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The incidence of hepatitis E continues to increase and in immunocompromised patients can lead to chronic infection. Management of hepatitis E has evolved over time, with the first step being a reduction of immunosuppression followed by treatment with ribavirin. The European Association for the Study of Liver guidelines support treatment with ribavirin although the optimum dose and regime is unknown. This series reviews eight chronically infected cases treated between 2018 and 2021 in two UK centres (Ipswich Hospital and Addenbrooke's Hospital). Treatment response was defined primarily as sustained virological response at 12 weeks (SVR12) following the cessation of treatment and secondly as sustained virological response at 24 weeks (SVR24). The median dose of ribavirin given daily was 600 mg. The management of five of the eight cases was in line with the guidelines, and treatment was stopped after 12 weeks. Two of these five patients achieved SVR (40%). The remaining three cases were given a 24-week course based on clinical judgement, and all achieved SVR (100%). The three patients who relapsed received a second 24-week course of treatment and achieved SVR. Therefore, with a 24-week course, a 100% treatment success rate was attained. In chronic hepatitis E, a 24-week course of ribavirin would achieve optimum clearance rates with a single course of treatment. Ensuring the highest dose of ribavirin as possible (aiming to reach 800 mg daily) and attempts to reduce immunosuppressive therapy safely may also be relevant to achieving SVR.

IntroductionObsolete bleep/long-range pager equipment remains firmly embedded in the NHS.ObjectiveTo introduce a secure, chart-integrated messaging system (Epic Secure Chat™) in a large NHS tertiary referral centre to replace non-emergency bleeps/long-range pagers.MethodsThe system was socialised in the months before go-live. Operational readiness was overseen by an implementation group with stakeholder engagement. Cutover was accompanied by a week of Secure Chat and bleeps running in parallel.ResultsEngagement due to socialisation was high with usage stabilising approximately 3 months after go-live. Contact centre internal call activity fell significantly after go-live. No significant patient safety concerns were reported.DiscussionStaff engagement and uptake was excellent. The majority of those who previously carried bleeps were content to use personal devices for messaging because of user convenience after reassurance about privacy.ConclusionAn integrated secure messaging system can replace non-emergency bleeps with beneficial impact on service.

Background In England, choice of hepatitis C therapy is determined by national contracts that change with time, facilitating comparisons between different regimens. England has a diverse population with hepatitis C including large proportions of uncommon viral genotypes. Aim To evaluate efficacy of directly acting anti-viral treatments for hepatitis C in England using real-world data from the national treatment registry. Methods Sustained virological response (SVR) rates 12 weeks after treatment completion for patients treated between 2014 and August 2018 who attended for SVR tests were analysed in univariate subgroups using Chi-squared tests. Multivariate models were constructed with clinically relevant variables to determine predictors of SVR and evaluate the impact of treatment regimens. Results SVR data were available on 14,603 treated patients. The overall SVR rate was 95.59% [95% CI 95.25%-95.91%]. Multivariable regression modelling in patients with genotype 1 infection showed that the odds of SVR with elbasvir/grazoprevir were higher than for those treated with sofosbuvir/ledipasvir (OR 1.891, 95% CI 1.072-3.336, P = 0.028). For genotype 3, we found no significant difference between any of the treatment regimens. Patients who completed at least one third of the planned treatment duration achieved SVR rates in excess of 80%. Conclusions All of the currently licensed hepatitis C direct-acting anti-viral regimens had similar efficacy (>95%) in an unselected population. Noncompletion of planned treatment duration still resulted in over 80% SVR rates provided that more than one third of treatment was completed.

Background and aimsTo determine the impact of the COVID-19 pandemic on the population with chronic Hepatitis B virus (HBV) infection under hospital follow-up in the UK, we quantified the coverage and frequency of measurements of biomarkers used for routine surveillance (ALT and HBV viral load).MethodsWe used anonymised electronic health record data from the National Institute for Health Research (NIHR) Health Informatics Collaborative (HIC) pipeline representing five UK NHS Trusts.ResultsWe report significant reductions in surveillance of both biomarkers during the pandemic compared to pre-COVID years, both in terms of the proportion of patients who had ≥1 measurement annually, and the mean number of measurements per patient.ConclusionsFurther investigation is required to determine whether these disruptions will be associated with increased rates of adverse chronic HBV outcomes.

PurposeThe National Institute for Health Research (NIHR) Health Informatics Collaborative (HIC) was established to enable re-use of routinely collected clinical data across National Health Service (NHS) Trusts in the United Kingdom to support translational research. Viral hepatitis is one of the first five exemplar themes and hepatitis B virus (HBV) is the current focus of the theme. The NIHR HIC HBV dataset, derived from the central data repository of NIHR HIC viral hepatitis theme, aims to describe and characterise HBV infection in secondary care in the United Kingdom, and provides a resource for translational research.ParticipantsThe dataset comprises >5000 individuals (99% adults aged ≥18, 1% children aged Findings to dateData on demographics, laboratory tests, antiviral treatment, elastography scores, imaging/biopsy reports, death information, and potential risk factors for liver disease have been collected. Data are captured by electronic patient record (EPR) systems, and records are updated prospectively as new results are added. This cohort profile describes the dataset in its current form. Among the adults, 55% are male, and the median age at index date (defined as the first recorded positive hepatitis B virus surface antigen (HBsAg) or HBV DNA in EPR systems) was 40 years (interquartile range [IQR]: 32-50). For those individuals with ethnicity reported, 30% were Asian, 24% were Black, 30% were White, and the remaining 16% were mixed or other ethnic groups. Currently, the median follow-up duration of the adult patients in this dataset was 5.0 (IQR: 2.7-7.5) years, with 9.3 (95% CI: 8.2-10.5) deaths per 1,000 person-years. We have already conducted several analyses using subsets of this dataset including an evaluation of distribution and trajectories of HBsAg and HBV viral load in CHB, reviewing the use of antiviral treatment, quantifying the burden of liver disease in the untreated population, and studying the use of laboratory biomarkers to improve stratification and surveillance.Future plansLongitudinal data collection is continuing, with the sample growing in size, more parameters being collected, average follow-up increasing, and more NHS Trusts participating. This dataset offers important opportunities for epidemiological studies and biomedical informatics research, as well as characterising an HBV population for clinical trials through external collaborations with industry.

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Introduction The management of COVID19 is complicated by vaccine availability, the modest efficacy of existing treatments, and the potential for viral resistance. Therefore, there is a pressing need for new prophylactic and therapeutic agents. The viral receptor ACE2 is an ideal target as it is required for SARS-CoV-2 entry in host cells. Modifying ACE2 expression could prevent infection and/or limit disease progression. Nevertheless, the mechanisms controlling ACE2 expression remain elusive. Aims To identify pathways controlling the transcriptional regulation of ACE2, and exploit them to reduce SARS-CoV-2 infection. Methods Organoids from primary biliary, intestinal and pulmonary epithelia were derived and cultured as previously described. Single-cell RNA sequencing, QPCR, immunofluorescence and flow cytometry were used to assess marker expression. Chromatin immunoprecipitation was used to assess FXR binding on DNA. Bronchoalveolar lavage SARS-CoV-2 patient isolates were used for infection experiments. Human livers not used for transplantation were connected to the metra (OrganOx) normothermic perfusion device and perfused ex-situ using therapeutic doses of UDCA for 12 hours. ACE2 activity was measured following manufacturer's instructions. Patient data from the COVID-Hep and SECURE-Liver registries were compared using propensity score matching for sex, age and Child-Turcotte-Pugh score. Results We first demonstrated that cholangiocytes are susceptible to SARS-CoV-2 infection in vivo and in organoid culture. We then used cholangiocyte organoids to identify FXR as a transcriptional regulator of ACE2. We validated our results in pulmonary and intestinal organoids, showing that ACE2 regulation by FXR represents a broad mechanism present in multiple COVID19-affected tissues. We then demonstrated that approved FXR inhibitors, such as ursodeoxycholic acid (UDCA) and z-guggulsterone (ZGG), decrease ACE2 levels and reduce viral infection in vitro in primary biliary, intestinal and pulmonary organoids. We interrogated the impact of systemic UDCA administration in human livers perfused ex-situ, demonstrating reduced ACE2 levels and SARS-CoV-2 infection. Furthermore, we showed that commencing UDCA treatment lowers ACE2 levels in primary biliary cholangitis (PBC) patients. Finally, we identified a correlation between UDCA treatment and better clinical outcome in COVID-19 patients, including hospitalisation, ICU admission, mechanical ventilation and death, using registry data. Conclusion We identified FXR as a novel master regulator of ACE2 expression. Using a bench-to-bedside approach we combined in vitro, ex-vivo and patient data to demonstrate the efficacy of ACE2 downregulation against SARS-CoV-2 infection and identified approved and inexpensive drugs (UDCA, ZGG) which could be repurposed as prophylactic and therapeutic agents against SARS-CoV-2 infection, paving the road for future clinical trials.

Direct‐acting antivirals (DAAs) have revolutionised the management of chronic hepatitis C virus (HCV) infection. We describe UK real‐world DAA experience. Individuals commencing HCV treatment containing a DAA regimen (Mar 2014‐Nov 2016), participating in the National HCV Research UK (HCVRUK) Cohort Study were recruited from 33 UK HCV centers. The data were prospectively entered at sites onto a centralised database. The data were reported as median (Q1‐Q3). Of the 1448 treated patients, 1054 (73%) were males, the median age being 54 years (47‐60), 900 (62%) being genotype 1 and 455 (31%) genotype 3. The majority, 887 (61%) had cirrhosis, and 590 (41%) were treatment‐experienced. DAA regimens utilised: genotype1 sofosbuvir (SOF)/Ledipasvir/±Ribavirin (625/900, 69%) and Ombitasvir/Paritaprevir/Dasabuvir/±RBV (220/900, 24%), and in genotype 3 SOF/Daclatasvir + RBV (256/455, 56%) and SOF/pegylated interferon/RBV (157/455, 35%). Overall, 1321 (91%) achieved sustained virological response (SVR12), genotype 1 vs 3, 93% vs 87%, P

Prevention of SARS-CoV-2 entry in cells through the modulation of viral host receptors, such as ACE2, could represent a new therapeutic approach complementing vaccination. However, the mechanisms controlling ACE2 expression remain elusive. Here, we identify the farnesoid X receptor (FXR) as a direct regulator of ACE2 transcription in multiple COVID19-affected tissues, including the gastrointestinal and respiratory systems. We demonstrate that FXR antagonists, including the over-the-counter compound z-guggulsterone (ZGG) and the off-patent drug ursodeoxycholic acid (UDCA), downregulate ACE2 levels, and reduce susceptibility to SARS-CoV-2 infection in lung, cholangiocyte and gut organoids. We then show that therapeutic levels of UDCA downregulate ACE2 in human organs perfused ex situ and reduce SARS-CoV-2 infection ex vivo. Finally, we perform a retrospective study using registry data and identify a correlation between UDCA treatment and positive clinical outcomes following SARS-CoV-2 infection, including hospitalisation, ICU admission and death. In conclusion, we identify a novel function of FXR in controlling ACE2 expression and provide evidence that this approach could be beneficial for reducing SARS-CoV-2 infection, thereby paving the road for future clinical trials.

Objective An estimated 250 million people worldwide are chronically infected with hepatitis B virus (HBV), the leading cause of hepatocellular carcinoma (HCC) globally. The novel Sars‐cov2 virus continues to spread at an alarming rate, and with guidance at the onset of the pandemic recommending the deferral of HCC surveillance, the implications on liver cancer care are now emerging and highlight the urgent need for reorganisation of services. Methods We analysed how five HCC risk prediction scores could aid stratification of patients with chronic HBV. We calculated scores using parameters measured from 3 years prior (where available, n = 17) and at the time of HCC diagnosis in all adult patients with chronic HBV diagnosed with HCC (n = 46), and controls (n = 100). We compared the number of patients requiring cancer surveillance according to each score and regional surveillance guidance. Results The aMAP score had the highest discriminatory performance in HCC risk prediction at 3 years (area under receiver‐operating characteristic curve (auROC) of 0.824), followed by the mREACH B score (auROC of 0.719), and mPAGE B score (auROC of 0.742). However, only the mREACH B score had a negative predictive value (NPV) >99%. Applying the mREACH B score to our HBV cohort identified 11 patients requiring HCC surveillance, compared with 62 under current guidelines. Conclusion The use of HCC risk prediction scores could streamline the surveillance of patients with chronic HBV at a time of extremely limited resources. Overall, the mREACH B score had both a strong discriminatory performance and a high NPV, thus safely identifying low risk patients not requiring surveillance.

ObjectiveThe National Institute for Health Research (NIHR) Health Informatics Collaborative (HIC) is a programme of infrastructure development across NIHR Biomedical Research Centres. The aim of the NIHR HIC is to improve the quality and availability of routinely collected data for collaborative, cross-centre research. This is demonstrated through research collaborations in selected therapeutic areas, one of which is viral hepatitis.DesignThe collaboration in viral hepatitis identified a rich set of datapoints, including information on clinical assessment, antiviral treatment, laboratory test results and health outcomes. Clinical data from different centres were standardised and combined to produce a research-ready dataset; this was used to generate insights regarding disease prevalence and treatment response.ResultsA comprehensive database has been developed for potential viral hepatitis research interests, with a corresponding data dictionary for researchers across the centres. An initial cohort of 960 patients with chronic hepatitis B infections and 1404 patients with chronic hepatitis C infections has been collected.ConclusionFor the first time, large prospective cohorts are being formed within National Health Service (NHS) secondary care services that will allow research questions to be rapidly addressed using real-world data. Interactions with industry partners will help to shape future research and will inform patient-stratified clinical practice. An emphasis on NHS-wide systems interoperability, and the increased utilisation of structured data solutions for electronic patient records, is improving access to data for research, service improvement and the reduction of clinical data gaps.

Introduction Anastomotic biliary strictures (ABS) have been reported in approximately 13% of patients undergoing orthotopic liver transplantation (OLT). Without treatment these can lead to progressive graft failure. Endoscopic management of these strictures with temporary fully covered self-expanding metal stents (SEMS) offers a non-surgical option for their management. This retrospective case series describes the outcomes of ABS managed using SEMS at our centre. Unit standard practice is to reserve endoscopic management for early ABS and undertake a biliary sphincterotomy to reduce pancreatitis risk. Methods The electronic records of all patients who underwent both OLT and endoscopic retrograde cholangiopancreatography (ERCP) between January 2013 and March 2020 were reviewed. Patients were selected from this group if they were found to have an ABS as diagnosed by biochemical liver function test derangement and corresponding characteristic radiological findings. Demographic data, technical aspects of the procedure, success rate, and complications were recorded. Results A total of 36 transplant recipients were diagnosed with ABS. This group underwent a total of 45 ERCP procedures. The median time from transplant to ABS diagnosis was 6 months (interquartile range (IQR) 2 – 22 months). There was a balloon dilatation prior to stent placement in 13 procedures (29%). There was a sphincterotomy either at the time of stent placement or during a preceding procedure in 33 cases (92%). There were ten cases of pancreatitis (22%), four cases of cholangitis (9%) and two of bile leak (4%). There were eight cases of pancreatitis in the group of 33 who had undergone sphincterotomy (24%) and two cases of pancreatitis in the group of three who had not (67%). There was one case of bleeding following sphincterotomy (3%) that occurred immediately and did not require transfusion. The median time to stent removal was 105 days (IQR 67 – 125). Only one case (3%) required surgical biliary reconstruction. The avoidance of the need for biliary reconstruction was regarded as the key outcome for successful endoscopic management of ABS and this was achieved in 35 cases (97%). Conclusion Early ABS following OLT were effectively managed using endoscopically placed biliary stents in the majority of cases. The rate of pancreatitis was lower in the sphincterotomy group. These data support the practice of temporary SEMS placement for early ABS and sphincterotomy to reduce pancreatitis risk.

The liver, sited in the right upper quadrant of the abdomen, comprises eight segments, each of which is a complete functional unit with a single portal pedicle and a hepatic vein. Within the functional segments, the structural unit is the hepatic lobule, a polyhedron surrounded by four to six portal tracts containing hepatic arterial and portal venous branches from which blood perfuses through sinusoids, surrounded by walls of hepatocytes that are a single cell thick and lined by specialized endothelial cells with ‘windows’ (fenestrae), to the centrilobular region and the central hepatic veins. Bile secreted through the canalicular membrane of the hepatocyte collects in biliary canaliculi, from which it passes through the biliary tract into the gut. The liver secretes bile, which aids digestion by emulsifying lipids, and has a central role in metabolism of (1) bilirubin, from haem; (2) bile salts, the principal mechanism for clearance of cholesterol; (3) carbohydrates; (4) amino acids and ammonia; (5) proteins, most circulating plasma proteins being produced by hepatocytes; and (6) lipid and lipoproteins. The pancreas lies in the retroperitoneum and is composed of (1) an exocrine portion centred on acini, producing an alkaline secretion containing digestive enzymes including serine proteases, exopeptidases, and lipolytic enzymes, draining through a ductal system into the duodenum; and (2) the islets of Langerhans, which secrete insulin (also glucagon, somatostatin, and pancreatic polypeptide).

Background: To determine the impact of the COVID-19 pandemic on the population with chronic Hepatitis B virus (HBV) infection under hospital follow-up in the UK, we quantified the coverage and frequency of measurements of biomarkers used for routine surveillance (alanine transferase [ALT] and HBV viral load). Methods: We used anonymized electronic health record data from the National Institute for Health Research (NIHR) Health Informatics Collaborative (HIC) pipeline representing five UK National Health Service (NHS) Trusts. Results: We report significant reductions in surveillance of both biomarkers during the pandemic compared to pre-COVID-19 years, both in terms of the proportion of patients who had ≥1 measurement annually, and the mean number of measurements per patient. Conclusions: These results demonstrate the real-time utility of HIC data in monitoring health-care provision, and support interventions to provide catch-up services to minimise the impact of the pandemic. Further investigation is required to determine whether these disruptions will be associated with increased rates of adverse chronic HBV outcomes.

Background: Post-transplant lymphoproliferative disease (PTLD) confers a high morbidity and mortality in a vulnerable population. We present the epidemiology and outcomes of PTLD in a large UK cohort of solid organ transplant (SOT) recipients who were transplanted over a 20-year period. Methods: This is a retrospective study of 5365 SOT recipients who had their first transplant between 2000 and 2021 at two UK transplant centres (Addenbrooke's Hospital and Papworth Hospital). We reviewed the records of all patients and found 142 who subsequently developed PTLD. For each type of transplant, we calculated the incidence rate of PTLD and cumulative incidence using a competing risk of death model. Survival was compared with the age-adjusted life expectancy of the UK population using the National life tables and a landmark analysis was performed to compare overall survival (OS) of PTLD patients from the date of diagnosis with the background survival of the transplant population. To compare treatment outcomes, a subset of 90 cases of monomorphic PTLD, DLBCL subtype were identified. 66 were treated with first-line Rituximab monotherapy and 24 received first-line R-Chemotherapy. Demographics, treatment response, and survival data were analysed with univariate and multivariate analysis to identify covariates associated with death in the first year post diagnosis of PTLD. Results: With a median follow-up time of 5.3 years, 142 of 5365 solid organ transplant recipients have developed PTLD (56/1965 kidney, 22/1428 liver, 12/327 simultaneous kidney-pancreas (SPK), 21/113 multivisceral (MVT), 10/778 heart, 15/503 bilateral lung, 3/148 single lung and 3/85 heart and lung). The incidence rate of PTLD was highest in the first year post-transplant in lung and MVT recipients. Cumulative incidence (shown in Figure 1) was 18% at 5 years post-MVT and 1-3% at 5 years following the other SOT types. Cumulative incidence was lowest for liver and heart transplants and was 10% at 20 years post-kidney transplantation. Median OS following SOT was 16 years which is significantly reduced compared with the age-adjusted UK population. There is a relatively high early mortality rate following diagnosis of PTLD and only patients surviving two years post diagnosis regained a similar longer-term survival to the non-PTLD SOT cohort. Treatment with rituximab monotherapy (RM) is now a standard of care for monomorphic PTLD 1. Outcomes for monomorphic patients were compared between those treated with RM (n=66, median follow-up 2.2 y) and R-Chemotherapy (n=24, median follow-up 5.2 y). The two groups were well matched for age and IPI. Of the 66 RM patients, 22 (33%) achieved complete remission with RM and required no further treatment. A further 18 (27%) patients achieved remission following further treatment with chemotherapy/surgery/CTL. 6/66 (9%) patients died of progressive disease (PD), 9/66 (14%) died pre-remission of non-PTLD causes and 11/66 (17%) died in remission of unrelated causes. In the R-Chemotherapy group, 22 patients received R-CHOP and 2 received R-CVP (n=24). 8 (33%) patients are alive and in remission after first line treatment and a further 3 patients (13%) after second line treatment. 2/24 (8%) patients died of PD, 4/24 (17%) died pre-remission of non-PTLD causes and 7/24 (30%) died post-remission of unrelated causes. There is no significant difference in OS between the two groups. Only a minority of deaths were due to PD and death from non-lymphoma causes pre and post remission remain considerably higher than non-PTLD SOT patients up to 2 years post treatment (Figure 1). Multivariate analysis of all 90 monomorphic PTLD patients identified IPI3+ as the strongest pre-treatment variable associating with inferior 1 year OS. Interestingly IPI3+ did not retain this significance when R-chemo patients were analysed alone. Conclusion: With this large SOT dataset we have mapped the cumulative incidence of PTLD over a 20 year period and highlight transplanted organ-specific differences in PTLD incidence over time. Treating monomorphic DLBL patients first-line with RM rather than R-chemotherapy does not appear to compromise OS, but the number of patients dying from non-lymphoma causes pre- and post-treatment remains high with both treatment approaches, with poor OS compared with age-matched non-PTLD SOT recipients. 1Trappe et al. Lancet Oncol; 2012 13(2):196-206 Figure 1 Figure 1. Disclosures Santarsieri: Janssen: Honoraria. Uttenthal: Roche: Other; Takeda: Other; Jazz: Other. Follows: Janssen, Abvie, Roche, AZ: Other.

ObjectiveThe National Institute of Health Research (NIHR) Health Informatics Collaborative (HIC) is a programme of infrastructure development across NIHR Biomedical Research Centres (BRCs). The aim of the NIHR HIC is to improve the quality and availability of routinely-collected data for collaborative, cross-centre research. This is demonstrated through research collaborations in selected therapeutic areas, one of which is viral hepatitis.DesignThe collaboration in viral hepatitis identified a rich set of data points, including information on clinical assessment, antiviral treatment, laboratory test results, and health outcomes. Clinical data from different centres was standardised and combined to produce a research-ready dataset; this was used to generate insights regarding disease prevalence and treatment response.ResultsA comprehensive database has been developed for potential viral hepatitis research interests, with a corresponding data dictionary for researchers across the centres. An initial cohort of 960 patients with chronic hepatitis B infections and 950 patients with chronic hepatitis C infections has been collected.ConclusionFor the first time, large prospective cohorts are being formed within NHS secondary care services that will allow research questions to be rapidly addressed using real world data. Interactions with industry partners will help to shape future research and will inform patient-stratified clinical practice. An emphasis on NHS-wide systems interoperability, and the increased utilisation of structured data solutions for electronic patient records, is improving access to data for research, service improvement and the reduction of clinical data gaps.SUMMARYWhat is already known?Electronic Patient Records in NHS trusts contain a wealth of routinely-collected clinical data useful for translational research. However, this data is not easily accessible to the individual NHS Trust or researchers.There is a shortage of detailed clinical data available for patients with viral hepatitis in the UK, in particular for patients infected with the hepatitis B or E viruses.What does this paper add?We present a comprehensive methodology that has been proposed, implemented and validated by the NIHR HIC for the development of a new data collection and management pipeline.We show that routinely-collected clinical data from patients with hepatitis C, B and E infection can be collated, integrated and made available to researchers automatically from 5 large NHS trusts.We describe the initial data collected from 906 hepatitis B infected patients and 1404 hepatitis C infected patients.

Organoids regenerate human bile ducts Bile ducts carry bile from the liver and gall bladder to the small intestine, where it aids digestion. Cholangiocytes are epithelial cells that line bile ducts and modify bile as its transported through the biliary tree. Chronic liver diseases involving cholangiocytes account for a large fraction of liver failure and the need for liver transplantation. Because liver donors are in short supply, Sampaziotis et al. used organoid technology to develop a cell-based therapy using human tissue (see the Perspective by Kurial and Willenbring). Cholangiocyte organoids were transplanted into the intrahepatic ducts of deceased human donor livers undergoing ex vivo normothermic perfusion. The livers could be maintained for up to 100 hours, and the transplanted organoids engrafted, exhibited function, and could repair bile ducts. Science , this issue p. 839 ; see also p. 786

We sought to identify factors that are predictive of liver transplantation or death in patients with primary sclerosing cholangitis (PSC), and to develop and validate a contemporaneous risk score for use in a real-world clinical setting. Analyzing data from 1,001 patients recruited to the UK-PSC research cohort, we evaluated clinical variables for their association with 2-year and 10-year outcome through Cox-proportional hazards and C-statistic analyses. We generated risk scores for short-term and long-term outcome prediction, validating their use in two independent cohorts totaling 451 patients. Thirty-six percent of the derivation cohort were transplanted or died over a cumulative follow-up of 7,904 years. Serum alkaline phosphatase of at least 2.4 × upper limit of normal at 1 year after diagnosis was predictive of 10-year outcome (hazard ratio [HR] = 3.05; C = 0.63; median transplant-free survival 63 versus 108 months; P < 0.0001), as was the presence of extrahepatic biliary disease (HR = 1.45; P = 0.01). We developed two risk scoring systems based on age, values of bilirubin, alkaline phosphatase, albumin, platelets, presence of extrahepatic biliary disease, and variceal hemorrhage, which predicted 2-year and 10-year outcomes with good discrimination (C statistic = 0.81 and 0.80, respectively). Both UK-PSC risk scores were well-validated in our external cohort and outperformed the Mayo Clinic and aspartate aminotransferase-to-platelet ratio index (APRI) scores (C statistic = 0.75 and 0.63, respectively). Although heterozygosity for the previously validated human leukocyte antigen (HLA)-DR*03:01 risk allele predicted increased risk of adverse outcome (HR = 1.33; P = 0.001), its addition did not improve the predictive accuracy of the UK-PSC risk scores. Conclusion: Our analyses, based on a detailed clinical evaluation of a large representative cohort of participants with PSC, furthers our understanding of clinical risk markers and reports the development and validation of a real-world scoring system to identify those patients most likely to die or require liver transplantation.

We present a case of a 49-year-old woman diagnosed with aquaporin-4 antibody-positive transverse myelitis, who developed a significant transaminitis 2 months after commencing mycophenolate mofetil (MMF) as a steroid-sparing agent. No other risk factors were identified, a blood liver panel was negative and liver biopsy showed features compatible with drug-induced liver injury (DILI). MMF was stopped with a corresponding normalisation of serum alanine aminotransferase over the next 2 months. This case highlights MMF as a rare cause of DILI and provides justification for monitoring of liver biochemistry on therapy.

We report a case of a 33-year-old man with a background of longstanding ileo-colonic Crohn’s disease and primary sclerosing cholangitis. Following a trip to India he developed diarrhoea which was treated as an exacerbation of Crohn’s disease. Liver tests became chronically deranged after increasing immunosuppression, which comprised mercaptopurine, adalimumab and prednisolone. Chronic genotype 1 hepatitis E was diagnosed and successfully treated with reduction of immunosuppression followed by a 24-week course of ribavirin. We believe that this is the first reported case of chronic hepatitis E in genotype 1. Deranged liver tests should prompt testing for hepatitis E infection in the context of immunosuppression for inflammatory bowel disease.

Following the introduction of direct-acting antivirals (DAA), there have been reports of declining incidence of hepatitis C (HCV)-related liver disease as a liver transplantation indication. In this study, we assessed the impact of DAA on liver transplant indications in the UK and waiting list outcomes for patients with HCV. We assessed UK adult elective liver transplant registrants between 2006 and 2017. The aetiology of liver disease at registration was reclassified using an accepted hierarchical system and changes were assessed over time and compared before and after the introduction of DAA. Registration UKELD scores and 1-year waiting list outcomes were also compared. The proportion of waiting list patients registered with HCV-related cirrhosis reduced after the introduction of DAA from 10.5% in 2013 to 4.7% in 2016 (P

OBJECTIVES Fully covered self-expanding metal stents (FCSEMS) constitute the first type of metal stent that can easily be removed endoscopically and/or intraoperatively, which may be advantageous in the management of distal malignant biliary strictures (DMBS). To assess the efficacy of FCSEMS as first-line treatment for DMBS, we compared patency, survival and complication rates between FCSEMS, uncovered self-expanding metal stents (USEMS) and plastic stents (PS). METHODS This was a multicentre retrospective study of 315 consecutive patients with DMBS, who underwent endoscopic retrograde cholangiopancreatography and stenting (FCSEMS, USEMS or PS) at two hospitals between 1 January 2007 and 31 December 2013. Stent patency and patient survival were compared using the Kaplan-Meier method; complication rates were compared using Fisher's exact test; and Cox regression analysis was used to screen for confounding factors. RESULTS FCSEMS were associated with prolonged stent patency (median=145 days) compared with USEMS (median=110 days, P

The study of biliary disease has been constrained by a lack of primary human cholangiocytes. Here we present an efficient, serum-free protocol for directed differentiation of human induced pluripotent stem cells into cholangiocyte-like cells (CLCs). CLCs show functional characteristics of cholangiocytes, including bile acids transfer, alkaline phosphatase activity, γ-glutamyl-transpeptidase activity and physiological responses to secretin, somatostatin and vascular endothelial growth factor. We use CLCs to model in vitro key features of Alagille syndrome, polycystic liver disease and cystic fibrosis (CF)-associated cholangiopathy. Furthermore, we use CLCs generated from healthy individuals and patients with polycystic liver disease to reproduce the effects of the drugs verapamil and octreotide, and we show that the experimental CF drug VX809 rescues the disease phenotype of CF cholangiopathy in vitro. Our differentiation protocol will facilitate the study of biological mechanisms controlling biliary development, as well as disease modeling and drug screening.

Background: Long-term real-world data are relatively sparse regarding recurrence of chronic hepatitis B virus (HBV) infection after liver transplantation using hepatitis B immunoglobulin (HBIg) and nucleos(t)ide analogue (NUC) prophylaxis.MAterial/Methods: Data from 371 adults transplanted for HBV-related disease at 20 European centers and given HBIg for >= 12 months +/- NUC therapy were analyzed retrospectively.Results: HBIg comprised Hepatect (R) (iv HBIgB; n=299), subcutaneous Zutectra (R) (sc HBIg, n=236), and other HBIg preparations (n=130); 93.5% received NUC therapy. Mean follow-up was 6.8 +/- 3.5 years. The primary efficacy variable, freedom from HBV recurrence, occurred in 95.7% of patients (95% CI [93.1%, 97.5%]). The observed incidence of recurrence was 16/371 (4.3%) (annual rate 0.65%); 5/16 patients with recurrence had discontinued HBIg and 7/16 had anti-HBs Conclusions: These results support the long-term use of HBIg with NUC therapy as an effective management strategy to minimize risk of HBV recurrence and virus-related complications after liver transplantation.

The treatment of common bile duct (CBD) disorders, such as biliary atresia or ischemic strictures, is restricted by the lack of biliary tissue from healthy donors suitable for surgical reconstruction. Here we report a new method for the isolation and propagation of human cholangiocytes from the extrahepatic biliary tree in the form of extrahepatic cholangiocyte organoids (ECOs) for regenerative medicine applications. The resulting ECOs closely resemble primary cholangiocytes in terms of their transcriptomic profile and functional properties. We explore the regenerative potential of these organoids $\textit{in vivo}$ and demonstrate that ECOs self-organize into bile duct–like tubes expressing biliary markers following transplantation under the kidney capsule of immunocompromised mice. In addition, when seeded on biodegradable scaffolds, ECOs form tissue-like structures retaining biliary characteristics. The resulting bioengineered tissue can reconstruct the gallbladder wall and repair the biliary epithelium following transplantation into a mouse model of injury. Furthermore, bioengineered artificial ducts can replace the native CBD, with no evidence of cholestasis or occlusion of the lumen. In conclusion, ECOs can successfully reconstruct the biliary tree, providing proof of principle for organ regeneration using human primary cholangiocytes expanded $\textit{in vitro}$.

OBJECTIVE The degree to which heterozygous forms of alpha-1 antitrypsin (A1AT), principally MZ, causes liver disease is uncertain. If heterozygosity is a relevant cofactor, over-representation in patients with end-stage liver disease would be predicted. We therefore assessed the prevalence and disease-related distribution of A1AT heterozygosity in the largest cohort to date for this purpose. METHODS We retrospectively analysed 1036 patients assessed for liver transplantation at our unit between 2003 and 2010. A1AT heterozygotes were identified on the basis of isoelectric focusing and/or histology, showing A1AT globule deposition consistent with an abnormal phenotype. RESULTS Z-allele frequency was the highest in patients with nonalcoholic steatohepatitis (NASH) cirrhosis (20.3%), followed by patients with 'other parenchymal' diseases (11.9%), alcohol-related liver disease (9.9%), autoimmune disease (8.6%), hepatitis C (6.1%), hepatitis B (3.0%) and biliary disease (1.9%). Compared with the heterozygote frequency in the general European population of 9.0%, the heterozygote frequency was significantly higher among patients with NASH cirrhosis (P≤0.0001) and lower in the biliary subgroup (P=0.004). The prevalence of MZ heterozygosity was significantly increased in cirrhosis because of both alcohol (9.9%) and NASH (17.3%) compared with the general European population (2.8%; P

Hepatitis B virus (HBV) is a small nonenveloped DNA virus that is a member of the Hepadnaviridae family. Chronic HBV infection is estimated to effect more than 350 million people worldwide with over 2 billion people being exposed to the virus. Risk factors for chronic infection include age of exposure to the virus, concurrent immunosuppression and HIV infection. Individuals chronically infected are 200 times more likely to develop hepatocellular carcinoma (HCC) than uninfected individuals and are at risk of developing cirrhosis and the risks of decompensated liver disease. This article focuses on the recent therapeutic advances that reduce the risk of developing these complications, those that prevent the spread of HBV and strategies for the prevention of post-liver-transplantation recurrence of HBV.

Enterohemorrhagic E.coli (EHEC) is an important foodborne pathogen in the developed world and can cause life-threatening disease particularly in children. EHEC persists in the human gut by adhering intimately to colonic epithelium and forming characteristic attaching/effacing lesions. In this study, we investigated the innate immune response to EHEC infection with particular focus on antimicrobial peptide and protein expression by colonic epithelium. Using a novel human colonic biopsy model and polarized T84 colon carcinoma cells, we found that EHEC infection induced expression of human β-defensin 2 (hBD2), whereas hBD1, hBD3, LL-37, and lysozyme remained unchanged. Infection with specific EHEC deletion mutants demonstrated that this was dependent on flagellin, and apical exposure to purified flagellin was sufficient to stimulate hBD2 and also interleukin (IL)-8 expression ex vivo and in vitro. Flagellin-mediated hBD2 induction was significantly reduced by inhibitors of NF-κB, MAP kinase p38 and JNK but not ERK1/2. Interestingly, IL-8 secretion by polarized T84 cells was vectorial depending on the side of stimulation, and apical exposure to EHEC or flagellin resulted in apical IL-8 release. Our results demonstrate that EHEC only induces a modest immune response in human colonic epithelium characterized by flagellin-dependent induction of hBD2 and low levels of IL-8.

Background. Late survival is not improving after liver transplantation. In this study, possible reasons for this were investigated. Methods. Mortality rates and causes of death were ascertained in 4483 adult primary liver allograft recipients surviving 1 year or more from engraftment, identified through the UK Transplant Database and transplanted between 1994 and 2007. Associations with death, cause of death, and retransplantation were assessed. Results. Mortality in those surviving beyond 1 year in UK liver transplant recipients was more than twice that expected in the general population and had not improved during the study period, independent of cause of liver disease, recipient age, recipient gender, and donor age. The major causes of death were malignancy (30.6%), multisystem failure (10.0%), infection (9.8%), cardiac disease (8.7%), and graft failure (9.8%). Associations with death after 1 year were pretransplant etiologies alcohol-related liver disease (hazard ratio [HR]=2.10), autoimmune hepatitis or cryptogenic (HR=1.68), hepatitis C virus (HR=2.51), and hepatocellular carcinoma (HR=4.19). Associations with retransplantation were recipient age (HR=0.95 per year), donor age (HR=1.02 per year), and hepatitis C virus (HR=2.04). Hepatocellular carcinoma and recipient age were associated with cancer-related death (odds ratio=1.87 and 1.02 per year). Recipient age was associated with cardiac death (odds ratio=1.06 per year). Conclusions. Strategies to reduce late mortality after liver transplantation are required. These may include prevention of disease recurrence, improved recipient selection, and addressing risk factors for death in late survivors of liver transplantation.

BACKGROUND Sirolimus is unlicensed for use in liver transplantation because of concerns over safety, particularly in regard to hepatic artery thrombosis and excess mortality. However, sirolimus offers potential advantages over calcineurin inhibitor-based immunosuppression, relating to its renal sparing and antiproliferative properties. METHODS A review was undertaken of 148 liver transplant patients converted to sirolimus over 10 years at a single center. RESULTS The main indications for sirolimus were renal impairment and hepatitis C virus fibrosis. One hundred eleven (75%) patients remained on sirolimus after median follow-up of 1006 days. Mean (+/-standard deviation) glomerular filtration rate improved significantly from 59+/-29 mL/min preconversion to 72+/-39 mL/min at censor point (P

This report describes a case of severe hepatitis in an individual returning from India which was found to be the result of infection with HEV genotype 4. HEV was diagnosed using a novel RT-PCR assay (with internal control) for HEV RNA detection/quantitation, described herein. This is the first documented report of zoonotic transmission of HEV genotype 4 infection acquired in India.

Hepatitis C virus (HCV) is a leading indication for liver transplantation worldwide, but graft infection with HCV frequently leads to hepatic fibrosis. Acute cellular rejection (ACR) can be difficult to distinguish confidently from HCV, even with histology, but accurate diagnosis is critical because treatment of ACR may accelerate HCV-related graft injury. Immunohistochemistry was undertaken on 99 liver biopsies from 31 patients with HCV graft infection, 22 patients with ACR, and 11 patients with HCV infection and unexplained graft dysfunction to investigate whether lymphocyte expression of minichromosome maintenance protein-2 (Mcm-2), a marker of licensed cell cycle entry, assessed in a novel semiautomated system could distinguish between ACR and graft infection with HCV. The portal tract area was greater in ACR than in HCV graft infection (P = 0.027), but there was considerable overlap. However, both the number of Mcm-2-positive lymphocytes per portal tract and the number of Mcm-2-positive lymphocytes per millimeter squared of portal tract distinguished between ACR and HCV graft infection (P < 0.0001). A cutoff value of 107 positive cells per portal tract had a sensitivity of 81.8% and a specificity of 91.9% (positive predictive value of 66.67% and negative predictive value of 95.75%). Of 11 HCV-infected patients with an uncertain diagnosis, 7 were deemed ultimately to have HCV graft infection, and 4 had superimposed corticosteroid-responsive ACR. The number of Mcm-2-positive cells per portal tract and per millimeter squared of portal tract again distinguished clearly between the groups (P = 0.012). In conclusion, lymphocyte Mcm-2 expression is a useful adjunct to histology in differentiating between HCV graft infection and ACR. Patients with a low number of Mcm-2-positive portal tract lymphocytes are less likely to have ACR.

It is unclear whether hepatitis C virus (HCV) has been eradicated or persists at a low level in HCV antibody–positive HCV RNA–negative individuals. The natural history and liver histology are not well characterized. One hundred seventy-two HCV antibody–positive, serum HCV RNA–negative patients underwent diagnostic liver biopsy between 1992 and 2000 and were followed a median 7 years (range, 5–12). Patients with any possible cause of liver injury other than HCV were excluded. A single histopathologist scored sections using Ishak criteria. Characterization of the inflammatory infiltrate in selected cases used a novel semiquantitative technique and compared with HCV RNA–positive patients and healthy controls. One hundred two patients were excluded because of a risk factor for liver injury other than HCV. Seventy patients met the study criteria; four (5.7%) became HCV RNA–positive during follow-up. Sixty-six cases remained HCV RNA–negative; five (7.5%) had a normal liver biopsy; 54 (82%) had fibrosis (stage 2 or 3 in 16 (24%)). Nonviremic cases revealed expanded portal tracts (P < 0.05), with fewer CD4+ (P < 0.05) and more CD8+ cells (P < 0.05) than healthy controls, but were indistinguishable from HCV RNA–positive cases for these parameters. Lobular CD4 staining, absent in healthy controls, was noted in both HCV RNA–negative and –positive cases and was more marked in the latter (P < 0.05) with a sinusoidal lining cell distribution. Conclusion: Nonviremic HCV antibody–positive patients have a liver biopsy that is usually abnormal. Fibrosis was present in most with similar inflammatory infiltrate to viremic cases. The presence of a CD8+ rich inflammatory infiltrate suggests an ongoing immune response in the liver, supporting the view that HCV may persist in the liver in the majority of HCV RNA–negative cases. (Hepatology 2008;48;1737-1745.)

Background/Aims Liver transplantation is an effective treatment for highly selected patients with hepatocellular carcinoma (HCC), but tumour recurrence remains an important cause of mortality. There are few data on the relation between the recurrence of HCC and lymphocytic infiltration following liver transplantation. Methods The tumour CD4 + , CD8 + , CD25 + and Foxp3 + lymphocyte infiltrate was assessed by immunohistochemistry in explant tissue of 69 patients who underwent liver transplantation for HCC between 1985 and 2001. The data were analysed according to HCC recurrence and factors known to be associated with outcome. Results Tumour size (Hazard ratio (95% CI: 1.19 (1.02, 1.39), P =0.03)), vascular invasion ( P =0.02), lymphocyte infiltration ( P =0.02) and CD4:CD8 ratio ( P =0.001) were identified as significant univariate predictors of tumour recurrence. On multivariate analysis CD4:8 ratio ( P =0.001), vascular invasion ( P =0.01), tumour size ( P =0.06) and reduced lymphocyte infiltration ( P =0.03) were significant independent predictors of recurrence. The presence of Foxp3 + T-lymphocytes was not predictive of recurrence, but was associated with vascular invasion (FE=9.02, P =0.04). Conclusions The data support the hypothesis that immune responses are important in HCC and that the phenotype of infiltrating lymphocytes is informative regarding prognosis.