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

Member Resources

Publications

Gut

Gut RSS feed -- current issue
Gut

Natural history studies provide invaluable data on the disease course. Rungoe et al1 report changes in medical treatment and surgery rates over the past three decades (1979–2011) using a large Danish population-based cohort of 48 467 patients with IBD issued from a Danish health administrative database. Interestingly, the authors found a decrease in surgery rates in both Crohn's disease (CD) and UC. Changes in surgery rates were accompanied by a significant decrease in the use of five aminosalicylic acids (5-ASA) and corticosteroids. The use of 5-ASA significantly decreased from 51% in 1995–2002 to 19% in 2003–2011 in CD; surprisingly, it also decreased in UC from 63% to 51%, while in UC 5-ASA remain the backbone therapy for mild-to-moderate UC according to recent international guidelines.2 As expected, there was a dramatic increase between 1995–2002 and 2003–2011 in the use of thiopurines and anti-tumor necrosis factor (TNF)...


While drug development for chronic constipation and IBS with constipation has moved ahead with the marketing of prucalopride and linaclotide in many countries, the development of agents for functional diarrhoea and IBS-D has been more troubled. With the limited availability of the serotonin (5-HT)3 antagonist alosetron, the global market of drugs for diarrhoeal disorders is still led by agents developed 40–60 years ago, including opioid receptor agonists (eg, loperamide), bile acid binders (eg, cholestyramine) and tricyclic antidepressants (eg, amitriptyline). Clearly, the development of new effective and safe drugs for diarrhoeal disorders is greatly needed to provide more options for patients and physicians, higher efficacy and fewer side effects. The problem is of great relevance as diarrhoea is the second leading gastrointestinal symptom after abdominal pain prompting an outpatient clinic visit in the USA. IBS-D affects about 3% of the general population and accounts for approximately 20% of gastroenterology outpatient visits...


Despite highly effective antiviral treatment options, chronic hepatitis B and its complications remain a medical challenge worldwide. Hepatocellular carcinoma (HCC) is still the fifth most common cause of cancer death in men and albeit surveillance programmes can principally reduce morbidity and mortality from HCC, the effect is modest and implementation of surveillance programmes is still inadequate.1 Depending on geographic region, hepatitis B is implicated as a cause of HCC in 5%–80% of patients. While antiviral therapy with interferon-α and nucleos(t)id analogues may stop disease progression in chronic hepatitis B, therapy is expensive, usually of long duration and not available in all parts of the world, particularly in many developing countries with a high prevalence of chronic hepatitis B. Moreover, depending on disease stage, a significant risk of HCC development may persist despite adequate viral suppression. Disappointingly, even in countries with high medical standards, implementation of treatment guidelines...


Liver cysts are a frequent finding on radiological imaging. Prevalence rates depend on the technique, but with CT or MRI, simple hepatic cysts are seen in approximately one-fifth of the population.1 Usually no more than one or two small (<3 cm) cysts are present. These cysts are innocuous and do not require immediate clinical attention. The situation is different when there are multiple and/or large liver cysts such as in polycystic liver disease (PLD). Though PLD is infrequent, patients are seen in every gastroenterology practice. Many patients give a positive family history of PLD. The majority of PLD patients will also have multiple renal cysts and suffer from autosomal dominant polycystic kidney disease (ADPKD). This is a progressive disorder that leads to end-stage renal disease. By contrast, some PLD patients do not have that renal phenotype and they are affected by isolated autosomal dominant polycystic liver disease (PCLD)....


Background

Current endoscopic therapy for neoplastic Barrett's oesophagus (BO) consists of complete resection/ablation of all Barrett's tissue including neoplastic lesions. Recurrence seems to be frequent after thermal therapy, such as radiofrequency ablation.

Objective

To analyse long-term recurrence of neoplasia and BO after successful widespread endoscopic mucosal resection (EMR).

Design

In a retrospective analysis, all patients undergoing widespread EMR of neoplastic BO between 2002 and 2007 at two referral centres were followed for at least 3 years after completion of endotherapy. Recurrence was diagnosed if neoplasia and/or BO were detected following previous successful complete removal, defined as at least two negative endoscopies and biopsies.

Results

Ninety patients undergoing widespread EMR were included (mean age 63 years; 82 male), 58% of whom underwent additional thermal ablation for minor residual disease. Complete eradication of neoplasia and Barrett's tissue was achieved in 90% of patients. On further follow-up (mean 64.8 months), recurrence of neoplastic and non-neoplastic BO was found in 6.2% and 39.5%, respectively. Recurring neoplasia (3 adenocarcinomas, 1 low-grade and 1 high-grade dysplasia) were found after a median of 44 months (range 38–85) and could be retreated endoscopically. In a multivariate analysis, Barrett's length was the only factor significantly associated with recurrence (OR 2.73).

Conclusions

Even after seemingly complete endoscopic resection, recurrence of BO is frequent and independent of additional thermal therapy. Due to the possibility of neoplasia recurrence even after long disease-free intervals, follow-up should be extended beyond 5 years.


Objective

Antireflux surgery (ARS) has been suggested as an alternative to lifelong use of proton pump inhibitors (PPI) in reflux disease. Data from clinical trials on PPI use after ARS have been conflicting. We investigated PPI use after ARS in the general Danish population using nationwide healthcare registries.

Design

A nationwide retrospective follow-up study of all patients aged ≥18 and undergoing first-time ARS in Denmark during 1996–2010. Two outcome measures were used: redemption of first PPI prescription after ARS (index prescription) and a marker of long-term use, defined by an average PPI use of ≥180 defined daily doses (DDDs) per year. Kaplan–Meier curves and Cox proportional hazards model were used for statistics.

Results

3465 patients entered the analysis. 12.7% used no PPI in the year before surgery, while 14.2%, 13.4% and 59.7% used 1–89 DDD, 90–179 DDD and ≥180 DDD, respectively. Five-, 10- and 15-year risks of redeeming index PPI prescription were 57.5%, 72.4% and 82.6%, respectively. Similarly, 5-, 10- and 15-year risks of taking up long-term PPI use were 29.4%, 41.1% and 56.6%. Female gender, high age, ARS performed in most recent years, previous use of PPI and use of nonsteroidal anti-inflammatory drugs or antiplatelet therapy significantly increased the risk of PPI use.

Conclusions

Risk of PPI use after ARS was higher than previously reported, and more than 50% of patients became long-term PPI users 10–15 years postsurgery. Patients should be made aware that long-term PPI therapy is often necessary after ARS.


Background

Helicobacter pylori-induced peptic ulceration is less likely to occur in patients with a strong gastric anti-inflammatory regulatory T cell (Treg) response. Migration of Tregs into the gastric mucosa is therefore important.

Objective

To identify the homing receptors involved in directing Tregs to the gastric mucosa, and investigate how H pylori stimulates the relevant chemokine responses.

Design

Gastric biopsy samples and peripheral blood were donated by 84 H pylori-infected and 46 uninfected patients. Luminex assays quantified gastric biopsy chemokine concentrations. Flow cytometry was used to characterise homing receptors on CD4+CD25hi Tregs. H pylori wild-type and isogenic mutants were used to investigate the signalling mechanisms behind CCL20 and IL-8 induction in gastric epithelial cell lines. Transwell assays were used to quantify Treg migration towards chemokines in vitro.

Results

CCL20, CXCL1-3 and IL-8 concentrations were significantly increased in gastric biopsy samples from H pylori-infected patients. CCR6 (CCL20 receptor), CXCR1 and CXCR2 (IL-8 and CXCL1-3 receptors) were expressed by a higher proportion of peripheral blood Tregs in infected patients. Most gastric Tregs expressed these receptors. H pylori induced CCL20 production by gastric epithelial cells via cag pathogenicity island (cagPAI)-dependent NF-B signalling. Foxp3+, but not Foxp3, CD4 cells from infected mice migrated towards recombinant CCL20 in vitro.

Conclusions

As well as increasing Treg numbers, H pylori infection induces a change in their characteristics. Expression of CCR6, CXCR1 and CXCR2 probably enables their migration towards CCL20 and IL-8 in the infected gastric mucosa. Such qualitative changes may also explain how H pylori protects against some extragastric inflammatory disorders.


Objective

The total enteroscopy rate of single-balloon enteroscopy (SBE) using air insufflation is not satisfactory, and whether carbon dioxide (CO2) insufflation increases the total enteroscopy rate of SBE is unknown. This randomised controlled trial aimed to determine whether CO2 insufflation facilitates the intubation depth and total enteroscopy rate of SBE.

Design

A total of 214 eligible patients referred for SBE were randomised to receive either air or CO2 insufflation, and included in the intention-to-test (ITT) analysis. In addition, 199 patients in whom enteroscopy was completed were included in the per-protocol (PP) analysis. Both the patients and endoscopists were blinded, and the intubation depth and total enteroscopy rate were defined as the primary outcomes.

Results

The CO2 group showed a superiority of intubation in the ITT analysis (oral route: 323.8±64.2 vs 238.3±68.6 cm; anal route: 261.6±74.2 vs 174.7±62.1 cm, both p<0.001), and the total enteroscopy rate (34.9% vs 17.6%, p=0.006). Similar results were obtained in a PP analysis for both outcomes. In addition, in the PP analysis, the addition of circumference after the procedure was less in the CO2 group (0.8±0.6 vs 3.3±1.8 cm, p=0.005) for the oral route. No serious complications were reported. The overall percentage of procedures with significant pathological findings was 52.8%; the rates were 58.5% and 47.2% (p=0.100, ITT analysis) in the CO2 and air groups, respectively.

Conclusions

CO2 insufflation improves the intubation depth and total enteroscopy rate in SBE with a good safety profile and acceptability compared with that of air, and thus is recommended for clinical utilisation.

Trial registration number

ClinicalTrial.gov identifier: NCT01758900.


Objective

No Crohn’s disease (CD) molecular maker has advanced to clinical use, and independent lines of evidence support a central role of the gut microbial community in CD. Here we explore the feasibility of extracting bacterial protein signals relevant to CD, by interrogating myriads of intestinal bacterial proteomes from a small number of patients and healthy controls.

Design

We first developed and validated a workflow—including extraction of microbial communities, two-dimensional difference gel electrophoresis (2D-DIGE), and LC-MS/MS—to discover protein signals from CD-associated gut microbial communities. Then we used selected reaction monitoring (SRM) to confirm a set of candidates. In parallel, we used 16S rRNA gene sequencing for an integrated analysis of gut ecosystem structure and functions.

Results

Our 2D-DIGE-based discovery approach revealed an imbalance of intestinal bacterial functions in CD. Many proteins, largely derived from Bacteroides species, were over-represented, while under-represented proteins were mostly from Firmicutes and some Prevotella members. Most overabundant proteins could be confirmed using SRM. They correspond to functions allowing opportunistic pathogens to colonise the mucus layers, breach the host barriers and invade the mucosae, which could still be aggravated by decreased host-derived pancreatic zymogen granule membrane protein GP2 in CD patients. Moreover, although the abundance of most protein groups reflected that of related bacterial populations, we found a specific independent regulation of bacteria-derived cell envelope proteins.

Conclusions

This study provides the first evidence that quantifiable bacterial protein signals are associated with CD, which can have a profound impact on future molecular diagnosis.


Objective

Crohn's disease (CD) is associated with intestinal dysbiosis, altered blood T cell populations, elevated faecal calprotectin (FC) and increased intestinal permeability (IP). CD-associated features present in siblings (increased risk of CD) but not in healthy controls, provide insight into early CD pathogenesis. We aimed to (1) Delineate the genetic, immune and microbiological profile of patients with CD, their siblings and controls and (2) Determine which factors discriminate between groups.

Design

Faecal microbiology was analysed by quantitative PCR targeting 16S ribosomal RNA, FC by ELISA, blood T cell phenotype by flow cytometry and IP by differential lactulose-rhamnose absorption in 22 patients with inactive CD, 21 of their healthy siblings and 25 controls. Subject's genotype relative risk was determined by Illumina Immuno BeadChip.

Results

Strikingly, siblings shared aspects of intestinal dysbiosis with patients with CD (lower concentrations of Faecalibacterium prausnitzii (p=0.048), Clostridia cluster IV (p=0.003) and Roseburia spp. (p=0.09) compared with controls). As in CD, siblings demonstrated a predominance of memory T cells (p=0.002) and elevated naïve CD4 T cell β7 integrin expression (p=0.01) compared with controls. FC was elevated (>50 μg/g) in 8/21 (38%) siblings compared with 2/25 (8%) controls (p=0.028); whereas IP did not differ between siblings and controls. Discriminant function analysis determined that combinations of these factors significantly discriminated between groups (2=80.4, df=20, p<0.001). Siblings were separated from controls by immunological and microbiological variables.

Conclusions

Healthy siblings of patients with CD manifest immune and microbiological abnormalities associated with CD distinct from their genotype-related risk and provide an excellent model in which to investigate early CD pathogenesis.


Background

ClC-3 channel/antiporter plays a critical role in a variety of cellular activities. ClC-3 has been detected in the ileum and colon.

Objective

To determine the functions of ClC-3 in the gastrointestinal tract.

Design

After administration of dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzenesulfonic acid (TNBS), intestines from ClC-3–/– and wild-type mice were examined by histological, cellular, molecular and biochemical approaches. ClC-3 expression was determined by western blot and immunostaining.

Results

ClC-3 expression was reduced in intestinal tissues from patients with UC or Crohn's disease and from mice treated with DSS. Genetic deletion of ClC-3 increased the susceptibility of mice to DSS- or TNBS-induced experimental colitis and prevented intestinal recovery. ClC-3 deficiency promoted DSS-induced apoptosis of intestinal epithelial cells through the mitochondria pathway. ClC-3 interacts with voltage-dependent anion channel 1, a key player in regulation of mitochondria cytochrome c release, but DSS treatment decreased this interaction. In addition, lack of ClC-3 reduced the numbers of Paneth cells and impaired the expression of antimicrobial peptides. These alterations led to dysfunction of the epithelial barrier and invasion of commensal bacteria into the mucosa.

Conclusions

A defect in ClC-3 may contribute to the pathogenesis of IBD by promoting intestinal epithelial cell apoptosis and Paneth cell loss, suggesting that modulation of ClC-3 expression might be a new strategy for the treatment of IBD.


Objective

Our aim was to determine whether or not specific microorganisms were transported selectively to lymph nodes in Crohn's disease (CD) by comparing node and mucosal microbial communities in patients and controls. We also sought evidence of dysbiosis and bacterial translocation.

Design

Lymph nodes, and involved and uninvolved mucosal samples were obtained from resections of 58 patients (29 CD, eight ‘other inflammatory bowel disease’ (IBD) and 21 non-IBD). Universal primers targeting V1–V3 regions of bacterial 16S rRNA genes were used to amplify bacterial DNA and amplicons sequenced using high throughput sequencing. 20 patients (eight CD (28%), two other IBD (25%) and 10 non-IBD (48%)) had PCR positive nodes.

Results

All samples from an individual were similar: there was no evidence of selective concentration of any microorganism in nodes. No specific microorganism was present in the nodes of all CD samples. Escherichia/Shigella were common in all patient groups but patients with ileal CD had a greater proportion of Escherichia coli reads in their nodes than other CD patients (p=0.0475). Campylobacter, Helicobacter and Yersinia were uncommon; Mycobacterium and Listeria were not detected. Dysbiosis was present in all groups but shifts were specific and no common pattern emerged.

Conclusions

It is unlikely that a single bacterium perpetuates inflammation in late stage CD; dysbiosis was common and we found no evidence of increased bacterial translocation. We believe that future studies should focus on early disease and viable bacteria in nodes, aphthous ulcers and granulomas, as they may be more relevant in the initiation of inflammation in CD.


Introduction

Treatment possibilities have changed in inflammatory bowel disease (IBD). We assessed changes in medical treatment and surgery over time and impact of medications on risk of surgery in a population-based cohort.

Methods

48 967 individuals were diagnosed with IBD (Crohn's disease (CD), 13 185; ulcerative colitis (UC), 35 782) during 1979–2011. Cumulative probability of receiving 5-aminosalicylic acids (5-ASA), topical, oral corticosteroids, thiopurines, and tumour necrosis factor-α (TNF-α) blockers, and of first minor or major surgery according to period of diagnosis, was estimated. Medication use and risk of surgery was examined by Cox regression.

Results

5-year cumulative probability of first major surgery decreased from 44.7% in cohort (1979–1986) to 19.6% in cohort (2003–2011) (p < 0.001) for CD, and from 11.7% in cohort (1979–1986) to 7.5% in cohort (2003–2011) (p < 0.001) for UC. Minor surgery risk decreased significantly in CD. From cohort (1995–2002) to cohort (2003–2011), a significant increase in use of thiopurines and TNF-α blockers was observed, paralleled by a significant decrease in use of 5-ASA and corticosteroids. Comparing use of azathioprine (or oral corticosteroids) to never-use, no convincing surgery-sparing effect was found. Comparing use in 3+ months of a given drug with use <3 months, only 3+ months use of oral corticosteroids reduced the risk of surgery in patients with disease duration of >1 year.

Conclusions

Parallel to an increasing use of thiopurines and TNF-α blockers in IBD over time, a persistent significant decrease in surgery rates was observed along with a significant decrease in use of 5-ASA and corticosteroids. However, no convincing surgery-sparing effect of newer medications was found.


Background

Irritable bowel syndrome with diarrhoea (IBS-D) is particularly debilitating due to urgency and episodic incontinence. Some 5-hydroxytryptamine 3 (5-HT3) receptor antagonists (5-HT3RAs) have proven effective but have serious side effects. Ondansetron, also a 5-HT3RA, has been widely used as an antiemetic with an excellent safety record for over two decades. Our aim was to assess its effectiveness in IBS-D.

Methods

120 patients meeting Rome III criteria for IBS-D entered a randomised, double-blind, placebo-controlled crossover study of 5 weeks of ondansetron 4 mg versus placebo with dose titration allowed, up to two tablets three times daily in the first 3 weeks. Patients completed daily diaries documenting stool consistency using the Bristol Stool Form score. Gut transit was measured in the last week of each treatment. The primary endpoint was average stool consistency in the last 2 weeks of treatment.

Results

Ondansetron significantly improved stool consistency (mean difference in stool form between ondansetron and placebo –0.9, 95% CI –1.1 to –0.6, p<0.001). Compared with placebo, patients on ondansetron experienced fewer days with urgency (p<0.001), lower urgency scores (p<0.001), reduced frequency of defaecation (p=0.002) and less bloating (p=0.002), although pain scores did not change significantly. IBS symptom severity score fell more with ondansetron than placebo (83±9.8 vs 37±9.7, p=0.001). 65% reported adequate relief with ondansetron but not placebo compared with 14% reporting relief with placebo but not ondansetron, relative risk 4.7, 95% CI 2.6 to 8.5, p<0.001.

Conclusions

Ondansetron relieves some of the most intrusive symptoms of IBS-D, namely loose stools, frequency and urgency.


Objective

Intraductal papillary mucinous neoplasm (IPMN) consists of four epithelial subtypes that correlate with histological grades and risks for malignant transformation. mAb Das-1 is a monoclonal antibody against a colonic epithelial phenotype that is reactive to premalignant conditions of the upper GI tract. We sought to assess the ability of mAb Das-1 to identify IPMN with high risk of malignant transformation.

Design

mAb Das-1 reactivity was evaluated in 94 patients with IPMNs by immunohistochemistry. Lesional fluid from 38 separate patients with IPMN (n=27), low-grade non-mucinous cystic neoplasms (n=7) and pseudocysts (n=4) was analysed by ELISA and western blot.

Results

Immunohistochemistry—Normal pancreatic ducts were non-reactive and low-grade gastric-type IPMN (IPMN-G) (1/17) and intermediate-grade IPMN-G (1/23) were minimally reactive with mAb Das-1. In contrast, mAb Das-1 reactivity was significantly higher in high-risk/malignant lesions (p<0.0001) including: intestinal-type IPMN with intermediate-grade dysplasia (9/10); high-grade dysplasia of gastric (4/7), intestinal (12/12), oncocytic (2/2) and pancreatobiliary types (2/2); and invasive tubular (8/12), colloid (7/7) and oncocytic (2/2) carcinoma. The sensitivity and specificity of mAb Das-1 for high-risk/malignantIPMNs were 85% and 95%, respectively. Lesional fluid—Samples from low- and intermediate-grade IPMN-G (n=9), and other low-grade/benign non-mucinous lesions demonstrated little reactivity with mAb Das-1. Conversely, cyst fluid from high-risk/malignant IPMNs (n=18) expressed significantly higher reactivity (p<0.0001). The sensitivity and specificity of mAbDas-1 in detecting high-risk/malignant IPMNs were 89% and 100%, respectively.

Conclusions

mAb Das-1 reacts with high specificity to tissue and cyst fluid from high-risk/malignant IPMNs and thus may help in preoperative clinical risk stratification.


Clinical presentation

A 24-year-old male presented with a 4-week history of right upper quadrant pain, lethargy, pyrexia, night sweats, anorexia and weight loss. Past medical history included Coeliac disease (compliant with a gluten free diet) and liver cysts. On examination the patient had a temperature of 38.2°C and tender hepato-splenomegaly. Blood tests showed bilirubin 16 μmol/L (normal range 10–20 μmol/L), ALT 28 IU/L (normal range 10–50 IU/L), ALP 274 IU/L (normal range 40–129 IU/L), albumin 48 g/L (normal range 34–50 g/L), GGT 205 (normal range 10–71 IU/L), INR 1.05 (normal range 0.9–1.1), WCC 14 (normal range 3–10 x 109) and CRP 199 mg/L (normal range 0–5 mg/L). A non-invasive liver screen was negative. A full septic screen was performed and empirical broad spectrum antibiotics commenced. A contrast CT of the abdomen and then MRCP (figures 1 and 2) were performed.

Question

What is the diagnosis?

See page 1625 for answer

Answer

See page 1606...


Background

Mounting epidemiological evidence supports a role for phosphatase and tensin homologue (PTEN)-T cell leukaemia 1 (Tcl1) signalling deregulation in hepatocarcinogenesis.

Objective

To determine the molecular and biochemical mechanisms by which the PTEN/Tcl1 axis regulates the pentose phosphate pathway (PPP) in hepatocellular carcinoma (HCC).

Methods

We compared levels of PTEN and glucose-6-phosphate dehydrogenase (G6PD) mRNA in human HCC and healthy liver tissue. We measured PPP flux, glucose consumption, lactate production, nicotinamide adenine dinucleotide phosphate (NADPH) levels and lipid accumulation. We investigated the PTEN/Tcl1 axis using molecular biology, biochemistry and mass spectrometry analysis. We assessed proliferation, apoptosis and senescence in cultured cells, and tumour formation in mice.

Results

We showed that PTEN inhibited the PPP pathway in human liver tumours. Through the PPP, PTEN suppressed glucose consumption and biosynthesis. Mechanistically, the PTEN protein bound to G6PD, the first and rate-limiting enzyme of the PPP and prevented the formation of the active G6PD dimer. Tcl1, a coactivator for Akt, reversed the effects of PTEN on biosynthesis. Tcl1 promoted G6PD activity and also increased G6PD pre-mRNA splicing and protein expression in a heterogeneous nuclear ribonucleoprotein (hnRNPK)-dependent manner. PTEN also formed a complex with hnRNPK, which inhibited G6PD pre-mRNA splicing. Moreover, PTEN inactivated Tcl1 via glycogen synthase kinase-3β (GSK3β)-mediated phosphorylation. Importantly, Tcl1 knockdown enhanced the sensitivity of HCC to sorafenib, whereas G6PD knockdown inhibited hepatocarcinogenesis.

Conclusions

These results establish the counteraction between PTEN and Tcl1 as a key mechanism that regulates the PPP and suggest that targeting the PTEN/Tcl1/hnRNPK/G6PD axis could open up possibilities for therapeutic intervention and improve the prognosis of patients with HCC.


Background and aims

The associations between long-term risk of hepatocellular carcinoma (HCC) and spontaneous seroclearance of HBV e antigen (HBeAg), HBV DNA and HBV surface antigen (HBsAg) have never been examined by a prospective study using serially measured seromarkers. This study aimed to assess the importance of spontaneous HBeAg, HBV DNA and HBsAg seroclearance in the prediction of HCC risk.

Methods

This study included 2946 HBsAg seropositive individuals who were seronegative for antibodies against HCV and free of liver cirrhosis. Serial serum samples collected at study entry and follow-up health examinations were tested for HBeAg, HBV DNA and HBsAg. Cox proportional hazards models were used to calculate the HRs of developing HCC after seroclearance of HBV markers.

Results

The HR (95% CI) of developing HCC after seroclearance of HBeAg, HBV DNA and HBsAg during follow-up was 0.63 (0.38 to 1.05), 0.24 (0.11 to 0.57) and 0.18 (0.09 to 0.38), respectively, after adjustment for age, gender and serum level of alanine aminotransferase at study entry. High HBV DNA levels at the seroclearance of HBeAg (mean±SD, 4.35±1.64 log10 IU/mL) may explain the non-significant association between HBeAg seroclearance and HCC risk. Among HBeAg seronegative participants with detectable serum HBV DNA at study entry, the lifetime (30–75-years-old) cumulative incidence of HCC was 4.0%, 6.6% and 14.2%, respectively, for those with seroclearance of both HBV DNA and HBsAg, seroclearance of HBV DNA only, and seroclearance of neither.

Conclusions

Spontaneous seroclearance of HBV DNA and HBsAg are important predictors of reduced HCC risk.


Objective

Polycystic liver diseases (PCLDs) are genetic disorders characterised by progressive bile duct dilatation and/or cyst development. Their pathogenesis is a consequence of hyperproliferation, hypersecretion and microRNA alterations in cholangiocytes. Here we evaluate the role of matrix metalloproteases (MMPs) in the hepatic cystogenesis of PCLDs.

Design

Metalloprotease activity was measured by microfluorimetric assays in normal and polycystic cholangiocyte cultures from humans and rats, and gene expression by real time quantitative PCR. The role of cytokines, oestrogens and growth factors present in the cystic fluid of PCLD patients was evaluated for MMP activity. The MMP inhibitor marimastat was examined for cystic expansion in vitro and in polycystic kidney (PCK) rats.

Results

Polycystic human and rat cholangiocytes displayed increased MMP activity, which was associated with increased mRNA levels of different MMPs. Interleukin (IL)-6 and IL-8, and 17β-oestradiol, all stimulated MMP activity in human cholangiocytes. The presence of antibodies against IL-6 and/or IL-8 receptor/s inhibited baseline MMP hyperactivity of polycystic human cholangiocytes but had no effect on normal human cholangiocytes. MMP-3 was overexpressed in cystic cholangiocytes from PCLD human and PCK rat livers by immunohistochemistry. Marimastat reduced MMP hyperactivity of polycystic human and rat cholangiocytes and blocked the cystic expansion of PCK cholangiocytes cultured in three-dimensions. Chronic treatment of 8-week-old PCK rats with marimastat inhibited hepatic cystogenesis and fibrosis.

Conclusions

PCLDs are associated with cholangiocyte MMP hyperactivity resulting from autocrine/paracrine stimulation by IL-6 and IL-8. Inhibition of this MMP hyperactivity with marimastat decreased hepatic cystogenesis in vitro and in an animal model of PCLD, offering a potential therapeutic tool.


The goal of personalised therapy based on hepatocellular carcinoma (HCC) molecular characteristics is still beyond our grasp. Systemic treatments show poor efficacy, mainly because of the great heterogeneity of the tumour. Indeed, differences in aetiology, disease stage and biochemical composition of the fibrotic liver make cirrhosis itself a highly dyshomogeneous disease. Cancer cells grow in a cirrhotic microenvironment, interacting with stromal cells and engaging matrix components that differ from patient to patient, hampering the development of drugs to treat all patients. Growing evidence suggests a role for the cross-talk between HCC and the host stroma in driving disease progression and hence prognosis and survival. Many efforts have been devoted to identifying genes responsible for good or bad prognosis, but no study has yet proven helpful in guiding therapeutic choices and management over time, also taking into account the development of drug resistance. The questions of what to target and in which patient are still unsolved. In the personalised therapy scenario, the patient rather than the disease becomes the target of the therapy. However, this still requires an evidence-based medical approach. Herein, we will discuss how individual differences in terms of quality and quantity of the tissue microenvironment components affect progression of HCC. Then, we will highlight potential druggable pathways, also considering ongoing clinical trials. The development of biomarkers will be discussed in the light of new experimental research conducted with the aim of moving towards personalised therapy in patients with HCC.


Basic scienceTH9 cells: new players in inflammatory bowel disease

 Gerlach K, Hwang Y, Nikolaev A, et al. TH9 cells that express the transcription factor PU.1 drive T cell-mediated colitis via IL-9 receptor signaling in intestinal epithelial cells. Nat Immunol 2014;15:676–86.

T lymphocyte subsets play a critical role in the pathogenesis of IBD, but the relationship between T cell activation and epithelial cell damage in IBD remains to be elucidated. An increase in TH17 cell responses along with a decrease in regulatory T cell responses are associated with UC and Crohn's disease (CD); however, UC patients have a stronger TH2-related immune response, while CD patients have increased levels of TH1-related cytokines. In this study, the authors set out to investigate the role that TH9 cells play in the pathogenesis of IBD by characterising interleukin 9 (IL-9) expression in patients with IBD and in mouse models of acute and...


Stomachs are thought to have first evolved about 350 million years ago. At about the same time our vertebrate ancestors developed jaws that made possible the relatively rapid consumption of bulky meals. The evolution of acid secretion by the stomach therefore provided a novel solution to the problem of limiting the growth of ingested microorganisms while food is temporarily retained prior to delivery to the small intestine for breakdown and absorption. The evolutionary success of the stomach is attested by the fact that what is easily recognisable as the same organ is found in virtually all living vertebrates above the Agnatha (although curiously a few species do manage to do without it). Nevertheless, the secretion of hydrochloric acid in high concentrations comes at a price. It is energetically expensive, there is an obvious need for elaborate defence mechanisms to resist auto-digestion and there can be substantial costs when these...