Louise China

Bile duct-ligated mice exhibit multiple phenotypic similarities to acute decompensation patients despite histological differences.

Patients with decompensated cirrhosis are susceptible to infection. Innate immune dysfunction and development of organ failure are considered to underlie this. A rodent model of liver disease sharing these phenotypic features would assist in vivo study of underlying mechanisms and testing of therapeutics. We evaluated three models to identify which demonstrated the greatest clinical and immunological phenotypic similarity to patients with acutely decompensated (AD) cirrhosis.

Albumin Counteracts Immune-Suppressive Effects of Lipid Mediators in Patients With Advanced Liver Disease

Background & Aims: Patients with acute decompensation and acute‐on‐chronic liver failure (AD/ACLF) have immune dysfunction, which increases their risk for infections; however, there are no effective treatments to restore their immune function. We investigated whether the potentially immune‐restorative effects of albumin are mediated by its effects on prostaglandin E2 (PGE2) and other lipids. Methods: We analyzed bloods samples from 45 of 79 patients with AD/ACLF and serum levels of albumin less than 30 g/L for whom infusion of 20% human albumin solution (HAS) increased serum levels of albumin 30 g/L or more in a feasibility study of effects of 20% HAS. Immune function was determined by comparison of macrophage function following addition of plasma samples. We also used samples from 12 healthy individuals. We measured binding of plasma proteins to PGE2 and serum levels of endotoxin (lipopolysaccharide) and cytokines; using 10 patients’ samples, we investigated the effects of PGE2 inhibitors. We performed a comprehensive lipid metabolomic analysis using samples from 10 different patients, before and after HAS administration. Results: At baseline, AD/ACLF patient plasma induced significantly lower production of tumor necrosis factor by healthy macrophages than plasma from healthy individuals (P <.0001). Plasma from patients after HAS infusion induced significantly higher levels of tumor necrosis factor production by macrophages (19.5 ± 4.8 ng/mL) compared with plasma collected before treatment (17.7 ± 4.5 ng/mL; P =.0013). There was a significantly lower proportion of plasma protein (albumin) binding to PGE2 from patients with AD/ACLF plasma (mean, 61.9%) compared with plasma from control subjects (77.1%; P =.0012). AD/ACLF plasma protein binding to PGE2 increased following HAS treatment compared with baseline (mean increase, 8.7%; P <.0001). Circulating levels of PGE2, lipopolysaccharide, and inflammatory or anti‐inflammatory cytokines were higher in patients with AD/ACLF than healthy volunteers. Unexpectedly, HAS infusion had no effect on mediator levels. Principal component analysis of baseline levels of lipids that induce or resolve inflammation identified 2 distinct groups of patients that differed according to baseline plasma level of lipopolysaccharide. Sample analyses after HAS treatment indicated that albumin regulates circulating levels of lipid mediators, but this effect was distinct in each group. Conclusions: Analysis of blood samples from patients with AD/ACLF participating in a feasibility study of 20% HAS infusions has shown that infusions to raise serum albumin above 30 g/L reversed plasma‐mediated immune dysfunction by binding and inactivating PGE2. We also describe a method to classify the inflammatory response in AD/ACLF, based on lipid profile, which could improve identification of patients most likely to respond to HAS treatment. A randomized controlled trial is needed to determine whether these effects of HAS reduce infections in AD/ACLF. Trial registered with European Medicines Agency (EudraCT 2014‐002300‐24) and adopted by NIHR (ISRCTN14174793).

ATTIRE: Albumin To prevenT Infection in chronic liveR failurE: study protocol for a single-arm feasibility trial.

Introduction Circulating prostaglandin E2 levels are elevated in acutely decompensated cirrhosis and have been shown to contribute to immune suppression. Albumin binds and inactivates this hormone. Human albumin solution could thus be repurposed as an immune restorative drug in these patients. This feasibility study aims to determine whether it is possible and safe to restore serum albumin to >30 g/L and maintain it at this level in patients admitted with acute decompensated cirrhosis using repeated 20% human albumin infusions according to daily serum albumin levels. Methods and analysis Albumin To prevenT Infection in chronic liveR failurE (ATTIRE) stage 1 is a multicentre, open label dose feasibility trial. Patients with acutely decompensated cirrhosis admitted to hospital with a serum albumin of <30 g/L are eligible, subject to exclusion criteria. Daily intravenous human albumin solution will be infused, according to serum albumin levels, for up to 14 days or discharge in all patients. The primary end point is daily serum albumin levels for the duration of the treatment period and the secondary end point is plasma-induced macrophage dysfunction. The trial will recruit 80 patients. Outcomes will be used to assist with study design for an 866 patient randomised controlled trial at more than 30 sites across the UK. Ethics and dissemination Research ethics approval was given by the London-Brent research ethics committee (ref: 15/LO/0104). The clinical trials authorisation was issued by the medicines and healthcare products regulatory agency (ref: 20363/0350/001-0001). Results Will be disseminated through peer reviewed journals and international conferences. Recruitment of the first participant occurred on 26/05/2015. Trial registration number The trial is registered with the European Medicines Agency (EudraCT 2014-002300-24) and has been adopted by the NIHR (ISRCTN 14174793). This manuscript refers to V.4.0 of the protocol; Pre-results.

Administration of Albumin Solution Increases Serum Levels of Albumin in Patients With Chronic Liver Failure in a Single-Arm Feasibility Trial

Background & Aims: Infections are life‐threatening to patients with acute decompensation and acute‐on‐chronic liver failure (AD/ACLF). Patients with AD/ACLF have prostaglandin E2–mediated immune suppression, which can be reversed by administration of albumin; infusion of 20% human albumin solution (HAS) might improve outcomes of infections. We performed a feasibility study to determine optimal trial design, assess safety, and validate laboratory assessments of immune function to inform design of a phase 3 trial. Methods: We performed a prospective multicenter, single‐arm, open‐label trial of 79 patients with AD/ACLF and levels of albumin lower than 30 g/L, seen at 10 hospitals in the United Kingdom from May through December 2015. Patients were given daily infusions of 20% HAS, based on serum levels, for 14 days or until discharge from the hospital. Rates of infection, organ dysfunction, and in‐hospital mortality were recorded. The primary end point was daily serum albumin level during the treatment period. Success would be demonstrated if 60% achieved and maintained serum albumin levels at or above 30 g/L on at least one third of days with recorded levels. Results: The patients’ mean model for end‐stage disease score was 20.9 ± 6.6. The primary end point (albumin ≥30 g/L on at least one third of days recorded) was achieved by 68 of the 79 patients; 75% of administrations were in accordance with suggested dosing regimen. Mean treatment duration was 10.3 days (104 ± 678 mL administered). There were 8 deaths and 13 serious adverse events, considered by the independent data‐monitoring committee to be consistent with those expected. Twelve of 13 patients that developed either respiratory or cardiovascular dysfunction (based on ward‐based clinical definitions) as their only organ dysfunction were alive at 30 days compared with 1 of 3 that developed renal dysfunction. Only 1 case of brain dysfunction was recorded. Conclusions: In a feasibility trial, we found that administration of HAS increased serum levels of albumin in patients with AD/ACLF. The dosing regimen was acceptable at multiple sites and deemed safe by an independent data‐monitoring committee. We also developed a robust system to record infections. The poor prognosis for patients with renal dysfunction was confirmed. However, patients with cardiovascular or respiratory dysfunction had good outcomes, which is counterintuitive. Severe encephalopathy appeared substantially under‐reported, indicating that ward‐based assessment of these parameters cannot be recorded with sufficient accuracy for use as a primary outcome in phase 3 trials. Trial registration no: EudraCT 2014‐002300‐24 and ISRCTN14174793.

The potential danger of empiric antimicrobial therapy for nosocomial SBP

tively impacted NASH resolution. In contrast, data from the LEAN trial indicated that histological improvements were not proportional to extent of WL and that the presence of diabetes did not affect NASH resolution rates. These findings probably should explain the low accuracy of the model in detecting patients with NASH resolution. In terms of NASH resolution, the patient’s response to therapeutic interventions depends partly on the patient’s characteristics and the histologic severity of NASH. Patients with unfavorable prognostic factors (i.e., older age, diabetes, or nonalcoholic fatty liver disease activity score 5) and lack of efficacy of the intervention suspected by surrogate markers (i.e., absence of ALT normalization or lower rates of WL) may have lower probabilities of NASH resolution. In the presence of the above-mentioned scenarios, the model should consistently identify patients without NASH resolution.

Attitudes to out-of-programme experiences, research and academic training of gastroenterology trainees between 2007 and 2016

Objective Academic medical training was overhauled in 2005 after the Walport report and Modernising Medical Careers to create a more attractive and transparent training pathway. In 2007 and 2016, national web-based surveys of gastroenterology trainees were undertaken to determine experiences, perceptions of and perceived barriers to out-of-programme research experience (OOP-R). Design, setting and patients Prospective, national web-based surveys of UK gastroenterology trainees in 2007 and 2016. Main outcome measure Attitudes to OOP-R of two cohorts of gastroenterology trainees. Results Response rates were lower in 2016 (25.8% vs 56.7%) (p<0.0001), although female trainees’ response rates increased (from 28.8% to 37.6%) (p=0.17), along with higher numbers of academic trainees. Over 80% of trainees planned to undertake OOP-R in both surveys, with >50% having already undertaken it. Doctor of Philosophy/medical doctorate remained the most popular OOP-R in both cohorts. Successful fellowship applications increased in 2016, and evidence of gender inequality in 2007 was no longer evident in 2016. In the 2016 cohort, 91.1% (n=144) felt the development of trainee-led research networks was important, with 74.7% (n=118) keen to get involved. Conclusions The majority of gastroenterology trainees who responded expressed a desire to undertake OOP-R, and participation rates in OOP-R remain high. Despite smaller absolute numbers responding than in 2007, 2016 trainees achieved higher successful fellowship application rates. Reassuringly more trainees in 2016 felt that OOP-R would be important in the future. Efforts are needed to tackle potential barriers to OOP-R and support trainees to pursue research-active careers.

Trends in UK endoscopy training in the BSG trainees’ national survey and strategic planning for the future

Background Improvements in the structure of endoscopy training programmes resulting in certification from the Joint Advisory Group in Gastrointestinal Endoscopy have been acknowledged to improve training experience and contribute to enhanced colonoscopy performance. Objectives The 2016 British Society of Gastroenterology trainees’ survey of endoscopy training explored the delivery of endoscopy training - access to lists; level of supervision and trainee’s progression through diagnostic, core therapy and subspecialty training. In addition, the barriers to endoscopy training progress and utility of training tools were examined. Methods A web-based survey (Survey Monkey) was sent to all higher specialty gastroenterology trainees. Results There were some improvements in relation to earlier surveys; 85% of trainees were satisfied with the level of supervision of their training. But there were ongoing problems; 12.5% of trainees had no access to a regular training list, and 53% of final year trainees had yet to achieve full certification in colonoscopy. 9% of final year trainees did not feel confident in endoscopic management of upper GI bleeds. Conclusions The survey findings provide a challenge to those agencies tasked with supporting endoscopy training in the UK. Acknowledging the findings of the survey, the paper provides a strategic response with reference to increased service pressures, reduced overall training time in specialty training programmes and the requirement to support general medical and surgical on-call commitments. It describes the steps required to improve training on the ground: delivering additional training tools and learning resources, and introducing certification standards for therapeutic modalities in parallel with goals for improving the quality of endoscopy in the UK.

OC-009 Progression of cirrhotic liver disease towards acute-on-chronic liver failure decompensation triggers changes in innate immune cell phenotype and their response to pro-inflammatory stimuli

Introduction Bacterial infection is a major cause of hospital admission in liver cirrhosis and patients are highly prone to nosocomial infection. Innate immune dysfunction is implicated in these patients. As there are no current strategies to reverse immune dysfunction, antibiotics are liberally used to treat patients in an era of increasing anti-microbial resistance. We aimed to determine whether progression to ACLF triggers a change in the receptor phenotype on innate immune cells reflecting impaired function. We also explored the response to inflammatory stimuli. Any changes in profile may reveal novel targets for immune therapy. Method Peripheral whole blood of healthy volunteers (HV), ambulant outpatients attending for drainage of ascites and acute decompensated (AD) cirrhotic patients was studied. Cells were analysed by flow cytometry for activation and cell type. Whole blood was stimulated ex vivo with 1 ng/ml lipopolysaccharide for 4 hours. Supernatants were analysed for cytokines. Cells were analysed by flow cytometry. Results Neutrophils demonstrated a significant decrease in CD88 (p=0.0006) from HV to ACLF, with decreasing trends of CD11b, CD54, CD66b and significant increases in CD62L (p=0.0298) observed as disease severity increased. When stimulated with LPS, increases in CD11b (p<0.0001), CD54 (p=0.0287) and CD66b (p=0.0340) were reduced in ACLF compared to HV. These observations were not seen in ambulant patients however trends in each marker were seen in the same direction as ACLF. In mononuclear phagocytes HLA-DR was significantly reduced between HV and both ambulant (p=0.0019) and ACLF (p<0.0001), and CD88 between HV and ACLF (p=0.0083). There were also trends of increased CD16, CD62L and CD64, with decreasing CD11b and CD54. When stimulated, there was a significant increases in CD64 (p=0.0004), and increasing trends in CD11b, CD54, CD32 and CD88 in ACLF patients, as well as a failure to increase HLA-DR. A significant difference was also observed between HV and ambulant patients in CD64 (p=0.0297), with trends in the other markers mirroring the ALCF patients but to a lesser degree. TNF levels in the supernatants of the stimulated blood were reduced in both ambulant and AD patients compared to HV. Conclusion The phenotype of innate immune cells in ACLF was altered reflecting immune dysfunction and potentially explaining increased rates of bacterial infection. The response of innate cells to stimulation was also modified. These changes reflect a markedly reduced bactericidal and phagocytic potential of these cells. This is mirrored by the reduced production of TNF-a by whole blood stimulation. Overall, we see an immune-fatigued phenotype in innate immunity. Disclosure of Interest None Declared

Is human albumin solution really the best resuscitation fluid for patients with advanced cirrhosis

Dear Sirs, We read with interest the revised consensus recommendations for management of acute kidney injury (AKI) ) in cirrhosis by the International Club of Ascites.1 We are concerned that plasma volume expansion only with albumin is recommended for stage 2 and 3 AKI and do not believe that this represents a balanced view of the available evidence. No one doubts that fluid resuscitation is an integral part of the management of AKI; however, studies to date have not established class 1 evidence for an advantage of the use of albumin over other colloids or crystalloids. It can be argued that albumin may represent a superior fluid resuscitation agent in cirrhotic patients. Certainly a …

P1327 : Attire: albumin to prevent infection in chronic liver failure

Background and Aims: Patients with cirrhosis are at a greatly increased risk of severe bacterial infection with survival directly related to extra-hepatic organ dysfunction. A defective innate immune response is considered to underlie this risk. There is however no medical strategy to restore immune competence in these patients. Elevated circulating Prostaglandin E2 (PGE2) levels contribute to immune suppression in acutely decompensated (AD) cirrhosis. PGE2 is more bioavailable because of decreased serum albumin levels in AD patients as albumin binds PGE2. The binding capacity of endogenous albumin is also known to be defective in cirrhosis. Human Albumin Solution (HAS), a safe and common intervention, could thus be repurposed as an immune restorative drug in AD patients. The primary aim of ATTIRE is to determine if raising serum albumin to >30 g/L in patients with decompensated cirrhosis will decrease rates of infection, extra hepatic organ dysfunction and death.