On gut microbiota profiles and obesity

Can we prevent obesity by controlling our intestinal flora?

According to a recent report from the Organisation for Economic Co-operation and Development (OECD), over half of all adults in the OECD area are overweight, and 18% of adults are obese.1 Environmental factors may be a major factor underlying the obesity ‘epidemic’, prompting researchers to harness the potential of metagenomics to comprehensively examine the communities of microorganisms inhabiting the human gut (known as the microbiota) as a novel environmental factor associated with obesity. Metagenomics is the genomic analysis of microbial DNA that enables culture-independent investigation of microbial communities in complex sample material, and the rationale is primarily that differences in the structure and function of the microbiota are key to individual differences in energy harvest and storage. Recently, Hu et al. carried out an in-depth analysis of the gut microbiota from 67 obese and 67 normal-weight  Korean adolescents.2 The researchers sequenced bacterial ribosomal genes (16S) obtained from stool samples in order to obtain data on the gut bacterial composition of the two groups according to taxonomic rank. Operational taxonomic units were identified using the much-used software QIIME, and taxonomic abundance was calculated using the RDP Classifier. Firmicutes/Bacteroidetes (F/B) ratios have often been calculated and used to identify potential differences in the microbiota of obese and non-obese individuals. The authors of the present study were not able to identify differences in F/B ratios among obese and non-obese adolescents; to this end, no differences could be detected between the two groups at the phylum level. Meanwhile, significant differences were noticed at the family and genus levels: the proportion of Bacteroides in normal-weight and obese adolescents was 45% and 25%, respectively. Conversely, the proportion of Prevotella in normal-weight adolescents was 16%, but in obese adolescents it was 35%. The authors developed an algorithm that enabled prediction of obesity versus non-obesity based on the relative composition of the genera Bacteroides, Alistipes, Prevotella, Faecalibacterium, and Oscillibacter. While the title of the article appears to imply that the development of obesity drives gut microbiota in a particular direction, the team does not actually show this. The data presented here are cross-sectional, and no longitudinal data are presented. This means that we do not know whether certain changes in the microbiota lead to obesity or obesity leads to certain changes in the microbiota. Safe to say, however, is that in this particular study cohort, obesity was associated with a certain microbiota profile at the family and genus level. Regardless of any shortcomings, the work is fascinating. In the event that methods (e.g. sampling methods, DNA extraction from stool, and taxonomic analysis) can be standardized, it may prove useful to simply look at the distribution of bacteria in stool samples in order to identify microbiota differences between disease phenotypes—in this case obesity versus non-obesity—with a view to manipulating the gut flora towards a healthy microbiota. However, there is still a need to identify to which extent the composition of bacterial communities present in stool in fact reflects the relative distribution of these bacteria in the digestive system. Probably even more importantly, it should be investigated to which extent different bacteria share functional properties. Hence, we need to know whether the function of one type of microbiota can be more or less the same as a different type of microbiota due to the potential ability of bacteria to adapt to various ecological and physiological situations.  Furthermore, variation in the structure and function of the microbiota due to differences in genetic factors (age, gender, ethnicity, etc.) should be investigated. While studies aiming to link microbiota profiles to obesity are booming, we still need large amounts of standardized data in order to answer the question as to if and how we may be able to prevent obesity and metabolic disorder by manipulating gut microbial communities (for instance by prebiotics and/or probiotics), or—potentially—more bespoke cocktails of bacteria. We also need to develop a deeper understanding of the potential short-term and long-term effects of changes in diet on our gut flora. The article by Hu et al. cites a good many papers that have been central to the research linking the gut microbiota with diet and metabolism, so if you’re new to the area, this is a good place to start! References
  1. OECD. Obesity update. June 2014.
  2. Hu H-J, Park S-G, Jang HB, et al. Obesity alters the microbial community profile in Korean adolescents. PLoS ONE 2015 10: e0134333.

Homing in on the mechanisms and treatment of inflammation in IBD

α4β7 integrin has recently emerged as a new target for therapy in patients with inflammatory bowel disease (IBD), via the monoclonal antibody vedolizumab. The therapeutic benefit of α4β7 integrin blockade using vedolizimab has been successfully shown for both Crohn’s disease and ulcerative colitis.1,2

The process by which T cells enter the gut mucosa is tightly controlled by a specific homing process involving regulatory molecules on the T-cell surface and their ligands on intestinal endothelial cells. The blockade of T-effector cells (Teff cells) has been demonstrated to be effective in IBD; however, little is known about the mechanisms that control the homing of regulatory T cells (Treg) to the inflamed bowel, although recent research has demonstrated that the G-protein-coupled homing receptor, GPR15, controls the homing of Treg cells to the colon in mice. In a new study in Gut, Fischer et al.3 studied the in vivo homing of Teff and Treg cells to the inflamed gut via α4β7 integrin and GPR15. The authors looked at expression of homing receptors on T cells from both peripheral blood and inflamed mucosa. They also used a ‘humanised’ mouse model in dextran sodium sulfate (DSS) treated mice to study the migration pattern and homing of Teff and Treg cells to inflamed gut. Expression of α4β7 integrin and GPR15 on human Treg cells was upregulated in ulcerative colitis, as opposed to Crohn’s disease and controls, and regulated by inflammatory cytokines. In addition, the in vivo homing of Treg cells from patients with ulcerative colitis to the inflamed colon in humanised mice was demonstrated to be augmented when compared with the homing of Treg cells from controls.  Using vedolizumab to block adhesion molecule function did not alter the homing of Treg cells from controls, but showed that α4β7 integrin rather than GPR15 is crucial for controlling homing of Treg cells of patients with ulcerative colitis to the inflamed colon in vivo. By contrast, both molecules were shown to be involved in Teff  cell homing in ulcerative colitis. Finally, the authors demonstrated that vedolizumab therapy results in the accumulation of Treg cells in the peripheral blood of patients with ulcerative colitis. This is an interesting study because it clearly identifies GPR15 as another potential therapeutic target for the blockade of Teff cell homing in IBD. However, possibly more significantly, via the use of the humanised mouse model, this study offers researchers another method to evaluate the use of anti-adhesion therapies and human T-cell homing in vivo in IBD.  References  1. Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013; 369: 699–710. 2. Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 2013; 369: 711–721. 3. Fischer A, Zundler A, Atraya R, et al. Differential effects of α4β7 and GPR15 on homing of effector and regulatory T cells from patients with UC to the inflamed gut in vivo. Gut Epub ahead of print 24 July 2015. doi:10.1136/gutjnl-2015-310022.

Visibility during endoscopy for upper GI bleeding: 

When to give erythromycin?

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

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

Endoscopic biopsy for coeliac disease diagnosis:

How many bites does it take?

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

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

The sessile serrated polyp

It is there if you look for it.

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

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

HCV treatment in the post-transplant setting:

Developing niche markets for therapy.

Patients who have active hepatitis C at the time of liver transplantation invariably become re-infected, with the subsequent risk of graft failure. The side effects of interferon (IFN)-based therapies are significant, hence the drive to develop new and effective therapies. Two recent studies have looked at the role of two different IFN-free regimes for the treatment of post-transplant patients infected with HCV.

Charlton et al. studied the role of the NS5B polymerase inhibitor sofosbuvir and ribavirin given for 24 weeks for the treatment of HCV patients post-liver transplantation.1 The 40 patients included in the study were infected with a mixture of HCV genotypes (GT): 29 (73%) GT1a, 22 (55%) GT1b, 6 (15%) GT3 and 1 GT4. A total of 16 patients (40%) were classified as having cirrhosis. Overall, an SVR12 (sustained virologic response at week 12 post-treatment; representative of successful viral clearance) was achieved in 70% of patients; viral eradication was successful in 73% of GT1a patients, 55% of GT1b patients and 100% of GT3 patients. It was the single patient infected with HCV GT4 who failed to achieve an SVR12. There were no episodes of graft failure or rejection, with no significant study-related side effects. Some modification of the immunosuppressants tacrolimus and ciclosporin was required, but not in all cases. Kwo et al. looked at the benefit of the ABT-450/r (ritonavir), ombitasvir, dasbuvir and ribavirin regime, given for 24 weeks to GT1-infected patients post-liver transplantation.2 ABT-450/r is a ritonavir-boosted protease inhibitor, ombitasvir is an NS5A inhibitor and dasabuvir is a non-nucleoside NSB5 polymerase inhibitor. In combination with ribavirin, this regime has produced favourable outcomes in phase 3 trials in GT1-infected non-transplant patients.3,4 34 patients (29 infected with HCV GT1a and 5 with GT1b) were enrolled in the study by Kwo and colleagues. No patients with cirrhosis were included. Overall, an SVR12 was achieved in 97% of the treatment group, with 100% seen in the GT1b cohort, and 1 patient who relapsed in the GT1a cohort (97%). Again, no cases of graft failure or rejection were seen, and most adverse events were mild to moderate. All patients had their baseline tacrolimus and ciclosporin dosing modified, but there was no mention of any undue long-term effects resulting from this modification. Both of these studies included a small number of patients, who were heterogenous with regard to their baseline characteristics. For this reason, no firm conclusions can be drawn. However, the SVR rates achieved are encouraging, as are the tolerability and drug–drug interaction profiles, and most importantly the absence of graft rejection or failure. Treatment options and combinations have progressed rapidly since these studies were designed. The latest EASL guidelines recommend the use of sofosbuvir with either daclatasvir or simeprevir for post-transplant patients (excluding those with GT2 disease).5 The ABT-450 regime is at yet unlicensed, and it is unclear how commissioning bodies will decide which therapies are cost-effective based on the many therapeutic options now available. What seems certain though is that the next year will see research focused at targeting special populations (e.g. those with HIV co-infection or renal failure) and hard-to-treat groups (e.g. those with GT3 infection), with the aim being to target new, niche markets. References
  1. Charlton M, Gane E, Manns MP, et al. Sofosbuvir and ribavirin for treatment of compensated recurrent hepatitis c virus infection after liver transplantation. Gastroenterology Epub ahead of print 7 October 2014. DOI:10.1053/j.gastro.2014.10.001.
  2. Kwo PY, Mantry PS, Coakley E, et al. An interferon-free antiviral regimen for HCV after liver transplantation. N Engl J Med Epub ahead of print 11 November 2014. DOI: 10.1056/NEJMoa1408921. 
  3. Feld J, Kowley KV, Coakley, E et al. Treatment of HCV with ABT-450/r-ombitasvir and dasbuvir with ribavirin. N Engl J Med 2014; 370: 1594–1603.
  4. Poordad F, Hezode C, Trinh R, et al. ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis c with cirrhosis. N Engl J Med 2014, 370: 1973–1982.
  5. EASL. EASL Recommendations on Treatment of Hepatitis C 2014, http://files.easl.eu/easl-recommendations-on-treatment-of-hepatitis-C/index.html (2014, accessed 9 December 2014). 

Can't get to the caecum! Now what?

Colon capsule endoscopy versus CT colonography.

Endoscopists usually resort to performing CT colonography (CTC) in cases of incomplete colonoscopy. Colon capsule endoscopy (CCE) is a new technique that has potential advantages over CTC.

Achieving a caecal intubation rate >90% is an essential requirement for demonstrating competency in colonoscopy. However, even the more experienced endoscopist who routinely achieves a higher caecal intubation rate occasionally encounters problems. Being unable to reach the caecum could be due to patient-related factors, such as previous abdominal or pelvic surgery, unusual anatomy and pain threshold. As up to 50% of colonic neoplasia develop in the proximal colon, caecal intubation with adequate mucosal visualization is mandatory before colonic pathology can be excluded. Options for failed or incomplete colonoscopy involve using a different technique to repeat the procedure (e.g. using a gastroscope if there is troublesome sigmoid diverticular disease or using a more pliable paediatric colonoscope). However, CTC has been endorsed by the AGA as the ideal next step for cases of incomplete colonoscopy. Spada and colleagues from the Catholic University in Rome, compared the performance of CCE with CTC after incomplete colonoscopy in a small, but prospective, single-blind trial that enrolled 100 patients.1 All patients underwent both CCE and CTC on the same day. CCE was always performed first and a second attempt at colonoscopy was performed in patients who had a positive finding. The primary end point in this study was the per-patient diagnostic yield of CCE and CTC for ≥6 mm polyps/mass undetected by previously incomplete colonoscopy. Post-CCE/CTC colonoscopy was used as the gold standard. Secondary end points were completion rate, rate of missed cancer at 1-year clinical follow up, level of bowel preparation and safety. For polyps ≥6mm, Spada et al. showed a two-fold increase in the diagnostic yield of CCE compared with CTC (24.5% versus 12.2%). However, there was no difference in the detection rate for lesions >10mm. The higher sensitivity of CCE was not associated with higher false-positive results. Both techniques were comparable in terms of completion rate and safety; neither method missed a cancer on follow up. Though the study has some limitations (single center, possible false negatives with both techniques, exclusion of patients with poor bowel preparation and strictures), it shows that the detection and characterization of smaller lesions is possible with CCE. CCE may, therefore, be an option for patients with incomplete colonoscopy. References
  1. Spada C, Hassan C, Barbaro B, et al. Colon capsule versus CT colonography in patients with incomplete colonoscopy: a prospective, comparative trial. Published Online First 24 June 2014. Gut doi:10.1136/gutjnl-2013-306550.
Further UEG Education Resources 
  1. Colon Capsule Demo. Presentation by Dirk Hartmann at UEG Week Berlin 2013 
  2. Colon Capsule Endoscopy: Could it become a gold standard? Presentation by Cristiano Spada at UEG Week Berlin 2013
  3. Colon Capsule: Any indication? Presentation by Cristiano Spada at UEG Week Barcelona 2012

SVR: 24, 12 or maybe 4?

A shortened SVR time point with sofosbuvir?

How long does it take to determine whether the treatment for chronic hepatitis C (HCV) has been successful? In the past, patients had to wait 24 weeks to assess whether they had achieved a sustained virological response (SVR24). A recent article by Yoshida et al. looks at the data to support using a shortened SVR time point with sofosbuvir, in the new wave of HCV treatments.

The traditional wait for 6 months following a demanding treatment regime to see if it has been successful is clearly unsatisfactory. Over the past few years there has been a move towards using a 12-week post-treatment marker as a predictor of long-term viral eradication (SVR12). The use of this time point has been endorsed by regulatory authorities for drug development,1 and features in the latest EASL guidelines on HCV.2 However, the high concordance in SVR rates at 12 and 24 weeks has principally been obtained from interferon (IFN)-based studies. Data are limited for the new direct-acting antivirals, which is a shortcoming in the IFN-free era that we are now entering. The study by Yoshida et al. provides welcome insight into this area, confirming good concordance rates for viral eradication with sofosbuvir at both 4 and 12 weeks compared with the standard 24 weeks.3 This is encouraging because the oral HCV polymerase inhibitor sofosbuvir is integral to most new drug regimes for the treatment of chronic hepatitis C. In their retrospective analysis, Yoshida and colleagues pooled data on SVR rates from 863 patients involved in phase 3 trials of sofosbuvir. The treatment cohort included treatment naive and experienced patients who were infected with HCV genotype 1, 2 or 3 (a handful were infected with HCV genotype 4–6). Patients infected with HCV genotype 1 received IFN in addition to sofosbuvir and ribavirin, whereas those infected with HCV genotype 2 or 3 received sofosbuvir and ribavirin therapy alone. Concordance rates were similar across all genotypes, and between IFN and non-IFN regimes. In all, 98% of patients who achieved an SVR at week 4 also achieved an SVR at week 12, and 99.7% of those with an SVR at week 12 achieved viral eradication at 24 weeks. However, about 10% of all patients in the trials relapsed post-treatment. Most relapses occurred by post-treatment week 4, but many other relapses occurred between week 4 and 12 of follow up, with only a minority (2.3%) occurring after week 12. The authors therefore conclude that an SVR4 can be unreliable and that SVR12 is preferable. One of the reasons this study stood out to me was my experience seeing the same relapse pattern at week 12 in a patient who was treated with one of the new oral-based regimes. Despite having a fantastic response throughout treatment and up to week 4, I had to break the news that he had relapsed at week 12 and consequently failed his third course of treatment. As yet, little is known to be able to explain to patients why this happens, and patients infected with HCV genotype 3 seem to be uniquely hard to treat, with disappointing cure rates in clinical trials when compared with patients infected with the other genotypes. Data from the Early Access Programme in the UK, and from other compassionate use programmes of the new oral HCV treatments, are eagerly awaited. Hopefully these data will provide an improved understanding of the real-world responses to treatment and better predictors of viral response.  References 
  1. Chen J, Florian J, Carter W, et al. Earlier sustained virological response end points for regulatory approval and dose selection of hepatitis C therapies; Gastroenterology 2013; 144: 1450–1455.
  2. EASL Recommendations on Treatment of Hepatitis C 2014, http://files.easl.eu/easl-recommendations-on-treatment-of-hepatitis-C/index.html (2014, accessed 13 November 2014).
  3. Yoshida EM, Sulkowski MS, Gane EJ, et al. Concordance of sustained virological response 4, 12 and 24 weeks post-treatment with sofosbuvir-containing regimes for hepatitis C virus. Hepatology. Epub ahead of print 14 October 2014. DOI: 10.1002/hep.27366
Further UEG Education Resources 
  1. The new drugs for HCV: Can we achieve interferon-free HCV treatment? Presentation by Christophe Hezode at UEG Week Berlin 2013.

Treatment failure in patients with chronic hepatitis E

Are we a step forward?

Ribavirin (RBV) is used for the treatment of patients with chronic hepatitis E, but RBV is associated with treatment failure and associated mortality. A new in vitro study identifies a virulence mutation in the hepatitis E virus (HEV) genome that may explain why treatment failures occur.

Awareness and detection of acute HEV infection is increasing, including in some regions where the infection was hitherto thought to be rare.1 Indeed, HEV is now thought to be most common cause of acute viral hepatitis. Most infected individuals remain asymptomatic and in most symptomatic patients the infection clears spontaneously; however, patients with chronic liver disease or haematological malignancies, solid organ recipients and other immunocompromised patients are at risk of developing a chronic HEV infection. Debing et al. studied the blood samples of 15 solid organ recipients with a chronic HEV infection who were treated with RBV, which is generally the treatment of choice.2 Two patients did not respond to treatment and one of them died. In both nonresponders, a nucleotide substitution was detected that resulted in a G1634R mutation in the C-terminal region of the HEV polymerase. To further assess the significance of this mutation, the 1634R mutation was introduced into a HEV genotype 3 replicon. RBV sensitivity did not differ between the 1634R construct and the wild-type replicon, but the luminescence signals yielded by the 1634R construct were consistently higher than those yielded by the wild-type replicon, suggesting that viral replication was increased. Similar observations were made when two hepatoma cell lines were transfected with 1634R, 1634K (the predominant amino acid at this position in genotype 1 HEV) or wild-type replicons. Quantification of viral RNA released from transfected Huh7 cells showed that 1634R and 1634K variants replicated to higher titres than the wild type at every time point. Finally, the fitness of G1634 and 1634R variants was assessed using direct competition assays. This demonstrated a relative fitness gain for 1634R of 7–9%. This study provides the first evidence of a viral polymerase mutation that contributes to increased HEV replication. Although there was no difference in RBV sensitivity, the authors suggest that it is the increased viral replication that leads to treatment failure. This is not entirely unexpected. In an abstract presented at UEG Week 2012, viral load was linked with the risk of acute liver failure.3 Another area of the HEV genome under scrutiny in relation to acute liver failure is the region encoding capsid proteins; the occurrence of nucleotide substitutions in this region was studied in another abstract presented at UEG Week 2013.4 The study by Debing et al. raises further questions. Could mutations at the 1634 locus help predict the outcomes of patients with a chronic HEV infection? Would combination antiviral therapy benefit these patients or should they be offered one of the newer antivirals? The current study is probably one of the first steps in the quest to find the answers.    References
  1. Salunke SS, Hunt AC, Laing RB, et al. Hepatitis E: An emerging infection in North of Scotland? Gut 2013;62:A186.
  2. Debing Y, Gisa A, Dalleier K, et al. A mutation in the hepatitis E virus RNA polymerase promotes its replication and associates with Ribavirin treatment failure in organ transplant recipients. Gastroenterology 2014; 147:1008–1011.e7. 
  3. Borkakoti J, Hazam RK, Kar P, et al. Viral load of hepatitis E virus: a key agent in acute liver failure during pregnancy. Gut 2012;61 (Suppl 3):A36.
  4. Borkakoti J, Ahmed G and Kar P. Nucleotide substitutions in the hepatitis E virus genome: a prime agent in acute liver failure. United European Gastroenterology Journal 2013;1 (Suppl 1):A299.
Further UEG Education resources
  1. Hepatitis E: Who, when and how to treat? Presentation by Robert A De Man at UEG Week Vienna 2014
  2. Hepatitis E. Presentation by Rakesh Aggarwal at UEG Week Berlin 2013

Finding the right level

Infliximab levels antibodies to infliximab and disease activity in Crohn's disease.

With the widespread use of biologics such as Infliximab (IFX) for the treatment of IBD, research has focused on why some individuals respond well to their use, whilst others lose response over time or don't respond at all. Attention has focused on the role of antibodies to IFX (ATI) and whether they are responsible, at least in part, for this phenomenon, and whether monitoring and measuring ATI is useful for frontline clinicians treating patients.

The development of anti-TNF drugs (biologics) to treat chronic inflammatory conditions such as Crohn's disease has brought about dramatic changes in disease management. However, over the past 10 years there has been growing recognition that disease activity may be inversely related to the circulating drug levels. In patients with Crohn's disease, low or undetectable serum trough levels of IFX are associated with worse clinical outcomes. ATI are thought to increase the clearance of IFX, resulting in low serum trough levels. As part of a multinational research group, Vande Casteele et al. investigated the clinical relevance of ATI in patients who had adequate IFX concentrations.1 In this observational study, 1,487 trough serum samples from 483 patients with Crohn's disease were analysed using a fluid phase mobility shift assay, which is sensitive for the identification of ATI in the presence of IFX. They found that IFX trough concentrations >2.79 mg/mL during maintenance therapy were associated with remission, as measured by a C-reactive protein concentration of <5mg/L.  In addition, an ATI concentration level <3.15 U/mL was also associated with remission. Multivariate analysis showed that both the IFX trough concentration and ATI concentration were independent predictors of remission. The authors concluded that any detectable concentration of ATI was associated with greater disease activity, even in the presence of an adequate IFX trough concentration. They also postulated that ATI impair the effect of IFX via an alternative mechanism than by simply increasing its clearance. This suggestion is in keeping with the conclusion of Van Moerkecke et al. reporting on IFX levels and primary non-response at UEG Week 2009.2 These results support the role of therapeutic drug monitoring in patients with Crohn's disease who are receiving IFX. The results also provide justification for dose intensification with IFX in those patients without ATI but with a low IFX trough level and evidence of ongoing disease activity.  Patients with both low IFX trough levels and high ATI levels may benefit from conversion to a different TNF antagonist or 'class' of biologic agent. In an era of personalised medicine, adjusting medications according to the particular pharmacokinetics and immune adaptations of the individual receiving the medication may become the future gold standard. References 
  1. Vande Casteele N, Khanna R, Levesque BG, et al. The relationship between infliximab concentrations, antibodies to infliximab and disease activity in Crohn's disease. Gut Epub ahead of print 21 October 2014. DOI: 10.1136/gutjnl-2014-307883. 
  2. Van Moerkecke W, Cleynen I, Compernolle G, et al. Trough levels of infliximab in a cohort of primary non-responders. Gut 2009; 58 (Suppl II): A70.

Cap, hood, cuff, balloon

What is next for colonoscopy?

Balloon colonoscopy is yet another invention that aims to improve the adenoma detection rate (ADR) during colonoscopy. A recent pilot study evaluated the safety and efficacy of a novel colonoscope with an inflatable balloon at the distal end, reporting no serious adverse events among the study population. Quality indicators such as caecal intubation rate, ADR and polyp detection rate were reported, but future studies are awaited to compare the ADR of balloon colonoscopy with that of standard colonoscopy.

Endoscopy is a great specialty, in which opportunities for research and development are abundant for the enthusiasts, owing to a steady stream of technological developments. This technological arms race has resulted in the emergence of numerous optical enhancement methods. High-definition scopes, narrow-band imaging (NBI), autofluorescence imaging (AFI), Fuji Intelligent Chromoendoscopy (FICE), i-SCAN image enhancement technology, wide angle endoscopes, the Third Eye retroscope, caps and more recently Full Spectrum Endoscopy (FUSE) are aimed at improving the detection and recognition of pathology. It is the limited visibility behind colonic folds, particularly in the right hemi-colon, that these new technologies are trying to overcome. Gralnek et al. now describe the use of a novel colonoscope with an integrated inflatable balloon situated behind the distal end of the colonoscope.1 A standard adult colonoscope was modified and only white light examination was performed. Two expert endoscopists from a single centre took part in this pilot study. Upon reaching the caecum the balloon was inflated for controlled withdrawal, the idea being that when inflated the balloon would straighten out the colonic fold and improve visualisation. 47 patients were included in the final analysis and the authors report no major adverse events following use of the novel colonoscope. The reported average caecal intubation time, withdrawal time and total procedure time were 4.3 minutes, 7.4 minutes and 16.5 minutes, respectively. The polyp detection rate and adenoma detection rate were 53.2% and 44.7%, respectively.  Unfortunately, there was no control group, which raises the question of whether a comparable adenoma detection rate might have been achieved with the use of a conventional endoscope, particularly if withdrawn slowly over a 7–8 minute period. The participants in this study were recruited from colorectal cancer and polyp surveillance groups, along with others (no breakdown provided) in whom the polyp burden was expected to be greater than in 'all comers'. It was unclear as to why terminal ileal intubation was successful in only 5 of 47 colonoscopies and rectal retroversion in 31 of 47 colonoscopies. Whether the impregnated balloon impairs manoeuvrability of the tip is not known. I guess that the aim of the study was to look only at safety outcomes. Intermediate results from a randomised controlled tandem study comparing standard colonoscopy with balloon colonoscopy were presented at the UEG Week Berlin 2013.2 The results were impressive, with 100% additional detection of polyps with second-pass balloon colonoscopy and a 5.6 % polyp miss-rate on first-pass balloon colonoscopy. The final report is still awaited, however, future research into right-sided adenoma detection and tip control for difficult polypectomy using balloon colonoscopy would be interesting. References
  1. Gralnek IM, Suissa A and Domanov S. Safety and efficacy of a novel balloon colonoscope: a prospective cohort study. Endoscopy. 2014; 46: 883–887.
  2. Shpak B HZ, Kiesslich R, Moshkowitz M, et al. Novel balloon-colonoscope for increased polyp detection rate—intermediate results of a randomized tandem study. United European Gastroenterology Week (UEGW); Oct 12-16 2013, Berlin, Germany.

Inflammatory Bowel Disease

When to screen for latent tuberculosis?

Current guidelines recommend using a sensitive interferon-gamma release assay (IGRA) to screen patients with IBD for latent tuberculosis prior to initiation of anti-TNF therapy. However, new findings suggest that such screening should be considered much earlier, before initiation of any immunosuppressive therapy.

In their study, Wong et al. considered the performance of an IGRA (QuantiFERON®-TB Gold; Cellestis) in a population at moderate-to-high risk of tuberculosis; 268 patients with IBD were compared with 234 healthy controls.1 Among the patients with IBD, half were taking at least one immunosuppressant, such as azathioprine. The authors found that patients who were taking an immunosuppressant were significantly less likely to have a positive test result than patients who were not taking any immunosuppressants (13% versus 29.6%, P=0.002), thereby possibly masking the true incidence of latent tuberculosis. This effect was most pronounced in patients taking azathioprine (11.8% versus 27.3%; P=0.006). A subsequent quantitative analysis confirmed that patients taking an immunosuppressant generated a significantly lower interferon-gamma response (0.45 IU/ml versus 1.27 IU/ml; P=0.005). Although this study was confined to a population at moderate-to-high risk of tuberculosis, similar findings were reported in a previous meta-analysis, which looked at 9 studies that included 1,309 patients from across Europe and the USA.2 Whilst IGRAs have been found to have a high specificity and negative predictive value in immunocompetent adults, an accurate result does depend on an intact cell-mediated immune response. The authors propose that screening patients with IBD for latent tuberculosis should be carried out prior to initiation of any immunosuppressive therapies. However, to screen all patients with IBD would have cost implications. In addition, despite finding the most pronounced negative impact among those on azathioprine, current evidence elsewhere does not clarify the impact of individual immunosuppressants on the outcome of IGRAs. Screening only those patients at moderate-to-high risk of tuberculosis or who have more severe IBD, prior to starting immunosuppressants, may therefore be more cost effective. References
  1. Wong SH, Ip M, Tang W, et al. Performance of interferon-gamma release assay for tuberculosis screening in inflammatory bowel disease patients. Inflamm Bowel Dis Epub ahead of print 26 August 2014. DOI 10.1097/MIB.0000000000000147.
  2. Shahidi N, Fu YT, Qian H, et al. Performance of interferon-gamma release assays in patients with inflammatory bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis 2012; 18: 2034–2042.

Barrett's high-grade dysplasia with oesophageal varices. A difficult case!

Cases of Barrett's high-grade dysplasia with underlying varices are extremely rare and there is very little published literature on how best to manage these patients. A new case report attempts to address this question by suggesting band ligation without resection, but is this the answer?

Barrett's high-grade dysplasia and intramucosal cancer are now usually managed endoscopically by endoscopic mucosal resection (EMR) of visible lesions and ablation of flat dysplasia. Patients who have portal hypertension and oesophageal varices pose a particular challenge as they are at increased risk of bleeding. The increased risk of bleeding is not only due to the presence of varices but also because these patients are often coagulapathic and thrombocytopenic. One way of managing such patients is by endoscopic eradication of the varices followed by confirmation of success by endoscopic ultrasound (EUS) before proceeding with EMR or ablation.1 Alternatively, portal pressure can be reduced by transjugular intrahepatic portosystemic shunt (TIPS) placement followed by endoscopic therapy.Band ligation without resection has also been reported as safe, effective and simple for curing patients with short-segment Barrett’s oesophagus.3 Now, a single case report with a video presents the attempt of Palmer et al. to use band ligation without resection to eradicate high-grade dysplasia with a focus of intramucosal carcinoma, as diagnosed via prior biopsy.4 Unfortunately, superficial mucosal biopsies underestimate the stage of disease. Decisions about 'endoscopic cure' of such lesions should be made after histological analysis of the resection specimen to determine the depth of invasion, degree of differentiation and exclude lymphovascular invasion. The authors attempted to address this shortcoming by taking samples from the pseudo polyps created by the band ligator, but this only showed low-grade dysplasia and the staging of the disease remained unclear. As such, the proposal to use band ligation without resection seems to be an unsatisfactory halfway house! References
  1. Aranda-Hernandez J, Cirocco M and Marcon N. Treatment of dysplasia in Barrett esophagus. Clin Endosc 2014; 47: 55–64. 
  2. NeSmith M, Jou J, Fennerty MB, et al. Transjugular intrahepatic portosystemic shunt prior to endoscopic mucosal resection for Barrett’s esophagus in the setting of varices. ACG Case Rep J 2014; 1: 189–192. 
  3. Diaz-Cervantes E, De-la-Torre-Bravo A, Spechler SJ, et al. Banding without resection (endoscopic mucosal ligation) as a novel approach for the ablation of short-segment Barrett's epithelium: results of a pilot study. Am J Gastroenterol 2007; 102:1640–1645. 
  4. Palmer WC, Di Leo M, Jovani M, et al. Endoscopic management of high-grade dysplastic Barrett’s oesophagus with oesophageal varices. Gastrointes Endosc Epub ahead of print 9 August 2014. DOI:10.1016/j.gie.2014.06.034

Polyp surveillance

New study from Norway published in the New England Journal of Medicine.

Evidence regarding surveillance post-adenoma resection and the risks of eventual colorectal cancer (CRC) incidence and mortality over time is limited. The findings of a recent study from Norway published in the New England Journal of Medicine show that high-risk adenoma patients have increased CRC-related mortality despite colonoscopy surveillance, and suggest that low-risk adenoma patients may not require this intervention.

A huge proportion of colonoscopy capacity is taken up by adenoma surveillance. Guidelines from the ESGE1 and IARC in Europe and the AGA2 in the USA broadly recommend a follow-up 5–10 years after resection for individuals with low-risk or intermediate-risk adenomas and ever 3 years for those with high-risk adenomas. By contrast, guidelines from the BSG3 recommend a first follow-up after 1 year for individuals with high-risk adenomas. The paper by Løberg et al. in the New England Journal of Medicine used Cancer Registry and Cause of Death Registry data from Norway to identify 40,826 patients who had colorectal adenomas resected between 1993 and 2007.4 The Norwegian surveillance guidelines are similar to the ESGE guidelines, with high-risk cases defined as those with 3 or more polyps. Such high-risk cases are offered their first surveillance colonoscopy after 3 years. Patients who had polyps harbouring high-grade dysplasia, with a villous morphology or those who had a polyp 10 mm or larger in size, were offered a follow-up surveillance colonoscopy after 5 years. Patients with any other finding were classified as low risk and were not offered any surveillance. CRC mortality was analysed for those in low-risk and high-risk adenoma groups, with standardised incidence-based mortality ratios (SMR) calculated in comparison to a matched Norwegian population cohort. The median follow-up period in the study was 7.7 years, with 1,273 patients given a diagnosis of CRC in this period. In spite of the index adenomas having been removed, the number of deaths seen due to CRC was found to be increased during follow-up in the high-risk adenoma group (expected deaths 209, observed deaths 242; SMR 1.16). In the low-risk adenoma group mortality from CRC was reduced (expected deaths 189, observed deaths 141; SMR 0.75). This study is reassuring in that those patients who had 1–2 small tubular adenomas removed had a below average risk of developing CRC later in life. For this reason, the authors propose that colonoscopic surveillance may not be indicated in the low-risk group of patients. It is intriguing that the risk of bowel cancer remained above average in patients with high-risk findings. Do we need to carry out more frequent surveillance in this group? British surveillance guidelines advise a first follow-up after 1 year in patients with 3 or more polyps. Might this interval be sufficient to reduce the risk of subsequent CRC to background risk? References
  1. Hassan C, Quintero E, Dumonceau J-M, et al. Post-polpyectomy colonoscopy surveillance: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy 2013; 45: 842–851
  2. Lieberman DA, Rex DK, Winawer SJ, et al. Guidelines for colonoscopy surveillance after screening and polypectomy: a consensus update by the US Multi-Society Task Force on colorectal cancer. Gastroenterology 2012; 143:844–857
  3. Atkin WS and Saunders BP. Surveillance guidelines after removal of colorectal adenomatous polyps. Gut 2002; 51 (Suppl V): v6–v9
  4. Løberg M, Kalager M, Holme O, et al. Long-term colorectal-cancer mortality after adenoma removal. New Engl J Med 2014; 371: 799–807

The Lancet and World Hepatitis Day

HEV, HCV and even some IBD!

As a junior gastroenterologist, Mondays are typically spent running around like a headless chicken sorting out jobs from the weekend. Despite this, I did eventually notice that Monday, July 28 was ‘World Hepatitis Day’ (http://www.worldhepatitisday.org), with The Lancet publishing a fascinating paper on hepatitis E and blood transfusions to mark the event, in addition to papers on both hepatitis C and ulcerative colitis.

The papers that caught my attention on World Hepatitis Day were the fascinating article on the prevalence and transmission of hepatitis E in the UK, the phase III data on daclatasvir and asunaprevir and the phase II data on sofosbuvir and simeprevir for patients infected with hepatitis C virus (HCV) genotype 1.  For those of us interested in inflammatory bowel disease (IBD), there were data on Etrolizumab in moderate-to-severe ulcerative colitis to consider. Starting though with the thought-provoking paper on hepatitis E, lead by members of Public Health England (previously known as the Health Protection Agency). The authors provide an interesting historical overview of hepatitis E, which was first identified from an outbreak in Kashmir in 1978, before moving onto the eye-catching data showing that up to 25% of people in their sixth or seventh decade are seropositive for hepatitis E virus (HEV) in England and Wales!1  This would make HEV the most likely cause of acute enterally transmitted viral hepatitis in those individuals without a recent travel history.  I have noticed an increasing trickle of patients infected with HEV and listening to the podcast accompanying the paper, the author believes that the reason for this is the current fashion for consuming meat that is less well cooked and also processed meats (sausages?). Similar results have been published by groups in Sweden and Germany, which implies that cooking practices may have to change throughout Northern Europe. Blood donors in the UK are not currently screened for HEV. Analysis of 225,000 blood donations in the study from Public Heath England identified HEV RNA in 0.04% of blood donations. This prevalence could have led to an extra 80,000–100,000 acute HEV infections during the study period! The HEV transmission rate from infected donations was 42%, but on follow up most individuals (two-thirds) had spontaneously cleared the virus. Delayed or chronic infection was more common in the severely immunosuppressed. This finding creates some dilemmas regarding monitoring practices for transplant patients, and a recent article in The New England Journal of Medicine on the use of ribavirin in HEV-infected solid-organ transplant recipients may be a useful reference in this scenario. In their discussion, the authors stop short of mandating HEV blood-donor screening, rather they imply that the aim should be to improve our cooking and dietary habits.2 Moving from hepatitis E to hepatitis C, I’m sure we’ve all been in awe, but perhaps somewhat saturated, at the huge advances made in the treatment of HCV over the past year. The Lancet has now published the findings of the phase III international study of the NS5A inhibitor daclatasvir and the NS3 protease inhibitor asunaprevir as a IFN-free treatment option in patients chronically infected with HCV genotype 1b.3 A successful SVR 12 (sustained virological response at 12 weeks post-treatment) was seen in 91% of treatment-naive patients, in 82% of previous non-responders to Peg-IFN and ribavirin, and in 83% of treatment-intolerant patients. Overall the study medications were well tolerated. Although viral resistance has been seen in the treatment failure groups, these SVR rates seem encouraging. Phase II data on the NS3/4A protease inhibitor simeprevir and sofosbuvir with or without ribavirin for chronic HCV genotype 1 infection have also been published in The Lancet.4 Simeprevir (along with sofosbuvir) is already licensed in the US and Europe, and aims to provide improved tolerability and efficacy compared with the current NS3/4A protease inhibitors telaprevir and boceprevir.  The study looked at IFN-free treatment with sofosbuvir or simeprevir with or without ribavirin for 12 or 24 weeks in two cohort groups, divided based on the severity of liver fibrosis (METAVIR scores F0-F2 or F3-F4). Results presented on an intention-to-treat basis showed SVR 12 rates of 90% and 94% in the two treatment groups, respectively. None of the patients included in the study had decompensated liver disease, and side effects from a mild to severe grading were seen in both groups, with viral resistance to simeprevir, but not sofosbuvir, noted in a small number of patients. The addition of ribavirin and treatment duration (12 or 24 weeks) did not seem to significantly alter the noted SVR rates. Both sofosbuvir and simeprevir feature as a treatment option in the latest EASL recommendations; however, this is one of several recommended options, and only one of many options that should soon receive EMA (European Medicines Agency) authorisation. Aside from viral hepatitis, the week’s print issue of The Lancet also contained the phase II trial of ertolizumab in patients with ulcerative colitis.5 Ertolizumab is one of a new wave of monoclonal antibodies that target integrins (transmembrane receptors that are important in the extracellular matrix) and their interaction with the MAdCAM-1 adhesion molecule, which is known to play a key role in the direction of lymphocyte traffic from the circulation into intestinal tissue. Patients with ulcerative colitis were randomly allocated to two different subcutaneous doses of ertolizumab or matching placebo in this double-blind placebo-controlled study. 124 adult patients with moderate-to-severe ulcerative colitis unresponsive to standard therapy with prednisolone, immunomodulators (azathioprine, methotrexate etc.) or anti-TNF therapy were included, with just over 60% of the patients having failed to respond to anti-TNF agents. Statistically significant improvement in disease remission at 10 weeks was seen in both ertolizumab groups compared with placebo; no patients in the placebo group achieved disease remission at week 10. Adverse events were noted at a similar rate in all three groups. There were no cases of progressive multifocal leukoencephalopathy, a nasty condition that has been seen in patients with multiple sclerosis who were treated with natalizumab (a non-selective anti-integrin antibody). The authors say that they did not expect to see any cases as ertolizumab is more selective, but also acknowledge that there is as yet limited safety data and patient numbers involved with this agent. The accompanying comment article praises the study for its rigorous design using a double-blind placebo-controlled approach, as well as the use of the Mayo Clinic Score in the assessments.6 The Lancet of course also included robust comment articles—on the escalating Ebola outbreak in Western Africa, Polio eradication in conflict zones, gruesome food-safety concerns in China, an interesting piece on the possible role of neuraminidase inhibitors (e.g. oseltamivir and zanamivir) in influenza and the crisis in Gaza—reflecting bleak times globally. One hopes for brighter comment pieces in the future. References 1. Hewitt P, et al. Hepatitis E virus in blood components: a prevalence and transmission study in southeast England. Lancet online July 28, 2014 doi:10.1016/S0140-6736(14)61034-5  2. Kamar N, et al. Ribavirin for chronic hepatitis E virus infected transplant recipients. N Engl J Med 2014 vol. 370 no. 12 1111–1120  3. Manns M, et al. All-oral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study. Lancet online July 28, 2014 doi:10.1016/S0140-6736(14)61059-X  4. Lawitz E, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype I in non-responsders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet online July 28, 2014 doi:10.1016/S0140-6736(14)61036-9  5. Vermeire S, et al. Ertolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial. Lancet 2014 vol. 384 no. 9940 309–318  6. Armuzzi A and Felice C. Etrolizumab in moderate-to-severe ulcerative colitis. Lancet 2014 vol. 384 no. 9940 285–286 

Impact of day of admission on mortality in upper gastrointestinal haemorrhage

Evidence suggests that death is more likely to occur for some patients who are admitted to hospital on a weekend rather than on a weekday, but that evidence is not conclusive. New findings now indicate that mortality from upper gastrointestinal bleeding does not differ by day of admission.

There is evidence that some patients are more likely to die if admitted to hospital on weekends; however, the evidence is not equivocal. For example, Goldacre and Maisonneuve found that there was no evidence of excess deaths from meningococcal disease when patients were admitted at the weekend rather than on a weekday.1  Emergency gastrointestinal bleeding is associated with a mortality rate of around 10% in the UK, and a UK-wide audit in 2007 highlighted significant deficiencies in the care of patients presenting with upper gastrointestinal bleeding.2 In particular, outcomes were less good for patients attending hospitals in which there was a lack of on-call consultant-led endoscopy in the out-of-hours setting.  For this reason, I was interested to read an American nationwide analysis with huge patient numbers showing that there is no difference in the mortality rates between patients with upper gastrointestinal bleeding admitted on weekends versus weekdays.3 An earlier American database study from 2004 had found that the risk of death was greater for weekend admissions.4 However, the current study used stricter criteria for the diagnosis of an upper gastrointestinal bleed. We do know from a recently presented study5 that presentation with coffee ground vomiting is associated with a similar risk of mortality (but with a significantly lower endoscopic yield) as presentation with haematemesis and melaena.  This difference in diagnostic criteria may be one of the reasons why previously published studies comparing mortality in patients with upper gastrointestinal bleeding have given conflicting results. Nevertheless, the paper by Salzman and colleagues3 may not be the end of the matter. The group only looked at new admissions, whilst it is well recognised that inpatients who develop emergency gastrointestinal bleeding as a complication whilst recovering from another condition have a higher risk of mortality. Furthermore, the patients in the study seemed to be a surprisingly healthy bunch.  The mortality rate was only 2.2%, only 1.6% of patients were admitted with variceal bleeding (which is known to be associated with a higher mortality rate) and the patients only stayed an average of 3 days in hospital! Understandably, the study was unable to provide detailed information on the emergency endoscopies themselves and some questions linger.  Why were 13% of patients with non-variceal bleeding not offered endoscopy?  What was the level of experience of the endoscopists staffing the units during the weekdays versus the weekends?  Were current guidelines on “dual modality therapy” adhered to?  What were the rebleeding rates in patients admitted at weekdays versus weekends? But for now, the findings of the study support the idea that there is no difference in mortality from upper gastrointestinal bleeding regardless of the day of admission. References 1. Goldacre MJ and Maisonneuve JJ. Mortality from meningococcal disease by day of the week: English national linked database study. Journal of Public Health 2013 vol. 35 no. 3 413–421 2. Hearnshaw SA, et al. Acute upper gastrointestinal bleeding in the UK: patients characteristics, diagnoses and outcomes in the 2007 UK audit. Gut 2011 vol. 60 no. 10 1327–1335 3. Abougergi MS, et al. Impact of day of admission on mortality and other outcomes in upper GI hemorrhage: a nationwide analysis. Gastrointestinal Endoscopy 2014 vol. 80, no. 2 228–235.e1 4. Barkun AN. Do predictors of mortality in upper gastrointestinal bleeding include a weekend time of admission? Clinical Gastroenterology and Hepatology 2009 vol. 7 no. 3 257–258 5. Schneider JR, et al. Is coffee ground vomiting important? Findings from a large bleeding unit database with outcomes at 30 days. Gut, 2014 vol. 63 no. 6  suppl. 1 A6

The enemy within

Dysbiosis and ulcerative colitis.

In recent years, there has been a growing recognition that the gut microbiota and the development of a microbial imbalance within the gastrointestinal tract—termed ‘dysbiosis’—are important in the pathogenesis of inflammatory bowel diseases, especially Crohn’s disease.

However, studies demonstrating dysbiosis in ulcerative colitis have been conflicting. A study from a group based in Belgium now adds to the evidence that dysbiosis is also important in ulcerative colitis, but indicates that the microbial signature differs to that found in patients with Crohn’s disease.  The group found a reduction in the abundance of butyrate-producing ‘good’ species Roseburia hominis and Faecalibacterium prausnitzii in patients with ulcerative colitis.1 This study also demonstrated that the abundance of these ‘good’ bacteria, both of which belong to the phylum Firmicutes, was inversely correlated with disease activity. This is an interesting finding since short-chain fatty acids (SCFA) potentially produced by such organisms not only provide energy for the mucosa but also exert anti-inflammatory effects.  However, the relationship is probably more complex than anticipated. Although patients with ulcerative colitis had reduced levels of SCFA, there was no correlation between the levels of SCFA and the presence or absence of these bacteria. Nevertheless, the discovery is important as it may pave the way for trials of selective therapeutic agents, such as probiotics, prebiotics and/or synbiotics, to restore these species in the gut microbiota of patients with ulcerative colitis to reduce disease activity. If you would like to read more on dysbiosis in colitis, please click the following link:  https://www.ueg.eu/education/document-detail/?name=digestive_functions_and_gut_microbiota&file=97297

References

1. Machiels K, Joossens M, Sabino J, et al. A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut 2014; 63: 1275–1283.  

How accurate is a Gastroenterologist's Gut Feeling?

June’s edition of the UEG Journal features a study that explores the accuracy of gastroenterologist’s estimates about outcomes – dubbed their ‘Gut Feeling’ – with interesting results.

I often have a gut feeling whether I will find something at endoscopy. With time I have learnt that I can not depend on this hunch. Patients with the mildest of symptoms often have the most severe disease. This study from the Netherlands put the gut feeling to the test. They found that the gut feeling was good but that scoring systems were better. The outcome was particularly unexpected as the scoring systems were not used for the purpose they were developed! The Rockall score was used to predict risk of rebleeding in all lesion although its primary purpose is to predict mortality in bleeding peptic  ulcers. The Blatchford score was used to predict mortality whilst its primary purpose is to predict risk of intervention being required in non-variceal bleeding. Makes you wonder how the hunch would have compared with the Italian PNED score and the AIM65 score!  De Groot, NL. et al. Prediction scores or gastroenterologists’ Gut Feeling for triaging patients that present with acute upper gastrointestinal bleeding United European Gastroenterology Journal 2014 vol. 2 no. 3 197-205