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Background: We evaluated the diagnostic accuracy of simple non-invasive tests(NITs) in NAFLD patients with type 2 diabetes(T2D). Methods: This was an individual patient data meta-analysis of 1780 patients with biopsy-proven NAFLD and T2D. The index tests of interest were FIB-4, NAFLD Fibrosis Score(NFS), APRI, liver stiffness measurement(LSM) by vibration-controlled transient elastography(VCTE) and AGILE 3+. The target conditions were advanced fibrosis, nonalcoholic steatohepatitis(NASH) and fibrotic NASH(NASH plus F2-F4 fibrosis). The diagnostic performance of NITs individually or in sequential combination was assessed by area under receiver operating characteristic curve(AUROC) and by decision curve analysis(DCA). Comparison with 2278 NAFLD patients without T2D was also made. Results: In NAFLD with T2D LSM and AGILE 3+ outperformed both NFS and FIB-4 for advanced fibrosis(AUROC:LSM 0.82,AGILE 3+ 0.82,NFS 0.72,FIB-4 0.75,APRI 0.68;p < 0.001 of LSM-based versus simple serum tests), with an uncertainty area of 12%-20%.The combination of serum-based with LSM-based tests for advanced fibrosis led to a reduction of 40% to 60% in necessary LSM tests. DCA showed that all scores had modest net benefit for ruling-out advanced fibrosis at the risk threshold of 5%-10% of missing advanced fibrosis. LSM and AGILE 3+ outperformed both NFS and FIB-4 for fibrotic NASH(AUROC LSM 0.79,AGILE 3+ 0.77,NFS 0.71,FIB-4 0.71;p < 0.001 of LSM-based versus simple serum tests). All noninvasive scores were sub-optimal for diagnosing NASH. Conclusions: LSM and AGILE 3+ individually or in low availability setting in sequential combination after FIB-4 or NFS have a similar good diagnostic accuracy for advanced fibrosis and an acceptable diagnostic accuracy for fibrotic NASH in NAFLD patients with T2D.

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Background: Endoscopy within 24 hours of admission (early endoscopy) is a quality standard in acute upper gastrointestinal bleeding (AUGIB). We aimed to audit time to endoscopy outcomes and identify factors affecting delayed endoscopy (>24h of admission). Methods: This prospective multicentre audit enrolled patients admitted with AUGIB who underwent inpatient endoscopy between Nov-Dec 2017. Analyses were performed to identify factors associated with delayed endoscopy, and to compare patient outcomes, including length of stay and mortality rates, between early and delayed endoscopy groups. Results: Across 348 patients from 20 centres, the median time to endoscopy was 21.2h (IQR 12.0- 35.7), comprising median admission to referral and referral to endoscopy times of 8.1h (IQR 3.7- 18.1) and 6.7h (IQR 3.0-23.1) respectively. Early endoscopy was achieved in 58.9%, although this varied by centre (range: 31.0% - 87.5%, p=0.002). On multivariable analysis, lower Glasgow-Blatchford score, delayed referral, admissions between 7am-7pm or via the Emergency Department were independent predictors of delayed endoscopy. Early endoscopy was associated with reduced length of stay (median difference 1d; p= 0.004), but not 30-day mortality (p=0.344). Conclusions: The majority of centres did not meet national standards for time to endoscopy. Strategic initiatives involving acute care services may be necessary to improve this outcome.

The British Society of Gastroenterology in collaboration with British Association for the Study of the Liver has prepared this document. The aim of this guideline is to review and summarise the evidence that guides clinical diagnosis and management of ascites in patients with cirrhosis. Substantial advances have been made in this area since the publication of the last guideline in 2007. These guidelines are based on a comprehensive literature search and comprise systematic reviews in the key areas, including the diagnostic tests, diuretic use, therapeutic paracentesis, use of albumin, transjugular intrahepatic portosystemic stent shunt, spontaneous bacterial peritonitis and beta-blockers in patients with ascites. Where recent systematic reviews and meta-analysis are available, these have been updated with additional studies. In addition, the results of prospective and retrospective studies, evidence obtained from expert committee reports and, in some instances, reports from case series have been included. Where possible, judgement has been made on the quality of information used to generate the guidelines and the specific recommendations have been made according to the ‘Grading of Recommendations Assessment, Development and Evaluation (GRADE)’ system. These guidelines are intended to inform practising clinicians, and it is expected that these guidelines will be revised in 3 years’ time.

Introduction Increasing rates of liver transplantation and improved outcomes have led to greater numbers of transplant recipients followed up in non-transplant centres. Our aim was to document long-term clinical outcomes of liver transplant recipients managed in this ‘hub-and-spoke’ healthcare model. Methods A retrospective analysis of all adult patients who underwent liver transplantation between 1987 and 2016, with post-transplant follow-up in two non-transplant centres in the UK (Nottingham) and Canada (Ottawa), was performed. Results The 1-, 5-, 10- and 20-year patient survival rates were 98%, 95%, 87% and 62%, and 100%, 96%, 88% and 62% in the Nottingham and Ottawa groups, respectively (p=0.87). There were no significant differences between the two centres in 1-, 5-, 10- and 20-year cumulative incidence of death-censored graft-survival (p=0.10), end-stage renal disease (p=0.29) or de novo cancer (p=0.22). Nottingham had a lower incidence of major cardiovascular events (p=0.008). Conclusion Adopting a new model of healthcare provides a means of delivering post-transplant patient care close to home without compromising patient survival and long-term clinical outcomes.

BACKGROUND Noninvasive assessment of dynamic changes in liver blood flow, perfusion, and oxygenation using MRI may allow detection of subtle hemodynamic alterations in cirrhosis. PURPOSE To assess the feasibility of measuring dynamic liver blood flow, perfusion, and T2 * alterations in response to meal, hypercapnia, and hyperoxia challenges. STUDY TYPE Prospective. SUBJECTS Ten healthy volunteers (HV) and 10 patients with compensated cirrhosis (CC). FIELD STRENGTH/SEQUENCE 3T; phase contrast, arterial spin labeling, and T2* mapping. ASSESSMENT Dynamic changes in portal vein and hepatic artery blood flow (using phase contrast MRI), liver perfusion (using arterial spin labeling), and blood oxygenation ( T2* mapping) following a meal challenge (660 kcal), hyperoxia (target PET O2 of 500 mmHg), and hypercapnia (target increase PET CO2 of ∼6 mmHg). STATISTICAL TESTS Tests between baseline and each challenge were performed using a paired two-tailed t-test (parametric) or Wilcoxon-signed-ranks test (nonparametric). Repeatability and reproducibility were determined by the coefficient of variation (CoV). RESULTS Portal vein velocity increased following the meal (70 ± 9%, P < 0.001) and hypercapnic (7 (5-11)%, P = 0.029) challenge, while hepatic artery flow decreased (-30 ± 18%, P = 0.005) following the meal challenge in HV. In CC patients, portal vein velocity increased (37 ± 13%, P = 0.012) without the decrease in hepatic artery flow following the meal. In both groups, the meal increased liver perfusion (HV: 82 ± 50%, P < 0.0001; CC: 27 (16-42)%, P = 0.011) with faster arrival time of blood (HV: -54 (-56-30)%, P = 0.074; CC: -42 ± 32%, P = 0.005). In HVs, T2* increased after the meal and in response to hyperoxia, with a decrease in hypercapnia (6 ± 8% P = 0.052; 3 ± 5%, P = 0.075; -5 ± 6%, P = 0.073, respectively), but no change in CC patients. Baseline between-session CoV

Siau et al question the recommended landmarks for performing large volume paracentesis (LVP) ‘at least 8 cm (laterally) from the midline and 5 cm above the symphysis (pubis)’.1 In their view, while this approach avoids puncturing vessels, there remains risk of injury to underlying solid organs.2 Our aim was to provide evidence-based guidance (https://blogs.bmj.com/gut/) where possible on the safest areas for performing therapeutic paracentesis.3 In fact, after systematically reviewing available evidence, our conclusion is that our recommended landmarks are appropriate.1 The most common (though still rare) complication overall after LVP remains bleeding (0%–2.7%) rather than organ …

We applied multiparametric MRI to assess changes in liver composition, perfusion and blood flow in 17 patients before direct-acting antiviral (DAA) therapy and after treatment completion (within 12 weeks of last DAA tablet swallowed). We observed changes in hepatic composition indicated by a reduction in both liver longitudinal relaxation time (T1, 35 ± 4 ms), transverse relaxation time (T2, 2.5 ± 0.8 ms; T2* 3.0 ± 0.7 ms), and liver perfusion (28.1 ± 19.7 ml/100 g/min) which we suggest are linked to reduced pro-inflammatory milieu, including interstitial oedema, within the liver. No changes were observed in liver or spleen blood flow, splenic perfusion, or superior mesenteric artery blood flow. For the first time, our study has shown that treatment of HCV with DAAs in patients with cirrhosis leads to an acute reduction in liver T1, T2 and T2* and an increase in liver perfusion measured using MR parameters. The ability of MRI to characterise changes in the angio-architecture of patients with cirrhosis after intervention in the short term will enhance our understanding of the natural history of regression of liver disease and potentially influence clinical decision algorithms. • DAAs have revolutionised the treatment of hepatitis C and achieve sustained virological response in over 95% of patients, even with liver cirrhosis. • Currently available non-invasive measures of liver fibrosis are not accurate after HCV treatment with DAAs, this prospective single-centre study has shown that MRI can sensitively measure changes within the liver, which could reflect the reduction in inflammation with viral clearance. • The ability of MRI to characterise changes in structural and haemodynamic MRI measures in the liver after intervention will enhance our understanding of the progression/regression of liver disease and could potentially influence clinical decision algorithms.

Liver biopsy is the standard test for the assessment of fibrosis in liver tissue of patients with chronic liver disease. Recent studies have used a non-invasive measure of T1 relaxation time to estimate the degree of fibrosis in a single slice of the liver. Here, we extend this work to measure T1 of the whole liver and investigate the effects of additional histological factors such as steatosis, inflammation and iron accumulation on the relationship between liver T1 and fibrosis. We prospectively enrolled patients who had previously undergone liver biopsy to have MR scans. A non-breath-holding, fast scanning protocol was used to acquire MR relaxation time data (T1 and T2*), and blood serum was used to determine the enhanced liver fibrosis (ELF) score. Areas under the receiver operator curves (AUROCs) for T1 to detect advanced fibrosis and cirrhosis were derived in a training cohort and then validated in a second cohort. Combining the cohorts, the influence of various histology factors on liver T1 relaxation time was investigated. The AUROCs (95% confidence interval (CI)) for detecting advanced fibrosis (F ≥ 3) and cirrhosis (F = 4) for the training cohort were 0.81 (0.65–0.96) and 0.92 (0.81–1.0) respectively (p

Portal pressure is the product of portal blood flow and resistance; an increase in either leads to increased portal pressure. Cirrhosis is the underlying cause in most cases, but portal hypertension can develop due to pre-, intra- and post-hepatic obstruction to the flow, secondary to a variety of causes. Diagnosis can be established by a combination of non-invasive imaging or portal vasculature and clinical or serological markers for the cause underlying cirrhosis. Development of gastro-oesophageal varices and ascites are the most important clinical manifestation of portal hypertension. Non-selective β-blockers and endoscopic band ligation are effective in primary and secondary prevention of variceal bleeding. Active variceal haemorrhage is managed using a combination of vasoactive drug (e.g. terlipressin) and endoscopic band ligation. If these measures fail, transjugular intrahepatic portosystemic shunt (TIPS) insertion achieves haemostasis. Diuretic therapy with spironolactone and furosemide are the mainstays of management of ascites. If ascites becomes refractory, repeat large volume paracentesis and TIPS in selected cases help to control symptoms. Development of ascites is an important landmark in the natural history of cirrhosis and liver transplantation should be considered definitive treatment.

Background & AimsHepatic venous pressure gradient (HVPG) measurement is currently the only validated technique to accurately evaluate changes in portal pressure. In this study, we evaluate the use of non-contrast quantitative magnetic resonance imaging (MRI) as a surrogate measure of portal pressure.MethodsThirty patients undergoing HVPG measurement were prospectively recruited. MR parameters of longitudinal relaxation time (T1), perfusion of the liver and spleen (by arterial spin labelling), and blood flow in the portal, splanchnic and collateral circulation (by phase contrast MRI) were assessed. We estimated the liver stiffness measurement (LSM) and enhanced liver fibrosis (ELF) score. The correlation of all non-invasive parameters with HVPG was evaluated.ResultsThe mean (range) HVPG of the patients was 9.8 (1–22) mmHg, and 14 patients (48%) had clinically significant portal hypertension (CSPH, HVPG ⩾10mmHg). Liver T1 relaxation time, splenic artery and superior mesenteric artery velocity correlated significantly with HVPG. Using multiple linear regression, liver T1 and splenic artery velocity remained as the two parameters in the multivariate model significantly associated with HVPG (R=0.90, p

Establishing the presence of fibrosis and cirrhosis is an essential step in the management of patients with chronic liver diseases (CLD). Liver stiffness measurement (LSM) based on transient elastography (TE) correlates well with the stages of liver fibrosis and has been developed as a non-invasive alternative to liver biopsy. The studies performed to date have used physician operators. With the potential use of TE for screening of community-based populations for liver disease, we aimed to evaluate the performance of nurse operators.Retrospective analysis.We reviewed the reliability and accuracy of LSMs performed by the nurse-led TE service at Queen's Medical Centre, Nottingham between May 2009 and January 2011. Consecutive patients with suspected CLD who underwent LSM were included.Over the study period 585 LSMs were performed. Analysis was performed on the 208 patients where LSM could be compared with liver biopsy findings. Of these 11 (5.3%) had unreliable LSM results (less than 10 valid shots or success rate60%). There were no LSM failures. Inadequate liver biopsy specimen led to exclusion in 26 (12.5%) patients. For the detection of significant fibrosis (Ishak stage2), a sensitivity of 0.78 and specificity of 0.81 was obtained, with a cut-off value of 8 kPa. Using a cut-off value of 13 kPa for detection of cirrhosis, a sensitivity and specificity of 0.8 and 0.92 was obtained.We have demonstrated that a nurse-led TE service can produce a low level of unreliable results and LSM failures, with comparable sensitivity and specificity for detecting significant fibrosis and cirrhosis to those reported in the literature. The demands on the use of TE could potentially be eased through the introduction of nurse-led service delivery.

Post-translational protein modification by the covalent conjugation of ubiquitin, originally implicated as a signal for proteolytic degradation by 26S proteasome, has now been realised to play important roles in the regulation of almost all biological processes in eukaryotes. In order to understand these processes in greater detail there is a requirement for techniques that can purify mixtures of ubiquitin-conjugated proteins, as a prerequisite to their identification and characterisation. Here we review the methods that have been applied to the bulk purification of ubiquitinated proteins and discuss their applications in proteomic analyses of the 'ubiquitome'.

Liver biopsy is the standard test for the assessment of fibrosis in liver tissue of patients with chronic liver disease. Recent studies have used a non-invasive measure of T1 relaxation time to estimate the degree of fibrosis in a single slice of the liver. Here, we extend this work to measure T1 of the whole liver and investigate the effects of additional histological factors such as steatosis, inflammation and iron accumulation on the relationship between liver T1 and fibrosis. We prospectively enrolled patients who had previously undergone liver biopsy to have MR scans. A non-breath-holding, fast scanning protocol was used to acquire MR relaxation time data (T1 and T2*), and blood serum was used to determine the enhanced liver fibrosis (ELF) score. Areas under the receiver operator curves (AUROCs) for T1 to detect advanced fibrosis and cirrhosis were derived in a training cohort and then validated in a second cohort. Combining the cohorts, the influence of various histology factors on liver T1 relaxation time was investigated. The AUROCs (95% confidence interval (CI)) for detecting advanced fibrosis (F ≥ 3) and cirrhosis (F = 4) for the training cohort were 0.81 (0.65-0.96) and 0.92 (0.81-1.0) respectively (p 0.01). Inflammation and iron accumulation were shown to significantly alter T1 in opposing directions in the absence of advanced fibrosis; inflammation increasing T1 and iron decreasing T1. A decision tree model was developed to allow the assessment of early liver disease based on relaxation times and ELF, and to screen for the need for biopsy. T1 relaxation time increases with advanced fibrosis in liver patients, but is also influenced by iron accumulation and inflammation. Together with ELF, relaxation time measures provide a marker to stratify patients with suspected liver disease for biopsy.

Introduction Directly-acting antiviral (DAA) therapy achieves sustained virological response (SVR) in over 90% of those with chronic hepatitis C (CHC), but even in those with SVR, the risk for liver related morbidity and mortality persists albeit at a lower level. It is hypothesised that the residual risk of liver related outcome in those with SVR is related to the progression or non-regression of structural and haemodynamic changes of advanced liver disease at the time of HCV therapy. Here, we investigate the effect of DAAs on the hepatic architecture and splanchnic haemodynamics in patients with decompensated cirrhosis, using quantitative MRI techniques. Method We prospectively recruited patients receiving DAAs for CHC related decompensated cirrhosis from the East Midlands hub of the Early Access Programme commissioned by NHS England. MRI was performed before and at the end of a 12-week treatment with Daclatasvir, Sofosbuvir and Ribavarin. A respiratory-triggered inversion recovery scheme was used to measure the longitudinal (T1) relaxation time of the liver employing a fat suppressed Echo Planar Imaging-acquisition. Phase-contrast (PC)-MRI was used to assess the velocity, area and bulk flow in the splanchnic circulation without any intravenous contrast agents. Results 9 patients have undergone baseline and post-treatment MR scans and end-of-treatment response (EOTR) was achieved in all 9 patients, but one patient has had virologic relapse. There was a significant reduction in the T1 relaxation time in patients with SVR (baseline T1: 765 ± 112 ms; post-treatment 737 ± 118 ms; p = 0.043) (Figure 1). There were no significant changes in the hepatic artery, portal vein, superior mesenteric artery and splenic artery flow. The changes in the Model for End-Stage Liver Disease (MELD) and United Kingdom Model for End-Stage Liver Disease (UKELD) score are shown in Table 1. Conclusion Treatment of decompensated CHC related cirrhosis with DAA is associated with early improvement in the MR markers of liver architecture. These early changes are likely to reflect the reduction in the inflammation associated with EOTR and is evident before any improvement in conventional liver function tests. This novel quantitative MR methodology will allow us to non-invasively monitor HCV related liver disease. Disclosure of interest None Declared.

Introduction The majority of complications in liver cirrhosis results from portal hypertension. The hepatic venous pressure gradient (HVPG) is the gold standard measure to assess portal pressure but this requires hepatic vein catheterisation which is an invasive procedure and available in only a few specialised liver units. We aim to develop a novel non-contrast quantitative MRI methodology to estimate portal pressure. Method We prospectively recruited patients undergoing HVPG measurement for clinical indications and MRI was performed within 6 weeks. A respiratory-triggered inversion recovery scheme was used to measure the longitudinal (T 1 ) relaxation time of the liver and spleen employing a fat suppressed Echo Planar Imaging-acquisition. Phase-contrast (PC)-MRI was used to assess the velocity, area and bulk flow in the splanchnic circulation without any intravenous contrast agents. Results 33 patients [alcoholic, 10 (30.3%); non-alcoholic fatty liver disease, 11 (33.3%); and autoimmune hepatitis, 5 (15.2%)], aged 55 ± 12 years (mean ± SD) were enrolled in this study. 4 patients were excluded due to claustrophobia (3) and non-cirrhotic portal hypertension (1). Liver and spleen T 1 relaxation time correlated significantly with HVPG (R = 0.797, p Conclusion We have demonstrated that parameters related to both hepatic architecture and splanchnic haemodynamics derived from non-contrast quantitative MR imaging techniques correlate significantly with HVPG. In future studies, these MRI techniques will be utilised for the non-invasive evaluation of portal hypertension. Disclosure of interest None Declared.

Introduction There is increasing evidence that the incidence of Barrett9s oesophagus (BO) is increasing and the majority of these are the short segment (SSBO) variety. At the same time the incidence of oesophageal adenocarcinoma is also on the rise. While it is generally accepted that long segment Barrett9s oesophagus (LSBO) is associated with an increased risk of developing dysplasia/cancer, the risk associated with SSBO is poorly defined. Aim To estimate the risk of developing high-grade dysplasia/cancer in patients with SSBE and LSBE undergoing surveillance endoscopy. Methods We identified patients, from the endoscopic records of Nottingham University Hospital, with a confirmed endoscopic and histological diagnosis of BO from 2002 to 2006. Duration of follow-up was calculated from the time the first histological diagnosis of BO was made to the time of the last endoscopy. Incidence density (ID) of developing high-grade dysplasia/cancer and incidence rate ratios (IRR) were calculated in patients with SSBE and LSBE. A Poisson distribution was assumed for purposes of calculation and analysis for IRR was adjusted for age and sex. Data were analysed using Stata V.9.1. Results 703 patients with a confirmed histological diagnosis of BO were identified from the database. 470 patients (339 male and 139 female) had LSBO and 233 patients (141 male and 92 female) had SSBO. There were 70 dysplastic lesions (54 HGD/cancer and 26 LGD) in patients with LSBO and 16 dysplastic lesions (10 HGD/cancer and six LGD) in patients with SSBO. The crude incidence density of developing HGD/cancer in patients with LSBO was 31.5/1000 pyd (person years duration) (95% CI 23.7 to 41.2) and in patients with SSBO was 15.1/1000 pyd (95% CI 7.3 to 27.8). The age and sex adjusted incidence rate ratio of developing HGD/cancer among patients with SSBO compared to LSBO was 0.99 (95% CI 0.93 to 1.06). Conclusion The risk of developing HGD/cancer in patients with SSBO appear to be similar to those with LSBO. Surveillance guidelines and physicians need to take this into account when planning surveillance strategies for patients with SSBO.

[Background and Aims] Vibration-controlled transient elastography (VCTE), point shear wave elastography (pSWE), 2-dimensional shear wave elastography (2DSWE), magnetic resonance elastography (MRE), and magnetic resonance imaging (MRI) have been proposed as non-invasive tests for patients with non-alcoholic fatty liver disease (NAFLD). This study evaluated their diagnostic accuracy for liver fibrosis and non-alcoholic steatohepatitis (NASH)., [Methods] PubMED/MEDLINE, EMBASE and the Cochrane Library were searched for studies examining the diagnostic accuracy of these index tests, against histology as the reference standard, in adult patients with NAFLD. Two authors independently screened and assessed methodological quality of studies and extracted data. Summary estimates of sensitivity, specificity and area under the curve (sAUC) were calculated for fibrosis stages and NASH, using a random effects bivariate logit-normal model., [Results] We included 82 studies (14,609 patients). Meta-analysis for diagnosing fibrosis stages was possible in 53 VCTE, 11 MRE, 12 pSWE and 4 2DSWE studies, and for diagnosing NASH in 4 MRE studies. sAUC for diagnosis of significant fibrosis were: 0.83 for VCTE, 0.91 for MRE, 0.86 for pSWE and 0.75 for 2DSWE. sAUC for diagnosis of advanced fibrosis were: 0.85 for VCTE, 0.92 for MRE, 0.89 for pSWE and 0.72 for 2DSWE. sAUC for diagnosis of cirrhosis were: 0.89 for VCTE, 0.90 for MRE, 0.90 for pSWE and 0.88 for 2DSWE. MRE had sAUC of 0.83 for diagnosis of NASH. Three (4%) studies reported intention-to-diagnose analyses and 15 (18%) studies reported diagnostic accuracy against pre-specified cut-offs., [Conclusions] When elastography index tests are acquired successfully, they have acceptable diagnostic accuracy for advanced fibrosis and cirrhosis. The potential clinical impact of these index tests cannot be assessed fully as intention-to-diagnose analyses and validation of pre-specified thresholds are lacking., [Lay summary] Non-invasive tests that measure liver stiffness or use magnetic resonance imaging (MRI) have been suggested as alternatives to liver biopsy for assessing the severity of liver scarring (fibrosis) and fatty inflammation (steatohepatitis) in patients with non-alcoholic fatty liver disease (NAFLD). In this study, we summarise the results of previously published studies on how accurately these non-invasive tests can diagnose liver fibrosis and inflammation, using liver biopsy as the reference. We found that some techniques that measure liver stiffness had a good performance for the diagnosis of severe liver scarring., This work has been undertaken as part of the LITMUS (Liver Investigation: Testing Marker Utility in Steatohepatitis) project. The LITMUS project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 777377. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and Europen Federation of Pharmaceutical Industries and Associations (efpia.eu).