• Home
  • News
  • Calendar
  • About DF/HCC
  • Membership
  • Visitor Center
 

Member Resources

Publications

Gut

Gut RSS feed -- current issue
Gut

Our journals came together to put forth a plan that highlights joint first-authors in citations that are part of the references section of original articles. This has already been implemented by some of us (Gastroenterology,1 2 Hepatology3) but is now part of the Instructions to Authors in all five partnering journals (Gastroenterology, Gastrointestinal Endoscopy, Gut, Hepatology, and Journal of Hepatology). Prior to this, we and most, if not all, other journals highlighted joint first-authors of articles they published on the first page of the article (though such acknowledgment is sometimes difficult to note in some journals). In practical terms, our plan implies that citations listed in the references section will use either bold lettering or an underline to highlight all joint first-authors of a listed reference (as an example, see Reference 1).

There are several reasons for coming together and featuring...


Hepatitis C virus infection, with both hepatic and extrahepatic manifestations, is an important issue for patients requiring renal replacement therapy (RRT) and for those who receive kidney transplants (KT). Registry studies show a clear adverse impact of HCV-positivity on RRT patient survival and on KT graft and patient survival.1 In pretransplant and post-transplant settings, HCV-positivity (vs uninfected patients) is clearly associated with a relatively increased liver-related mortality and morbidity. However, reflecting the frequent comorbid cardiovascular disease that is observed in these settings, the absolute risk for cardiovascular mortality is much greater than risk of HCV-related mortality in patients with RRT and KT. Remarkably, the risk for cardiovascular disease appears increased in HCV-positive versus HCV-negative patients.

There are obvious merits in HCV clearance for selected patients on RRT. Successful treatment should prevent or substantially reduce the risk for liver-related problems including hepatic decompensation and primary liver cancer. These...


One of the conundrums of chronic infection with the hepatitis B virus (HBV) is identifying those individual patients who are at risk for the development of the serious sequelae of cirrhosis and hepatocellular carcinoma (HCC). It has been estimated that 25–40% of patients with chronic hepatitis B (CHB) who acquire the virus early in life (perinatal or early horizontal transmission from an HBeAg-positive source) will eventually develop these serious and disastrous consequences.1 Viral factors associated with the outcome of CHB include hepatitis B e antigen (HBeAg) status, HBV DNA and HBsAg levels (>2000 IU/mL) in serum, HBV genotype and HBV variants, all of which have been shown to positively enhance the risk for disease progression.2–4 The viral variants considered significant risk factors include the basal core promoter (BCP) mutants A1762T/G1764A which have been strongly associated with the development of HCC.


Patients infected with HCV usually have a long period of mild disease of 15–25 years. After this period, a substantial number of patients develop liver-associated morbidity and mortality, including clinical complications of liver cirrhosis such as ascites, variceal haemorrhage, hepatic encephalopathy, hepatocellular carcinoma (HCC) or liver-related death. This natural course of disease has been best described in young and mostly healthy women who were infected by a contaminated anti-D immunoglobulin preparation in East Germany in 1978/1979. Less than 2% of women with chronic HCV infection developed liver cirrhosis or HCC in the first 25 years of infection, while this number increased substantially to approximately 15% in the 35-year follow-up.1 2 These data were discussed controversially, since this initially mild course was partially attributed to the cohort of young, female patients with few comorbidities. A recent evaluation of a cohort of intravenous drug users (IVDU) who were followed...


Objective

Stress in the endoplasmic reticulum (ER) leads to activation of the unfolded protein response (UPR). Xbp1, a key component of the UPR has recently been linked to the risk of developing oesophageal squamous cell carcinoma, suggesting an important role for the UPR in the oesophageal epithelium. Here we examined the role of ER stress and the UPR in oesophageal epithelial homoeostasis.

Design

We examined the expression of components of the UPR in the oesophageal epithelium. We used a pharmacological approach and a genetic approach to examine the effects of ER stress in vivo in the mouse oesophagus. The oesophagus of these mice was examined using immunohistochemistry and real-time reverse transcription (RT)-PCR.

Results

Components of the UPR were heterogeneously expressed in the basal layer of the epithelium. Induction of ER stress by 24-h treatment with thapsigargin resulted in depletion of proliferating cells in the basal layer of the oesophagus and induced differentiation. We next activated the UPR by inducible deletion of the major ER chaperone Grp78 in Ah1Cre-Rosa26-LacZ-Grp78–/– mice in which mutant cells could be traced by expression of LacZ. In these mice LacZ-positive mutant cells in the basal layer lost their proliferative capacity, migrated towards the oesophageal lumen and were replaced by LacZ-negative non-mutant cells. We observed no apoptosis in mutant cells.

Conclusions

These results show that ER stress induces epithelial differentiation in precursor cells in the oesophageal epithelium. This UPR induced differentiation may serve as a quality control mechanism that protects against oesophageal cancer development.


Objective

Gastric cancer (GC) remains difficult to cure due to heterogeneity in a clinical challenge and the molecular mechanisms underlying this disease are complex and not completely understood. Accumulating evidence suggests that microRNAs (miRNAs) play an important role in GC, but the role of specific miRNAs involved in this disease remains elusive. We performed next generation sequencing (NGS)-based whole-transcriptome profiling to discover GC-specific miRNAs, followed by functional validation of results.

Design

NGS-based miRNA profiles were generated in matched pairs of GCs and adjacent normal mucosa (NM). Quantitative RT-PCR validation of miR-29c expression was performed in 274 gastric tissues, which included two cohorts of matched GC and NM specimens. Functional validation of miR-29c and its gene targets was undertaken in cell lines, as well as K19-C2mE and K19-Wnt1/C2mE transgenic mice.

Results

NGS analysis revealed four GC-specific miRNAs. Among these, miR-29c expression was significantly decreased in GC versus NM tissues (p<0.001). Ectopic expression of miR-29c mimics in GC cell lines resulted in reduced proliferation, adhesion, invasion and migration. High miR-29c expression suppressed xenograft tumour growth in nude mice. Direct interaction between miR-29c and its newly discovered target, ITGB1, was identified in cell lines and transgenic mice. MiR-29c expression demonstrated a stepwise decrease in wild type hyperplasia-dysplasia cascade in transgenic mice models of GC.

Conclusions

MiR-29c acts as a tumour suppressor in GC by directly targeting ITGB1. Loss of miR-29c expression is an early event in the initiation of gastric carcinogenesis and may serve as a diagnostic and therapeutic biomarker for patients with GC.


Question

A 62-year-old woman presented with abdominal pain and diarrhoea. She had a history of primary biliary cirrhosis and renal transplantation secondary to reflux nephropathy. Cross-sectional imaging and a colonoscopy demonstrated terminal ileal inflammation and ulceration, but histological biopsies were inconclusive and cytomegalovirus staining was negative. The patient subsequently developed spontaneous small bowel perforation due to deep ulceration, necessitating an emergency right hemicolectomy. Her postoperative period was complicated by several episodes of rectal bleeding. After a prolonged admission at her local hospital, the patient was referred to our unit for further management.

On arrival, the patient's immunosuppression consisted of tacrolimus and low-dose prednisolone. Mycophenolate mofetil (MMF) had been discontinued prior to transfer due to concerns that MMF toxicity was the cause of her ileal disease. Laboratory evaluation revealed a haemoglobin of 83 g/L with a raised C-reactive protein (21 mg/L). CT angiography showed no active bleeding despite clinical evidence of...


Objectives

IBS aggregates in families, but the familial risk of IBS has only been determined in first-degree relatives and spouses. This nationwide study aimed to determine the familial risk of IBS in first-degree, second-degree, and third-degree relatives and spouses of affected individuals in order to estimate the relative influences of genes and shared family environment.

Methods

We performed a case-cohort study. The Swedish Multigeneration Register was linked to the Hospital Discharge Register for the period 1987–2010 and the Swedish Outpatient Care Register for 2001–2010. ORs for IBS were calculated for relatives of individuals who had been diagnosed with IBS compared with relatives of individuals unaffected by IBS as the reference group. ORs were also determined for IBS cases diagnosed in primary healthcare in four Swedish counties (2001–2007).

Results

The ORs for IBS were 1.75 in siblings (95% CI 1.63 to 1.89), 1.82 in offspring (1.67 to 1.97), 1.90 in parents (1.76 to 2.05), 1.10 in maternal half-siblings (0.88 to 1.39), 1.78 in paternal half-siblings (1.48 to 2.15), 1.27 in nieces/nephews (1.18 to 1.38), 1.11 in cousins (1.04 to 1.18), and 1.51 in spouses (1.24 to 1.84) of probands diagnosed with IBS. The OR for probands diagnosed in primary healthcare was 1.82 in siblings (1.52 to 2.18), and 1.82 in offspring (1.49 to 2.21).

Conclusions

The increased IBS risk among first-degree relatives and also second-degree and third-degree relatives indicates a genetic component of the familial clustering of IBS. However, a non-genetic contribution is also suggested by the increased risk among spouses.


Objective

Antimicrobial peptides (AMP) provide protection from infection by pathogenic microorganisms and restrict bacterial growth at epithelial surfaces to maintain mucosal homeostasis. In addition, they exert a significant anti-inflammatory activity. Here we analysed the anatomical distribution and biological activity of an orally administered AMP in the context of bacterial infection and host–microbial homeostasis.

Design

The anatomical distribution as well as antibacterial and anti-inflammatory activity of the endogenous AMP cryptdin 2 and the synthetic peptide Pep19-2.5 at the enteric mucosal surface were analysed by immunostaining, functional viability and stimulation assays, an oral Salmonella enterica subsp. enterica sv. Typhimurium (S. Typhimurium) model and comparative microbiota analysis.

Results

Endogenous cryptdin 2 was found attached to bacteria of the enteric microbiota within the intestinal mucus layer. Similarly, the synthetic peptide Pep19-2.5 attached rapidly to bacterial cells, exhibited a marked affinity for the intestinal mucus layer in vivo, altered the structural organisation of endotoxin in a mucus matrix and demonstrated potent anti-inflammatory and antibacterial activity. Oral Pep19-2.5 administration induced significant changes in the composition of the enteric microbiota as determined by high-throughput 16S rDNA sequencing. This may have contributed to the only transient improvement of the clinical symptoms after oral infection with S. Typhimurium.

Conclusions

Our findings demonstrate the anti-inflammatory activity and mucus affinity of the synthetic AMP Pep19-2.5 and characterise the influence on microbiota composition and enteropathogen infection after oral administration.


Background

Anti-tumour necrosis factor α (TNFα) therapy effectively induces and maintains remission in Crohn's disease (CD). Up to 40% of patients, however, fail to respond to anti-TNFα.

Objective

To identify the mechanisms underlying the persistence of mucosal lesions in patients who fail to respond to anti-TNFα therapy.

Design

An observational study based on whole-genome transcriptional analysis was carried out using intestinal biopsy specimens from patients with CD receiving (n=12) or not (n=10) anti-TNFα therapy. The transcriptional signature of responders was compared with that of non-responders after anti-TNFα therapy. Controls with non-inflammatory bowel disease (non-IBD) (n=17) were used for comparisons. Genes of interest were validated by real-time RT-PCR in an independent cohort of patients with CD receiving (n=17) or not (n=16) anti-TNFα and non-IBD controls (n=7).

Results

We confirmed that response to anti-TNFα is accompanied by significant regulation of a large number of genes, including IL1B, S100A8, CXCL1, which correlated with endoscopic activity. Remarkably, patients who failed to respond to anti-TNFα showed a mixed signature, maintaining increased expression of IL1B, IL17A and S100A8, while showing significant modulation of other genes commonly upregulated in active CD, including IL6 and IL23p19.

Conclusions

Our results show that anti-TNFα therapy significantly downregulates a subset of inflammatory genes even in patients who fail to achieve endoscopic remission, suggesting that these genes may not be dominant in driving inflammation in non-responders. On the other hand, we identified IL1B and IL17A as genes that remained altered in non-responders, pointing to potentially more relevant targets for modulating mucosal damage in refractory patients.


Objective

Interleukin-13 (IL-13) has been implicated as a key driver of UC. This trial evaluates the efficacy and safety of tralokinumab, an IL-13-neutralising antibody, as add-on therapy in adults with moderate-to-severe UC despite standard treatments.

Design

Non-hospitalised adults with UC (total Mayo score ≥6) were randomised to receive tralokinumab 300 mg or placebo subcutaneously every 2 weeks for 12 weeks. The primary end point was the rate of clinical response at week 8. Secondary efficacy end points included clinical remission and mucosal healing rates at week 8 and changes in total Mayo score, total modified Riley score, partial Mayo score and disease activity markers.

Results

Clinical response rate was 38% (21/56) for tralokinumab vs 33% (18/55) for placebo (p=0.406). Clinical remission rate was 18% (10/56) vs 6% (3/55) (p=0.033) and mucosal healing rate was 32% (18/56) vs 20% (11/55) (p=0.104) for tralokinumab vs placebo. Changes to week 8 in total Mayo score and total modified Riley score were similar for tralokinumab and placebo (least-squares mean difference between groups: –0.49 (p=0.394) and 0.25 (p=0.449), respectively). Partial Mayo score at week 4 was lower with tralokinumab than placebo (least-squares mean difference between groups: –0.90 (p=0.041)). No consistent patterns were observed for disease activity markers. Tralokinumab had an acceptable safety profile.

Conclusions

Add-on therapy with tralokinumab did not significantly improve clinical response. However, the higher clinical remission rate with tralokinumab than placebo suggests that tralokinumab may benefit some patients with UC. Tralokinumab was well tolerated.

Trial registration number

ClinicalTrials.gov number: NCT01482884.


Objective

Genome-wide association studies (GWAS) have identified genetic variants within multiple risk loci as predisposing to intestinal inflammatory diseases, including Crohn's disease, ulcerative colitis and coeliac disease. Most risk variants affect regulation of transcription, but a critical challenge is to identify which genes and which cell types these variants affect. We aimed to characterise whole transcriptomes for each common T lymphocyte subset resident within the gut mucosa, and use these to infer biological insights and highlight candidate genes of interest within GWAS risk loci.

Design

We isolated the four major intestinal T cell populations from pinch biopsies from healthy subjects and generated transcriptomes for each. We computationally integrated these transcriptomes with GWAS data from immune-related diseases.

Results

Robust, high quality transcriptomic data were generated from 1 ng of RNA from precisely sorted cell subsets. Gene expression patterns clearly differentiated intestinal T cells from counterparts in peripheral blood and revealed distinct signalling pathways for each intestinal T cell subset. Intestinal-specific T cell transcripts were enriched in GWAS risk loci for Crohn's disease, ulcerative colitis and coeliac disease, but also specific extraintestinal immune-mediated diseases, allowing prediction of novel candidate genes.

Conclusions

This is the first report of transcriptomes for minimally manipulated intestinal T lymphocyte subsets in humans. We have demonstrated that careful processing of mucosal biopsies allows the generation of transcriptomes from as few as 1000 highly purified cells with minimal interindividual variation. Bioinformatic integration of transcriptomic data with recent GWAS data identified specific candidate genes and cell types for inflammatory pathologies.


Objective

Programmed death-ligand 1 (PD-L1) has been shown to negatively regulate immune responses via its interaction with PD-1 receptor. In this study, we investigated the effects of PD-L1-Fc treatment on intestinal inflammation using two murine models of inflammatory colitis induced by dextran sulfate sodium (DSS) and T-cell transfer.

Design

The anti-colitis effect of adenovirus expressing Fc-conjugated PD-L1 (Ad/PD-L1-Fc) and recombinant PD-L1-Fc protein was evaluated in DSS-treated wild-type and Rag-1 knockout (KO) mice. We examined differentiation of T-helper cells, frequency of innate immune cells, and cytokine production by dendritic cells (DCs) in the colon from DSS-treated mice after PD-L1-Fc administration. In Rag-1 KO mice reconstituted with CD4 CD45RBhigh T cells, we assessed the treatment effect of PD-L1-Fc protein on the development of colitis.

Results

Administration of Ad/PD-L1-Fc significantly ameliorated DSS-induced colitis, which was accompanied by diminished frequency of interleukin (IL)-17A-producing CD4 T cells and increased interferon--producing CD4 T cells in the colon of DSS-fed mice. The anti-colitic effect of PD-L1-Fc treatment was also observed in DSS-treated Rag-1 KO mice, indicating lymphoid cell independency. PD-L1-Fc modulated cytokine production by colonic DCs and the effect was dependent on PD-1 expression. Furthermore, PD-L1-Fc protein could significantly reduce the severity of colitis in CD4 CD45RBhigh T-cell-transferred Rag-1 KO mice.

Conclusions

Based on the protective effect of PD-L1-Fc against DSS-induced and T-cell-induced colitis, our results suggest that PD-1-mediated inhibitory signals have a crucial role in limiting the development of colonic inflammation. This implicates that PD-L1-Fc may provide a novel therapeutic approach to treat inflammatory bowel disease.


Objective

In case of incomplete colonoscopy, several radiologic methods have traditionally been used, but more recently, capsule endoscopy was also shown to be accurate. Aim of this study was to compare colon capsule endoscopy (CCE) and CT colonography (CTC) in a prospective cohort of patients with incomplete colonoscopy.

Design

Consecutive patients with a previous incomplete colonoscopy underwent CCE and CTC followed by colonoscopy in case of positive findings on either test (polyps/mass lesions ≥6 mm). Clinical follow-up was performed in the other cases to rule out missed cancer. CTC was performed after colon capsule excretion or 10–12 h postingestion. Since the gold standard colonoscopy was performed only in positive cases, diagnostic yield and positive predictive values of CCE and CTC were used as study end-points.

Results

100 patients were enrolled. CCE and CTC were able to achieve complete colonic evaluation in 98% of cases. In a per-patient analysis for polyps ≥6 mm, CCE detected 24 patients (24.5%) and CTC 12 patients (12.2%). The relative sensitivity of CCE compared to CTC was 2.0 (95% CI 1.34 to 2.98), indicating a significant increase in sensitivity for lesions ≥6 mm. Of larger polyps (≥10 mm), these values were 5.1% for CCE and 3.1% for CTC (relative sensitivity: 1.67 (95% CI 0.69 to 4.00)). Positive predictive values for polyps ≥6 mm and ≥10 mm were 96% and 85.7%, and 83.3% and 100% for CCE and CTC, respectively. No missed cancer occurred at clinical follow-up of a mean of 20 months.

Conclusions

CCE and CTC were of comparable efficacy in completing colon evaluation after incomplete colonoscopy; the overall diagnostic yield of colon capsule was superior to CTC.

Trial registration number

NCT01525940.


Objective

To examine patterns of colorectal cancer (CRC) screening uptake over three biennial invitation rounds in the National Health Service (NHS) Bowel Cancer Screening Programme (BCSP) in England.

Methods

We analysed data from the BCSP's Southern Hub for individuals (n=62 099) aged 60–64 years at the time of first invitation to screening with a follow-up period that allowed for two further biennial invitations. Data on sex, age and a neighbourhood-level measure of socioeconomic deprivation were used in the analysis. Outcomes included uptake of guaiac-based faecal occult blood (gFOB) test screening, inadequate gFOB screening (≥1 test kit(s) returned but failed to complete further gFOB tests needed to reach a conclusive test result), test positivity, compliance with follow-up examinations (usually colonoscopy) and diagnostic outcomes.

Results

Overall gFOB uptake was 57.4% in the first, 60.9% in the second and 66.2% in third biennial invitation round. This resulted in 70.1% of the initial cohort having responded at least once, 60.7% at least twice and 44.4% three times. Participation in the first round was strongly predictive of participation in the second round (‘Previous Responders’: 86.6% vs ‘Previous Non-Responders’: 23.1%). Participation in the third round was highest among ‘Consistent Screeners’ (94.5%), followed by ‘Late Entrants’ (78.0%), ‘Dropouts’ (59.8%) and ‘Consistent Non-Responders’ (14.6%). Socioeconomic inequalities in uptake were observed across the three rounds, but sex inequalities decreased over rounds. Inadequate gFOB screening was influenced by screening history and socioeconomic deprivation. Screening history was the only significant predictor of follow-up compliance.

Conclusions

Screening history is associated with overall gFOB uptake, inadequate gFOB screening and follow-up compliance. Socioeconomic deprivation is also consistently associated with lower gFOB uptake and inadequate gFOB screening. Improving regular screening among identified ‘at-risk’ groups is important for the effectiveness of CRC screening programmes.


Background and objective

Precore (PC) variant (G1896A) and basal core promoter (BCP) variant (A1762T/G1764A) of HBV are associated with risk of hepatocellular carcinoma in HBV carriers. However, little is known about their impact on the adverse outcomes of hepatitis B e antigen (HBeAg)-negative hepatitis and liver cirrhosis.

Methods

251 spontaneous HBeAg seroconverters who had genotype B or C infection and received a long-term follow-up were enrolled. PC and BCP mutants were determined qualitatively and quantitatively to correlate with these adverse outcomes. The findings were validated by an independent case–control study, which included 184 patients with biopsy-proven liver fibrosis stages.

Results

In the longitudinal cohort study, BCP mutant and possibly PC wild type were associated with cirrhosis development, but not HBeAg-negative hepatitis. Multivariable analysis showed that only BCP mutant was an independent risk factor for cirrhosis development. Using quantitative analysis of BCP mutant, a higher proportion of BCP mutant, defined as a continuous variable, a dichotomous variable or an ordinal variable, was associated with a higher risk of cirrhosis. If we chose 45% of BCP mutant as the cut-off, the risk of cirrhosis was higher in patients with BCP mutant ≥45% compared to <45% in the longitudinal cohort; this finding was validated by the case–control study (adjusted OR: 2.81, 95% CI 1.40 to 5.67).

Conclusions

A higher proportion of BCP mutant increases the risk of liver cirrhosis development in HBV carriers with genotype B or C infection.


Objective

Data comparing the efficacy and safety of combination therapy with peginterferon plus low-dose ribavirin and peginterferon monotherapy in treatment-naive haemodialysis patients with hepatitis C virus genotype 2 (HCV-2) infection are limited.

Design

In this randomised trial, 172 patients received 24 weeks of peginterferon alfa-2a 135 μg/week plus ribavirin 200 mg/day (n=86) or peginterferon alfa-2a 135 μg/week (n=86). The efficacy and safety endpoints were sustained virological response (SVR) rate and adverse event (AE)-related withdrawal rate.

Results

Compared with monotherapy, combination therapy had a greater SVR rate (74% vs 44%, relative risk (RR): 1.68 [95% CI 1.29 to 2.20]; p<0.001). The beneficial effect of combination therapy was more pronounced in patients with baseline viral load ≥800 000 IU/mL than those with baseline viral load <800 000 IU/mL (RR: 3.08 [95% CI 1.80 to 5.29] vs RR: 1.11 [95% CI 0.83 to 1.45]; interaction p=0.001). Patients receiving combination therapy were more likely to have a haemoglobin level of <8.5 g/dL (70% vs 8%, risk difference (RD): 62% [95% CI 50% to 73%]; p<0.001) and required a higher dosage [mean: 13 417vs 6667 IU/week, p=0.027] of epoetin β to manage anaemia than those receiving monotherapy. The AE-related withdrawal rates were 6% and 3% in combination therapy and monotherapy groups, respectively (RD: 2% [95% CI –4% to 9%]).

Conclusions

In treatment-naive haemodialysis patients with HCV-2 infection, combination therapy with peginterferon plus low-dose ribavirin achieved a greater SVR rate than peginterferon monotherapy. Most haemodialysis patients can tolerate combination therapy.

Trial registration number

ClinicalTrial.gov number, NCT00491244.


Objective

Following chronic liver injury or when hepatocyte proliferation is impaired, ductular reactions containing hepatic progenitor cells (HPCs) appear in the periportal regions and can regenerate the liver parenchyma. HPCs exist in a niche composed of myofibroblasts, macrophages and laminin matrix. Galectin-3 (Gal-3) is a β-galactoside-binding lectin that binds to laminin and is expressed in injured liver in mice and humans.

Design

We examined the role of Gal-3 in HPC activation. HPC activation was studied following dietary induced hepatocellular (choline-deficient ethionine-supplemented diet) and biliary (3,5-diethoxycarbonyl-1,4-dihydrocollidine supplemented diet) injury in wild type and Gal-3(–/–) mice.

Results

HPC proliferation was significantly reduced in Gal-3(–/–) mice. Gal-3(–/–) mice failed to form a HPC niche, with reduced laminin formation. HPCs isolated from wild type mice secrete Gal-3 which enhanced adhesion and proliferation of HPCs on laminin in an undifferentiated form. These effects were attenuated in Gal3(–/–) HPCs and in wild type HPCs treated with the Gal-3 inhibitor lactose. Gal-3(–/–) HPCs in vitro showed increased hepatocyte function and prematurely upregulated both biliary and hepatocyte differentiation markers and regulated cell cycle genes leading to arrest in G0/G1.

Conclusions

We conclude that Gal-3 is required for the undifferentiated expansion of HPCs in their niche in injured liver.


Objective

Reliable tools to predict long-term outcome among patients with well compensated advanced liver disease due to chronic HCV infection are lacking.

Design

Risk scores for mortality and for cirrhosis-related complications were constructed with Cox regression analysis in a derivation cohort and evaluated in a validation cohort, both including patients with chronic HCV infection and advanced fibrosis.

Results

In the derivation cohort, 100/405 patients died during a median 8.1 (IQR 5.7–11.1) years of follow-up. Multivariate Cox analyses showed age (HR=1.06, 95% CI 1.04 to 1.09, p<0.001), male sex (HR=1.91, 95% CI 1.10 to 3.29, p=0.021), platelet count (HR=0.91, 95% CI 0.87 to 0.95, p<0.001) and log10 aspartate aminotransferase/alanine aminotransferase ratio (HR=1.30, 95% CI 1.12 to 1.51, p=0.001) were independently associated with mortality (C statistic=0.78, 95% CI 0.72 to 0.83). In the validation cohort, 58/296 patients with cirrhosis died during a median of 6.6 (IQR 4.4–9.0) years. Among patients with estimated 5-year mortality risks <5%, 5–10% and >10%, the observed 5-year mortality rates in the derivation cohort and validation cohort were 0.9% (95% CI 0.0 to 2.7) and 2.6% (95% CI 0.0 to 6.1), 8.1% (95% CI 1.8 to 14.4) and 8.0% (95% CI 1.3 to 14.7), 21.8% (95% CI 13.2 to 30.4) and 20.9% (95% CI 13.6 to 28.1), respectively (C statistic in validation cohort = 0.76, 95% CI 0.69 to 0.83). The risk score for cirrhosis-related complications also incorporated HCV genotype (C statistic = 0.80, 95% CI 0.76 to 0.83 in the derivation cohort; and 0.74, 95% CI 0.68 to 0.79 in the validation cohort).

Conclusions

Prognosis of patients with chronic HCV infection and compensated advanced liver disease can be accurately assessed with risk scores including readily available objective clinical parameters.


The microbiota of the human metaorganism is not a mere bystander. These microbes have coevolved with us and are pivotal to normal development and homoeostasis. Dysbiosis of the GI microbiota is associated with many disease susceptibilities, including obesity, malignancy, liver disease and GI pathology such as IBD. It is clear that there is direct and indirect crosstalk between this microbial community and host immune response. However, the precise mechanism of this microbial influence in disease pathogenesis remains elusive and is now a major research focus. There is emerging literature on the role of the microbiota in the pathogenesis of autoimmune disease, with clear and increasing evidence that changes in the microbiota are associated with some of these diseases. Examples include type 1 diabetes, coeliac disease and rheumatoid arthritis, and these contribute significantly to global morbidity and mortality. Understanding the role of the microbiota in autoimmune diseases may offer novel insight into factors that initiate and drive disease progression, stratify patient risk for complications and ultimately deliver new therapeutic strategies. This review summarises the current status on the role of the microbiota in autoimmune diseases.


Colorectal cancer (CRC) is the second most common cancer and second most common cause of cancer-related deaths in Europe. The introduction of CRC screening programmes using stool tests and flexible sigmoidoscopy, have been shown to reduce CRC-related mortality substantially. In several European countries, population-based CRC screening programmes are ongoing or being rolled out. Stool tests like faecal occult blood testing are non-invasive and simple to perform, but are primarily designed to detect early invasive cancer. More invasive tests like colonoscopy and CT colonography (CTC) aim at accurately detecting both CRC and cancer precursors, thus providing for cancer prevention. This review focuses on the accuracy, acceptance and safety of CTC as a CRC screening technique and on the current position of CTC in organised population screening. Based on the detection characteristics and acceptability of CTC screening, it might be a viable screening test. The potential disadvantage of radiation exposure is probably overemphasised, especially with newer technology. At this time-point, it is not entirely clear whether the detection of extracolonic findings at CTC is of net benefit and is cost effective, but with responsible handling, this may be the case. Future efforts will seek to further improve the technique, refine appropriate diagnostic algorithms and study cost-effectiveness.


Basic scienceIL-22 and complement mediate systemic elimination of pathobionts

Hasegawa M, Yada S, Liu, MZ, et al. Interleukin-22 regulates the complement system to promote resistance against pathobionts after pathogen-induced intestinal damage. Immunity 2014;41:620–32.

While the intestinal microbiota provides many benefits to the host, it also contains potentially dangerous species called pathobionts that play a critical role in disease development, particularly in immunocompromised hosts. When the healthy microbiota is disrupted, an accumulation of pathobionts and disease may result. Clostridium difficile, a Gram-positive anaerobic bacterium, overgrows in patients receiving broad-spectrum antibiotics and causes diarrhoea and life-threatening pseudomembranous colitis. Overgrowth of this bacteria is normally prevented by commensals when the immune system is intact. Recent studies indicate that pathobionts that have breached the compromised epithelial barrier during C. difficile infection and accumulate in extraintestinal organs and tissues contribute to disease pathogenesis and mortality. In this study, the authors investigate...


We read with great interest the article by Shanahan et al1 describing the roles of environmental conditions, notably co-housing with wild type (WT) littermates, and mouse genetic background in nucleotide-binding oligomerisation domain-containing protein 2 (NOD2)-dependent production of anti-microbial peptides in the mouse intestine. These authors demonstrate that expression, translation and anti-microbial activity of α-defensins are independent of NOD2.1 Robertson et al2 recently confirmed that housing conditions rather than NOD2 status influenced intestinal microbiota composition. Shanahan et al address the question whether an increase in the number of Paneth cells could compensate for a NOD2-dependent reduction in the level of defensin production in Paneth cells. Using a combination of hematoxylin and eosin staining (to assess crypt numbers), immunohistochemistry (using anti-lyzozyme staining) and flow cytometry (sorting for expression of lyzozyme and lack of expression of CD45—a haematopoietic cell marker) of the entire ilea of WT...


Ma et al1 comprehensively assessed the association of previously reported genetic variants with colorectal cancer (CRC) risk. The meta-analyses revealed strong evidence for association with rare MUTYH variants, even when excluding cases with MUTYH-associated polyposis. An article by Nieuwenhuis et al2 accurately defined the phenotypical features of MUTYH-associated polyposis. However, the study was performed on clinic-based series ascertained based on the inheritance model or the presence of polyps, which may miss additional phenotypes relevant to improve the disease characterisation and therefore, its genetic diagnosis. To illustrate this, we report a family with a clinical phenotype that resembled Lynch syndrome but was caused by MUTYH mutations.

To identify novel hereditary CRC genes, we studied an Amsterdam I family (hereditary non-polyposis CRC) with no mutations in the DNA mismatch repair (MMR) genes (figure 1, table 1). By exome sequencing performed on four cancer-affected...


We note with great interest the finding by Vanheel et al of increased intestinal permeability in a series of patients with functional dyspepsia (FD). This represents an important contribution to the study of this disease.1 This has previously been observed in patients with IBS, which has led researchers to consider whether the two disorders, customarily considered to be functional, might have an underlying organic basis.2

Nevertheless, we find the information provided about the patient selection criteria to be insufficient, and we would like a complementary explanation of this matter.

The 15 patients with FD included in this study were all negative for Helicobacter pylori. The fulfilment of this requirement may partially account for the small sample, but we would be in a better position to judge this if we knew the mean prevalence of H pylori infection in the adult population of Belgium, how many...


We thank Prof Rodrigo and colleagues for their comments1 on our recent paper on increased permeability and low-grade inflammation in functional dyspepsia (FD).2

However, we disagree that our study is underpowered, which was confirmed by highly significant differences between the groups. As indicated in the manuscript, we calculated the minimum sample size and even included more subjects than statistically required. We also want to point out that our n-values are in the upper range for a study that combines functional and structural measurements of epithelial integrity.

Questions were raised about the absence of Helicobacter pylori (HP) in our participants. Ten years ago, the prevalence of HP in the FD patient population of Belgium was low (17%), and has decreased even further since then.3 All patients were found to be negative for HP using immunohistochemical staining of gastric biopsies and had never received eradication...


A recent study by Ward et al1 elegantly highlighted the steep and long learning curve for novice endoscopists to achieve competency in colonoscopy. In the study, they acquired data from the Joint Advisory Group (JAG) e-portfolio database which includes procedural outcomes from all training centres in the UK. The aim of the study was to establish the number of colonoscopies to be completed to achieve competency, defined as a caecal intubation rate (CIR) of ≥90%. They found that the endoscopy trainees obtained a CIR of ≥90% at 233 colonoscopies. The authors should be congratulated on a study that is by far the largest (over 36 000 colonoscopies and 300 trainees) on learning colonoscopy and achieving competency. Based on this study, it should be asked is 233 the new magic number of colonoscopies needed to be termed ‘competent’?

A few points may suggest that 233 may be still...


We read the article by Schnúr et al1 and the letter by Atsushi et al2 reporting the functional aspects and Asian predominance of the p.G208A variant of the serine protease 1 gene (PRSS1) with great interest. Schnúr et al found that p.G208A is a rare variant of PRSS1 and suggested that, together with four other PRSS1 mutants, it is a mild pathogenic variant causing a moderate secretion defect and hereditary pancreatitis. Atsushi et al reported a relatively high prevalence of p.G208A variants in alcoholic and idiopathic Japanese patients with chronic pancreatitis (CP). We previously described two Korean children with the p.G208A variant of PRSS1 who presented with CP and necrotising acute pancreatitis,3 and recently encountered a further three children with CP with the PRSS1 p.G208A variant. In our experience, therefore, p.G208A is the most common variant of PRSS1 in Korean children with...