The introduction of immune checkpoint inhibitor (ICI) based therapies has significantly improved the prognosis of patients with unresectable hepatocellular carcinoma (HCC). However, the variable treatment response and the uncertain benefit in patients with advanced liver cirrhosis emphasise the urgent need for prognostic and predictive biomarkers guiding patient selection. The soluble urokinase plasminogen activator receptor (suPAR) is strongly associated with inflammation, liver cirrhosis and various types of cancer. In this study, we investigated suPAR as a potential novel biomarker in patients with unresectable HCC.

This multicenter retrospective study, conducted at three German tertiary care centers, included 90 patients with unresectable HCC and suPAR measurements prior to and during atezolizumab/bevacizumab therapy. Patients with liver cirrhosis without HCC (n = 235) and non-cirrhotic patients with other gastrointestinal tumours (n = 155) were selected as control cohorts.

Median suPAR levels were significantly higher in patients with liver cirrhosis compared to non-cirrhotic cancer patients. A strong association with parameters of liver function, but not with HCC characteristics, was observed. In patients with HCC receiving atezolizumab/bevacizumab, suPAR was the most accurate independent predictor of hepatic decompensation and overall survival (OS). In addition, suPAR was able to stratify the risk of hepatic decompensation within the different Child-Pugh classes.

SuPAR represents a promising novel biomarker in patients with HCC treated with ICI-based therapies and bears the potential to guide the selection of antitumoral systemic therapies in patients with advanced liver cirrhosis.

Cirrhosis is the end stage of many chronic liver diseases, which seriously affects the quality of life of patients. The alkaline phosphatase to albumin ratio (APAR) index is a new indicator related to the prognostic risk of many diseases. This study was aimed at exploring the association between the APAR index and the risk of all-cause mortality in patients with cirrhosis.

Patients with cirrhosis who were 18 years of age or older and admitted to the intensive care unit were included from the Medical Information Mart for Intensive Care IV (MIMIC-IV) - Version 3.0 database in this study. The primary endpoint of this study was all-cause mortality at 365- days, with secondary endpoints at 90-days and 28-days after admission. The hazard ratio (HR) and 95% CI between the APAR index and endpoints were calculated using the Cox proportional hazards model. A restricted cubic spline (RCS) regression model was created to explore the relationship between the APAR index and cirrhosis. Furthermore, we explored the predictive value of the APAR index in different populations of cirrhosis through subgroup analysis.

A total of 2,109 patients with cirrhosis were included from the MIMIC-IV database. After adjusting for potential covariates, APAR as a continuous variable was significantly positively associated with all-cause mortality at 28-days (HR: 2.007, 95% CI: 1.369, 2.948; P < 0.001), 90-days (HR: 2.392, 95% CI: 1.642, 3.495; P < 0.001), and 365-days (HR: 2.418, 95% CI: 1.660, 3.534; P < 0.001) in cirrhotic patients. When APAR was a categorical variable, compared with patients in the lower APAR group, the risk of 365-days all-cause mortality in patients of the higher APAR group significantly increased (HR: 1.451, 95%CI: 1.197, 1.758). APAR was linearly related to all-cause mortality at 28-days, 90-days and 365-days after admission (P for non-linearity = 0.221, 0.390, and 0.344, respectively). Subgroup analysis indicated that among patients with cirrhosis complicated with hepatorenal syndrome, those without spontaneous peritonitis or portal hypertension/esophageal varices, and those receiving human albumin infusion, elevated APAR levels were significantly associated with an increased risk of long-term death.

A higher APAR index is significantly associated with the risk of all-cause mortality in cirrhosis. APAR may be a potential biomarker for evaluating the long-term prognosis of critically ill patients with cirrhosis.

Acute-on-chronic liver failure (ACLF) represents the terminal and most lethal phase of acute decompensated cirrhosis. Systemic inflammation plays a critical role in the pathogenesis of ACLF. Systemic inflammation reaction syndrome (SIRS) is a marker of ongoing inflammation. Therefore, we aim to evaluate the relationship of sterile SIRS with hepatitis B virus (HBV)-related ACLF (HBV-ACLF).

HBV-ACLF patients with sterile SIRS who were hospitalized between December 2016 and December 2018 were retrospectively analyzed. All patients were followed up until 90 days. Risk factors associated with 90-day mortality and sterile SIRS development were assessed.

Among 151 HBV-ACLF patients without infection, 37 patients (24.5%) presented with or developed sterile SIRS. During the 90-day follow-up, 23 of the 37 patients with sterile SIRS died (62.2%), compared to 40 patients without sterile SIRS (35.1%, P  = 0.004). Univariate analysis showed that age, total bilirubin (TBIL), international normalized ratio, ammonia, presence of sterile SIRS, model for end-stage liver disease score, presence of complications, and organ failures were associated with 90-day mortality. In multivariate analyses, the presence of sterile SIRS was an independent risk factor for 90-day mortality. Among SIRS components, heart rate (HR) was the most frequently met criterion (56 patients, 37.09%). Patients who met the HR or temperature criterion had lower 90-day survival rate than those who did not (46.4 vs 65.3%, P  = 0.020; 16.7 vs 60.0%, P  = 0.020).

The presence of sterile SIRS in HBV-ACLF patients was closely associated with prognosis.

The pathogenesis of autoimmunity is incompletely understood which limits the development of effective therapies. New compelling evidence indicates that the pentose phosphate pathway (PPP) profoundly regulate lineage development in the immune system that are influenced by genetic and environmental factors during metabolic stress underlying the development of autoimmunity. The PPP provides two unique metabolites, ribose 5-phosphate for nucleotide biosynthesis in support of cell proliferation and NADPH for protection against oxidative stress. The PPP operates two separate branches, oxidative (OxPPP) and non-oxidative (NOxPPP). While the OxPPP functions in all organisms, the NOxPPP reflects adaptation to niche-specific metabolic requirements. The OxPPP primarily depends on glucose 6-phosphate dehydrogenase (G6PD), whereas transaldolase (TAL) controls the rate and directionality of metabolic flux though the NOxPPP. G6PD is essential for normal development but its partial deficiency protects from malaria. Although men and mice lacking TAL develop normally, they exhibit liver cirrhosis progressing to hepatocellular carcinoma. Mechanistic target of rapamycin-dependent loss of paraoxonase 1 drives autoimmunity and cirrhosis in TAL deficiency, while hepatocarcinogenesis hinges on polyol pathway activation via aldose reductase (AR). Accumulated polyols, such as erythritol, xylitol, and sorbitol, which are commonly used as non-caloric sweeteners, may act as pro-inflammatory oncometabolites under metabolic stress, such as TAL deficiency. The TAL/AR axis is identified as a checkpoint of pathogenesis and target for treatment of metabolic stress-driven systemic autoimmunity with relevance for inflammatory liver, renal and cardiovascular disorders, diabetes, carcinogenesis, and aging.

Portal hypertension (PHT) is a life-threatening complication of cirrhosis, often resulting in gastrointestinal bleeding that requires transjugular intrahepatic portosystemic shunt (TIPS). While TIPS effectively reduces portal pressure, predicting long-term survival remains challenging due to the multifactorial nature of patient outcomes. Accurate survival prediction tools are lacking, and existing models often omit critical factors such as portal vein diameter. This study aimed to develop and validate a nomogram incorporating key clinical and biochemical variables to predict 1-year and 2-year survival following TIPS in PHT patients. We hypothesized that this model would provide improved risk stratification and guide clinical decisions.

To develop and validate a nomogram for predicting 1-year and 2-year survival in PHT patients post-TIPS.

This retrospective cohort study included 848 TIPS-treated PHT patients with gastrointestinal bleeding from two tertiary hospitals (2013-2021). Mortality was the primary endpoint. Predictive variables were selected using least absolute shrinkage and selection operator regression, and a nomogram was developed with Cox regression to predict 1-year and 2-year survival. Model performance was evaluated through receiver operating characteristic curves, calibration plots, and decision curve analysis.

The mean age of the included (848) patients was 53.00 years ± 12.51, where 69.58% were men. Results showed that portal vein diameter, serum creatinine, potassium, and alpha-fetoprotein were the independent predictors of post-TIPS survival. Besides, the model showed strong discriminatory ability (C-index, 0.816 in the training set; 0.827 in the validation set) and good calibration. The area under the curve for 1-year and 2-year survival in the training set were 0.890 [95% confidence interval (CI): 0.802-0.948] and 0.838 (95%CI: 0.803-0.869), respectively. The area under the curve for 1-year and 2-year survival in the validation set were 0.934 (95%CI: 0.815-0.987) and 0.864 (95%CI: 0.811-0.907), respectively.

The developed nomogram could reliably predict 1-year and 2-year survival in patients undergoing TIPS for PHT-induced gastrointestinal bleeding.

The recent introduction of the term metabolic-dysfunction-associated steatotic liver disease (MASLD) has highlighted the critical role of metabolism in the disease's pathophysiology. This innovative nomenclature signifies a shift from the previous designation of non-alcoholic fatty liver disease (NAFLD), emphasizing the condition's progressive nature. Simultaneously, MASLD has become one of the most prevalent liver diseases worldwide, highlighting the urgent need for research to elucidate its etiology and develop effective treatment strategies. This review examines and delineates the revised definition of MASLD, exploring its epidemiology and the pathological changes occurring at various stages of the disease. Additionally, it identifies metabolically relevant targets within MASLD and provides a summary of the latest metabolically targeted drugs under development, including those in clinical and some preclinical stages. The review finishes with a look ahead to the future of targeted therapy for MASLD, with the goal of summarizing and providing fresh ideas and insights.

Nanoparticles (NPs) are beneficial for delivery of drugs in a variety of settings, serving to protect their cargo and allow for sustained release. Polymeric NPs offer several advantages as therapeutics carriers due to their tunable characteristics like size and shape, ease of manufacturing, and biocompatibility. Despite this, there are no polymeric NPs that are approved for treatment of liver diseases. This is surprising since─when administered intravenously─the majority of NPs accumulate in cells in the liver. NP characteristics like size and surface charge can be altered to affect distribution to the liver, and even cellular distribution, but the conjugation of targeting ligands onto the NP surface for specific receptors on the cells is an important approach for enhancing cell specific delivery. Enhancing cell-specific targeting of conjugated NPs in the liver has two major hurdles: 1) avoiding accumulation of NPs in the liver resident macrophages known as Kupffer cells, which are optimized to phagocytose particulates, and 2) overcoming the transport barriers associated with architectural changes of the diseased liver. To identify the structures and mechanisms most important in NP design, NP administration during ex vivo perfusion (EVP)─achieved by anatomically isolating an organ by perfusing it outside the body─may be the most important and efficient approach. However, EVP is currently underutilized in the NP field, with limited research published on NPs delivered during liver EVP, and therefore representing an opportunity for future investigations.

Carvedilol has limited research on decompensated cirrhosis. This study compared the effects of carvedilol, traditional nonselective beta blockers (NSBBs), including propranolol and nadolol, and other interventions in patients using carvedilol or traditional NSBBs for secondary prophylaxis of variceal hemorrhage (VH) and portal hypertension (PH)-related complications.

A systematic search of databases, including PubMed, Embase, Cochrane Library, and Scopus, was conducted through October 2023. Randomized controlled trials (RCTs) evaluating carvedilol or traditional NSBBs for secondary prophylaxis of VH were included. The outcomes were the occurrence of VH and portal PH-related complications, including new or worsening ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, and hepatorenal syndrome. A network meta-analysis was performed using a random-effects model.

A total of 60 RCTs involving 5,600 patients with a median Child Pugh score of 8.0 (range 6.8-10) were included. The risk of carvedilol plus variceal band ligation (VBL) on VH was lower than placebo (relative risk (RR) 0.24; 95% confidence interval (CI): 0.10-0.57), and the risk of carvedilol on new or worsening ascites was lower than placebo (RR = 0.10, 95%CI; 0.01-0.93). Traditional NSBBs plus VBL also had preventive effects on VH compared to placebo (RR = 0.31, 95%CI; 0.18-0.54). However, there were no differences between carvedilol and traditional NSBBs in other outcomes.

Carvedilol can prevent PH-related complications, including VH and new or worsening ascites, in cirrhosis patients with a history of VH. No significant differences were observed between the effects of carvedilol and traditional NSBBs, both combined with VBL.

Portal hypertension is the main pathophysiological driver of decompensation in patients with liver cirrhosis. Epithelial cell death markers, m30 and m65, correlate with hepatic injury and predict outcomes across various stages of liver disease. We aim (i) to evaluate whether portal hypertension itself contributes to liver outcome-relevant epithelial injury, and (ii) to analyse the capacity of m30/m65 to predict outcome in patients receiving a transjugular intrahepatic portosystemic shunt (TIPS) for refractory ascites.

Sixty-six patients undergoing TIPS placement for refractory ascites and 20 patients with compensated cirrhosis as controls were prospectively enrolled in this monocentric cohort study. Epithelial cell death markers were analysed pre-TIPS, as well as 1-3 and 6-9 months post-TIPS. The capacity of baseline levels of m30/m65 in predicting six-month transplant-free survival rates was analysed by multivariable Cox proportional hazards regression.

Levels of m30 and m65 were higher in patients with decompensated cirrhosis (pre-TIPS) compared with compensated cirrhosis (controls). Following correction of portal hypertension by TIPS and recompensation, both markers decreased over time, reaching levels comparable to patients with compensated cirrhosis. On multivariable analysis, pre-TIPS baseline levels of m30 and m65 were not predictive for six-month survival.

Correction of portal hypertension via TIPS reduces levels of epithelial cell death markers, indicating that portal hypertension is a driver of outcome-relevant, hepatic cell death in patients with decompensated cirrhosis. Baseline m30/m65 values do not affect six-month survival rates, which suggests that TIPS placement overcomes the unfavourable spontaneous prognosis otherwise indicated by elevated baseline m30/65 levels.

Background: Chronic liver disease (CLD) and cirrhosis contribute to approximately 2 million deaths annually, with primary causes including alcohol-related liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and chronic hepatitis B and C infections. Among these, MASLD has emerged as a significant global health concern, closely linked to metabolic disorders and a leading cause of liver failure and transplantation. Objective: This review aims to highlight the interplay between cirrhosis and cardiac dysfunction, emphasizing the pathophysiology, diagnostic criteria, and management of cirrhotic cardiomyopathy (CCM). Methods: A comprehensive literature review was conducted to evaluate the hemodynamic and structural cardiac alterations in cirrhosis. Results: Cirrhosis leads to portal hypertension and systemic inflammation, contributing to CCM, which manifests as subclinical cardiac dysfunction, impaired contractility, and electrophysiological abnormalities. Structural changes, such as increased left ventricular mass, myocardial fibrosis, and ion channel dysfunction, further impair cardiac function. Vasodilation in the splanchnic circulation reduces peripheral resistance, triggering compensatory tachycardia, while the activation of the renin-angiotensin-aldosterone system (RAAS) promotes fluid retention and increases cardiac preload. Chronic inflammation and endotoxemia exacerbate myocardial dysfunction. The 2005 World Congress of Gastroenterology (WCG) and the 2019 Cirrhotic Cardiomyopathy Consortium (CCC) criteria provide updated diagnostic frameworks that incorporate global longitudinal strain (GLS) and tissue Doppler imaging (TDI). Prolonged QT intervals and arrhythmias are frequently observed. Managing heart failure in cirrhotic patients remains complex due to intolerance to afterload-reducing agents, and beta-blockers require careful use due to potential systemic hypotension. The interaction between CCM and major interventions, such as transjugular intrahepatic portosystemic shunt (TIPS) and orthotopic liver transplantation (OLT), highlights the critical need for thorough preoperative cardiac evaluation and vigilant postoperative monitoring. Conclusions: CCM is a frequently underdiagnosed yet significant complication of cirrhosis, impacting prognosis, particularly post-liver transplantation. Early identification using echocardiography and thorough evaluations of arrhythmia risk in cirrhotic patients are critical for optimizing management strategies. Future research should focus on targeted therapeutic approaches to mitigate the cardiac burden in cirrhotic patients and improve clinical outcomes.

BackgroundHistorically, preclinical studies with rat models have been carried out only with male animals. Current regulations require sex parity in experimental procedures. Several studies have shown significant sex differences in rat models of liver fibrosis, but there is no data available in end-stage liver disease. The aim was to describe sex-related differences in a carbon tetrachloride (CCl4)-induced rat model of cirrhosis with ascites.MethodsFifty-two rats, 26 of each sex, fed ad libitum with phenobarbital-enriched drinking water (5 mmol/l). CCl4 was administered orally weekly, adjusting doses to weight changes after CCl4 administration until ascites development.ResultsMedian time to ascites development was significantly higher in females (19 vs. 10 weeks). Males showed significantly greater weight changes 48 h after CCl4 administration. The cumulative dose of CCl4 was significantly higher in females, both at the time of diagnosis of ascites (10.7 vs. 1.5 ml) and at week 10 (median time to ascites development in males) (3.9 vs. 1.5 ml). There were no significant sex differences in model associated mortality (31% males vs. 27% females).ConclusionsSex differences have a significant impact on CCl4-induced end-stage liver disease; classical models should be redesigned to appropriately encompass both sexes.

Cachexia is a systemic response syndrome characterized by disabling wasting during disease progression. This study aimed to elucidate factors associated with cachexia in patients with cirrhosis and to examine the impact of cachexia on patient survival.

This multicenter retrospective cohort study included patients with cirrhosis admitted to two distinct institutes in Japan. Cachexia was diagnosed according to the criteria proposed by the Asian Working Group for Cachexia. Factors associated with cachexia and the prognostic impact of cachexia were assessed using logistic regression and Cox proportional hazards regression, respectively.

Of the 723 patients enrolled (median [interquartile range] age, 71 [64-77] years; 456 [63%] were male; and 390 [54%] had viral hepatitis), 200 (28%) met the criteria for cachexia diagnosis, with the prevalence increasing with Child-Pugh class from A (17%) to B (40%) and C (66%). Multivariable logistic regression analysis revealed that age and indices of liver function reserve, including Child-Pugh score, were associated with cachexia, whereas sex, etiology of cirrhosis, and complications with hepatocellular carcinoma (HCC) were not. During a median follow-up period of 3.2 years, 264 (37%) patients died. Multivariable Cox regression analyses showed that cachexia was independently associated with increased mortality (adjusted hazard ratio, 1.59; 95% confidence interval, 1.43-1.77), along with factors related to liver function, HCC, and alcohol-associated liver disease as the etiology.

Cachexia is associated with poor liver function in patients with cirrhosis and is an independent prognostic factor.

Background/Objectives: Critically ill patients with liver cirrhosis impose a substantial health burden on the world. Rifaximin is a potential treatment option for such patients. Methods: We extracted critically ill patients with liver cirrhosis from the Medical Information Mart for Intensive Care (MIMIC) IV database. Based on study outcomes, the current study included prevention and treatment cohorts. A 1:1 propensity score matching (PSM) analysis was performed to match the characteristics of patients. The risk of ICU admission and intensive care unit (ICU), in-hospital, 90-day, and 180-day death were explored. Cox regression analyses were conducted, and hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Kaplan-Meier curves were further drawn to demonstrate the cumulative 90-day and 180-day survival rate. Results: Overall, 5381 critically ill patients with liver cirrhosis were included. In the prevention cohort, rifaximin could decrease the risk of ICU admission (HR = 0.427, 95%CI: 0.338-0.539, p < 0.001). In the treatment cohort, rifaximin could decrease the risk of ICU (HR = 0.530, 95%CI: 0.311-0.902, p = 0.019) and in-hospital death (HR = 0.119, 95%CI: 0.033-0.429, p = 0.001) in critically ill patients with liver cirrhosis. However, rifaximin could not decrease the risk of 90-day (HR = 0.905, 95%CI: 0.658-1.245, p = 0.541) and 180-day (HR = 1.043, 95%CI: 0.804-1.353, p = 0.751) death in critically ill patients with liver cirrhosis. Kaplan-Meier curve analyses also showed that rifaximin could not significantly decrease the 90-day (p = 0.570) and 180-day (p = 0.800) cumulative mortality. Conclusions: This study suggests that rifaximin can significantly decrease the risk of ICU admission and improve short-term survival but does not impact long-term survival in critically ill patients with liver cirrhosis.

Acute-on-chronic liver failure (ACLF) is a syndrome that develops in approximately 30% of patients hospitalised with cirrhosis and is characterised by an acute decompensation of liver function associated with extra-hepatic organ failures and a high short-term mortality. At present, no specific therapies are available for ACLF, and current management is limited to treatment of the precipitating event and organ support. Given the high prevalence and high mortality of this severe liver disease, there is an urgent need for targeted treatments. There is increasing evidence of the important role played by systemic inflammation and immune dysfunction in the pathophysiology of ACLF and a better understanding of these immune processes is resulting in new therapeutic targets. The aim of this review is to present an overview of ongoing studies of potentially promising therapies and how they could be utilised in the management of ACLF.

Acute-on-chronic liver failure (ACLF) is a severe condition in patients with decompensated liver cirrhosis, marked by high short-term mortality. Recent experimental and clinical evidence has linked intestinal dysfunction to both the initiation of ACLF as well as disease outcome. This review discusses the significant role of the gut-liver axis in ACLF pathogenesis, highlighting recent advances. Gut mucosal barrier disruption, gut dysbiosis, and bacterial translocation emerge as key factors contributing to systemic inflammation in ACLF. Different approaches of therapeutically targeting the gut-liver axis via farnesoid X receptor agonists, nonselective beta receptor blockers, antibiotics, and probiotics are discussed as potential strategies mitigating ACLF progression. The importance of understanding the distinct pathophysiology of ACLF compared with other stages of liver cirrhosis is highlighted. In conclusion, research findings suggest that disruption of intestinal integrity may be an integral component of ACLF pathogenesis, paving the way for novel diagnostic and therapeutic approaches to manage this syndrome more effectively.

Background Liver cirrhosis (LC) is characterized by the development of fibrosis and nodules within the liver, leading to progressive liver dysfunction. The mortality rate associated with LC has consistently remained high over the years. Prognostic tools such as the Child-Turcotte-Pugh (CTP) score and the Model for End-Stage Liver Disease (MELD) score are commonly used to predict mortality and assess the severity of LC. Both scoring systems rely on laboratory parameters, including serum albumin, total bilirubin, and international normalized ratio (INR) levels. However, the CTP score interpretation can be variable, and INR testing is not routinely performed in many clinical settings, which may limit its utility. This study aims to assess the MELD and CTP scores, along with a new predictive tool, in estimating 30-day mortality for patients with LC. Methodology This retrospective cohort study focuses on patients diagnosed with LC at Ngoerah Central General Hospital. Physical examination data and laboratory ratios, including neutrophil-to-lymphocyte ratio (NLR), aspartate transaminase (AST) to alanine transaminase (ALT) ratio (de Ritis), neutrophil-to-lymphocyte-to-albumin (NLA) ratio, albumin bilirubin index (ALBI), and blood urea nitrogen-to-albumin ratio (BAR), were collected from medical records. Optimal cutoff values were established using receiver operating characteristic (ROC) curves. Survival analysis was performed using the Kaplan-Meier method, and multivariate Cox regression was employed to determine the hazard ratio (HR) for each variable that was statistically significant as a predictor of 30-day mortality. Results In this study, a total of 140 samples were analyzed. Kaplan-Meier analysis revealed that hepatic encephalopathy (HE) met the criteria, while interaction analysis testing was required for other variables. Results from the multivariate Cox regression interaction model showed that ALBI-HE (HR = 1.743, 95% confidence interval [CI] 1.102-2.759, P = 0.018), BAR-HE (HR = 0.577, 95% CI 0.367-0.905, P = 0.017), and NLA-HE (HR = 0.332, 95% CI 0.195-0.563, P < 0.001) were significant independent predictors of 30-day mortality in LC. CTP, MELD, NLR, and de Ritis did not demonstrate statistical significance. ALBI-HE emerged as the strongest predictor based on its HR. Conclusions ALBI-HE, BAR-HE, and NLA-HE have emerged as novel predictors for assessing 30-day mortality in LC. ALBI-HE is the strongest predictor of 30-day mortality in LC.

Acute-on-chronic liver failure (ACLF) is a complex syndrome defined by the existence of different organ failures (OFs) in patients with chronic liver disease, mainly cirrhosis. Several definitions have been proposed to define the syndrome, varying in the grade of the subjacent liver disease, the type of precipitants and the organs considered in the definition. Liver, coagulation, brain, kidney, circulatory and pulmonary are the six types of OFs proposed in the different classifications, with different prevalence worldwide. Irrespective of the definition used, patients who develop ACLF present a hyperactive immune system, profound haemodynamic disturbances and several metabolic alterations that finally lead to organ dysfunction. These disturbances are triggered by different factors such as bacterial infections, alcoholic hepatitis, gastrointestinal bleeding or hepatitis B virus flare, among others. Because patients with ACLF present high short-term mortality, a prompt recognition is needed to start treatment of the trigger event and specific organ support. Liver transplantation is also feasible in carefully selected patients and should be evaluated.

Accurate prediction of survival in patients with cirrhosis is crucial, as patients who are unlikely to survive in the short-term need to be oriented to liver transplantation and to novel therapeutic approaches. Patients with acute decompensation of cirrhosis without or with organ dysfunction/failure, the so-called acute-on-chronic liver failure (ACLF), have a particularly high short-term mortality. Recognizing the specificity of this clinical situation, dedicated classifications and scores have been developed over the last 15 years, including variables (e.g. organ failures and systemic inflammation) not part of the formerly available cirrhosis severity scores, namely Child-Pugh score or MELD. For patients with acute decompensation of cirrhosis, it led to the development of a dedicated score, the Clif-C-AD score, independently validated. For more severe patients, three different scoring systems have been proposed, by European, Asian and North American societies namely Clif-C-ACLF, AARC score and NASCELD-ACLF respectively. These scores have been validated, and are widely used across the world. The differences and similarities between these scores, as well as their validation and limitations are discussed here. Even if these scores and classifications have been a step forward in favouring homogeneity between studies, and in helping making decisions for individual patients, their predictive value for mortality can still be improved as their area under the ROC curve does not exceed .8. Novel scores including biomarkers reflecting the pathophysiology of acute decompensation of cirrhosis might help reach that goal.

The identification of systemic inflammation (SI) as a central player in the orchestration of acute-on-chronic liver failure (ACLF) has opened new avenues for the understanding of the pathophysiological mechanisms underlying this disease condition. ACLF, which develops in patients with acute decompensation of cirrhosis, is characterized by single or multiple organ failure and high risk of short-term (28-day) mortality. Its poor outcome is closely associated with the severity of the systemic inflammatory response. In this review, we describe the key features of SI in patients with acutely decompensated cirrhosis and ACLF, including the presence of a high blood white cell count and increased levels of inflammatory mediators in systemic circulation. We also discuss the main triggers (i.e. pathogen- and damage-associated molecular patterns), the cell effectors (i.e. neutrophils, monocytes and lymphocytes), the humoral mediators (acute phase proteins, cytokines, chemokines, growth factors and bioactive lipid mediators) and the factors that influence the systemic inflammatory response that drive organ failure and mortality in ACLF. The role of immunological exhaustion and/or immunoparalysis in the context of exacerbated inflammatory responses that predispose ACLF patients to secondary infections and re-escalation of end-organ dysfunction and mortality are also reviewed. Finally, several new potential immunogenic therapeutic targets are debated.

Normothermic machine perfusion (NMP) is a technique for donor liver preservation and assessment in transplantation. NMP has gained momentum recently by enabling safer use of higher risk organs via organ viability assessment. It also offers a platform for investigating ex vivo organ biology.

In this exploratory study, we completed a complex vascular reconstruction of explanted, diseased livers from patients undergoing transplantation and then perfused them normothermically on a closed perfusion circuit. We compared these livers to non-diseased donor livers via perfusate samples collected during perfusion.

Five hepatectomized grafts and eight donor livers were perfused for 1 h or longer. Four hepatectomized livers cleared lactate, and all consumed glucose; all control livers cleared lactate, and seven utilized glucose. Significantly higher portal vein flows were achieved in the control group.

Our findings illustrate the feasibility of using closed-circuit NMP as a platform to study hepatectomized organs, which could reshape the research landscape in mechanisms of disease and applied therapeutics for patients with end-stage liver disease.

Acute-on-chronic liver failure (ACLF) is a critical syndrome that develops in patients with chronic liver disease and is characterized by acute decompensation, single- or multiple-organ failure and high short-term mortality. Over the past few decades, ACLF has been progressively recognized as an independent clinical entity, and several criteria and prognostic scores have been proposed and validated by different scientific societies. However, controversies still exist in some aspects across regions, which mainly involve whether the definition of underlying liver diseases should include cirrhosis and non-cirrhosis. The pathophysiology of ACLF is complicated and remains unclear, although accumulating evidence based on different aetiologies of ACLF shows that it is closely associated with intense systemic inflammation and immune-metabolism disorder, which result in mitochondrial dysfunction and microenvironment imbalance, leading to disease development and organ failure. In-depth insight into the biological pathways involved in the mechanisms of ACLF and potential mechanistic targets that improve patient survival still needs to be investigated. Omics-based analytical techniques, including genomics, transcriptomics, proteomics, metabolomics and microbiomes, have developed rapidly and can offer novel insights into the essential pathophysiologic process of ACLF. In this paper, we briefly reviewed and summarized the current knowledge and recent advances in the definitions, criteria and prognostic assessments of ACLF; we also described the omics techniques and how omics-based analyses have been applied to investigate and characterize the biological mechanisms of ACLF and identify potential predictive biomarkers and therapeutic targets for ACLF. We also outline the challenges, future directions and limitations presented by omics-based analyses in clinical ACLF research.

Ascites is the most common complication from cirrhosis related to portal hypertension and depicts the onset of hepatic decompensation. Ranging from uncomplicated to refractory ascites, the progression carries prognostic value by reflecting the deterioration of underlying cirrhosis and portal hypertension. Diuretics have been the mainstay of treatment to control ascites, but the side effects heighten when the dosage is escalated. Non-selective beta-blockers (NSBBs) are widely used nowadays to prevent hepatic decompensation and variceal hemorrhage. However, with worsening systemic vasodilation and inflammation when ascites progresses, patients on NSBBs are at risk of hemodynamic collapse leading to renal hypoperfusion and thus hepatorenal syndrome. Long-term albumin infusion was studied to prevent the progression of ascites. However, the results were conflicting. Sodium-glucose cotransporter-2 inhibitors are under investigation to control refractory ascites. With that, patients with refractory ascites may require regular large-volume paracentesis. With an aging population, more patients are put on anti-thrombotic agents and their risks in decompensated cirrhosis and invasive procedures have to be considered. In general, decompensated cirrhosis with ascites poses multiple issues to pharmacological treatment. In the present review, we discuss the challenges and controversies in the pharmacological treatment of ascites.

Serum insulin-like growth factor 1 (IGF-1), a hepatocyte-derived cytokine, has been suggested to reflect hepatic function reserve. The aim of this systematic review and meta-analysis was to investigate the association between serum IGF-1 levels on the admission and prognosis of patients with advanced liver diseases.

A thorough examination of the literature was conducted across various databases, namely PubMed, Embase, Web of Science, Wanfang, and CNKI, with the aim of identifying relevant cohort studies. The data were synthesized using the random-effects model, taking into account the potential impact of heterogeneity.

A total of 9 cohorts were included. Patients with a low serum level of IGF-1, as compared with those with a high IGF-1 at baseline, exhibited a significantly poorer transplant-free survival (risk ratio: 3.03, 95% confidence interval: 2.17 to 4.22, P < 0.001), with no significant heterogeneity observed ( P for Cochrane Q test = 0.92, I2 = 0%). A sensitivity analysis, which was conducted by excluding 1 study at a time, yielded consistent results (risk ratio: 2.94-3.24, P all < 0.05). In addition, consistent results were observed in further subgroup analyses based on various factors, including cutoffs of IGF-1, country of the study, patient diagnosis, methods for measuring serum IGF-1, follow-up duration, analytic model, and quality scores ( P for subgroup difference all > 0.05).

A diminished serum IGF-1 level on admission could potentially serve as an indicator for an unfavorable prognosis among patients afflicted with advanced liver disease, such as severe hepatitis and cirrhosis.

Post-paracentesis circulatory dysfunction (PPCD) is a well-known complication in patients with decompensated cirrhosis undergoing large-volume paracentesis (>5 L ascites removal). PPCD can cause acute kidney injury (AKI) and hyponatremia. Given the generally smaller body size observed in patients of Asian descent, we hypothesized that the removal of <5 L of ascitic fluid (modest-volume paracentesis; MVP) might also contribute to the development of PPCD. We investigated whether MVP could lead to AKI/hyponatremia in Thai patients with cirrhosis and identified the factor(s) associated with these outcomes. This was a retrospective, single-center study that included all consecutive patients with cirrhosis who underwent MVP at our unit between 2020 and 2021. Baseline characteristics and laboratory results obtained within 3 days prior to and 7 to 28 days following paracentesis were collected. The occurrence of AKI or hyponatremia was recorded, and the characteristics and laboratory findings of patients who developed these complications were compared with those who did not. During the study period, 73 MVPs were performed in 39 patients. Eight patients (20.5%) developed AKI/hyponatremia within 7 to 28 days of the procedure. Baseline serum sodium level was significantly lower in patients who developed AKI/hyponatremia compared to those who did not (131.0 ± 5.9 vs 135.6 ± 3.0 mEq/L, P = .004). A serum sodium cutoff value of 132 mEq/L showed a specificity and sensitivity of 0.9 and 0.63, respectively, for predicting the development of AKI/hyponatremia, with an area under the curve of 0.81. These findings highlight that PPCD resulted in AKI/hyponatremia, which was previously not anticipated, can indeed occur after paracentesis of <5 L in Thai cirrhotic patients. These results may have significant implications for clinical decision-making regarding the administration of albumin replacement therapy in Asian patients with cirrhosis who are to undergo paracentesis in future clinical practice.

The Freiburg index of post-TIPS survival (FIPS) defines a high-risk group of patients with significantly reduced survival following transjugular intrahepatic portosystemic shunt (TIPS) implantation. However, the clinical hallmarks responsible for these patients' unfavorable outcome remain to be identified. Therefore, the present study aimed to characterize the clinical course after TIPS implantation according to the FIPS.

A total of 1,359 patients with cirrhosis allocated to TIPS implantation for treatment of recurrent or refractory ascites or secondary prophylaxis of variceal bleeding from eight tertiary centers were retrospectively included. The patients' clinical course following TIPS placement was analyzed, stratified according to the FIPS. The primary study outcome was further decompensation within 90 days after TIPS; secondary outcomes were acute-on-chronic liver failure (ACLF) within 90 days and 1-year transplant-free survival.

Further decompensation after TIPS implantation was significantly more frequent in FIPS high-risk patients compared to low-risk patients (cumulative incidence function 0.58 vs. 0.38, p <0.001). Moreover, FIPS high-risk patients developed ACLF significantly more often (0.18 vs. 0.08; p = 0.008). Uni- and multivariable competing risk regression analyses confirmed that high-risk FIPS independently predicted further decompensation (subdistribution hazard ratio 1.974; 95% CI 1.531-2.544; p <0.001) and ACLF (subdistribution hazard ratio 2.586; 95% CI 1.449-4.616; p = 0.001) after TIPS. Importantly, further decompensation and ACLF after TIPS were associated with significantly reduced transplant-free survival.

The present study reveals that the FIPS predicts development of further decompensation and ACLF after TIPS implantation. These events are responsible for impaired transplant-free survival in FIPS high-risk patients. These results pave the way for the development of tailored clinical management strategies.

Prognostication after transjugular intrahepatic portosystemic shunt (TIPS) implantation is challenging. Several clinical scores have been proposed in this context, such as the Freiburg index of post-TIPS survival (FIPS). The FIPS can identify a high-risk group of patients with significantly reduced survival after TIPS. However, to understand the reasons for these patients' unfavorable outcome, their clinical course after TIPS needs to be characterized. This study reveals that the FIPS predicts development of further decompensation and acute-on-chronic liver failure after TIPS implantation, which are responsible for the poor prognosis of FIPS high-risk patients. Therefore, the present results may be useful for tailored decision making in patients allocated to TIPS implantation.

Acute-on-chronic liver failure (ACLF) is a condition associated with high mortality in the absence of liver transplantation. There have been various definitions proposed worldwide. The first consensus report of the working party of the Asian Pacific Association for the Study of the Liver (APASL) set in 2004 on ACLF was published in 2009, and the "APASL ACLF Research Consortium (AARC)" was formed in 2012. The AARC database has prospectively collected nearly 10,500 cases of ACLF from various countries in the Asia-Pacific region. This database has been instrumental in developing the AARC score and grade of ACLF, the concept of the 'Golden Therapeutic Window', the 'transplant window', and plasmapheresis as a treatment modality. Also, the data has been key to identifying pediatric ACLF. The European Association for the Study of Liver-Chronic Liver Failure (EASL CLIF) and the North American Association for the Study of the End Stage Liver Disease (NACSELD) from the West added the concepts of organ failure and infection as precipitants for the development of ACLF and CLIF-Sequential Organ Failure Assessment (SOFA) and NACSELD scores for prognostication. The Chinese Group on the Study of Severe Hepatitis B (COSSH) added COSSH-ACLF criteria to manage hepatitis b virus-ACLF with and without cirrhosis. The literature supports these definitions to be equally effective in their respective cohorts in identifying patients with high mortality. To overcome the differences and to develop a global consensus, APASL took the initiative and invited the global stakeholders, including opinion leaders from Asia, EASL and AASLD, and other researchers in the field of ACLF to identify the key issues and develop an evidence-based consensus document. The consensus document was presented in a hybrid format at the APASL annual meeting in Kyoto in March 2024. The 'Kyoto APASL Consensus' presented below carries the final recommendations along with the relevant background information and areas requiring future studies.