Tranexamic acid in upper gastrointestinal bleed in patients with cirrhosis: A randomized controlled trial.

BACKGROUND AND AIMS: Patients with Child-Turcotte-Pugh class B and C cirrhosis with upper gastrointestinal bleeding (UGIB) have systemic as well as localized (in the mucosa of the esophagus and stomach) fibrinolysis. The aim of this study was to evaluate the efficacy and safety of tranexamic acid in the treatment of acute UGIB in patients with cirrhosis. APPROACH AND RESULTS: A total of 600 patients with advanced liver cirrhosis (Child-Turcotte-Pugh class B or C) presenting with UGIB were randomly allocated to either the tranexamic acid (n=300) or the placebo group (n=300). The primary outcome measure was the proportion of patients developing 5-day treatment failure. Failure to control bleeding by day 5 was seen in 19/300 (6.3%) patients in the tranexamic acid group and 40/300 (13.3%) patients in the placebo group ( p =0.006). Esophageal endoscopic variceal ligation (EVL) site as a source of failure to control bleeding by day 5 among patients undergoing first-time esophageal EVL (excluding patients with a previous post-EVL ulcer as a source of bleed) was seen in 11/222 (4.9%) patients in the tranexamic acid group and 27/225 (1212.0%) patients in the placebo group ( p =0.005). However, 5-day and 6-week mortality was similar in the tranexamic acid and placebo groups. CONCLUSIONS: Tranexamic acid significantly reduces the failure to control bleeding by day 5 and failure to prevent rebleeding after day 5 to 6 weeks in patients with advanced liver cirrhosis (Child-Turcotte-Pugh class B or C) presenting with UGIB, by preventing bleeding from the EVL site.

Determinants of clinical response to empirical antibiotic treatment in patients with cirrhosis and bacterial and fungal infections-Results from the ICA "Global Study" (EABCIR-Global Study).

BACKGROUND: The administration of an appropriate empirical antibiotic treatment is essential in cirrhosis and severe bacterial infections. We aimed to investigate the predictors of clinical response of empirical antibiotic treatment in a prospective cohort of patients with cirrhosis and bacterial and fungal infections included in the International Club of Ascites "Global Study." METHODS: Patients hospitalized with cirrhosis and bacterial/fungal infection were prospectively enrolled at 46 centers. Clinical response to antibiotic treatment was defined according to changes in markers of infection/inflammation, vital signs, improvement of organ failure, and results of cultures. RESULTS: From October 2015 to September 2016, 1302 patients were included at 46 centers. A clinical response was achieved in only 61% of cases. Independent predictors of lack of clinical response to empirical treatment were C-reactive protein (OR = 1.16; 95% CI = 1.02-1.31), blood leukocyte count (OR = 1.39;95% CI = 1.09-1.77), serum albumin (OR = 0.70; 95% CI = 0.55-0.88), nosocomial infections (OR = 1.96; 95% CI = 1.20-2.38), pneumonia (OR = 1.75; 95% CI = 1.22-2.53), and ineffective treatment according to antibiotic susceptibility test (OR = 5.32; 95% CI = 3.47-8.57). Patients with a lack of clinical response to first-line antibiotic treatment had a significantly lower resolution rate of infections (55% vs. 96%; p < 0.001), a higher incidence of second infections (29% vs. 15%; p < 0.001), shock (35% vs. 7%; p < 0.001) and new organ failures (52% vs. 19 %; p < 0.001) than responders. Clinical response to empirical treatment was an independent predictor of 28-day survival ( subdistribution = 0.20; 95% CI = 0.14-0.27). CONCLUSIONS: Four out of 10 patients with cirrhosis do not respond to the first-line antibiotic therapy, leading to lower resolution of infections and higher mortality. Broader-spectrum antibiotics and strategies targeting systemic inflammation may improve prognosis in patients with a high degree of inflammation, low serum albumin levels, and severe liver impairment.

A global action agenda for turning the tide on fatty liver disease.

BACKGROUND AND AIMS: Fatty liver disease is a major public health threat due to its very high prevalence and related morbidity and mortality. Focused and dedicated interventions are urgently needed to target disease prevention, treatment, and care. APPROACH AND RESULTS: We developed an aligned, prioritized action agenda for the global fatty liver disease community of practice. Following a Delphi methodology over 2 rounds, a large panel (R1 n = 344, R2 n = 288) reviewed the action priorities using Qualtrics XM, indicating agreement using a 4-point Likert-scale and providing written feedback. Priorities were revised between rounds, and in R2, panelists also ranked the priorities within 6 domains: epidemiology, treatment and care, models of care, education and awareness, patient and community perspectives, and leadership and public health policy. The consensus fatty liver disease action agenda encompasses 29 priorities. In R2, the mean percentage of "agree" responses was 82.4%, with all individual priorities having at least a super-majority of agreement (> 66.7% "agree"). The highest-ranked action priorities included collaboration between liver specialists and primary care doctors on early diagnosis, action to address the needs of people living with multiple morbidities, and the incorporation of fatty liver disease into relevant non-communicable disease strategies and guidance. CONCLUSIONS: This consensus-driven multidisciplinary fatty liver disease action agenda developed by care providers, clinical researchers, and public health and policy experts provides a path to reduce the prevalence of fatty liver disease and improve health outcomes. To implement this agenda, concerted efforts will be needed at the global, regional, and national levels.

An artificial intelligence-generated model predicts 90-day survival in alcohol-associated hepatitis: A global cohort study.

BACKGROUND AND AIMS: Alcohol-associated hepatitis (AH) poses significant short-term mortality. Existing prognostic models lack precision for 90-day mortality. Utilizing artificial intelligence in a global cohort, we sought to derive and validate an enhanced prognostic model. APPROACH AND RESULTS: The Global AlcHep initiative, a retrospective study across 23 centers in 12 countries, enrolled patients with AH per National Institute for Alcohol Abuse and Alcoholism criteria. Centers were partitioned into derivation (11 centers, 860 patients) and validation cohorts (12 centers, 859 patients). Focusing on 30 and 90-day postadmission mortality, 3 artificial intelligence algorithms (Random Forest, Gradient Boosting Machines, and eXtreme Gradient Boosting) informed an ensemble model, subsequently refined through Bayesian updating, integrating the derivation cohort's average 90-day mortality with each center's approximate mortality rate to produce posttest probabilities. The ALCoholic Hepatitis Artificial INtelligence Ensemble score integrated age, gender, cirrhosis, and 9 laboratory values, with center-specific mortality rates. Mortality was 18.7% (30 d) and 27.9% (90 d) in the derivation cohort versus 21.7% and 32.5% in the validation cohort. Validation cohort 30 and 90-day AUCs were 0.811 (0.779-0.844) and 0.799 (0.769-0.830), significantly surpassing legacy models like Maddrey's Discriminant Function, Model for End-Stage Liver Disease variations, age-serum bilirubin-international normalized ratio-serum Creatinine score, Glasgow, and modified Glasgow Scores ( p < 0.001). ALCoholic Hepatitis Artificial INtelligence Ensemble score also showcased superior calibration against MELD and its variants. Steroid use improved 30-day survival for those with an ALCoholic Hepatitis Artificial INtelligence Ensemble score > 0.20 in both derivation and validation cohorts. CONCLUSIONS: Harnessing artificial intelligence within a global consortium, we pioneered a scoring system excelling over traditional models for 30 and 90-day AH mortality predictions. Beneficial for clinical trials, steroid therapy, and transplant indications, it's accessible at: https://aihepatology.shinyapps.io/ALCHAIN/ .

Combination of carvedilol with variceal band ligation in prevention of first variceal bleed in Child-Turcotte-Pugh B and C cirrhosis with high-risk oesophageal varices: the 'CAVARLY TRIAL'.

OBJECTIVES: Beta-blockers and endoscopic variceal band ligation (VBL) have been preferred therapies for primary prophylaxis of variceal bleeding. However, the choice of therapy in patients with advanced liver disease with high-risk varices is not clear. A comparison of these therapies alone or in combination to prevent the first variceal bleed in advanced cirrhosis patients was carried out. DESIGN: 330 Child-Turcotte-Pugh (CTP) B and C cirrhosis patients, with 'high-risk' varices were prospectively enrolled (n=110 per group) to receive carvedilol (group A), VBL (group B) or combination (group C). Primary endpoint was reduction in the incidence of first variceal bleed at 12 months. The secondary endpoints included overall mortality, bleed-related mortality, new-onset decompensation, change in hepatic vein pressure gradient (HVPG) and treatment-related adverse events. RESULTS: The patients were predominantly males (85.2%), aged 51.4±10.5 years with CTP score of 8.87±1.24, MELD score 15.17±3.35 and HVPG-16.96±3.57 mm Hg. The overall incidence of variceal bleed was 23.8% (n=78) at 1 year. Intention-to-treat analysis showed that the combination arm (group C) significantly reduced the incidence of first variceal bleed by 62.9% as compared with group B (HR 0.37, 95% CI 0.192 to 0.716, p<0.003) and by 69.3% as compared with group A (HR 0.31, 95% CI 0.163 to 0.578, <0.001). The overall mortality was 13.6% (45/330). The 1-year mortality in group C was lowest among the three groups (A, B, C=20%, 14.5%, 6.3%, p=0.012). Reduction in HVPG (20.8% vs 25.1%, p=0.54) and the rate of non-response to carvedilol (53.4% vs 41.25%, p=0.154) were not different between group A and C patients. The incidence of new-onset ascites, spontaneous bacterial peritonitis, shock, and acute kidney injury and postbleed organ failure was also comparable between the groups. CONCLUSION: In CTP B and C cirrhosis patients with high-risk varices, combination of carvedilol and VBL is more effective than either therapy alone, for primary prevention of variceal bleeding. TRIAL REGISTRATION NUMBER: NCT03069339.

Management of Portal vein Thrombosis in Cirrhosis.

Portal vein thrombosis (PVT) is one of the common complications of cirrhosis. The incidence of PVT correlates with liver disease severity-higher incidence in patients with Child-Turcotte-Pugh (CTP) C, large spontaneous portosystemic shunts, hepatofugal portal flow, and in the presence of hepatocellular carcinoma. PVT may worsen ascites, increase the risk and poor control of variceal bleeding. The occurrence of PVT may increase morbidity and lower survival after a liver transplant. Using statins prevents the occurrence of PVT, whereas beta-blockers may aggravate its occurrence. Cross-sectional imaging is mandatory for the precise diagnosis and classification of PVT. Symptomatic, occlusive PVT and candidacy for liver transplantation are the main indications for anticoagulation. Vitamin K antagonists, low-molecular-weight heparin, and newer anticoagulants are effective and safe in cirrhosis. Direct-acting oral anticoagulants are agents of choice in early cirrhosis (CTP A, B). The duration of anticoagulant therapy, predictors of response, and management of complications of cirrhosis while on therapy require in-depth knowledge and individualized treatment. Transjugular intrahepatic porto-systemic shunt can be considered in nonresponsive cases or when anticoagulants are contraindicated. This manuscript reviews the latest updated knowledge about managing PVT in cirrhosis.

Acute-on-chronic liver failure - steps towards harmonization of the definition!

Acute-on-chronic liver failure (ACLF), usually precipitated by alcohol misuse or viral reactivation, is characterised by rapid onset and usually reversible liver failure. Various definitions of ACLF have been proposed and widely used across the globe, including those by APASL, COSSH, EASL-CLIF, Japanese experts, and NACSELD. Although all the definitions have several similarities and connote high short-term mortality, a clear and standardised definition is still lacking, hampering research in this key area. In this review, we discuss the similarities and differences among various definitions and propose steps to harmonise EASL-CLIF, APASL, NACSELD, Japanese, and Chinese definitions of ACLF.

Secondary bile acids in portal blood contribute to liver regeneration in a rat model of partial hepatectomy.

Gut metabolites via the portal vein affect several liver functions, including regeneration. Here, we investigated gut microbiota-derived metabolites in portal and peripheral serum during liver regeneration. We developed rat models of 70% partial hepatectomy (PHx) with and without prior gut microbiota modulation by three-week antibiotic (Abx) treatment. Sham without Abx were used as controls and compared to sham with Abx. Liver regeneration at day 2 following PHx was assessed by expression of proliferating cell nuclear antigen (PCNA) protein in liver tissues and cyclin genes in primary hepatocytes. High pressure liquid chromatography-mass spectrometry (HPLC-MS) based portal and peripheral venous serum metabolomics was performed to identify differentially altered metabolites (DAMs). Compared to controls, rat livers at day 2 post-PHx showed significant upregulation in the average number of PCNA-positive cells, which positively correlated with the expression of cell cycle genes in hepatocytes. In Abx-treated PHx, we observed reduced PCNA-positivity and downregulation in gene expression of various cyclins in hepatocytes compared to PHx. We identified 224 DAMs between controls vs PHx and 189 DAMs between Abx-treated PHx vs PHx in portal serum. Many common DAMs showed opposite expression trends in PHx vs controls and then Abx+PHx vs PHx in portal serum, such as sphingosine-1-phosphate and deoxycholic acid. In vitro studies with deoxycholic acid demonstrated that it enhanced the viability and proliferation of primary hepatocytes and hepatocyte organoids. The study underscores the critical role of deoxycholic acid in portal blood in enhancing hepatocyte proliferation and subsequently, liver regeneration.

Regional Differences in Clinical Presentation and Prognosis of Patients With Post-Sustained Virologic Response Hepatocellular Carcinoma.

BACKGROUND & AIMS: Widespread use of direct-acting antivirals for hepatitis C virus infection has been paralleled with increased numbers of patients with hepatocellular carcinoma (HCC) after achieving sustained virologic response (post-SVR HCC) worldwide. Few data compare regional differences in the presentation and prognosis of patients with post-SVR HCC. METHODS: We identified patients with advanced fibrosis (F3/F4) who developed incident post-SVR HCC between March 2015 and October 2021 from 30 sites in Europe, North America, South America, the Middle East, South Asia, East Asia, and Southeast Asia. We compared patient demographics, liver dysfunction, and tumor burden by region. We compared overall survival by region using Kaplan-Meier analysis and identified factors associated with survival using multivariable Cox regression analysis. RESULTS: Among 8796 patients with advanced fibrosis or cirrhosis who achieved SVR, 583 (6.6%) developed incident HCC. There was marked regional variation in the proportion of patients detected by surveillance (range: 59.5%-100%), median maximum tumor diameter (range, 1.8-5.0 cm), and the proportion with multinodular HCC (range, 15.4%-60.8%). The prognosis of patients highly varied by region (hazard ratio range, 1.82-9.92), with the highest survival rates in East Asia, North America, and South America, and the lowest survival rates in the Middle East and South Asia. After adjusting for geographic region, HCC surveillance was associated with early stage detection (Barcelona Clinic Liver Cancer stage 0/A, 71.0% vs 21.3%; P < .0001) and lower mortality rates (adjusted hazard ratio, 0.29; 95% CI, 0.18-0.46). CONCLUSIONS: Clinical characteristics, including early stage detection, and prognosis of post-SVR HCC differed significantly across geographic regions. Surveillance utilization appears to be a high-yield intervention target to improve prognosis among patients with post-SVR HCC globally.

Rapid Electrochemical Detection of Bacterial Sepsis in Cirrhotic Patients: A Microscaffold-Based Approach for Early Intervention.

Sepsis is a dysregulated inflammatory response leading to multiple organ failure. Current methods of sepsis detection are time-consuming, involving nonspecific clinical signs, biomarkers, and blood cultures. Hence, efficient and rapid sepsis detection platforms are of utmost need for immediate antibiotic treatment. In the current study, a noninvasive rapid monitoring electrochemical sensing (ECS) platform was developed for the detection and classification of plasma samples of patients with liver cirrhosis by measuring the current peak shifts using the cyclic voltammetry (CV) technique. A total of 61 hospitalized cirrhotic patients with confirmed (culture-positive) or suspected (culture-negative) sepsis were enrolled. The presence of bacteria in the plasma was observed by growth kinetics, and for rapidness, the samples were co-encapsulated in microscaffolds with carbon nanodots that were sensitive enough to detect redox changes occurring due to the change in the pH of the surrounding medium, causing shifts in current peaks in the voltammograms within 2 h. The percentage area under the curve for confirmed infections was 94 and that with suspected cases was 87 in comparison to 69 and 71 with PCT, respectively. Furthermore, the charge was measured for class identification. The charge for LPS-absent bacteria ranged from -400 to -600 µC, whereas the charge for LPS-containing bacteria class ranged from -290 to -300 µC. Thus, the developed cost-effective system was sensitive enough to detect and identify bacterial sepsis.

Granulocyte Colony-Stimulating Factor Improves Prednisolone Responsiveness and 90-Day Survival in Steroid-Eligible Severe Alcohol-Associated Hepatitis: The GPreAH Study a Randomized Trial.

INTRODUCTION: Severe alcohol-associated hepatitis (SAH) carries high 1-month mortality. Corticosteroids provide a modest 28-day but not 90-day survival benefit, due to development of infections and organ failures. Granulocyte colony-stimulating factor (GCSF) has shown promise in patients with SAH by its immunomodulatory and regenerative capabilities. We studied the safety and efficacy of combination (GCSF + prednisolone, GPred) therapy in management of steroid-eligible patients with SAH. METHODS: Steroid eligible patients with SAH (discriminant function scores 32-90) were randomized to receive prednisolone (GrA, n = 42), GPred (GrB, n = 42), or GCSF alone (GrC, n = 42). GCSF was given as 150-300 mcg/d for 7 days followed by every third day for a maximum of 12 doses in 1 month. Prednisolone 40 mg/d was given for 7 days and continued for 28 days in responders (Lille score <0.45). RESULTS: Baseline characteristics of patient groups were comparable. On intention-to-treat analysis, the primary endpoint of 90-day survival was achieved in 64.3% (27/42) in prednisolone, 88.1% (37/42) in GPred, and 78.6%(33/42) in GCSF groups, respectively ( P = 0.03, prednisolone vs GPred). The 28-day survival was not different between the groups (85.7%, 95.2%, and 85.7%, respectively [ P = 0.27]). The GPred group had more responders by day 7 (71.4% vs 92.9% vs 76.2%, P = 0.037) and had greater reduction in discriminant function (-7.33 ± 4.78, -24.59 ± 3.7, -14.59 ± 3.41, P = 0.011) and MELDNa (-1.69 ± 1.26, -7.02 ± 1.24, -3.05 ± 0.83, P = 0.002) by day 90. The prednisolone-only group had higher incidence of new infections (35.7%, 19%, 7.1%, respectively, P < 0.002). Acute kidney injury (33.3%, 7.1%, 11.9%, P = 0.002), hepatic encephalopathy (35.7%, 9.5%, 26.2%, P = <0.001), and rehospitalizations (59.5%, 14.3%, 30.9%, P =<0.01) were lower in the GPred group. CONCLUSION: Addition of GCSF to prednisolone improves steroid responsiveness and 90-day survival with fewer infections and new onset complications in patients with SAH.

Tropifexor plus cenicriviroc combination versus monotherapy in nonalcoholic steatohepatitis: Results from the phase 2b TANDEM study.

BACKGROUND AND AIMS: With distinct mechanisms of action, the combination of tropifexor (TXR) and cenicriviroc (CVC) may provide an effective treatment for NASH. This randomized, multicenter, double-blind, phase 2b study assessed the safety and efficacy of TXR and CVC combination, compared with respective monotherapies. APPROACH AND RESULTS: Patients (N = 193) were randomized 1:1:1:1 to once-daily TXR 140 µg (TXR 140 ), CVC 150 mg (CVC), TXR 140 µg + CVC 150 mg (TXR 140 + CVC), or TXR 90 µg + CVC 150 mg (TXR 90 + CVC) for 48 weeks. The primary and secondary end points were safety and histological improvement, respectively. Rates of adverse events (AEs) were similar across treatment groups. Pruritus was the most frequently experienced AE, with highest incidence in the TXR 140 group (40.0%). In TXR and combination groups, alanine aminotransferase (ALT) decreased from baseline to 48 weeks (geometric mean change: -21%, TXR 140 ; -16%, TXR 140 + CVC; -13%, TXR 90 + CVC; and +17%, CVC). Reductions in body weight observed at week 24 (mean changes from baseline: TXR 140 , -2.5 kg; TXR 140 + CVC, -1.7 kg; TXR 90 + CVC, -1.0 kg; and CVC, -0.1 kg) were sustained to week 48. At least 1-point improvement in fibrosis stage/steatohepatitis resolution without worsening of fibrosis was observed in 32.3%/25.8%, 31.6%/15.8%, 29.7%/13.5%, and 32.5%/22.5% of patients in the TXR 140 , CVC, TXR 140 + CVC, and TXR 90 + CVC groups, respectively. CONCLUSIONS: The safety profile of TXR + CVC combination was similar to respective monotherapies, with no new signals. TXR monotherapy showed sustained ALT and body weight decreases. No substantial incremental efficacy was observed with TXR + CVC combination on ALT, body weight, or in histological end points compared with monotherapy.

Effect of midodrine on HVPG in advanced chronic liver disease and acute-on-chronic liver failure-A pilot study.

BACKGROUND AND AIMS: Nonselective beta-blockers (NSBB) are the mainstay for treatment of portal hypertension (PH), but require caution in decompensated cirrhosis (DC) or acute-on-chronic liver failure (ACLF) with hypotension, hyponatremia, acute kidney injury (AKI) or type 2 hepatorenal syndrome (HRS). Midodrine is oral, rapidly acting, α1-adrenergic agonist. We evaluated acute effects of midodrine on hepatic venous pressure gradient (HVPG) in DC and ACLF with contraindications to NSBB. METHODS: Patients of DC (n = 30) with grade III ascites and serum sodium (Na) <130/systolic blood pressure (SBP) <90/type II HRS (group I) and ACLF patients (n = 30) with Na <130/SBP <90/AKI (group II) were included. HVPG was done at baseline and repeated 3 h after 10 mg midodrine. Primary outcome was HVPG response (reduction by >20% or to <12 mmHg). RESULTS: In group I, midodrine significantly reduced HVPG (19.2 ± 4.6 to 17.8 ± 4.2, p = .02) and heart rate (HR) (86.3 ± 11.6 to 77.9 ± 13.1, p < .01) and increased mean arterial pressure (MAP) (74.1 ± 6.9 to 81.9 ± 6.6 mmHg, p < .01). In group II also, midodrine reduced HVPG (19.1 ± 4.1 to 17.0 ± 4.2) and HR (92.4 ± 13.7 to 84.6 ± 14.1) and increased MAP (85.4 ± 7.3 to 91.2 ± 7.6 mmHg), p < .01 for all. HVPG response was achieved in 3/30 (10%) in group I and 8/30 (26.7%) in group II. On logistic regression analysis, prerenal AKI (OR 11.04, 95% CI 1.83-66.18, p < .01) and increase in MAP (OR 1.22, 95% CI 1.03-1.43, p = .02) were independent predictors of response. Increase in MAP by 8.5 mmHg with midodrine had best cut-off with AUROC of .76 for response. CONCLUSION: In decompensated cirrhosis and ACLF patients with contraindications to NSBB, midodrine is useful in decreasing HVPG. Dose of midodrine should be titrated to increase MAP atleast by 8.5 mmHg.

Targeted HBx gene editing by CRISPR/Cas9 system effectively reduces epithelial to mesenchymal transition and HBV replication in hepatoma cells.

BACKGROUND AND AIMS: Hepatitis B virus X protein (HBx) play a key role in pathogenesis of HBV-induced hepatocellular carcinoma (HCC) by promoting epithelial to mesenchymal transition (EMT). In this study, we hypothesized that inhibition of HBx is an effective strategy to combat HCC. METHODOLOGY AND RESULTS: We designed and synthesized novel HBx gene specific single guide RNA (sgRNA) with CRISPR/Cas9 system and studied its in vitro effects on tumour properties of HepG2-2.15. Full length HBx gene was excised using HBx-CRISPR that resulted in significant knockdown of HBx expression in hepatoma cells. HBx-CRISPR also decreased levels of HBsAg and HBV cccDNA expression. A decreased expression of mesenchymal markers, proliferation and tumorigenic properties was observed in HBx-CRISPR treated cells as compared to controls in both two- and three- dimensional (2D and 3D) tumour models. Transcriptomics data showed that out of 1159 differentially expressed genes in HBx-CRISPR transfected cells as compared to controls, 70 genes were upregulated while 1089 genes associated with cell proliferation and EMT pathways were downregulated. CONCLUSION: Thus, targeting of HBx by CRISPR/Cas9 gene editing system reduces covalently closed circular DNA (cccDNA) levels, HBsAg production and mesenchymal characteristics of HBV-HCC cells. We envision inhibition of HBx by CRISPR as a novel therapeutic approach for HBV-induced HCC.

Comparative metabolome analysis reveals higher potential of haemoperfusion adsorption in providing favourable outcome in ACLF patients.

BACKGROUND AND AIMS: Acute-on-chronic liver failure (ACLF) is a serious illness associated with altered metabolome, organ failure and high mortality. Need for therapies to improve the metabolic milieu and support liver regeneration are urgently needed. METHODS: We investigated the ability of haemoperfusion adsorption (HA) and therapeutic plasma exchange (TPE) in improving the metabolic profile and survival in ACLF patients. Altogether, 45 ACLF patients were randomized into three groups: standard medical therapy (SMT), HA and TPE groups. Plasma metabolomics was performed at baseline, post-HA and TPE sessions on days 7 and 14 using high-resolution mass spectrometry. RESULTS: The baseline clinical/metabolic profiles of study groups were comparable. We identified 477 metabolites. Of these, 256 metabolites were significantly altered post 7 days of HA therapy (p < .05, FC > 1.5) and significantly reduced metabolites linked to purine (12 metabolites), tryptophan (7 metabolites), primary bile acid (6 metabolites) and arginine-proline metabolism (6 metabolites) and microbial metabolism respectively (p < .05). Metabolites linked to taurine-hypotaurine and histidine metabolism were reduced and temporal increase in metabolites linked to phenylalanine and tryptophan metabolism was observed post-TPE therapy (p < .05). Finally, weighted metabolite correlation network analysis (WMCNA) along with inter/intragroup analysis confirmed significant reduction in inflammatory (tryptophan, arachidonic acid and bile acid metabolism) and secondary energy metabolic pathways post-HA therapy compared to TPE and SMT (p < .05). Higher baseline plasma level of 11-deoxycorticosterone (C03205; AUROC > 0.90, HR > 3.2) correlated with severity (r2 > 0.5, p < .05) and mortality (log-rank-p < .05). Notably, 51 of the 64 metabolite signatures (ACLF non-survivor) were reversed post-HA treatment compared to TPE and SMT(p < .05). CONCLUSION: HA more potentially (~80%) improves plasma milieu compared to TPE and SMT. High baseline plasma 11-deoxycorticosterone level correlates with early mortality in ACLF patients.

Severity of Acute Portal Hypertension Determines the Clinical Outcomes in Severe Alcoholic Hepatitis.

BACKGROUND: Severe alcohol-associated hepatitis (SAH) presenting as acute-on-chronic liver failure (ACLF) has high mortality. Severe hepatic inflammation and ongoing hepatocellular cell death lead to rapid rise in portal pressure, a hyperdynamic circulation that might precipitate infections and organ failures. METHODS: Consecutive SAH patients were classified based on baseline HVPG measurement as 6to < 12 mmHg, 12to < 20 mmHg, and ≥ 20 mmHg. We analyzed portal hypertension severity in relation to fibrosis stage, ACLF at presentation, response to prednisolone, severity scores(MELD and Maddrey's Discriminant Function, mDF), and 90-day mortality. RESULTS: Of 819 SAH patients (94.6% ACLF, 85.4% histological cirrhosis, median MELD and mDF scores 25 and 66, respectively), 250(30.5%) had HVPG ≥ 20 mmHg. Patients with HVPG ≥ 20 mmHg more often had large esophageal varices (25.2%vs.13.2%; p-0.001), higher baseline MELD (27.1 ± 5.6vs.25.3 ± 5.2; p-0.001), and mDF(76.1 ± 16vs.68.4 ± 15.1; p-0.01) scores. No patient without ACLF had HVPG ≥ 20 mmHg. Moreover, during hospital course these patients had higher incidence of variceal bleed (17.2%vs.8.8%; p-0.001), acute kidney injury (36.4%vs.25.3%; p-0.001), and spontaneous bacterial peritonitis (6.4%vs.3.5%; p-0.05). Of 412(50.3%) eligible patients treated with prednisolone, 69.2% showed response at day 7(Lille's score < 0.45). 90-day mortality was 27.6%; and baseline MELD > 25.5[HR 1.78], HVPG ≥ 20 mmHg [HR 1.86], the presence of HE[HR 1.63], and prednisolone ineligibility due to sepsis[HR 1.27] were independent predictors. Mortality was unrelated to varices grade, variceal bleed, and histological cirrhosis. Repeat HVPG performed in 114(19.2%) patients after a median of 5.2 months showed significant decrease (3.6 mmHg; p-0.001) which correlated with improvement in MELD score(13points; p-0.05). CONCLUSION: Development of ACLF and complications in SAH are likely a result of acute rise in HVPG. "High-risk" SAH are SAH patients with HVPG ≥ 20 mmHg in the presence of ascites. Understanding the drivers for acute rise in portal pressure in SAH ACLF might help introduction of newer therapies.

Derivation of Splenic Stiffness in Subjects with Normal Liver Stiffness and No Vascular Liver Disease Using Transient Elastography with a Spleen-Dedicated Module: A Large Cross Sectional Study.

BACKGROUND: Liver and splenic stiffness measurements (LSM and SSM) are useful to predict varices and clinical decompensation in cirrhosis. SSM values are highly variable and overlapping and no guidelines exists on what constitutes normal SSM, that might limit interpretation of results. METHODS: Consecutive subjects with LSM < 6 kPa and reliable SSM (FibroScan630 Expert device with spleen-dedicated module) and no vascular liver disease were analysed for significant correlations of SSM values with age, sex, BMI, portal and splenic vein diameter, splenic diameter, liver fat and diabetes. Based on timeline of SSM, subjects were randomly assigned in 70:30 ratio into derivation [n = 502] and validation subset [n = 214]. RESULTS: Of 7200 subjects with simultaneous reliable LSM and SSM, 715 fulfilled the selection criteria (mean age: 43.8 ± 12.8 years, 67.2% male, mean BMI-26.4 ± 4.5 kg/m2). The mean SSM was 22.6 ± 5.8 kPa (c10-c90 percentile range: 15.2-31.3 kPa) and followed the normal distribution curve. In the derivation subset, mean SSM for males was higher than female (23.06 ± 6.2 vs. 21.78 ± 5.93 kPa; p = 0.028). SSM value correlated with LSM (r = 0.454, p = 0.001). Mean SSM in subjects with LSM 3-4, 4.1-5 and 5.1-6 kPa were 21.7 ± 5.8, 22.27 ± 5.67 and 23.76 ± 5.88 kPa (p value = 0.001). There was no difference in SSM based on age, BMI, diabetes and liver fat on ultrasound. Above results hold true for subjects in validation subset. CONCLUSION: SSM range in subjects with normal LSM and no vascular liver disease using spleen-dedicated module varies from 15.2 to 31.3 kPa, values being higher in male and not affected by Age, BMI, spleen size, liver fat and diabetes. Our results may serve as reference point in evaluation of SSM in compensated advanced liver disease patients.

Predictors and Outcomes of Post-transjugular Intrahepatic Portosystemic Shunt Liver Failure in Patients with Cirrhosis.

BACKGROUND: Post-transjugular intrahepatic portosystemic shunt (TIPS) liver failure (PTLF) is a serious complication of TIPS procedure with poor patient prognosis. This study tried to investigate the incidence of PTLF following elective TIPS procedure and evaluated possible predictive factors for the same. METHODS: A retrospective analysis of patients who underwent elective TIPS placement between 2012 and 2022 and was conducted to determine development of PTLF (≥ 3-fold bilirubin and/or ≥ 2-fold INR elevation from the baseline) within 30 days following TIPS procedure. Medical record review was done and factors predicting development of PTLF and the 90-day transplant-free survival was determined. RESULTS: Thirty of 352 (8.5%) patients developed PTLF within 30 days of TIPS (mean age 54.2 ± 9.8 years, 83% male). The etiology of cirrhosis was related to non-alcoholic steatohepatitis (NASH) in 50%, alcohol in 33.3%, and hepatitis B/C virus infection in 16.7% of the patients. The mean Child-Turcotte-Pugh (CTP) score was 9.5 ± 1.2 and mean model for end stage liver disease (MELD) score was 14.6 ± 4.5 at the time of admission in patients who developed PTLF. The indication for TIPS was recurrent variceal bleed in 50% (15 of 30) and refractory ascites in 46.7% (14 of 30) patients with PTLF. Multivariate analysis identified prior HE (OR 6.1; CI 2.57-14.5, p < 0.0001) and higher baseline CTP score (OR 1.47; CI 1.07-2.04; p = 0.018) as predictors of PTLF. PTLF was associated with significantly lower 90-day transplant-free survival, as compared to patients without PTLF (40% versus 96%, p < 0.001). CONCLUSION: Almost 10% of patients with cirrhosis develop post-TIPS liver failure and is associated with significant early mortality and morbidity. Higher baseline CTP score and prior HE were identified as predictors for PTLF.

Early Versus Standard Initiation of Terlipressin for Acute Kidney Injury in ACLF: A Randomized Controlled Trial (eTerli Study).

BACKGROUND AND AIMS: Terlipressin infusion is effective in hepatorenal syndrome (HRS-AKI). However, its efficacy for HRS-AKI resolution in acute-on-chronic liver failure (ACLF) patients has been suboptimal. Progression of AKI is rapid in ACLF. We investigated whether early initiation of terlipressin(eTerli) can improve response rates. METHODS: Consecutive ACLF patients with stage II/III AKI despite albumin resuscitation (40 g) were randomized to receive terlipressin at 2 mg/24 h plus albumin at 12 h (ET, n = 35) or at 48 h as standard therapy (ST, n = 35). (June 22, 2020 to June 10, 2022). The primary end-point was AKI reversal by day7. RESULTS: Baseline parameters including AKI stage and ACLF-AARC scores in two arms were comparable. Full AKI response at day 7 was higher in ET [24/35 (68.6%)] than ST arm [11/35 (31.4%; P 0.03]. Day3 AKI response was also higher in ET arm [11/35 (31.4%) vs. 4/35 (11.4%), P 0.04]. Using ST compared to ET [HR 4.3; P 0.026] and day 3 serum creatinine > 1.6 mg/dl [HR 9.1; AUROC-0.866; P < 0.001] predicted HRS-AKI non-response at day 7. ET patients showed greater improvement in ACLF grade, mean arterial pressure, and urine output at day 3, and required lower albumin within 7 days than ET arm (149.1 ± 41.8 g vs. 177.5 ± 40.3 g, P 0.006) and had lower 28-day mortality: 40% vs. 65.7%, P 0.031]. Early use of terlipressin than ST [HR 2.079; P 0.038], baseline HE [HR 2.929; P 0.018], and AKI persistence at day 3 [HR 1.369; P 0.011] predicted 28-day mortality. Fifteen (21.4%) patients had treatment related adverse effects, none was life threatening. CONCLUSION: In ACLF patients, early initiation of terlipressin for AKI persisting after 12 h of volume expansion with albumin helps in reduced short-term mortality and early AKI reversal with regression of ACLF stage. These results indicate need for change in current practice for terlipressin usage in HRS-AKI.

Ethanol with thioacetamide murine model of alcoholic liver disease identifies hepatic pathways as targets for the human disease.

INTRODUCTION AND OBJECTIVES: Hepatic proteome and gut microbiota alterations are known in alcohol-associated hepatitis (AAH). Current animal models sparsely mimic human AAH. We aimed to develop an murine model that closely resembled human AAH. MATERIALS AND METHODS: Male C57BL/6N mice were pair-fed control/incremental ethanol Lieber-DeCarli diets and thioacetamide (TAA) for 12-weeks to induce AAH. Hepatic proteome was analyzed using LC-MS/MS. Gut-bacteria was determined using 16s-rRNA sequencing. RESULTS: Mice exposed to EtOH+TAA displayed higher expression of liver triglycerides (1.5-fold, p = 0.001), pro-inflammatory (IL6, 1.5-fold, p = 0.002 and TNFα, 1.7-fold, p = 0.01), fibrotic (TGF-ß, 2.7-fold, p = 0.01 and Col1α1, 2-fold, p = 0.01) and oxidative markers (GSH and SOD (-1.5 fold, p = 0.004 & 0.005 respectively)) as compared to EtOH alone. Histology of EtOH+TAA liver displayed pericellular liver fibrosis, increased steatosis, and neutrophil infiltration, which resembled human AAH. In the 12wk EtOH+TAA group, Desulfobacteria, Campylobacteria, and Patescibacteria increased by 2-fold (p = 0.02). Pathway combined score (CS, log10) in EtOH+TAA treatment showed upregulated hepatic ethanol oxidation (CS=1.93), fatty acid biosynthesis (CS=2.48), necrosis (CS=1.59), collagen formation (CS=1.28) and hypoxia (CS=0.68) and downregulated fatty acid beta-oxidation (CS=2.37), PPAR signaling (CS=1.35) fatty acid degradation (CS=2.35), bile acid metabolism (CS=1.87), and oxidative phosphorylation (CS=1.50), as observed in human disease. CONCLUSIONS: Using an ethanol-thioacetamide combination in mice results in a faster establishment of AAH with fibrosis than previously known models. Differential protein expression strongly correlates with pathways found altered in human AAH, thus making the model mimic human disease better than other known models., respectively. Thioacetamide (TAA) was administered to enhance liver fibrosis and mimic human AAH.