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Background & Aims: There is a need to reduce the screen failure rate (SFR) in metabolic dysfunction-associated steatohepatitis (MASH) clinical trials (MASH+F2-3; MASH+F4) and identify people with high-risk MASH (MASH+F2-4) in clinical practice. We aimed to evaluate non-invasive tests (NITs) screening approaches for these target conditions., Methods: This was an individual participant data meta-analysis for the performance of NITs against liver biopsy for MASH+F2-4, MASH+F2-3 and MASH+F4. Index tests were the FibroScan-AST (FAST) score, liver stiffness measured using vibration-controlled transient elastography (LSM-VCTE), the fibrosis-4 score (FIB-4) and the NAFLD fibrosis score (NFS). Area under the receiver operating characteristics curve (AUROC) and thresholds including those that achieved 34% SFR were reported., Results: We included 2281 unique cases. The prevalence of MASH+F2-4, MASH+F2-3 and MASH+F4 was 31%, 24% and 7%, respectively. Area under the receiver operating characteristics curves for MASH+F2-4 were .78, .75, .68 and .57 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F2-3 were .73, .67, .60, .58 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F4 were .79, .84, .81, .76 for FAST, LSM-VCTE, FIB-4 and NFS. The sequential combination of FIB-4 and LSM-VCTE for the detection of MASH+F2-3 with threshold of .7 and 3.48, and 5.9 and 20 kPa achieved SFR of 67% and sensitivity of 60%, detecting 15 true positive cases from a theoretical group of 100 participants at the prevalence of 24%., Conclusions: Sequential combinations of NITs do not compromise diagnostic performance and may reduce resource utilisation through the need of fewer LSM-VCTE examinations., (© 2024 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background: Seladelpar is a potent and selective peroxisome proliferator-activated receptor-δ agonist that targets multiple cell types involved in primary biliary cholangitis (PBC), leading to anti-cholestatic, anti-inflammatory and anti-pruritic effects., Aims: To evaluate the long-term safety and efficacy of seladelpar in patients with PBC., Methods: In an open-label, international, long-term extension study, patients with PBC completing seladelpar lead-in studies continued treatment. Seladelpar was taken orally once daily at doses of 5 or 10 mg with dose adjustment permitted for safety or tolerability. The primary analysis was for safety and the secondary efficacy analysis examined biochemical markers of cholestasis and liver injury. The study was terminated early due to the unexpected histological findings in a concurrent study for non-alcoholic steatohepatitis, which were subsequently found to predate treatment. Safety and efficacy data were analysed through 2 years., Results: There were no serious treatment-related adverse events observed among 106 patients treated with seladelpar for up to 2 years. There were four discontinuations for safety, one possibly related to seladelpar. Among 53 patients who completed 2 years of seladelpar, response rates increased from years 1 to 2 for the composite endpoint (alkaline phosphatase [ALP] <1.67 × ULN, ≥15% decrease in ALP, and total bilirubin ≤ULN) and ALP normalisation from 66% to 79% and from 26% to 42%, respectively. In those with elevated bilirubin at baseline, 43% achieved normalisation at year 2., Conclusions: Seladelpar was safe, and markedly improved biochemical markers of cholestasis and liver injury in patients with PBC. These effects were maintained or improved throughout the second year., Clinicaltrials: gov: NCT03301506; Clinicaltrialsregister.eu: 2017-003910-16., (© 2023 CymaBay Therapeutics, Inc and The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: The prognosis of acute kidney disease (AKD), defined as a glomerular filtration rate of <60 ml/min/1.73 m 2 or a rise in serum creatinine (sCr) of <50% for <3 months, is not clearly known., Aim: To study the prevalence, predictive factors and clinical outcomes in hospitalized cirrhotic patients with AKD., Methods: The North American Consortium for the Study of End-Stage Liver Disease prospectively enrolled hospitalized decompensated cirrhotic patients. Patients were separated into those with normal renal function (controls or C), AKD or stage 1 AKI as their worst renal dysfunction per International Club of Ascites definition and compared. Parameters assessed included demographics, laboratory data, haemodynamics, renal and patient outcomes., Results: 1244 patients with cirrhosis and ascites (C: 704 or 57%; AKD: 176 or 14%; stage 1 AKI: 364 or 29%) with similar demographics were enrolled. AKD patients had similar baseline sCr but higher hospital admission in the previous 6 months, and higher peak sCr, compared to controls, with their peak sCr being lower than that in stage 1 AKI patients (all P < .0001). The in-hospital and 30-day survival for AKD patients were intermediary between that for controls and stage 1 AKI patients (96% vs 91% vs 86%, P < .0001). The strongest predictors for AKD development while in hospital were the presence of a second infection (OR: 2.44) and diabetes (OR: 1.53)., Conclusions: Patients with AKD had intermediate outcomes between stage 1 AKI and controls. AKD patients, especially those with diabetes and a second infection, need careful monitoring and prompt treatment for AKD to prevent negative outcomes., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Patients with non-alcoholic steatohepatitis (NASH) and fibrosis stage ≥2 comprise a target population for pharmacotherapy. Liver biopsy, the reference standard for identifying this population, requires complete and accurate assessment of steatohepatitis and fibrosis. Aims To investigate the completeness of real-world NASH-related pathology reports, assess concordance between site pathologists and central expert interpretation of the histologic elements of NASH, and determine concordance between biopsy-diagnosed NASH and a pragmatic clinical definition of NASH., Methods: Liver pathology reports from 222 patients across 38 TARGET-NASH sites were analysed for documentation of the histologic features of NASH. Biopsy slides were over-read by a blinded central expert pathologist. Concordance of histologic scores and interpretation was assessed. Histologic concordance with a clinical definition of NASH was determined. TARGET-NASH clinically defined NASH: elevated ALT, hepatic steatosis on biopsy or imaging and ≥1 of the following: BMI ≥30 kg/m 2 , type 2 diabetes mellitus and dyslipidaemia., Results: Documentation of steatosis, lobular inflammation, portal inflammation and ballooning were missing from 21%, 35%, 46% and 40% of reports, respectively. There was slight-to-fair concordance (weighted kappa 0.01-0.35) between site and central pathologists for inflammatory features, and moderate concordance (weighted kappa 0.56-0.57) for fibrosis staging. Clinical definition of NASH was 75%-91% concordant (94%-95% sensitive) with biopsy-diagnosed NASH., Conclusions: There is substantial variability in reporting and grading NASH and fibrosis staging in clinical practice. This heterogeneity may adversely impact patient assessment and translation of practice guidelines into reality. The TARGET-NASH pragmatic clinical definition may serve as a valuable tool to accurately identify NASH patients in clinical practice., (© 2021 John Wiley & Sons Ltd.)

Background: Cirrhotic coagulopathy is a delicate interplay comprising deficiencies of both procoagulant and anticoagulant factors., Aim: To identify the relationship between international normalised ratio [INR] with periprocedural bleeding risk among patients with cirrhosis., Methods: Following a thorough database search of the primary literature, 29 studies were targeted for analysis, including 13 276 patients with cirrhosis undergoing indicated procedures., Results: There was no significant association between periprocedural bleeding events and pre-procedural INR [pooled odds ratio 1.52; 95% CI 0.99, 2.33; P = 0.06]. Furthermore, there was no significant difference in mean INR [pooled mean difference 0.05; 95% CI -0.03, 0.13; P = 0.23] upon comparison of patients who either did or did not experience a periprocedural bleeding event. Significant heterogeneity among some studies was primarily fuelled by significant subgroup effects of both specific procedure types performed. Additionally, there were markedly inconsistent transfusion practices across studies., Conclusions: INR fails to serve as a significant correlate for periprocedural bleeding events among patients with cirrhosis. Ideally, these new findings will help serve as a springboard for future studies, as well as to minimize transfusion of blood products, which command a myriad of adverse effects among patients with cirrhosis., (© 2020 John Wiley & Sons Ltd.)

Background: Hepatic encephalopathy (HE) can adversely affect outcomes in both in-patients and out-patients with cirrhosis., Aim: To define targets for improving quality of care in HE management in the multi-centre North American Consortium for End-Stage Liver Disease (NACSELD) cohort., Method: NACSELD in-patient cohort was analysed for (a) medication-associated precipitants, (b) aspiration pneumonia development, (c) HE medication changes, and (d) 90-day HE recurrence/readmissions. Comparisons were made between patients on no-therapy, lactulose only, rifaximin only or both. Ninety-day HE-readmission analysis was adjusted for MELD score., Results: Two thousand eight hundred and ten patients (1102 no-therapy, 659 lactulose, 154 rifaximin, 859 both) were included. HE on admission, and HE rates during hospitalisation were highest in those on lactulose only or dual therapy compared to no-therapy or rifaximin only (P < 0.001). Medications were the most prevalent precipitants (32%; 21% lactulose over/underuse, 5% benzodiazepines, 4% opioids, 1% rifaximin underuse, 1% hypnotics). Patients with medication-associated precipitants had a better prognosis compared to other precipitants. A total of 23% (n = 217) reached grade 3/4 HE, of which 16% developed HE-related aspiration pneumonia. Two thousand four hundred and twenty patients were discharged alive without liver transplant (790 no-therapy, 639 lactulose, 136 rifaximin, 855 both); 12.5% (n = 99) of no-therapy patients did not receive a discharge HE therapy renewal. Ninety-day HE-related readmissions were seen in 16% of patients (9% no-therapy, 9% rifaximin only, lactulose only 18%, dual 21%, <0.001), which persisted despite MELD adjustment (P = 0.009)., Conclusion: Several targets to improve HE management were identified in a large cohort of hospitalised cirrhotic patients. Interventions to decrease medication-precipitated HE, prevention of aspiration pneumonia, and optimisation of HE medications are warranted., (© 2019 John Wiley & Sons Ltd.)

Background & Aims: Daclatasvir has achieved high sustained virologic response (SVR) rates in diverse hepatitis C virus (HCV) populations. This study evaluated the long-term efficacy and safety of daclatasvir-based regimens administered during clinical studies., Methods: Patients enrolled within 6 months of parent study completion or protocol availability at the study sites. The primary objective was durability of SVR at follow-up Week 12 (SVR12). Secondary objectives included analysing HCV sequences in non-responders or responders who relapsed, and characterization of liver disease progression., Results: Between 24 February 2012 and 17 July 2015, this study enrolled and began following 1503 recipients of daclatasvir-based regimens (follow-up cut-off, 13 October 2015); 60% were male, 18% aged ≥65 years, 87% had genotype-1a (42%) or -1b (45%) infection, and 18% had cirrhosis. Median follow-up from parent study follow-up Week 12 was 111 (range, 11-246) weeks. 1329/1489 evaluable patients were SVR12 responders; 1316/1329 maintained SVR until their latest visit. Twelve responders relapsed by (n = 9) or after (n = 3) parent study follow-up Week 24; one was reinfected. Relapse occurred in 3/842 (0.4%) and 9/487 (2%) responders treated with interferon-free or interferon-containing regimens, respectively. Hepatic disease progression and new hepatocellular carcinoma were diagnosed in 15 and 23 patients, respectively. Among non-responders, emergent non-structural protein-5A (NS5A) and -3 (NS3) substitutions were replaced by wild-type sequences in 27/157 (17%) and 35/47 (74%) patients, respectively., Conclusions: SVR12 was durable in 99% of recipients of daclatasvir-based regimens. Hepatic disease progression and new hepatocellular carcinoma were infrequent. Emergent NS5A substitutions persisted longer than NS3 substitutions among non-responders., (© 2017 The Authors. Liver International Published by John Wiley & Sons Ltd.)

Background and Aims: This phase-2b study examined the safety and efficacy of an all-oral, interferon-free combination of the NS5A replication complex inhibitor daclatasvir (DCV), the NS3 protease inhibitor asunaprevir (ASV), and the nonnucleoside NS5B polymerase inhibitor beclabuvir (BCV) with or without ribavirin in patients with HCV genotype (GT) 1 infection., Methods: A total of 187 patients received 12 weeks of DCV 30 mg BID plus ASV 200 mg BID and BCV 150 mg BID (n = 86) or 75 mg BID with (n = 21) or without (n = 80) weight-based ribavirin BID. The primary endpoint was HCV RNA <25 IU/ml at post-treatment week 12 (SVR12)., Results: Overall, 90% of patients (169/187) in the combined treatment groups achieved SVR on or after post-treatment week 12. SVR rates were similar across subgroups (by mITT analysis), i.e. patients with cirrhosis (88%, 14/16), HCV GT-1a (90%, 137/155), and IL28B non-CC genotype (90%, 115/128). There were no drug-related serious AEs or grade 4 AEs. The most frequently reported AEs were headache, diarrhoea, fatigue and nausea. Addition of ribavirin to DCV+ASV+BCV was associated with decreased haemoglobin, compared with DCV+ASV+BCV alone. There were six grade 3/4 laboratory abnormalities noted, all unrelated to the study drugs. Viral breakthrough occurred in 2.5-4.8% of patients across groups and appeared unrelated to BCV dose or ribavirin inclusion., Conclusions: Results support phase 3 evaluation of a twice-daily, fixed-dose formulation of this DCV+ASV+BCV regimen with or without ribavirin in HCV GT-1-infected patients., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: RWJ-351647 is a selective V2 receptor antagonist that inhibits vasopressin-induced water reabsorption in the kidney., Aim: To investigate the safety and tolerability of RWJ-351647 compared with placebo after single oral dose administration to patients with cirrhosis and ascites, on a stable treatment with furosemide and spironolactone., Methods: Single oral doses of 1, 2 and 5 mg of RWJ-351647 were administered to 24 patients with ascites on stable concomitant diuretic treatment., Results: RWJ-351647 had a tmax of 1 to 1.1 h and mean half-life of 10.4-17.4 h. There was no affect on the pharmacokinetics of concomitant diuretics. Increases in cumulative urine volume and free water excretion, and a decrease in urine osmolality were noted in a dose-dependent manner reaching the statistical significance at the 5-mg dose. Four patients exhibited a decrease of > 2 kg in weight in the 24 h after dosing. RWJ-351647 was well tolerated, with no evidence of a dose-related increase in adverse events when compared with placebo. No changes in either serum chemistry or plasma AVP (arginine vasopressin) and renin levels were observed despite the observed aquaresis., Conclusion: RWJ-351647 is an effective aquaretic causing dose-dependent increases in urine output and free water clearance, when co-administered with conventional diuretics in patients with cirrhosis and ascites.

Background: It has been suggested that the introduction of model for end-stage liver disease (MELD) for organ allocation may reduce overall graft and patient survival since elevated serum creatinine is an important predictor of poor outcome after liver transplantation., Objective: In this study, we determined the outcomes of liver transplantation before (PreMELD group, 1998-February, 2002) and after (MELD group, March-December, 2002, n = 4642) the introduction of MELD score, and examined the impact of MELD scores on the outcome in the United States (US)., Patients & Methods: After excluding patients for a variety of reasons (children, live-donor, fulminant liver failure, patients with hepatoma and others who received extra MELD points, multiple organ transplantation, re-transplantation, incomplete data), there were 3227 patients in the MELD group. These patients were compared with 14,593 patients in the preMELD group after applying similar exclusion criteria. The survival was compared using Kaplan-Meier survival analysis and Cox regression survival analysis., Results: There was no difference in short-term (up to 10 months) graft and patient survival between MELD and preMELD groups. However, graft and patient survival was lower in patients with MELD score > or = 30 when compared with those with MELD score <30 after adjusting for the confounding variables., Conclusion: Introduction of MELD score for organ prioritization has not reduced the short-term survival of patients, but patients with MELD score of 30 or higher had a relatively poor outcome.

Background: A prolonged QTc interval has been reported in patients with liver disease. The objectives of our study were to determine whether a prolonged QTc interval was an independent predictor of mortality in patients with cirrhosis and to examine the effect of liver transplantation (LT) on QTc interval., Patients and Methods: We retrospectively studied two cohorts of patients - QTc interval was measured in 409 patients (pre-transplant group), and in 162 patients (transplant group) before and 6 months after LT. QT interval (mean) corrected (QTc) for ventricular rate was read from a 12-lead EKG. Patients with known cardiovascular disease or other risk factors that are known to cause a prolonged QTc interval were excluded., Results: Pre-transplant group. One hundred and sixty-two patients (40%) had a prolonged QTc interval (>440 ms). By binary logistic regression, age (P=0.005), alcoholic cirrhosis (P=0.007) and Child-Pugh scores (P=0.007) were independent predictors of prolonged QTc interval. Sixty-six patients died during a mean follow-up of 8.9 years. Although the Kaplan-Meier survival curve showed a lower survival in patients with a prolonged QTc interval (P=0.03 by log rank test), when survival was adjusted for the Child-Pugh score by Cox regression survival analysis, there were no survival differences in patients with and without prolonged QTc interval. Cox regression analysis showed that the Child-Pugh score (hazard ratio 1.5, CI 1.3-1.6, s<0.001) was the only independent predictor of survival. Transplant group. In this cohort, 91 patients (56%) had prolonged QTc (>440 ms) before LT. Mean QTc improved significantly after LT (429 +/- 29 ms vs. 450 +/- 39 ms P<0.002). Of the 91 patients with prolonged QTc, 50 (55%) normalized, three (3.3%) remained unchanged, 12 (13.3%) showed further prolongation, and 26 (28%) showed improvement but remained above normal limits. An additional nine patients who had normal QTc before LT developed prolonged QTc (>440 ms) after LT., Conclusion: A prolonged QTc interval was common in patients with cirrhosis, but its presence had no independent effect on mortality. Prolonged QTc returns to normal values in about half of the patients after LT, suggesting that liver disease plays a role, but may not be the only factor in the pathogenesis of prolonged QTc.

Unlabelled: Biliary complications following orthotopic liver transplantation (OLT) may be associated with significant morbidity and mortality. In this report, we reviewed our endoscopic experience of managing post OLT biliary complications in 79 patients over a 12-year period., Methods: OLT (n = 423) recipients between 10/86 and 12/98 were obtained from the transplant registry at the Johns Hopkins Hospital. OLT recipient who underwent at least one endoscopic retrograde cholangiography (ERC) were identified through a radiology database. Indications, findings and interventions performed were noted for each ERC report. Outpatient and inpatients medical records were reviewed for outcome and complications., Results: Seventy-nine (79/423, 18.7%) patients had at least one ERC for suspected biliary complication. Sixty-four (15.1%) patients had at least one or more biliary complications. The mean follow-up for patients with abnormal ERC was 33.9 months. Nineteen patients had bile leaks; 10 of these patients had leak at the exit site of the T-tube and five patients had at the anastomosis. Biliary stenting with or without endoscopic sphincterotomy led to resolution of bile leak in 16 patients. Three patients failed endoscopic therapy: one underwent surgery and two had percutaneous drainage. Twenty-five patients presented with biliary strictures. Nineteen strictures were at the anastomotic or just proximal to the anastomosis, one at the hilum (ischemic in nature) and three were at the distal, recipient common bile duct; one had strictures at the anastomosis as well as the distal recipient bile duct and another had diffuse intrahepatic strictures. Seventeen patients in the stricture group improved with endoscopic intervention. One patient was re-transplanted (diffuse intrahepatic strictures), but no patient underwent percutaneous drainage., Conclusions: ERC is safe and effective in the diagnosis and management of biliary complications following liver transplantation with choledochocholedochal anastomosis and obviates the need for surgical or percutaneous transhepatic approaches in majority of cases.