Acute decompensation (AD) is defined as the development of complications related to portal hypertension and liver dysfunction that affect the progression of chronic liver disease (CLD) or liver cirrhosis (LC). Variations exist in patient demographics and prognostic outcomes of AD based on the aetiology of CLD, encompassing LC. However, limited research has been conducted to analyse these discrepancies across aetiologies.

The prospective Korean Acute-on-Chronic Liver Failure (KACLiF) cohort consisted of 1,501 patients who were hospitalized with AD of CLD from July 2015 to August 2018. In this study, we assess the clinical attributes and prognostic implications of AD with CLD/LC stratified by the aetiology.

Among 1,501 patients, the mean age was 54.7 years old and 1,118 patients (74.5%) were men. The common events of AD were GI bleeding (35.3%) and jaundice (35.0%). There was a median follow-up of 8.0 months (1.0-16.0 months). The most common aetiology of CLD was alcohol (n = 1021), followed by viral hepatitis (n = 206), viral hepatitis with alcohol-related (n = 129), cryptogenic (n = 108) and autoimmune (n = 37). Viral hepatitis with alcohol-related CLD showed a poor liver function profile and a high frequency of acute-on-chronic liver failure (ACLF) [22.1% vs. 19.6% (alcohol CLD), 8.1% (viral CLD), 5.6% (autoimmune related CLD and 16.0% (cryptogenic CLD)] with worse adverse outcomes (mortality or liver transplantation) than other aetiologies. The difference in aetiology was a significant factor for 28-day adverse outcomes in multivariate analysis even in a high MELD score (≥15), which indicated poor baseline liver function and prognosis (p < 0.001).

The aetiology of CLD constitutes a pivotal determinant influencing both short- and long-term adverse outcomes of AD in CLD, even among individuals presenting with elevated MELD scores. Notably, patients afflicted with viral hepatitis should exercise caution even in the consumption of modest quantities of alcohol that induced the exacerbations in the adverse outcomes associated with AD.

Early diagnosis and accurate prognostic evaluation are important for guiding clinical treatment and reducing mortality in patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). The present study established novel prognostic scoring models to guide the clinical treatment of patients with HBV-ACLF. We performed a retrospective analysis of clinical data from two cohorts of patients diagnosed with HBV-ACLF. By comparing differences in baseline characteristics and clinical indicators between the survival (n = 102) and dead (n = 64) groups in the derivation cohort(n = 166), four laboratory indicators (age, INR, TBIL, and HBeAg status) and three clinical signs (extrahepatic infection, ascites, and hepatic encephalopathy) were identified as independent risk factors. Logistic regression and nomogram models were used to construct three novel predictive models. By comparing the death and survival groups, we found that the three new models had higher predictions for AUROC (average of 0.856) than the three old models (average of 0.773). Model 1 had the strongest predictive power for the short-term survival rate of HBV-ACLF patients. Finally, we verified the predictive value of the new models for HBV-ACLF in a validation cohort (n = 42), and the Model 2 demonstrated good predictive accuracy for the 30-day survival rate of patients. The novel model based on seven predictors could accurately predict short-term mortality in patients with HBV-ACLF, which is promising for guiding clinical management and addressing the aetiological differences in Asian populations.

Liver disease, responsible for around two million deaths annually, remains a pressing global health challenge. Microbial interactions within the microbiota-gut-liver axis play a substantial role in the pathogenesis of various liver conditions, including early chronic liver disease (eCLD), chronic liver disease (CLD), acute liver failure (ALF), acute-on-chronic liver failure (ACLF), non-alcoholic fatty liver disease (NAFLD), steatohepatitis, and cirrhosis. This study aimed to identify key molecular signatures involved in liver disease progression by analyzing transcriptomic and gut microbiome data, and to evaluate their diagnostic utility using machine learning models.

Transcriptomic analysis identified differentially expressed genes (DEGs) that, when integrated with regulatory elements microRNAs, transcription factors, receptors, and the gut microbiome highlight disease-specific molecular interactions. To assess the diagnostic potential of these molecular signatures, a two-step analysis involving principal component analysis (PCA) and Random Forest classification was conducted, achieving accuracies of 75% for ALF and 89% for NAFLD. Additionally, machine learning algorithms, including K-neighbors, multi-layer perceptron (MLP), decision tree, Random Forest, logistic regression, gradient boosting, CatBoost, Extreme Gradient Boosting (XGB), and Light Gradient Boosting Machine (LGBM), were applied to gene expression data for ALF and NAFLD.

Key genes including CLDN14, EGFR, GSK3B, MYC, and TJP2, alongside regulatory miRNAs let-7a-5p, miR-124-3p, and miR-195-5p and transcription factors NFKB1 and SP1 may be suggested as critical to liver disease progression. Additionally, gut microbiota members, Dictyostelium discoideum and Eikenella might be novel candidates associated with liver disease, highlighting the importance of the gut-liver axis. The Random Forest model reached 75% accuracy and 83% area under the curve for ALF, while NAFLD classification achieved 100% accuracy, precision, recall, and area under the curve underscoring robust diagnostic potential.

This study establishes a solid foundation for further research and therapeutic advancement by identifying key biomolecules and pathways critical to liver disease. Additional experimental validation is needed to confirm clinical applicability.

Chronic liver diseases (CLD) may progress to cirrhosis, decompensation and death. An intervening insult may lead to acute decompensation (AD); patients with AD may fulfil criteria for acute-on-chronic liver failure (AD-ACLF). While the outcome of ACLF and priority for liver transplantation have been studied, data on outcome in a non-transplant setting is sparse. We evaluated three international consensus criteria for definition of ACLF to determine the number of patients satisfying these definitions and their accuracy in predicting mortality and compare mortality in a non-transplant setting.

Total 341 consecutive patients with CLD of any etiology were enrolled and followed up. All significant clinical events and changes in laboratory data were noted to classify patients into no AD, AD-ACLF and AD-non-ACLF.

Total 150 (44%) patients had non-alcoholic fatty liver disease as etiology. As many as 197 (57.8%) patients had AD; of these, 54 (27.4%) met at least one definition of ACLF: 50 (92.6%) fulfilled EASL-CLIF criteria, 31 (57.4%) NACSELD and 22 (40.7%) APASL. The most common precipitating event (59.2%) was infection. Forty-six (13.5%) patients died during the study period - 52% of those with AD-ACLF and 12.6% with AD-non-ACLF (p < 0.00001). The accuracy of EASL-CLIF, NACSELD and APASL definitions in determining mortality was 79.7%, 86.3% and 77.7%, respectively.

Total 16% of patients with CLD developed AD-ACLF by any definition; one-half of them died. EASL-CLIF criteria identified maximum number of patients with AD-ACLF, but NACSELD criteria had highest accuracy for predicting mortality in AD-ACLF. These findings may help prioritize patients with ACLF for intensive care in the absence of easy access to liver transplantation.

The AST/ALT ratio is a biochemical marker associated with poor clinical outcomes in various patients, but its role in severe cirrhosis is unclear. This study investigated the relationship between the AST/ALT ratio and mortality in the intensive care unit (ICU) patients with cirrhosis.

This retrospective cohort study analyzed 2,090 liver cirrhosis patients from the MIMIC-IV database, focusing on their first ICU admission between 2008 and 2019. The AST/ALT ratio, measured within 24 h of admission, was the exposure variable, and the main outcome was 28-day mortality. A multivariable logistic regression model evaluated the link between the AST/ALT ratio and mortality. Nonlinear relationships were explored using smooth curve fitting and saturation effect analyses. Stratified analyses and interaction tests were also performed based on demographic and clinical characteristics.

The study involved 2,090 critically ill liver cirrhosis patients, averaging 59.1 years old, with 65% male and a 28-day post-ICU admission mortality rate of 29%. The AST/ALT ratio was linked to mortality risk (adjusted odds ratio (OR) 1.1, 95% confidence interval (CI) 1.0-1.2; p = 0.015), showing a nonlinear pattern with a critical point at 3.6. Below this, each unit increase raised mortality risk by 40% (adjusted OR 1.4, 95% CI 1.2-1.6, p < 0.001), but the effect plateaued beyond this level (adjusted OR 1.0, 95% CI 0.8-1.1, p = 0.600). Subgroup analyses confirmed the consistent association, with interaction P values over 0.05.

The AST/ALT ratio is an independent predictor of 28-day mortality in critically ill cirrhotic patients, with a nonlinear relationship (risk increases up to a ratio of ~ 3.6, then plateaus). This marker could enhance ICU risk stratification and inform clinical decision-making.

Over the last few years, the approach to clinical recognition and risk stratification of advanced liver disease has changed substantially, and liver cirrhosis has been increasingly conceptualized as a clinical rather than a histopathologic condition. In this Clinical Insight, we summarize the latest developments on recognition and management of 'clinically' advanced chronic liver disease.

In patients with acutely decompensated cirrhosis (ADC) who present with clinically apparent precipitants (i.e., infections, acute liver injury), alterations in blood markers of inflammation associate with progression toward severe phenotypes (e.g., acute-on-chronic liver failure [ACLF]). However, it is unclear whether alterations in blood inflammatory markers associate with progression of ADC independently of precipitants.

We prospectively enrolled 394 patients admitted for ADC who were classified into four phenotypes of increasing severity: no organ dysfunction (n = 168), organ dysfunction alone (n = 72), organ failure without ACLF (n = 91), and ACLF (n = 63). Clinical blood cell counts and serum levels of inflammatory markers (including soluble markers related to type-1, type-2, and type-3 inflammation) were obtained at enrollment. Ordinal regression with adjacent categories logit model adjusted for confounders (including precipitants) was used to analyze associations between changes in each blood inflammatory marker and the worsening of ADC.

Inflammatory markers that were associated with a higher risk of progressing to the next more severe stage were as follows: increasing neutrophil counts (adjusted common odds ratio [cOR] 1.17, 95% CI 1.06-1.28); increasing levels of the type-2 cytokine interleukin (IL)-25 (cOR 1.21, 95% CI 1.06-1.39), type-3 cytokines IL-6 (cOR 1.15, 95% CI 1.02-1.28) and IL-22 (cOR 1.16, 95% CI 1.03-1.30), or anti-inflammatory soluble CD163 (cOR 1.94, 95% CI 1.58-2.38); decreasing lymphocyte counts (cOR 0.77, 95% CI 0.68-0.87); or decreasing levels of the type-1 cytokine IFN-γ (cOR 0.85, 95% CI 0.75-0.95).

Among patients with ADC, alterations in blood levels of cytokines related to type-1, type-2 and type-3 inflammation, together with neutrophilia, lymphopenia and elevated anti-inflammatory signals were individually associated with an increased risk of progressing toward ACLF, independently of the presence of clinically apparent precipitants.

This study reveals that among patients with acutely decompensated cirrhosis, alterations in blood levels of cytokines related to type-1, type-2 and type-3 inflammation, together with neutrophilia, lymphopenia and elevated anti-inflammatory signals were individually associated with increased risk of progressing toward acute-on-chronic liver failure, independently of the presence of clinically apparent precipitants. These findings raise questions about the role of impaired barrier tissues and dysregulated production of blood immune cells in the pathophysiology of severe phenotypes of acutely decompensated cirrhosis, stimulating research to identify potential new biomarkers and targets for novel therapeutic approaches.

The utilization of extracorporeal liver support systems is increasingly prevalent for the management of acute-on-chronic liver failure in clinical settings. Yet, the efficacy of these interventions in terms of tangible clinical benefits for patients remains a matter of debate, underscoring the need for meta-analysis.

An updated meta-analysis was performed to elucidate the relationship between the application of extracorporeal liver support versus standard pharmacological treatment and the prognostic endpoints of patient survival, specifically assessing 1-month and 3-month mortality rates, as well as the incidence of complications such as hepatic encephalopathy, spontaneous bacterial peritonitis, and hepatorenal syndrome. Literature were searched via PubMed, EMBASE, and Web of Science.

The meta-analysis revealed the following: the odds ratio for 1-month mortality was 0.63 (95% confidence interval [CIs]: 0.51-0.76), for 3-month mortality was 0.70 (95% CI: 0.61-0.81), for hepatic encephalopathy was 0.81 (95% CI: 0.67-0.97), for spontaneous bacterial peritonitis was 0.66 (95% CI: 0.44-0.99), and for hepatorenal syndrome was 0.68 (95% CI: 0.51-0.92). These results suggest that patients with acute-on-chronic liver failure undergoing extracorporeal liver support system therapy have significantly better survival rates and lower complication incidences compared to those receiving conventional drug therapy. Further subgroup analysis indicated that patients with lower model for end-stage liver disease (MELD) scores and reduced total bilirubin (Tbil) levels demonstrated greater benefits from extracorporeal hepatic support.

This study establishes that in the management of acute-on-chronic liver failure, extracorporeal liver support systems confer a survival advantage and reduce complications relative to standard pharmacotherapy.

The use of methylprednisolone (MP) is still controversial for hepatitis B virus related acute-on-chronic liver failure (HBV-ACLF). We aimed to explore the change in dendritic cells (DCs) during MP treatment in HBV-ACLF to guide the use of MP to improve patient's prognosis.

Patients with HBV-ACLF were prospectively allocated to groups given methylprednisolone intravenously (1.5 mg/kg/day for the first 3 days, 1 mg/kg/day for the second 2 days, and 0.5 mg/kg/day for the last 2 days, MP group, n = 36) plus standard treatment or standard treatment only (CM group, n = 34). The phenotype [myeloid and plasmacytoid DCs (mDCs, pDCs)] and function of DCs (IL-12 and IFN-α production) were measured at baseline (0d), 3d, 7d, 10d, 14d, 28d, and then monthly until 3 months. Patients' survival was assessed until day 90.

The 3-month survival rate was significantly higher in the MP group than the control (72.0 % vs. 35.5 %，P < 0.01). The phenotype and function of DCs were suppressed in the MP group. The mDCs counts was lower in non-survivors compared to survivors at baseline. Patients with a decline in mDCs counts at the 7th day and a continuous increase in mDCs counts from the 10th day presented a better outcome for patients with MP treatment. Bilirubin was the only relative factor for the restoration of mDCs in the MP group (odds ratio, 0.991; 95 % confidence interval, 0.984-0.999; P = 0.023).

Methylprednisolone could improve the outcome of HBV-ACLF by inhibiting the circulating mDCs counts. And the recovery of mDCs counts after methylprednisolone treatment could represent a favorable response. We can consider monitoring the circulating DCs counts to guide the use of MP in HBV-ACLF in order to improve patient outcomes.

Major advances in managing critically ill patients with liver disease have improved their prognosis and access to intensive care facilities. Acute-on-chronic liver failure (ACLF) is now a well-defined disease and these patients can be fast-tracked for liver transplantation (LT) with good outcomes if there are no contraindications. In acute liver failure, plasma exchange has improved prognosis for patients not eligible for immediate transplant. Further advances in novel therapies and refinement of the criteria for early LT in ACLF and also clinical implementation of artificial intelligence tools will probably constitute the next major breakthroughs in critically ill patients with liver disease.

The liver fulfils a plethora of vital functions and, due to their importance, liver dysfunction has life-threatening consequences. Liver disorders currently account for more than two million deaths annually worldwide and can be classified broadly into three groups, considering their onset and aetiology, as acute liver diseases, inherited metabolic disorders and chronic liver diseases. In the most advanced and severe forms leading to liver failure, liver transplantation is the only treatment available, which has many associated drawbacks, including a shortage of organ donors. Cell therapy via fully mature cell transplantation is an advantageous alternative that may be able to restore a damaged organ's functionality or serve as a bridge until regeneration can occur. Pioneering work has shown that transplanting adult hepatocytes can support liver recovery. However, primary hepatocytes cannot be grown extensively in vitro as they rapidly lose their metabolic activity. Therefore, different cell sources are currently being tested as alternatives to primary cells. Human pluripotent stem cell-derived cells, chemically induced liver progenitors, or 'liver' organoids, hold great promise for developing new cell therapies for acute and chronic liver diseases. This Review focuses on the advantages and drawbacks of distinct cell sources and the relative strategies to address different therapeutic needs in distinct liver diseases.

Astragaloside IV (C41H68O14, AS-IV) is a naturally occurring saponin isolated from the root of Astragalus membranaceus, a widely used traditional Chinese botanical drug in medicine. In recent years, AS-IV has attracted considerable attention for its hepatoprotective properties, which are attributed to its low toxicity as well as its anti-inflammatory, antioxidant and antitumour effects. Numerous preclinical studies have demonstrated its potential in the prevention and treatment of various liver diseases, including multifactorial liver injury, metabolic-associated fatty liver disease, liver fibrosis and liver cancer. Given the promising hepatoprotective potential of AS-IV and the growing interest in its research, this review provides a comprehensive summary of the current state of research on the hepatoprotective effects of AS-IV, based on literature available in databases such as CNKI, PubMed, ScienceDirect, Google Scholar and Web of Science. The hepatoprotective mechanisms of AS-IV are multifaceted, encompassing the inhibition of inflammatory responses, reduction of oxidative stress, improvement of insulin and leptin resistance, modulation of the gut microbiota, suppression of hepatocellular carcinoma cell proliferation and induction of tumour cell apoptosis. Notably, key molecular pathways involved in these effects include Nrf2/HO-1, NF-κB, NLRP3/Caspase-1, JNK/c-Jun/AP-1, PPARα/FSP1 and Akt/GSK-3β/β-catenin. Toxicity studies indicate that AS-IV has a high level of safety. In addition, this review discusses the sources, physicochemical properties, and current challenges in the development and clinical application of AS-IV, providing valuable insights into its potential as a hepatoprotective agent in the pharmaceutical and nutraceutical industries.

Acute-on-chronic liver failure (ACLF) is a major clinical event in cirrhosis that is characterized by high mortality rates and a short window for liver transplantation. N-terminal pro-B-type natriuretic peptide (NT-proBNP) has been suggested as a prognostic biomarker in cirrhosis. However, its accuracy in predicting the development of ACLF or mortality in candidates for liver transplantation remains unknown. This observational, retrospective, single-center study included 277 consecutive patients with cirrhosis who were listed for liver transplantation between 2014 and 2020 in Hospital Italiano, Buenos Aires, Argentina. Clinical data, including sarcopenia, serum cystatin C (CysC), and NT-proBNP levels, were collected at listing. The median MELD-Na and NT-proBNP levels at the time of listing were 16 points (13-22) and 123 (58-257) pg/mL, respectively. High NT-proBNP levels (≥125 pg/mL) were associated with the development of ACLF (subhazard ratio: 4.00, 95% CI: 1.76-9.10; p <0.001) and mortality (subhazard ratio: 3.89, 95% CI: 1.28-11.79, p =0.02) after adjusting for MELD-Na and CysC. Patients with NT-proBNP ≥125 pg/mL showed a significantly higher incidence of ACLF at 3 months (28.5% vs. 3.6%; p <0.001) and 12 months (49.2% vs. 6.1%; p <0.001). Mortality in the waiting list at 1 year was also significantly higher in patients with NT-proBNP ≥125 pg/mL (22.3% vs. 4%; p <0.001). Serum NT-proBNP emerges as a promising prognostic biomarker for ACLF development and mortality in patients with cirrhosis on the waiting list. Its integration into clinical practice could facilitate preventive interventions and improve prioritization on the waiting list.

We have innovatively amalgamated membrane blood purification and centrifugal blood cell separation technologies to address the limitations of current artificial liver support (ALS) models, and develop a versatile plasma purification system (VPPS) through centrifugal plasma separation.

To investigate the influence of VPPS on long-term rehospitalization and mortality rates among patients with acute-on-chronic liver failure (ACLF).

This real-world, prospective study recruited inpatients diagnosed with ACLF from the Second Xiangya Hospital of Central South University between October 2021 and March 2024. Patients were categorized into the VPPS and non-VPPS groups based on the distinct ALS models administered to them. Self-administered questionnaires, clinical records, and self-reported data served as the primary methods for data collection. The laboratory results were evaluated at six distinct time points. All patients were subjected to follow-up assessments for > 12 months. Kaplan-Meier survival analyses and Cox proportional hazards models were used to evaluate the risks of hospitalization and mortality during the follow-up period.

A cohort of 502 patients diagnosed with ACLF was recruited, with 260 assigned to the VPPS group. On comparing baseline characteristics, the VPPS group exhibited a significantly shorter length of stay, higher incidence of spontaneous peritonitis and pulmonary aspergillosis compared to the non-VPPS group (P < 0.05). Age [hazard ratio (HR) = 1.142, 95%CI: 1.01-1.23, P = 0.018), peritonitis (HR = 2.825, 95%CI: 1.07-6.382, P = 0.026), albumin (HR = 0.67, 95%CI: 0.46-0.942, P = 0.023), total bilirubin (HR = 1.26, 95%CI: 1.01-3.25, P = 0.021), international normalized ratio (HR = 1.97, 95%CI: 1.21-2.908, P = 0.014), and VPPS/non-VPPS (HR = 3.24, 95%CI: 2.152-4.76, P < 0.001) were identified as significant independent predictors of mortality in both univariate and multivariate analyses throughout the follow-up period. Kaplan-Meier survival analyses demonstrated significantly higher rehospitalization and mortality rates in the non-VPPS group compared to the VPPS group during follow-up of ≥ 2 years (log-rank test, P < 0.001).

These findings suggest that VPPS is safe and has a positive influence on prognostic outcomes in patients with ACLF.

Hepatitis B virus-associated chronic acute liver failure (HBV-ACLF) is the leading cause of ACLF, affecting approximately 90% of patients with ACLF. The objective of this study was to investigate the clinical relevance of miR-126-3p on HBV-ACLF as well as the regulatory impact of ERRFI1 and miR-126-3p on the inflammatory response caused by ACLF via in vitro experimental methodologies. RT-qPCR was utilized to quantify the expression levels of miR-126-3p, ERRFI1, NLRP3, caspase 1, and IL-1β. The clinical function of miR-126-3p was assessed using ROC analysis or Kaplan-Meier curve. Cell proliferation was quantified via the CCK-8 assay, while the dual-luciferase reporter assay was employed to confirm the specific binding interaction between miR-126-3p and ERRFI1. In patients with HBV-ACLF, a significant downregulation of miR-126-3p expression was observed; The level of miR-126-3p served as a prognostic indicator for the progression of HBV-ACLF, with reduced expression being associated with an unfavorable clinical outcome. In addition, miR-126-3p was found to modulate LPS-induced cell proliferation, and inflammation in THLE-2 cells through the regulation of ERRFI1 expression. Therefore, miR-126-3p might serve as a biomarker for HBV-ACLF.

Acute-on-chronic liver failure (ACLF) is a complex syndrome with limited treatment options. This study aims to investigate the impact of artificial liver support system (ALSS) on the one-year prognosis of patients with Hepatitis B virus (HBV)-associated ACLF.

A retrospective study was conducted on 239 patients with HBV-ACLF in Nanfang Hospital from January 2016 to June 2021. Patients were divided into the ALSS group (n = 103) and the Standard Medical Therapy (SMT group, n = 136). Demographic, clinical, and laboratory data were collected before the first ALSS treatment for patients in ALSS group, while baseline data were collected in SMT group. According to receiving different ALSS modes, patients in ALSS group were divided into plasma exchange (PE) group and non-PE group.

The 12-week and 1-year liver transplant (LT) free survival rates in the ALSS group were significantly higher than that in the SMT group (65.05% vs 52.21%, p = 0.0011; 63.11% vs. 48.53%, p = 0.0006). ALSS therapy was the independent predictive factors associated with 12-week and 1-year mortality (hazard ratio, HR: 0.59, p = 0.04, and HR: 0.54, p = 0.01). Comparatively more ALSS-related complications were observed in PE group. After Propensity Score Matching, the 12-week and 1-year LT-free survival rates between PE and non-PE group were similar (88% vs. 80%, p = 0.227, 88% vs. 80%, p = 0.227).

ALSS therapy is a safe and effective treatment for HBV-ACLF. ALSS improves 1-year prognosis of patients with HBV-ACLF.

The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) and its complication, MAFLD-related acute-on-chronic liver failure (MAFLD-ACLF), is rising. Yet, factors determining patient outcomes in MAFLD-ACLF remain understudied.

Patients with MAFLD-ACLF were recruited from the Asian Pacific Association for the Study of the Liver-ACLF Research Consortium (AARC registry). The diagnosis of MAFLD-ACLF was made when the treating unit had identified the etiology of chronic liver disease as MAFLD (or previous nomenclature such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, or non-alcoholic steatohepatitis-cirrhosis). Patients with coexisting other etiologies of chronic liver disease (such as alcohol, hepatitis B virus, hepatitis C virus, etc.) were excluded. Data were randomly split into derivation (n = 258) and validation (n = 111) cohorts at a 70:30 ratio. The primary outcome was 90-day mortality. Only the baseline clinical, laboratory features and severity scores were considered.

The derivation group had 258 patients; 60% were male, with a mean age of 53. Diabetes was noted in 27% and hypertension in 29%. The dominant precipitants included viral hepatitis (hepatitis A virus and hepatitis E virus, 32%), drug-induced injury (drug-induced liver injury, 29%), and sepsis (23%). Model for End-Stage Liver Disease-Sodium (MELD-Na) and AARC scores on admission averaged 32 ± 6 and 10.4 ± 1.9. At 90 days, 51% survived. Nonviral precipitant, diabetes, bilirubin, international normalized ratio, and encephalopathy were independent factors influencing mortality. Adding diabetes and precipitant to MELD-Na and AARC scores, the novel MAFLD-MELD-Na score (+12 for diabetes, +12 for nonviral precipitant), and MAFLD-AARC score (+5 for each) were formed. These outperformed the standard scores in both cohorts.

Almost half of patients with MAFLD-ACLF die within 90 days. Diabetes and nonviral precipitants such as drug-induced liver injury and sepsis lead to adverse outcomes. The new MAFLD-MELD-Na and MAFLD-AARC scores provide reliable 90-day mortality predictions for patients with MAFLD-ACLF.

Acute-on-chronic liver failure (ACLF) is a complicated syndrome associated with high short-term mortality and reversibility. Whether the prior decompensation should be included in the definition of ACLF is controversial.

A total of 532 patients with decompensation (prior or first) of chronic liver disease were retrospectively enrolled and analyzed from January 2018 to June 2023. Clinical data were used to identify the characteristics and determine prognosis.

Of the 532 patients, 99 patients did not meet APASL-ACLF criteria due to the existence of prior decompensation and 433 patients met the Asian Pacific Association for the Study of the Liver (APASL)-ACLF criteria. The two groups had similar characteristics including prognosis scores (Chinese Group on the Study of Severe Hepatitis B (COSSH)-ACLF II score: 7.59 vs. 7.67, p = 0.934; Chronic Liver Failure (CLIF) Consortium ACLF score: 42.90 vs. 44.81, p = 0.273), the distribution of patients with APASL ACLF research consortium score (AARC score) (5-7: 19.2%/12.0%; 8-10: 56.6%/55.0%; 11-15: 24.2%/33.0%, p > 0.05) and the 28-/90-day mortality rates (30.5%/43.2% vs. 36.3%/43.1%, p = 0.267/0.978). In all integrated ACLF patients, Receiver Operating Characteristic (ROC) curve analysis and decision curve analysis (DCA) showed that COSSH-ACLF IIs had higher prognostic efficiency and clinical net benefit than AARC score and CLIF-C ACLFs for 28-/90-day mortality.

Prior decompensated patients exhibited clinical characteristics and high short-term mortality similar to those of first decompensated patients. The COSSH-ACLF IIs demonstrated the highest prognostic efficiency for all integrated ACLF patients. Including prior decompensation in the ACLF definition can help to simplify and improve clinical management.

Liver transplantation (LT) is recognized as an effective approach that offers survival benefits for patients with acute-on-chronic liver failure (ACLF). However, controversies remain regarding the LT selection criteria, and meta-analyses reporting overall survival outcomes across different ACLF severity grades are lacking.

To depict a comprehensive postoperative picture of patients with ACLF of varying severity and contribute to updating LT selection.

Systematic searches in Web of Science, EMBASE, PubMed, and Cochrane databases were performed, from inception to December 26, 2023, for studies exploring post-transplant outcomes among ACLF patients, stratified by severity grades as identified by the European Association for the Study of the Liver-Chronic Liver Failure criteria. The primary outcome of interest was the survival rate within one year, with post-transplant complications as secondary outcomes. Additionally, the subgroup analysis examined region-specific one-year survival rates.

A total of 17 studies involving 28025 participants were included. Patients with ACLF-1 and ACLF-2 have favorable survival within one year, with survival rates reaching 87% [95% confidence interval (CI): 84%-91%] and 86% (95%CI: 81%-91%), respectively. Despite the relatively lower survival (73%, 95%CI: 66%-80%) and higher incidence of infection (48%, 95%CI: 29%-67%) observed in ACLF-3 patients, their survival exceeds that of those who do not undergo LT. Moreover, post-transplant survival was highest in North America across all ACLF grades.

LT can provide survival advantages for ACLF patients. To optimize the utilization of scarce donor organs and improve prognosis, comprehensive preoperative health evaluations are essential, especially for ACLF-3 patients.

Acute organ injuries represent a major public health concern, driven by inflammation and mitochondrial dysfunction, leading to cell damage and organ failure. In this study, we engineered neutrophil membrane-fused mitochondria (nMITO), which combine the injury-targeting and anti-inflammatory properties of neutrophil membrane proteins with the cell repairing function of mitochondria. nMITO effectively blocked inflammatory cascades and restored mitochondrial function, targeting both key mechanisms in acute organ injuries. In addition, nMITO selectively targeted damaged endothelial cells via β-integrins and were delivered to injured tissues through tunneling nanotubes, enhancing their regulatory effects on inflammation and cell damage. In mouse models of acute myocardial injury, liver injury, and pancreatitis, nMITO notably reduced inflammatory responses and repaired tissue damage. These findings suggest that nMITO is a promising therapeutic strategy for managing acute organ injuries.

Acute-on-chronic liver failure (ACLF) is a clinical syndrome characterized by organ failure and high short-term mortality. Since its first definition in 2013, many international organizations have defined this syndrome and, till now, there has been no agreement regarding definitions and diagnostic criteria. Although the precise mechanism of ACLF is unknown, precipitant factors and the systemic inflammation response play a major role. Specific management of this high-mortality syndrome is still under development, but a general consensus in the diagnosis and management of ACLF is needed.

Liver cirrhosis is a common cause of morbidity and mortality worldwide. Excessive alcohol consumption and metabolic associated steatotic liver disease are the most common etiological factors of cirrhosis in our region. Cirrhosis occurs in two well-differentiated phases, compensated and decompensated, depending on the absence or presence of complications, respectively. Current therapeutic strategies are aimed at controlling these complications (such as ascites, hepatic encephalopathy, bacterial infections, or digestive hemorrhage, among others) or performing a liver transplant if there are no contraindications. However, it is important to eliminate the etiological factor responsible for the disease, as this can lead to the disappearance of complications, a state known as recompensation. This article proposes an updated review of the epidemiology of cirrhosis and its main causes, and offers an overview of the clinical features and treatment of the disease's complications, in addition to outlining future lines of research in this field.

The study aimed to quantitatively detect the suppressors of cytokine signaling (SOCS) 3 promoter methylation levels, investigate the relationship between SOCS3 methylation and gene expression, and construct a prognosis prediction model combined with clinical indicators for Acute-on-chronic Hepatitis B Liver Failure (ACHBLF).

A total of 135 ACHBLF patients were enrolled and randomly divided into the training cohort and validation cohort. The SOCS3 mRNA and promoter methylation in peripheral blood mononuclear cells (PBMCs) of ACHBLF patients were quantitative measured. A clinical prediction model was established based on SOCS3 promoter methylation and clinical indicators. The prediction model was evaluated by the area under the receiver operating characteristic curve, the Hosmer-Lemeshow (H-L) goodness-of-fit test, and decision curve analysis.

In this study, compared with ACHBLF survivals, SOCS3 showed lower mRNA levels and higher methylation levels in ACHBLF non-survivals. The SOCS3 methylation rates were negatively correlated with SOCS3 mRNA levels. PT-INR, IL-6, and percentage of the methylation reference (PMR) value (SOCS3) were used to establish a clinical model for predicting ACHBLF patients' prognosis. The results of AUC, the Hosmer-Lemeshow (H-L) goodness-of-fit test and decision curve analysis (DCA) showed that the prediction model had good clinical applicability. The prediction model was visualized.

A prognosis prediction model for ACHBLF was developed based on PMR (SOCS3), PT-INR and IL-6, which may have a good potential clinical application value.

There are no useful treatments to prevent the development of severe complications of liver cirrhosis. Simvastatin and rifaximin have shown beneficial effects in liver cirrhosis.

To assess whether simvastatin combined with rifaximin improves outcomes in patients with decompensated cirrhosis.

Double-blind, placebo-controlled, phase 3 trial conducted among patients with decompensated cirrhosis in 14 European hospitals between January 2019 and December 2022. The last date of follow-up was December 2022.

Patients were randomly assigned to receive simvastatin, 20 mg/d, plus rifaximin, 1200 mg/d (n = 117), or identical-appearing placebo (n = 120) for 12 months in addition to standard therapy, stratified according to Child-Pugh class B or C.

The primary end point was incidence of severe complications of liver cirrhosis associated with organ failure meeting criteria for acute-on-chronic liver failure. Secondary outcomes included transplant or death and a composite end point of complications of cirrhosis (ascites, hepatic encephalopathy, variceal bleeding, acute kidney injury, and infection).

Among the 237 participants randomized (Child-Pugh class B: n = 194; Child-Pugh class C: n = 43), 72% were male and the mean age was 57 years. There were no differences between the 2 groups in terms of development of acute-on-chronic liver failure (21 [17.9%] vs 17 [14.2%] patients in the treatment and placebo groups, respectively; hazard ratio, 1.23; 95% CI, 0.65-2.34; P = .52); transplant or death (22 [18.8%] vs 29 [24.2%] patients in the treatment and placebo groups, respectively; hazard ratio, 0.75; 95% CI, 0.43-1.32; P = .32); or development of complications of cirrhosis (50 [42.7%] vs 55 [45.8%] patients in the treatment and placebo groups, respectively; hazard ratio, 0.93; 95% CI, 0.63-1.36; P = .70). Incidence of adverse events was similar in both groups (426 vs 419; P = .59), but 3 patients in the treatment group (2.6%) developed rhabdomyolysis.

The addition of simvastatin plus rifaximin to standard therapy does not improve outcomes in patients with decompensated liver cirrhosis.

ClinicalTrials.gov Identifier: NCT03780673.

HBV infection is a major etiology of acute-on-chronic liver failure (ACLF). At present, the pattern and regulation of hepatocyte death during HBV-ACLF progression are still undefined. Evaluating the mode of cell death and its inducers will provide new insights for developing therapeutic strategies targeting cell death. In this study, we aimed to elucidate whether and how immune landscapes trigger hepatocyte death and lead to the progression of HBV-related ACLF.

We identified that pyroptosis represented the main cell death pattern in the liver of patients with HBV-related ACLF. Deficiency of MHC-I in HBV-reactivated hepatocytes activated cytotoxic NK cells, which in turn operated in a perforin/granzyme-dependent manner to trigger GSDMD/caspase-8-dependent pyroptosis of hepatocytes. Neutrophils selectively accumulated in the pyroptotic liver, and HMGB1 derived from the pyroptotic liver constituted an important factor triggering the generation of pathogenic extracellular traps in neutrophils (NETs). Clinically, elevated plasma levels of myeloperoxidase-DNA complexes were a promising prognostic biomarker for HBV-related ACLF. More importantly, targeting GSDMD pyroptosis-HMGB1 release in the liver abrogates NETs that intercept the development of HBV-related ACLF.

Studying the mechanisms that selectively modulate GSDMD-dependent pyroptosis, as well as its immune landscapes, will provide a novel strategy for restoring the liver function of patients with HBV-related ACLF.

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.

Prior studies show severe acute-on-chronic liver failure (ACLF) at liver transplantation (LT) negatively impacts short-term, but not long-term, post-LT outcomes. However, not accounting for ACLF's time-varying effect on the waitlist may underappreciate its dynamic nature. Moreover, excluding those who died or dropped off the waitlist raises concerns about selection bias.

This US nationwide retrospective cohort study estimated the effect of severe ACLF (grade 3) (ACLF-3) on post-LT outcomes, including adult, first-time deceased donor LT candidates listed from June 2013 to May 2023. A marginal structural model (MSM) to address selection bias and time-varying exposure (ACLF-3) was applied, with extended Cox proportional hazard models using a Heaviside step function to assess the hazard of death after LT.

Among 31,267 eligible candidates for LT (baseline cohort), 11.3% (n = 3518) had ACLF-3 at listing; 13.6% (n = 4243) died or dropped out while on the LT waitlist. Of the 27,024 patients who received LT (transplanted cohort), 12.3% (n = 3333) had ACLF-3 at LT. ACLF-3 at LT (but not at waitlisting) was associated with a higher hazard of death, with the hazard ratio of 1.80 (95% CI: 1.09-2.97) within 1 year after LT but not thereafter. This marginal structural model effect size was 9% higher than conventional multivariable Cox proportional hazard models. Sensitivity analyses corroborated these findings.

Compared to previous studies, ACLF-3 at LT in our marginal structural model was associated with a discernible increase in short-term mortality after transplant, presumably due to our addressing of selection bias, while long-term survival was similar to those without severe ACLF at LT. However, potential vulnerability to posttransplant complications warrants further investigation.

Acute-on-chronic liver failure (ACLF) is defined by acute decompensation, organ failure and a high risk of short-term mortality. This condition is characterized by an overwhelming systemic inflammatory response. Despite treating the precipitating event, intensive monitoring and organ support, clinical deterioration can occur with very poor outcomes. During the last decades, several extracorporeal liver support systems have been developed to try to reduce ongoing liver injury and provide an improved environment for the liver to regenerate or as a bridging therapy until liver transplantation. Several clinical trials have been performed to evaluate the clinical efficacy of extracorporeal liver support systems, but no clear impact on survival has been proven. DIALIVE is a novel extracorporeal liver support device that has been built to specifically address the pathophysiological derangements responsible for the development of ACLF by replacing dysfunctional albumin and removing pathogen and damage-associated molecular patterns (PAMPs and DAMPs). In phase II clinical trial, DIALIVE appears to be safe, and it seems to be associated with a faster time to the resolution of ACLF compared with standard medical treatment. Even in patients with severe ACLF, liver transplantation saves lives and there is clear evidence of transplant benefit. Careful selection of patients is required to attain good results from liver transplantation, but many questions remain unanswered. In this review, we describe the current perspectives on the use of extracorporeal liver support and liver transplantation for ACLF patients.