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Gut

  • Colorectal cancer can occur via more than one molecular pathway. The serrated pathway probably accounts for 20%–30% of colorectal cancer.

  • Histopathological nomenclature for serrated lesions varies internationally. We suggest the terms hyperplastic polyp (HP), sessile serrated polyp (SSP), and traditional serrated adenoma to describe these lesions.

  • Colonoscopy is the best detection tool for serrated polyps, but detection rates are variable.

  • Chromoendoscopy and slower withdrawal time are the only interventions that have been demonstrated to increase serrated lesion detection. High-definition endoscopy and right colon retroflexion may have a role.

  • All polyps proximal to the recto-sigmoid junction should be removed. A benchmark rate of 4.5% for detection of proximal serrated lesions (HPs plus SSPs proximal to splenic flexure) in screening has been suggested for US-based colonoscopic screening, but implementing a target for serrated lesions in clinical practice is currently impractical.

  • DNA-based detection...


    Basic scienceLocalisation of CD8+TRM cells in infected intestine determines their phenotype and function

    Bergsbaken T, Bevan M. Proinflammatory microenvironments within the intestine regulate the differentiation of tissue-resident CD8+ T cells responding to infection. Nat Immunol 2015;16:406–14.

    Effector CD8+ T cells produced during bacterial or viral infection undergo an activation phase. This allows entry into a number of peripheral tissues, including the GI tract. CD8+ T cells then acquire a tissue-resident memory T cell (TRM cell) phenotype. Intestinal CD8+ TRM cells remain in the tissue to provide local protection against future infections. The control of TRM cell development, specifically during local infection, is not well defined. In this study, the recruitment of CD8+ T cells to the intestine and the role that distinct microenvironments within the infected intestine can play in regulating cell development was investigated. The authors used Yersinia pseudotuberculosis (Yptb) infection as a model to...


    Austin and colleagues1 offer an opinion that the recent BSG guidelines on adult coeliac disease are regressive for not considering a biopsy avoidance strategy in patients with positive serological findings.2 The authors cite a positive predictive value (PPV) of up to 100% for serological testing, however studies reporting these findings are from highly selected populations where coeliac disease prevalence is high (six studies, coeliac disease prevalence between 21% and 100%). The most important data that clearly refutes Austin and colleagues’ suggestion is a study of 2000 patients attending endoscopy, where coeliac disease prevalence was 3.9%.3 In this study the PPV of anti-tissue transglutaminase antibody (tTG) was only 28.6%, despite sensitivity and specificity of greater than 90%, which only increased to 71.7% when combined with a positive endomysial antibody (EMA). In simple terms if we follow the approach advocated by Austin and colleagues 3...


    By definition, portal hypertension means pathological elevation of the portal pressure gradient (PPG), the direct measurement of which is extremely invasive. This has prompted the use of the less invasive hepatic venous pressure gradient (HVPG), widely accepted as the PPG equivalent.1–3 In a recent article in Gut, HVPG was used as the only criterion to assess haemodynamic response (reduction in HVPG of ≥20% or to values <12 mm Hg) rates to carvedilol in propranolol non-responders.1 Although accurate, HVPG is still invasive, and thus not routinely performed in all centres.2 3 As HVPG becomes standard practice, repeated invasive measurement has stimulated the search for non-invasive techniques to measure PPG.3–5 Here, we present a virtual PPG (vPPG) based on CT angiography and Doppler ultrasound.

    The VIRGIN Study was a multicentre, blinded, prospective, analytical trial carried...


    We read the article of Seto et al1 and we were really surprised by a very high rate of virological relapse (91%), much higher than 58% in a similar study by Jeng et al,2 and their conclusion that "the high rates of virologic relapse suggest that nucleos(t)ide analogue (NA) therapy should be continued indefinitely until the recognised treatment endpoint of HBsAg seroclearance".

    However, in hitherto conducted studies in Asian and Western patients with HBeAg-negative chronic hepatitis B, virological relapses alone defined as HBV DNA >2000 IU/mL with normal ALT levels, have first been monitored at frequent intervals while initiation of NA therapy again was considered only if ALT levels also increased >2x upper limit of normal, that means when virological relapses changed to clinical ones.2–4 In Seto's study all patients with post-treatment virological relapse up to week 48 were treated...


    Sir,

    Zorzi et al1 are to be commended for their timely analysis of the impact of using a faecal immunochemical test (FIT) on colorectal cancer mortality in their screening programme. The 24% colorectal cancer mortality reduction they report will surely give impetus to efforts to introduce FIT into other screening programmes. As they rightly observe, the impact of these newer screening tests is likely only to be determined from observational studies such as their study rather than further randomised trials.

    Nevertheless, some of their findings are quite surprising. It is remarkable that the mortality reduction they report should have been evident so early, within 5 years of starting to screen, when in the randomised trials a lower mortality from colorectal cancer was not apparent until over 5 years after screening started and for the reduction to be substantially greater in women than men when in these same trials the...


    We thank Logan and Halloran for their interest in our study1 and admit that we were equally surprised at the early impact of screening programmes on colorectal cancer mortality rates.2

    With respect to incidence trends, rates peaked during the prevalence round and showed a sharp reduction below the prescreening values within 5 years of screening set-up.2 These results are in line with the few evidences in the literature that evaluated the effect of population screening programmes based on the faecal occult blood test. Ventura et al3 compared the cumulative incidence between cohorts of screened and non-screened individuals. The rise of cumulative incidence was higher in screened individuals than in controls only during the first 2 years, then the value dropped and equalised with that of the non-attendees’ cohort around year 6. These figures translate into an initial increase of incidence rates followed by...


    To the editor,

    The serrated pathway is an established sequence to colorectal cancer (CRC), but little is known about the exact malignant potential of serrated polyps (SPs). Therefore, we have read with great interest the article by Holme et al1 who evaluated the long-term risk of CRC in individuals with large (≥10 mm) SPs as well as the natural course of these lesions. Based on their results, the authors state that the increased CRC risk for individuals with large SPs may not be due to the malignant growth of the SP itself, but rather to an overall field effect in patients with these lesions. However, this statement warrants careful interpretation as we believe that both the timeframe and study design imply a major negative effect on the external validity of this study.

    First of all, the long-term risk for CRC is assessed after an initial screening sigmoidoscopy performed...


    Kalla R, Ventham NT, Kennedy NA, et al. MicroRNAs: new players in inflammatory bowel disease. Gut 2015;64:504–13. The Open Access licence has been corrected to CC BY.


  • Gut RSS feed -- current issue
    Gut

    Contrary to a decade ago, clinical development in ulcerative colitis (UC) has become highly active with multiple promising innovative assets currently in early and late phase clinical studies. The anti-integrin α4β7 monoclonal antibody vedolizumab has been leading this wave, and has received marketing authorisation by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) based on an excellent efficacy and safety record.

    One of the targets that had raised high hopes several years ago was interleukin 13 (IL-13), together with IL-4 and IL-5 the signature cytokine of a T helper 2 (Th2) immune response. As such, its blockade was hypothesised as a brilliant therapeutic strategy in diseases such as allergic asthma and UC. However, in this issue of Gut, results from a trial with anrukinzumab in active UC are reported,1 which, together with results of a trial with tralokinumab reported in the...


    The intestinal tract is one of the most complex organs of our body because it has to perform several functions, including digestion and absorption of nutrients. Being exposed to a continuous insult by the local microbiota, the intestinal epithelium is constantly renewed from Lgr5+ stem cell progenitors located in the crypts of Lieberkuhn.1 These progenitors have been recently exploited to regenerate ‘mini-guts’ (organoids) in vitro.2 An appropriate cocktail of small molecules and growth factors has been identified that preserves stemness but also favours the differentiation of enterocytes and Paneth cells thus forming the organotypic structure of a crypt-villous organoid (for a review, see ref. 3).

    In this issue of Gut, VanDussen et al4 show a powerful method of growing human epithelial cells in culture from biopsies of several intestinal segments of either healthy individuals or patients with several pathologies.

    The authors established a...


    With the introduction of direct-acting antivirals (DAA), the treatment for chronic hepatitis C is evolving at an astonishingly rapid pace.1 Among DAAs, HCV NS5A inhibitors show substantial promise as anti-HCV therapeutics. NS5A inhibitors in clinical development include daclatasvir (DCV), ledipasvir, ombitasvir and MK-8742.2 With in vitro anti-HCV activities in the low picomolar range, these represent the most potent class of DAAs to target HCV. The HCV NS5A protein is known to function in multiple aspects of the HCV life cycle, including roles in viral replication and assembly, as well as complex interactions with cellular factors. Not being associated with any measurable enzymatic activity, NS5A was not considered ‘druggable’ for a very long time. In fact, the first small-molecule NS5A inhibitors were discovered by random screening using the HCV replicon system. The initial lead compounds had only moderate potency, but subsequent medicinal chemistry efforts resulted in...


    WHO estimates suggest that worldwide 150–200 million people are chronic carriers of HCV. Of these up to 30% will develop chronic liver inflammation and fibrosis and progress to cirrhosis or hepatocellular carcinoma (HCC) in the long term. New HCV infections are still occurring, and most HCV carriers are unaware of their status. Therefore incidences of HCV-induced liver disease and cancer are predicted to rise in the coming decade in spite of important recent progress in the development of direct antiviral agents. These new treatments appear to have greatly improved efficacies and safety profiles combined with a high genetic barrier and they are likely to introduce an era of interferon-free therapy in the near future.1 Virological cure in the form of a sustained virological response (SVR) is predicted to become attainable for most patients, including HCV carriers that were previously difficult to treat.1 A number of...


    Objective

    Surveillance is recommended for Barrett's oesophagus (BO) to detect early oesophageal adenocarcinoma (OAC). The aim of this study was to evaluate the cost-effectiveness of surveillance.

    Design

    We included 714 patients with long-segment BO in a multicentre prospective cohort study and used a multistate Markov model to calculate progression rates from no dysplasia (ND) to low-grade dysplasia (LGD), high-grade dysplasia (HGD) and OAC. Progression rates were incorporated in a decision-analytic model, including costs and quality of life data. We evaluated different surveillance intervals for ND and LGD, endoscopic mucosal resection (EMR), radiofrequency ablation (RFA) and oesophagectomy for HGD or early OAC and oesophagectomy for advanced OAC. The incremental cost-effectiveness ratio (ICER) was calculated in costs per quality-adjusted life-year (QALY).

    Results

    The annual progression rate was 2% for ND to LGD, 4% for LGD to HGD or early OAC and 25% for HGD or early OAC to advanced OAC. Surveillance every 5 or 4 years with RFA for HGD or early OAC and oesophagectomy for advanced OAC had ICERs of 5.283 and 62.619 per QALY for ND. Surveillance every five to one year had ICERs of 4.922, 30.067, 32.531, 41.499 and 75.601 per QALY for LGD. EMR prior to RFA was slightly more expensive, but important for tumour staging.

    Conclusions

    Based on a Dutch healthcare perspective and assuming a willingness-to-pay threshold of 35.000 per QALY, surveillance with EMR and RFA for HGD or early OAC, and oesophagectomy for advanced OAC is cost-effective every 5 years for ND and every 3 years for LGD.


    Objective

    The increasing prevalence of obesity and type 2 diabetes (T2D) demonstrates the failure of conventional treatments to curb these diseases. The gut microbiota has been put forward as a key player in the pathophysiology of diet-induced T2D. Importantly, cranberry (Vaccinium macrocarpon Aiton) is associated with a number of beneficial health effects. We aimed to investigate the metabolic impact of a cranberry extract (CE) on high fat/high sucrose (HFHS)-fed mice and to determine whether its consequent antidiabetic effects are related to modulations in the gut microbiota.

    Design

    C57BL/6J mice were fed either a chow or a HFHS diet. HFHS-fed mice were gavaged daily either with vehicle (water) or CE (200 mg/kg) for 8 weeks. The composition of the gut microbiota was assessed by analysing 16S rRNA gene sequences with 454 pyrosequencing.

    Results

    CE treatment was found to reduce HFHS-induced weight gain and visceral obesity. CE treatment also decreased liver weight and triglyceride accumulation in association with blunted hepatic oxidative stress and inflammation. CE administration improved insulin sensitivity, as revealed by improved insulin tolerance, lower homeostasis model assessment of insulin resistance and decreased glucose-induced hyperinsulinaemia during an oral glucose tolerance test. CE treatment was found to lower intestinal triglyceride content and to alleviate intestinal inflammation and oxidative stress. Interestingly, CE treatment markedly increased the proportion of the mucin-degrading bacterium Akkermansia in our metagenomic samples.

    Conclusions

    CE exerts beneficial metabolic effects through improving HFHS diet-induced features of the metabolic syndrome, which is associated with a proportional increase in Akkermansia spp. population.


    Part 1: Case report

    A 65-year-old man was referred for assessment of advanced liver disease. Seventeen years previously he had been diagnosed with ulcerative colitis, and 7 years later with primary sclerosing cholangitis (PSC). After several episodes with variceal bleeding caused by secondary biliary cirrhosis, a transjugular intrahepatic portosystemic shunt (TIPS) was created. Because of recurrent bacterial cholangitis, endoscopic retrograde cholangiography was performed, showing irregular narrowing of the intrahepatic bile ducts with saccular dilatations, findings considered compatible with PSC (figure 1). Also, a round filling defect in the common bile duct (CBD) was noted. After biliary sphincterotomy, a 6 mm polyp was removed. Histopathology review revealed a papillary adenoma with low-grade dysplasia.

    Cholangioscopy showed no evidence of residual polypous tissue or cancer. However, visualisation was difficult due to abundant mucus. Given the finding of a biliary adenoma against a background of PSC, the patient was considered to be...


    Objective

    Repetitive interaction with microbial stimuli renders epithelial cells (ECs) hyporesponsive to microbial stimulation. Previously, we have reported that buccal ECs from a subset of paediatric patients with Crohn's disease are not hyporesponsive and spontaneously released chemokines. We now aimed to identify kinetics and mechanisms of acquisition of hyporesponsiveness to microbial stimulation using primary human buccal epithelium.

    Design

    Buccal ECs collected directly after birth and in later stages of life were investigated. Chemokine release and regulatory signalling pathways were studied using primary buccal ECs and the buccal EC line TR146. Findings were extended to the intestinal mucosa using murine model systems.

    Results

    Directly after birth, primary human buccal ECs spontaneously produced the chemokine CXCL-8 and were responsive to microbial stimuli. Within the first weeks of life, these ECs attained hyporesponsiveness, associated with inactivation of the NF-B pathway and upregulation of the novel NF-B inhibitor SLPI but no other known NF-B inhibitors. SLPI protein was abundant in the cytoplasm and the nucleus of hyporesponsive buccal ECs. Knock-down of SLPI in TR146-buccal ECs induced loss of hyporesponsiveness with increased NF-B activation and subsequent chemokine release. This regulatory mechanism extended to the intestine, as colonisation of germfree mice elicited SLPI expression in small intestine and colon. Moreover, SLPI-deficient mice had increased chemokine expression in small intestinal and colonic ECs.

    Conclusions

    We identify SLPI as a new player in acquisition of microbial hyporesponsiveness by buccal and intestinal epithelium in the first weeks after microbial colonisation.


    Objective

    Interleukin 13 (IL-13) is thought to play a key role as an effector cytokine in UC. Anrukinzumab, a humanised antibody that inhibits human IL-13, was evaluated for the treatment of UC.

    Design

    In a multicentre, randomised, double-blind, placebo-controlled study, patients with active UC (Mayo score ≥4 and <10) were randomised to anrukinzumab 200, 400 or 600 mg or placebo. Patients received five intravenous administrations over 14 weeks. The primary endpoint was fold change from baseline in faecal calprotectin (FC) at Week 14. Secondary endpoints included safety, pharmacokinetics and IL-13 levels.

    Results

    The modified intention-to-treat population included 84 patients (21 patients/arm). Fold change of FC from baseline at Week 14 was not significantly different for any treatment groups compared with the placebo. The study had a high dropout rate, in part, related to lack of efficacy. The exploratory comparisons of each dose were not significantly different from placebo in terms of change from baseline in total Mayo score, clinical response, clinical remission and proportion of subjects with mucosal healing. An increase in serum total IL-13 (free and bound to anrukinzumab) was observed for all anrukinzumab groups but not with placebo. This suggests significant binding of anrukinzumab to IL-13. The safety profile was not different between the anrukinzumab and placebo groups.

    Conclusions

    A statistically significant therapeutic effect of anrukinzumab could not be demonstrated in patients with active UC in spite of binding of anrukinzumab to IL-13.

    Trial registration number

    ClinicalTrials.gov number NCT01284062.


    Background and aims

    Immune tolerance breakdown during UC involves the peroxisome proliferator-activated receptor- (PPAR), a key factor in mucosal homoeostasis and the therapeutic target of 5-aminosalycilates, which expression is impaired during UC. Here we assess the impact of glucocorticoids (GCs) on PPAR expression, focusing especially on extra-adrenal cortisol production by colonic epithelial cells (CECs).

    Methods

    Activation of PPAR in the colon was evaluated using transgenic mice for the luciferase gene under PPAR control (peroxisome proliferator response element-luciferase mice). Protein and mRNA expression of PPAR were evaluated with colon fragments and purified CEC from mice. Cortisol production and steroidogenic factor expression were quantified in human CEC of patients with UC and those of controls. Gene expression knockdown by short hairpin RNA in Caco-2 cells was used for functional studies.

    Results

    GCs were able to raise luciferase activity in peroxisome proliferator response element-luciferase mice. In the mice colons and Caco-2 cells, PPAR expression was increased either with GCs or with an inducer of steroidogenesis and then decreased after treatment with a steroidogenesis inhibitor. Cortisol production and steroidogenic factor expression, such as liver receptor homologue-1 (LRH-1), were decreased in CEC isolated from patients with UC, directly correlating with PPAR impairment. Experiments on Caco-2 cells lacking LRH-1 expression confirmed that LRH-1 controls PPAR expression by regulating GC synthesis in CEC.

    Conclusions

    These results demonstrate cortisol control of PPAR expression in CEC, highlighting cortisol production deficiency in colonocytes as a key molecular event in the pathophysiology of UC.


    Objective

    The technology for the growth of human intestinal epithelial cells is rapidly progressing. An exciting possibility is that this system could serve as a platform for individualised medicine and research. However, to achieve this goal, human epithelial culture must be enhanced so that biopsies from individuals can be used to reproducibly generate cell lines in a short time frame so that multiple, functional assays can be performed (ie, barrier function and host–microbial interactions).

    Design

    We created a large panel of human gastrointestinal epithelial cell lines (n=65) from patient biopsies taken during routine upper and lower endoscopy procedures. Proliferative stem/progenitor cells were rapidly expanded using a high concentration of conditioned media containing the factors critical for growth (Wnt3a, R-spondin and Noggin). A combination of lower conditioned media concentration and Notch inhibition was used to differentiate these cells for additional assays.

    Results

    We obtained epithelial lines from all accessible tissue sites within 2 weeks of culture. The intestinal cell lines were enriched for stem cell markers and rapidly grew as spheroids that required passage at 1:3–1:4 every 3 days. Under differentiation conditions, intestinal epithelial spheroids showed region-specific development of mature epithelial lineages. These cells formed functional, polarised monolayers covered by a secreted mucus layer when grown on Transwell membranes. Using two-dimensional culture, these cells also demonstrated novel adherence phenotypes with various strains of pathogenic Escherichia coli.

    Conclusions

    This culture system will facilitate the study of interindividual, functional studies of human intestinal epithelial cells, including host–microbial interactions.


    Objective

    We aimed to better clarify the role of germline variants of the FCG2 receptor, FCGR2A-H131R and FCGR3A-V158F, on the therapeutic efficacy of cetuximab in metastatic colorectal cancer (mCRC). A large cohort with sufficient statistical power was assembled.

    Design

    To show a HR advantage of 0.6 in progression-free survival (PFS) for FCGR2A-HH versus the rest and FCGR3A-VV versus the rest, with an 80% power, 80 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) wild-type (KRAS-WT) and 52 KRAS-WT patients are required, respectively. This leads to a total sample size of 952 and 619 patients, respectively. Samples were collected from 1123 mCRC patients from 15 European centres treated with cetuximab alone or in combination with chemotherapy. Fc gamma receptor (FCGR) status was centrally genotyped. Two additional externally genotyped series were included.

    Results

    Incidences of FCGR2A-HH and FCGR3A-VV in KRAS-WT patients were 220/660 (33%) and 109/676 (16.1%) respectively. There was no difference in median PFS (mPFS) for KRAS-WT patients with FCGR2A-HH (22.0 weeks; 95% CI18.8 to 25.2) versus non-HH (22.0 weeks; 95% CI 19.4 to 24.6) or for FCGR3A-VV (16.4 weeks; 95% CI 13.0 to 19.8) versus non-VV (23 weeks; 95% CI 21.1 to 24.9) (p=0.06). Median overall survival, response rate and disease control rate assessments showed no benefit for either HH or VV.

    Conclusions

    No differences in mPFS were found between the FCGR polymorphisms HH and the others and VV versus the others in KRAS-WT mCRC patients refractory to irinotecan, oxaliplatin and 5-fluorouracil treated with cetuximab. We cannot confirm the effects of other IgG1 antibodies, which may be weaker than previously suggested. Other markers may be needed to study the actual host antibody response to cetuximab.


    Objective

    Although serrated polyps may be precursors of colorectal cancer (CRC), prospective data on the long-term CRC risk in individuals with serrated polyps are lacking.

    Design

    In a population-based randomised trial, 12 955 individuals aged 50–64 years were screened with flexible sigmoidoscopy, while 78 220 individuals comprised the control arm. We used Cox models to estimate HRs with 95% CIs for CRC among individuals with ≥1 large serrated polyp (≥10 mm in diameter), compared with individuals with adenomas at screening, and to population controls, and multivariate logistic regression to assess polyp risk factors for CRC.

    Results

    A total of 103 individuals had large serrated polyps, of which 81 were included in the analyses. Non-advanced adenomas were found in 1488 individuals, advanced adenomas in 701. Median follow-up was 10.9 years. Compared with the control arm, the HR for CRC was 2.5 (95% CI 0.8 to 7.8) in individuals with large serrated polyps, 2.0 (95% CI 1.3 to 2.9) in individuals with advanced adenomas and 0.6 (95% CI 0.4 to 1.1) in individuals with non-advanced adenomas. A large serrated polyp was an independent risk factor for CRC, adjusted for histology, size and multiplicity of concomitant adenomas (OR 3.3; 95% CI 1.3 to 8.6). Twenty-three large serrated polyps found at screening were left in situ for a median of 11.0 years. None developed into a malignant tumour.

    Conclusions

    Individuals with large serrated polyps have an increased risk of CRC, comparable with individuals with advanced adenomas. However, this risk may not be related to malignant growth of the serrated polyp.

    Trial registration number

    The Norwegian Colorectal Cancer Screening trial is registered at clinicaltrials.gov (NCT00119912).


    Objective

    Pancreatic acinar cell maturation is dependent on the activity of the pancreas transcription factor 1 (PTF1) complex. Induction of pancreatitis leads to MAP kinase activation and transient suppression of the acinar differentiation programme. We investigated the role of MAP kinase-interacting kinase 1 (Mnk1) in mouse exocrine pancreas development and in the response to secretagogue-induced pancreatitis.

    Design

    Mnk1 expression was analysed using immunohistochemistry, RT-qPCR and western blotting. Ptf1a binding to Mnk1 was assessed by chromatin immunoprecipitation and qPCR. Acute pancreatitis was induced in wild type and Mnk1–/– mice by 7 h intraperitoneal injections of caerulein. In vitro amylase secretion and trypsinogen activation were assessed using freshly isolated acinar cells. In vivo secretion was quantified by secretin-stimulated MRI.

    Results

    Mnk1 is expressed at the highest levels in pancreatic acinar cells and is a direct PTF1 target. Mnk1 is activated upon induction of pancreatitis and is indispensable for eIF4E phosphorylation. The pancreas of Mnk1–/– mice is histologically normal. Digestive enzyme content is significantly increased and c-Myc and Ccnd1 levels are reduced in Mnk1–/– mice. Upon induction of acute pancreatitis, Mnk1–/– mice show impaired eIF4E phosphorylation, activation of c-Myc and downregulation of zymogen content. Acinar cells show defective relocalisation of digestive enzymes, polarity defects and impaired secretory response in vitro and in vivo.

    Conclusions

    Mnk1 is a novel pancreatic acinar cell-specific stress response kinase that regulates digestive enzyme abundance and eIF4E phosphorylation. It is required for the physiological secretory response of acinar cells and for the homeostatic response to caerulein administration during acute pancreatitis.


    Objective

    To evaluate the safety and efficacy of daclatasvir, an HCV NS5A inhibitor with pangenotypic activity, administered with peginterferon-alfa-2a/ribavirin.

    Design

    In this Phase 2b double-blind, placebo-controlled study, treatment-naive adults with HCV genotype 1 (N=365) or 4 (N=30) infection were randomly assigned (2:2:1) to daclatasvir 20 mg or 60 mg, or placebo once daily plus weekly peginterferon-alfa-2a and twice-daily ribavirin. Daclatasvir recipients achieving protocol-defined response (PDR; HCV-RNA<lower limit of quantitation at Week 4 and undetectable at Week 10) were rerandomised at Week 12 to continue daclatasvir/peginterferon-alfa-2a/ribavirin for 24 weeks total duration or to placebo/peginterferon-alfa-2a/ribavirin for another 12 weeks. Patients without PDR and placebo patients continued peginterferon-alfa/ribavirin through Week 48. Primary efficacy endpoints were undetectable HCV-RNA at Weeks 4 and 12 (extended rapid virologic response, eRVR) and at 24 weeks post-treatment (sustained virologic response, SVR24) among genotype 1-infected patients.

    Results

    Overall, eRVR was achieved by 54.4% (80/147) of genotype 1-infected patients receiving daclatasvir 20 mg, 54.1% (79/146) receiving 60 mg versus 13.9% (10/72) receiving placebo. SVR24 was achieved among 87 (59.2%), 87 (59.6%), and 27 (37.5%) patients in these groups, respectively. Higher proportions of genotype 4-infected patients receiving daclatasvir 20 mg (66.7%; 8/12) or 60 mg (100.0%; 12/12) achieved SVR24 versus placebo (50.0%; 3/6). A majority of daclatasvir-treated patients achieved PDR and experienced less virologic failure and higher SVR24 rates with a shortened 24-week treatment duration. Adverse events occurred with similar frequency across all treatment groups.

    Conclusions

    The combination of daclatasvir/peginterferon-alfa/ribavirin was generally well tolerated and achieved higher SVR24 rates compared with placebo/peginterferon-alfa/ribavirin among patients infected with HCV genotype 1 or 4.

    Trial registration number

    NCT01125189.


    Background

    Chronic HCV infection is associated with the development of hepatic fibrosis. The direct role of HCV in the fibrogenic process is unknown. Specifically, whether HCV is able to infect hepatic stellate cells (HSCs) is debated.

    Objective

    To assess whether human HSCs are susceptible to HCV infection.

    Design

    We combined a set of original HCV models, including the infectious genotype 2a JFH1 model (HCVcc), retroviral pseudoparticles expressing the folded HCV genotype 1b envelope glycoproteins (HCVpp) and a subgenomic genotype 1b HCV replicon, and two relevant cellular models, primary human HSCs from different patients and the LX-2 cell line, to assess whether HCV can infect/replicate in HSCs.

    Results

    In contrast with the hepatocyte cell line Huh-7, neither infectious HCVcc nor HCVpp infected primary human HSCs or LX-2 cells. The cellular expression of host cellular factors required for HCV entry was high in Huh-7 cells but low in HSCs and LX-2 cells, with the exception of CD81. Finally, replication of a genotype 2a full-length RNA genome and a genotype 1b subgenomic replicon was impaired in primary human HSCs and LX-2 cells, which expressed low levels of cellular factors known to play a key role in the HCV life-cycle, suggesting that human HSCs are not permissive for HCV replication.

    Conclusions

    Human HSCs are refractory to HCV infection. Both HCV entry and replication are deficient in these cells, regardless of the HCV genotype and origin of the cells. Thus, HCV infection of HSCs does not play a role in liver fibrosis. These results do not rule out a direct role of HCV infection of hepatocytes in the fibrogenic process.


    Background

    Chronic hepatitis B infection is endemic in New Zealand and has high prevalence in New Zealand Māori. Previous longitudinal studies in populations with predominantly vertically acquired chronic hepatitis B have shown low spontaneous hepatitis B surface-antigen (HBsAg) seroclearance rates: 0.5–1.4% annually (mean age of clearance 48 years). We report the 28-year follow-up data on clinical and serological outcomes in indigenous New Zealand Māori with early horizontally acquired HBV.

    Methods

    In 1984, community seroprevalence study identified 572 HBsAg-positive individuals, followed for 28 years. Liver-related mortality and hepatocellular carcinoma (HCC) incidence were compared between these 572 HBV carriers and 1140 HBsAg-negative matched case-controls. Surviving HBsAg-positive individuals have been followed up in 2012 with clinical assessment, blood tests and liver transient elastography. Rates of hepatitis B e-antigen (HBeAg) and HBsAg seroconversion were determined.

    Results

    After total 13 187.4 person-years follow-up, 15 HBsAg-positive patients have developed HCC compared with none of the HBsAg-negative controls (p<0.001). 12 HBsAg-positive patients died from liver-related causes compared with none in the controls (p<0.001). Spontaneous HBeAg-seroconversion occurred in 91% of HBeAg-positive patients. Spontaneous HBsAg loss occurred in 33% overall (annual clearance rate 1.34%), with higher rates at older ages (1.05% in patients<20 years at entry vs 4.3% per annum >40 years at entry, p<0.0001). Median ages of HBeAg loss and HBsAg loss were 23 years (range 6–66 years) and 40 years (range 4–80 years), respectively.

    Conclusions

    Horizontally transmitted HBV in Maori is similarly associated with increased risk of liver-related mortality and HCC compared with Chinese, although absolute incidence rates are lower. The rates of HBeAg and HBsAg loss are high, and occur at an earlier age than previously reported.


    Objective

    Bone morphogenetic protein 6 (BMP6) has been identified as crucial regulator of iron homeostasis. However, its further role in liver pathology including non-alcoholic fatty liver disease (NAFLD) and its advanced form non-alcoholic steatohepatitis (NASH) is elusive. The aim of this study was to investigate the expression and function of BMP6 in chronic liver disease.

    Design

    BMP6 was analysed in hepatic samples from murine models of chronic liver injury and patients with chronic liver diseases. Furthermore, a tissue microarray comprising 110 human liver tissues with different degree of steatosis and inflammation was assessed. BMP6-deficient (BMP6–/–) and wild-type mice were compared in two dietary NASH-models, that is, methionine choline-deficient (MCD) and high-fat (HF) diets.

    Results

    BMP6 was solely upregulated in NAFLD but not in other murine liver injury models or diseased human livers. In NAFLD, BMP6 expression correlated with hepatic steatosis but not with inflammation or hepatocellular damage. Also, in vitro cellular lipid accumulation in primary human hepatocytes induced increased BMP6 expression. MCD and HF diets caused more hepatic inflammation and fibrosis in BMP6–/– compared with wild-type mice. However, only in the MCD and not in the HF diet model BMP6–/– mice developed marked hepatic iron overload, suggesting that further mechanisms are responsible for protective BMP6 effect. In vitro analysis revealed that recombinant BMP6 inhibited the activation of hepatic stellate cells (HSCs) and reduced proinflammatory and profibrogenic gene expression in already activated HSCs.

    Conclusions

    Steatosis-induced upregulation of BMP6 in NAFLD is hepatoprotective. Induction of BMP6-signalling may be a promising antifibrogenic strategy.


    Screening for colorectal cancer has been proven to be effective in reducing colorectal cancer incidence and mortality. While the precise benefit of screening exclusively by colonoscopy is not yet known, unarguably, the exam is central to the success of any screening programme. The test affords the opportunity to detect and resect neoplasia across the entire large bowel and is the definitive examination when other screening tests are positive. However, colonoscopy is invasive and often requires sedation as well as extensive bowel preparation, all of which puts the patient at risk. Furthermore, the test can technically be demanding and, unarguably, there is variation in how it is performed. This variation in performance has now been definitively linked to important outcome measures. For example, interval cancers are more common in low adenoma detectors as compared with high adenoma detectors. This review outlines the most current thinking regarding the effectiveness of colonoscopy as a screening tool. It also outlines key concepts to optimise its performance through robust quality assurance programmes and high-quality training.


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