. Mucosal impedance discriminates GERD from non-GERD conditions. Gastroenterology 2015; 148: 334–343.
Benign or malignant disease?
The photo shows the findings in a 65 year-old woman.
Is your ward happy?
All health services in Europe are under immense pressure …
I was woken up whilst on call recently by one of the staff nurses on our gastroenterology ward. It had been a busy day and, in addition to five new admissions, one patient—a withdrawing alcoholic—had become encephalopathic and was in the process of using a chair to try to smash through a window on the fifth floor. Earlier in the evening the same nurse had been hit in the mouth when she told another liver patient that he couldn’t go for a cigarette.The 50 inpatient beds in our ward are always occupied by a mixture of patients who have alcoholic liver disease, inflammatory bowel disease, emergency GI bleeding, infective diarrhoea, GI cancer or eating disorders of such severity that they are unable to maintain their weight let alone their electrolyte balance. In my opinion, gastroenterology wards are undoubtedly the most challenging in any hospital. No other hospital ward hosts such a wide-ranging mixture of disease, affecting patients of any age and with such severity! In spite of the state-of-the-art care that we provide, we have more deaths on our ward than any other ward in our hospital. This is because our patients are the sickest. Of course all health services in Europe are under immense pressure. In the UK, the number of patients presenting to GPs and Accident & Emergency departments is increasing, as is the number of patients admitted to hospital.1 As the workload increases, hospital cost cutting has led to a reduction the number of nurses and an increasing pressure to squeeze as much work as possible out of the existing workforce. In the NHS, 12-hour shifts are now the norm. I am sceptical that a 12-hour working day is compatible with the provision of compassionate, expert care to a complex GI patient and would like to see the evidence that this is achievable. The “Registered Nurse Forecast Study”, published in the Lancet in February 2014, looked at the impact of nursing numbers on patient mortality in 300 hospitals across Norway, Ireland, Netherlands, Finland, Sweden, Switzerland, England, Belgium and Spain.2 The authors found that hospitals in which trained nurses cared for an average of 6 patients had almost 30% lower mortality than in hospitals where nurses cared for an average of 8 patients. Similarly, a study by Rafferty et al.3 showed that in the UK “Patients and nurses in the quartile of hospitals with the best staffing levels had consistently better outcomes.” Mortality was 31% worse in hospitals where a single nurse cared for 8 patients compared with those hospitals where a single nurse cared for only 4 patients. Naturally, morale drops as workloads and stress increase. A study by Aiken et al.4 looked at staffing levels at Canadian, American, English and Scottish sites. Higher staffing levels led to higher nurse reported satisfaction with care given, resulting in better nurse retention and reduced burn out. Similarly a study of the safety and quality of hospital care across 12 European countries and the US concluded that better ratios of patients to nurses were associated with increased care quality and patient satisfaction.5 The UK nursing trade union UNISON conduct an annual survey of workload. In 2014, 51% of nurses said that they did not have sufficient staff numbers to deliver dignified, compassionate care.6 Furthermore, an astonishing 48% of respondents described their organisation as being at risk of a similar situation to "the Staffordshire Hospital". The Francis report7 into the Staffordshire Hospital scandal concluded that quality of care had become a secondary priority to financial savings. As a result, the Staffordshire Hospital failed in its duty of care to hundreds of patients and families. Patients died needlessly and loved ones were left in the dark without adequate answers or explanations. There are no European guidelines on minimum nurse staffing levels. In every country, it remains up to each institution to decide how many nurses it should employ. Unfortunately, many hospital managers seem to have no idea of the challenges faced on gastroenterology wards, which have to accommodate the widest range of the most complex conditions in patients aged anywhere between 15 and 115 years old (our oldest ever patient). Next time you do your ward round, make a note of the patient-to-staff ratio and ask yourself whether it is good enough. References
- The King’s Fund. What’s going on in A&E? The key questions answered, http://www.kingsfund.org.uk/projects/urgent-emergency-care/urgent-and-emergency-care-mythbusters (14 January 2015, accessed 7 May 2015)
- Aiken LH, et.al. Nurse Staffing and education and hospital mortality in nine European countries; a retrospective observational study. Lancet 2014; 383:1824–1830.
- Rafferty AM, et al. Outcomes of variation in hospital nurse staffing in English hospitals: cross-sectional analysis of survey data and discharge records, Int J Nursing Studies 2007; 44: 175–182.
- Aiken LH, Clarke SP and Sloane DM. Hospital staffing, organization, and quality of care: cross-national findings, Int J Quality in Health Care 2002; 14: 5–13.
- Aiken LH, et al. Patient safety, satisfaction, and quality of hospital care: cross sectional surveys of nurses and patients in 12 countries in Europe and the United States. BMJ 2012;344:e1717.
- UNISON. Running on Empty—NHS staff stretched to the limit: UNISON’s staffing levels survey 2014, https://www.unison.org.uk/upload/sharepoint/On%20line%20Catalogue/22245.pdf (14 May 2014, accessed 7 May 2015).
- Francis R. Report of the Mid Staffordshire NHS Foundation Trust Public Inquiry Executive Summary, http://www.midstaffspublicinquiry.com/sites/default/files/report/Executive%20summary.pdf (6 February 2013, accessed 7 May 2015).
A 30-year-old diagnosis.
An elderly patient being investigated for iron deficiency anaemia.
The photograph shows what was found in an elderly patient who was being investigated for iron deficiency anaemia.WHAT IS THE MOST LIKELY DIAGNOSIS? a) Gastritis associated with Helicobacter pylori infection b) Gastric cytomegalovirus infection c) Cameron ulceration d) NSAID-induced ulceration e) Ulceration from a diffusely infiltrating gastric cancer
ERCP & EUS
ESGE is combining forces with EASL and ESGAR for this symposium.
To what extent do gut microbes contribute to obesity?
Obesity—morbid overweight—is usually defined by a body mass index (BMI) >30. The condition can develop into metabolic syndrome, a rapidly emerging global epidemic that is associated with the development of multiple gastrointestinal (GI) disorders, including GI cancer.In one of the presentations now available for viewing from the "EAGEN Obesity Course—metabolic and nutritional problems in Western and Eastern Europe", which was held in October 2014, Professor Peter Malfertheiner dishes out quite a few disturbing facts.1 In 2005, 1 billion people worldwide were overweight and 300 million were obese. Ten years on and the numbers have risen to 2.3 billion overweight people and 700 million obese. This means that 14% of the world’s population is now pre-obese (7%) or obese (7%). One of the main concerns regarding obesity is the level of co-morbidity and reduction in life expectancy that is associated with it. Indeed, at the age of 40, the life expectancy of obese individuals is reduced by 7 years compared with that of non-obese individuals. However, it is not the actual BMI level per se, but the number of years living with obesity that is the stronger predictor of mortality, which is why strategies to delay the onset of obesity should be developed and implemented. Distinctions are also made between ‘benign’ and ‘malign’ obesity, the latter being synonymous with ‘visceral obesity’ (or ‘central obesity’), which is linked to inflammatory processes and insulin resistance, and which is labelled metabolic syndrome. Professor Malfertheiner explains how an inappropriate diet may lead to dysbiosis, increased gut permeability and gut bacterial lipopolysaccharide-associated metabolic endotoxaemia, with deterioration in gut, liver and endocrine functions. Professor Malfertheiner also discusses how obesity-associated non-alcoholic fatty liver disease (NAFLD) may develop into hepatocellular cancer (HCC) and underlines the fact that patients receiving insulin have a much higher risk of developing colorectal cancer (CRC). In general, the role of metabolic syndrome in cancer development is currently under intense scrutiny. In his talk ‘The link between obesity and lower GI tract diseases’, Dr Lazlo Herzeny mentions that 15% and 20% of cancer deaths in men and women, respectively, can be attributed to visceral/central obesity.2 Allegedly, 40%, 30% and 10% cases of oesophageal carcinoma, HCC and CRC, respectively, are associated with this type of obesity. In their study, Kang et al.3 showed that visceral obesity and insulin resistance are risk factors of colorectal adenoma, and Rampal et al.4 found an association between metabolic syndrome and colorectal adenoma. Be sure to look up Dr Herzeny’s talk to learn more about the factors potentially involved in obesity-related tumour development and progression. Incidentally, the EAGEN meeting included a pro-con debate on the role of obesity in GI cancers. Citing a study by Danaei et al.,5 Professor Borut Stabuc argues that obesity is on its way to outcompeting tobacco as the number one preventable cause of cancer.6 He talks us through reviews and meta-analyses that provide data evidencing links between metabolic syndrome and various types of cancer. However, gender differences are seen, and the relative risks associating metabolic syndrome with cancer are generally quite modest. As Professor Jaroslaw Regula points out in his talk,7 we are swamped with epidemiological data evidencing associations between metabolic syndrome and GI cancer, but these associations do not necessarily represent causal relationships. Professor Regula gives examples of some of the caveats when interpreting epidemiological data and calls into question the overall applicability of BMI in epidemiological studies, since BMI is not a direct indicator of visceral obesity. Moreover, there are few intervention studies and they do not necessarily show the same trends for men and women.8 The composition of the gut microbiota varies substantially among individuals, but within individuals it is also dynamic and susceptible to change by diet and administration of antimicrobial agents. The term ‘MicrObesity’ (microbes and obesity), coined by Drs Cani and Delzenne, is about deciphering the specific role of intestinal microbiota dysbiosis and its impact on host metabolism and energy storage.9 Microbes take up approximately 1 kg of our body weight, with most microbes being in the gut. Perturbations of the intestinal microbiota can have severe implications for our health, and several diseases appear to stem from intestinal dysbiosis. According to Lopez-Legarrea et al.,10 the majority of the bacterial phylotypes found in the intestine are members of two phyla: the Firmicutes (e.g. Clostridium, Enterococcus, Lactobacillus, Ruminococcus), which make up 60% of the gut microbiota, and the Bacteroidetes (e.g. Bacteroides, Prevotella), which account for about 15%. Other phyla include Actinobacteria (e.g. Bifidobacterium) and Proteobacteria (Helicobacter, Escherichia). In her talk, Dr Darij Vranesic Bender points out that a Mediterranean diet, which is high in polyphenols and polyunsaturated fatty acids, leads to increases in Prevotella, Enterococcus, Bifidobacteria, Latobacillus and Bacteroides, while a decrease in obesity-associated Clostridium is seen.11 Changes in the relative balance of bacterial groups may be directly associated with nutritional uptake, but the situation is complex and influenced by host factors such as genetics/co-evolution and physical activity. Also, one might ask how do changes in microbiota structure and function impact benign and malign (visceral/central) obesity? Data are still scarce, but a study recently published in Gut showed that cranberry extract administered to mice fed on a high-fat/high-sucrose (HFHS) diet reduced HFHS-induced weight gain and visceral obesity.12 Cranberry extract treatment markedly increased the proportion of the mucin-degrading bacterium Akkermansia muciniphila, which has previously been shown to be decreased in obese individuals, and which may be a bacterium actively fighting obesity and diabetes.13 As pointed out by Professor Krznaric in his talk “The role of microbiota in the pathophysiology of obesity”, imbalances in the relative proportion of Bacteroides to Firmicutes may lead to obesity.14 Of particular interest is the recognition of obesity-associated gut microbiomes with increased capacity for energy harvest, since the human microbiota—in this rising era of microbiota transplantation—can be remodelled in different cohorts (obese vs underweight) with a view to optimising nutritional intake. Part of the mechanism underlying this is the role of short-chain fatty acids that are not only a source of energy for the intestinal epithelium, but also act as signalling molecules with implications for fat metabolism. Professor Krznaric also underlines the possibility that long-term exposure to low-dose antibiotics, for instance through foods, may lead to intestinal dysbiosis and obesity. Moreover, as pointed out by Professor Malfertheiner, non-caloric artificial sweeteners—quite paradoxically—drive the development of glucose intolerance, which is associated with insulin resistance, due to alterations of the structure and function of the intestinal microbiota.2 Given this complex situation it will be challenging to come up with one-size-fits-all strategies for combatting obesity in the future. Nonetheless, Professors Petr Díte and Tomica Milosavljevic both attempt to do this. To learn about their thoughts and to update yourself with much more news in the field interfacing obesity and GI diseases, please do listen to their talks.15,16 Gut microbiota manipulation appears to be critical to future advances in preventing and treating obesity, and the effect of diet on gut microbiota structure and function is probably one of today’s hottest research areas. The collection of talks from the EAGEN meeting includes a variety of other obesity-associated topics, including endoscopic approaches to obesity, an update on bariatric surgery and epidemiology, clinical presentation and management of non-alcoholic steatohepatitis (NASH), to mention just some. Why not sit down with a nice cup of coffee and have a browse yourself, though you may want to try the coffee without the sugar or sweetener … and skip the biscuits! References
- Malfertheiner, P. Epidemiological trends of metabolic syndrome affecting GI diseases. Presentation at EAGEN Obesity Course - metabolic & nutritional problems in Western and Eastern Europe.
- Herzeny, L. The link between obesity and lower GI tract diseases. Presentation at EAGEN Obesity Course - metabolic & nutritional problems in Western and Eastern Europe.
- Kang HW, et al. Visceral Obesity and Insulin Resistance as Risk Factors for Colorectal Adenoma: A Cross-Sectional, Case–Control Study. Am J Gastroenterol 2010; 105: 178–187.
- Rampal S, et al. Association Between Markers of Glucose Metabolism and Risk of Colorectal Adenoma. Gastroenterology 2014; 147: 78–87.
- Danaei G, et al. Causes of cancer in the world: comparative risk assessment of nine behavioural and environmental risk factors. Lancet 2005; 366: 1784–1793.
- Stabuc B. Debate: Obesity and the risk of GI cancer – PRO. Presentation at EAGEN Obesity Course - metabolic & nutritional problems in Western and Eastern Europe.
- Regula J. Debate: Obesity and the risk of GI cancer – CONTRA. Presentation at EAGEN Obesity Course - metabolic & nutritional problems in Western and Eastern Europe.
- Sjöström L. Review of the key results from the Swedish Obese Subjects (SOS) trial - a prospective controlled intervention study of bariatric surgery. J Intern Med 2013; 273: 219–234.
- Cani PD and Delzenne NM. The gut microbiome as therapeutic target. Pharmacol Ther 2011; 130: 202–212.
- Lopez-Legarrea P, et al. The influence of Mediterranean, carbohydrate and high protein diets on gut microbiota composition in the treatment of obesity and associated inflammatory state. Asia Pac J Clin Nutr 2014; 23: 360–368.
- Bender DV. Protein, carbs and fats in personalised weight control - efficacy and safety. Presentation at EAGEN Obesity Course - metabolic & nutritional problems in Western and Eastern Europe.
- Anhê FF et al. A polyphenol-rich cranberry extract protects from diet-induced obesity, insulin resistance and intestinal inflammation in association with increased Akkermansia spp. population in the gut microbiota of mice. Gut (Epub ahead of print 30 July 2014) doi:10.1136/gutjnl-2014-307142.
- Everarda, A et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci 2013; 110: 9066–9071.
- Krznarik Z. The role of microbiota in the pathophysiology of obesity. Presentation at EAGEN Obesity Course - metabolic & nutritional problems in Western and Eastern Europe.
- Díte P. Health strategies to manage the epidemics of metabolic syndrome. Presentation at EAGEN Obesity Course - metabolic & nutritional problems in Western and Eastern Europe.
- Milosavljevic T. Health strategies to manage the epidemics of metabolic syndrome. Presentation at EAGEN Obesity Course - metabolic & nutritional problems in Western and Eastern Europe.
Research Course - 29 young investigators gathered this weekend
29 young investigators gathered this weekend
Participants had a busy schedule with best practices in preparing scientific abstracts, presentation training and professional networking.
An easy diagnosis but difficult aetiology
Try your diagnostic skills!
The photograph shows the mucosal appearance throughout the colon in a 49-year-old woman undergoing investigations for abdominal pain and diarrhoea.WHAT IS THE CAUSE OF THE MUCOSAL APPEARANCE? a) Melanin b) Lipofuscin c) Haemosidderin d) Food colourings e) Cyanosis
Application is open
ESPGHAN invites those who want to gain further experience of endoscopy and paediatric gastroenterology to participate in their Endoscopy Summer School
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
- 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).
- Blatchford O, Murray WR, Blatchford M. A risk score to predict need for treatment for upper-gastrointestinal haemorrhage. Lancet 2000; 356: 1318–1321.
- Rockall TA, Logan RF, Devlin HB, et al. Risk assessment after acute upper gastrointestinal haemorrhage. Gut 1996; 38: 316–321.
- 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.
- 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.
- 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.
- 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.
- 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:
- 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
- Leffler DA, Dennis M, Hyett B, et al. Etiologies and predictors of diagnosis in nonresponsive celiac disease. Clin Gastroenterol Hepatol 2007; 5: 445-450.
- Makharia GK. Current and emerging therapy for celiac disease. Front Med 2014; 1: 6.
- 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
- 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
- Gopalakrishnan S, Durai M, Kitchens K, et al. Larazotide acetate regulates epithelial tight junctions in vitro and in vivo. Peptides 2012; 35: 86–94.
- Gopalakrishnan S, Tripathi A, Tamiz AP, et al. Larazotide acetate promotes tight junction assembly in epithelial cells. Peptides 2012; 35: 95–101.
- 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.
- 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.
EFISDS & EDS Postgraduate Course: “Challenges in Gastrointestinal 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
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.
- Anderson LO, Nielsen HV and Stensvold CR. Waiting for the human intestinal Eukaryotome. ISME J 2013; 7: 1253–1255.
- 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.
- 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.
- Ianiro G. Gut Mycome. Presentation at the EAGEN Gut Microbiota 2014: EAGEN Advances on Gut Microbiota and Fecal Microbiota Transplantation.
- Huffnagle GB and Noverr MC. The emerging world of the fungal microbiome. Trends Microbiol 2013; 21: 334–341.
- 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.
- Mukherjee PK, Sendid B, Hoarau G, et al. Mycobiota in gastrointestinal disease. Nat Rev Gastroenterol Hepatol 2015; 12: 77–87.
- Brown GD. Dectin-1: a signaling non-TLR pattern-recognition receptor. Nat Reviews Immunol 2006; 6: 33–43.
- 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.
- Gouba N and Drancourt M. Digestive tract mycobiota: A source of infection. Med Mal Infect 2015; 45: 9–16.
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.8 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
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Association of European Coeliac Societies. Improving Diagnosis of Coeliac Disease (accessed 25 February 2015).
- 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.