Limited data exist on the role of systemic inflammation and gut barrier dysfunction in acute variceal bleed (AVB). We studied inflammatory markers and changes in the intestinal barrier in patients with AVB and assessed if these can be used to identify a higher risk subgroup with regard to outcomes.

In this prospective observational study, patients with cirrhosis and AVB presenting at a tertiary care center were stratified by whether or not they developed acute decompensation (AD) over 6 weeks follow-up. Utility of systemic inflammatory markers (interleukin-6 [IL-6], C-reactive protein), endotoxinemia (serum IgM/IgG anti-endotoxin antibodies), and duodenal epithelial tight junction proteins (TJPs) by immunohistochemistry (IHC) for tight-junction proteins (claudin-2,-4, zonula occludens-1(ZO-1), junctional adhesion molecule (JAM)) was assessed to predict the outcomes. These parameters were compared with a pre-existing cohort of patients with cirrhosis and no recent variceal bleed and with those without cirrhosis (dyspepsia with no endoscopic pathology). A nomogram was developed from multivariate model to predict 6-wk AD in patients with AVB.

Patients with AVB(n = 66) (age:46.4 ± 11.7 years; etiology: alcohol/NASH/HBV/HCV [48.5%/12.1%/12.1%/7.6%]) were included. Twenty-four (36.3%) patients developed 6-wk AD. Patients with 6-wk AD had higher serum IL-6 (median: 156.14 pg/ml [IQR: 136.12-170.52] vs 58.28 pg/ml [31.70-110.67]; P < 0.001) and Child score (median: 9 [6.75-10.25] vs 7 [6-9]; P = 0.042) at baseline. Serum endotoxinemia and duodenal epithelial TJP were similar. A nomogram combining CTP and IL-6 was generated that predicted 6-wk AD with optimism-corrected c-statistic of 0.87. Comparison with non-bleeder cirrhosis (n = 52) (7.57 [5.48-9.87]) and dyspepsia controls (n = 53) (5.72 [4.40-6.45]; P < 0.001) also identified significant elevation of serum IL-6, not entirely explainable by derangements in TJP and bacterial translocation markers.

6-wk AD rates in patients with cirrhosis and AVB can be predicted using combination of Child score and serum IL-6.

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.

Two main stages are differentiated in patients with advanced chronic liver disease (ACLD), one compensated (cACLD) with an excellent prognosis, and the other decompensated (dACLD), defined by the appearance of complications (ascites, variceal bleeding and hepatic encephalopathy) and associated with high mortality. Preventing the progression to dACLD might dramatically improve prognosis and reduce the burden of care associated with ACLD. Portal hypertension is a major driver of the transition from cACLD to dACLD, and a portal pressure of ≥10 mmHg defines clinically significant portal hypertension (CSPH) as the threshold from which decompensating events may occur. In recent years, innovative studies have provided evidence supporting new strategies to prevent decompensation in cACLD. These studies have yielded major advances, including the development of noninvasive tests (NITs) to identify patients with CSPH with reasonable confidence, the demonstration that aetiological therapies can prevent disease progression and even achieve regression of cirrhosis, and the finding that non-selective β-blockers can effectively prevent decompensation in patients with cACLD and CSPH, mainly by reducing the risk of ascites, the most frequent decompensating event. Here, we review the evidence supporting new strategies to manage cACLD to prevent decompensation and the caveats for their implementation, from patient selection using NITs to ancillary therapies.

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.

Transjugular intrahepatic portosystemic shunt (TIPS) effectively treats complications of cirrhosis. Systemic inflammation (SI) is linked to acute-on-chronic liver failure (ACLF) and liver-related death. We aimed to assess the trajectory and clinical impact of SI parameters after TIPS implantation.

Consecutive patients undergoing elective implantation of covered TIPS for recurrent/refractory ascites or portal-hypertensive bleeding at the Medical University Vienna (NCT03409263; n = 58) and at the Hannover Medical School (NCT04801290, n = 51) were included. IL-6 was assessed at baseline (BL), 3 months (M3) and up to 6 (M6; Hannover cohort) or 9 months (M9; Vienna cohort) of follow-up; C-reactive protein (CRP) and lipopolysaccharide-binding protein (LBP) were assessed in the Vienna cohort only.

In 109 patients (66.1% male, median age 57 years) receiving TIPS mainly (72.4%) by indication ascites the median BL IL-6 levels were 10.5 pg/ml; and 41.3% (n = 45/109) patients exhibiting IL-6 ≥14 pg/ml. From BL to M3, IL-6 decreased in 63.8% (n = 37/58; Vienna cohort) and in 68.6% (n = 35/51; Hannover cohort) of patients, respectively. Similar rates of decreases were observed also for CRP (in 62.1%) and for LBP (in 77.4%). A considerable IL-6 reduction (≥50% of baseline) was noted in 41 (37.6%) patients during follow-up. Competing risk regression in the combined cohort adjusted for age, albumin, and model for end-stage liver disease revealed that IL-6 decrease at M3 was an independently protective factor for the development of ACLF (adjusted subdistribution hazard ratio [asHR]: 0.26; 95% CI: 0.09-0.77; p = 0.016) and liver-related death (asHR: 0.26; 95% CI: 0.07-0.95; p = 0.042).

TIPS leads to a sustained reduction of SI and bacterial translocation in patients with decompensated cirrhosis. Decreasing IL-6 levels three months after TIPS implantation indicate a lower risk of ACLF and liver-related death in patients with cirrhosis.

Systemic inflammation is a major driver of disease progression in patients with decompensated advanced chronic liver disease (dACLD). This study demonstrates that systemic inflammation (i.e. interleukin-6 [IL-6]) effectively and sustainedly decreases after transjugular intrahepatic portosystemic shunt (TIPS) implantation. A decrease of IL-6 3 months after TIPS implantation is a protective factor for acute-on-chronic liver failure and liver-related death. Thus, our results suggest that TIPS reduces systemic inflammation in a clinically meaningful way.

Acute-on-chronic liver failure (ACLF) is characterized by fast progression and high mortality, with systemic inflammation and immune paralysis as its key events. While natural killer (NK) cells are key innate immune cells, their unique function and subpopulation heterogeneity in ACLF have not been fully elucidated. This study aimed to investigate the characteristics of NK cell subsets in the peripheral blood of patients with ACLF and determine their roles in the inflammatory responses.

Circulating NK cells (14 751 cells) from patients with ACLF and healthy controls (HCs) were subjected to single-cell RNA sequencing (scRNA-seq). Clustering and annotation were used to identify the features of NK cell subsets and the characteristics of disease progression in ACLF.

Four NK cell subsets were obtained, including adaptive NK cells, mature NK cells, inflamed NK cells, and CD56bright NK cells. Compared with the HCs, the patients with ACLF had a significantly lower proportion of Mature NK cells and a higher proportion of Inflamed NK cells. Quasi-temporal analysis showed that Inflamed NK cells were highly enriched in the late quasi-temporal sequence, and genes related to pro-inflammatory were significantly up-regulated in Inflamed NK cells. In addition, scRNA-seq and flow cytometry confirmed that the expression level of cell migration inducing hyaluronidase 2 (CEMIP2) in NK cells progressively increased from the HC group to the ACLF survival group and then to the ACLF death group.

scRNA-seq reveals that Inflamed NK cell subsets are associated with ACLF progression and poor prognosis. CEMIP2 may be a molecular marker for ACLF progression.

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.

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.

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 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.

In the traditional view, the occurrence of cirrhosis-related complications, such as hepatic encephalopathy, formation of ascites or variceal haemorrhage, marks the transition to the decompensated stage of cirrhosis. Although the dichotomous stratification into a compensated and decompensated state reflects a prognostic water-shed moment and remains to hold its prognostic validity, it represents an oversimplification of clinical realities. A broadening understanding of pathophysiological mechanisms underpinning decompensation have led to the identification of distinct prognostic subgroups, associated with different clinical courses following decompensation. Data provided by the PREDICT study uncovered three distinct sub-phenotypes of acute decompensation (AD). Moreover, acute-on-chronic liver failure (ACLF) has been established as a distinct clinical entity for many years, which is associated with a high short-term mortality. Recently, non-acute decompensation (NAD) has been proposed as a distinct pathway of decompensation, complementing current concepts of the spectrum of decompensation. In contrast to AD, NAD is characterized by a slow and progressive development of complications, which are often presented at first decompensation and/or in patients in an earlier stage of chronic liver disease. Successful treatment of AD or NAD may lead to a clinical stabilization or even the concept of recompensation. This review aims to provide an overview on current concepts of decompensation and to delineate recent advances in our clinical and pathophysiological understanding.

Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome characterized by decompensation of cirrhosis, severe systemic inflammation and organ failures. ACLF is frequently triggered by intra- and/or extrahepatic insults, such as bacterial infections, alcohol-related hepatitis or flares of hepatic viruses. The imbalance between systemic inflammation and immune tolerance causes organ failures through the following mechanisms: (i) direct damage of immune cells/mediators; (ii) worsening of circulatory dysfunction resulting in organ hypoperfusion and (iii) metabolic alterations with prioritization of energetic substrates for inflammation and peripheral organ 'energetic crisis'. Currently, the management of ACLF includes the support of organ failures, the identification and treatment of precipitating factors and expedited assessment for liver transplantation (LT). Early LT should be considered in patients with ACLF grade 3, who are unlikely to recover with the available treatments and have a mortality rate > 70% at 28 days. However, the selection of transplant candidates and their prioritization on the LT waiting list need standardization. Future challenges in the ACLF field include a better understanding of pathophysiological mechanisms leading to inflammation and organ failures, the development of specific treatments for the disease and personalized treatment approaches. Herein, we reviewed the current knowledge and future perspectives on mechanisms and treatment of ACLF.

Acute-on-chronic liver failure (ACLF) is a severe clinical condition with high short-term mortality, in part due to the dysfunctional immune response. Identifying immune mechanism under ACLF is critical to understand its pathogenesis and to develop novel targeted therapeutics. Among the immune cells, how are B cells involved in ACLF remains largely unknown. We performed scRNA-seq on peripheral blood mononuclear cells from clinical ACLF patients and healthy controls. Integrated analysis was performed to identify the role of B cells in ACLF. Subsequently, different subsets of B cells in ACLF were validated through flow cytometry based on their highlighted markers. Six B-cell subgroups, including naive B cells, naive B2 cells, nonclass-switched memory B cells, class-switched memory B cells, autoimmune-related B cells and plasma B cells were identified. The proportions of naive B cells significantly expand in ACLF, compared with healthy control. Function enrichment analysis revealed the activation of inflammatory response in naive B cells. Further flow cytometry confirmed the elevated circulating naive B cells in ACLF. Our study uncovered the altered immune landscape of circulating B cells after ACLF. The proportion dynamics and functional perturbation indicate the potential of naive B cells as intervention targets in the future ACLF therapy.

Acute on chronic liver failure (ACLF) reflects the development of organ failure(s) in a patient with cirrhosis and is associated with high short-term mortality. Given that ACLF has many different 'phenotypes', medical management needs to take into account the relationship between precipitating insult, organ systems involved and underlying physiology of chronic liver disease/cirrhosis. The goals of intensive care management of patients suffering ACLF are to rapidly recognize and treat inciting events (e.g. infection, severe alcoholic hepatitis and bleeding) and to aggressively support failing organ systems to ensure that patients may successfully undergo liver transplantation or recovery. Management of these patients is complex since they are prone to develop new organ failures and infectious or bleeding complications. ICU therapy parallels that applied in the general ICU population in some complications but differs in others. Given that liver transplantation in ACLF is an emerging and evolving field, multidisciplinary teams with expertise in critical care and transplant medicine best accomplish management of the critically ill ACLF patient. The focus of this review is to identify the common complications of ACLF and to describe the proper management in critically ill patients awaiting liver transplantation in our centres, including organ support, prognostic assessment and how to assess when recovery is unlikely.

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.

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.

Coronary artery disease (CAD) is increasingly observed in patients with liver cirrhosis. However, data on the incidence and prevalence of CAD in cirrhotic patients are heterogeneous, and the association remains uncertain. In this study, we aimed to conduct a systematic review and meta-analysis to address these issues.

PubMed, EMBASE, and Cochrane Library databases were searched. Incidence, prevalence, and factors associated with CAD were pooled using a random-effects model. Risk ratio (RR) and odds ratio (OR), with their 95% confidence interval (CI), were calculated to evaluate differences in CAD incidence and prevalence between patients with and without liver cirrhosis.

Fifty-one studies were included. The pooled incidences of CAD, acute coronary syndromes, and myocardial infarction (MI) were 2.28%, 2.02%, and 1.80%, respectively. Liver cirrhosis was not significantly associated with CAD incidence (RR = 0.77; 95% CI = 0.46-1.28) or MI (RR = 0.87; 95% CI = 0.49-1.57). The pooled prevalence of CAD, acute coronary syndromes, and MI was 18.87%, 12.54%, and 6.12%, respectively. Liver cirrhosis was not significantly associated with CAD prevalence (OR = 1.29; 95% CI = 0.83-2.01) or MI (OR = 0.58; 95% CI = 0.28-1.22). Non-alcoholic steatohepatitis, hepatitis C virus, advanced age, male sex, diabetes mellitus, hypertension, hyperlipidemia, smoking history, and family history of CAD were significantly associated with CAD in cirrhotic patients.

CAD is common in cirrhotic patients, but cirrhosis itself may not be associated with an increased CAD risk. In addition to traditional risk factors, non-alcoholic steatohepatitis and hepatitis C virus infection are also associated with CAD presence in cirrhotic patients.

Quantifying systemic inflammation (SI) in acutely decompensated cirrhosis (ADC) is of major importance because SI is a driver of the most severe forms of ADC, including acute-on-chronic liver failure (ACLF). Blood biomarkers of SI already evaluated in ADC failed to appropriately assess SI in ADC. We aimed to investigate whether gene expression related to circulating immune cells could quantify SI in ADC.

Standard biomarkers (white cell count, C reactive protein, cytokines) and genome-wide RNA expression (RNA-sequencing) were obtained in blood from 700 patients with ADC at the time of their hospital admission. A composite score based on standard biomarkers of SI (Chronic Liver Failure-Standard Biomarkers Composite (CLIF-SBC) score) and a gene score (CLIF-Systemic Inflammation Gene (SIG) score) composed of the 28 top differentially expressed immune cell-related genes in the comparison between high-severity and low-severity clinical phenotypes were computed. Among the 700 patients, the CLIF-SIG score was repeated once during follow-up in 375 patients, and 3 times or more in 46 patients.

The CLIF-SIG score was more accurate in reflecting clinical severity induced by SI than the CLIF-SBC score (area under the curve 0.803 vs 0.658). A CLIF-SIG score of 0.386 (Youden Index) was the best cut-off level discriminating patients with poor outcomes from the others, in all clinical scenarios. Sequential measurement of the CLIF-SIG score showed that 78% of patients were admitted at the peak or descending part of the SI-wave. ACLF developed during hospitalisation in 80% of patients with a CLIF-SIG score >0.386 on admission.

In patients with ADC, the CLIF-SIG score is an accurate estimator of SI, clinical course severity and prognosis.

Acute-on-chronic liver failure (ACLF) is a severe syndrome that manifests as acute liver function deterioration and organ failure. Coinfection with invasive pulmonary aspergillosis (IPA) in ACLF patients is characterized by high mortality and increasing morbidity. The aim of this study was to explore the early warning factors and prognosis of ACLF patients with IPA coinfection.

In this retrospective study, we collected clinical, biochemical, and microbiological data from patients with ACLF and IPA from May 2019 to May 2023. Univariable and multivariate analyses were used to identify independent risk factors for IPA in ACLF patients. Moreover, the area under the curve (AUC) and decision curve analysis (DCA) were used to evaluate the model performance.

A total of 438 patients with ACLF were enrolled, 408 (93.2%) non-IPA patients and 30 IPA (6.8%) including 29 probable cases and one proven case. The 28-day case fatality rate (56.7% vs 29.4%) was higher in ACLF patients with IPA than in ACLF patients without IPA, but without statistical difference. Multivariate analysis revealed that early warning factors for IPA coinfection in ACLF patients included nausea (p = 0.010), expectoration (p < 0.001), bacterial and fungal infections (p < 0.001), corticosteroid use (p = 0.037), surgery (p = 0.081), haemoptysis (p = 0.015) and increased leukocyte counts (p = 0.010). The AUC was 0.934 (p < 0.001), and DCA verified the validity and clinical effectiveness of our model.

These findings provide valuable insights for clinicians in the early diagnosis of IPA in ACLF patients and may facilitate timely intervention and treatment.

Posttranslational modifications (PTM) of albumin occur in liver diseases; however, little is known about the source and function of sulfonated albumin, a significant modification of albumin occurring in nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the mechanism underlying sulfonated albumin production and its role in the progression of NAFLD-related liver fibrosis.

Serum samples from healthy controls and patients with NAFLD were used to measure the proportion of sulfonated albumin. Mice models with NAFLD fed with high-fat diet (HFD) and methionine choline-deficient diet (MCD) were constructed. RNA sequencing, KEGG analysis, and GSEA were used to explore the mechanism of sulfonated albumin production and its mechanism of activating hepatic stellate cells (HSCs) and promoting the progression of liver fibrosis in NAFLD.

Sulfonated albumin levels increased significantly in both human and mouse NAFLD serum samples. In vivo studies in mice have shown that the intraperitoneal injection of sulfonated albumin promotes inflammation, hepatic steatosis, and liver fibrosis in NAFLD. In addition, autophagy has been verified as a key mechanism in the regulation of sulfonated albumin production. We also demonstrated that reactive oxygen species (ROS) production depends on the accumulation of damaged mitochondria and affects the production of sulfonated albumin under the regulation of autophagy. Hepatocyte-derived sulfonated albumin activates HSCs through the GAL3 receptor, thereby activating the endoplasmic reticulum (ER) stress pathway and promoting profibrotic activation of HSCs.

Our study demonstrated that sulfonated albumin activated HSCs through GAL3, thereby accelerating NAFLD-related liver fibrosis. Serum sulfonated albumin may be a potential diagnostic marker for liver fibrosis and an important target for the treatment of NAFLD-related liver fibrosis.

The risk of microbial infections is increased in cirrhosis and other forms of advanced liver disease such as alcohol-associated hepatitis. Such infections may precipitate new or further decompensation and death, especially in patients with clinical features of acute-on-chronic liver failure. The severe immune dysfunction or "immune paralysis" caused by advanced liver disease is associated with high short-term mortality. However, the pathogenic mechanisms underlying immune dysfunction and immunodeficiency are incompletely understood. Evidence to date suggests a complex, dynamic process that perturbs the physiological roles of the liver as a master regulator of systemic immunity and protector against noxious effects of exogenous molecules in the portal vein flowing from the gut. Thus, in cirrhosis and severe alcohol-associated hepatitis, the ability of hepatocytes and intrahepatic immune cells to balance normal context-dependent dichotomous responses of tolerance vs immune activation is lost. Contributing factors include loss of the gut barrier with translocation of microbial products through the portal vein, culminating in development of functional defects in innate and adaptive immune cells, and generation of immune-regulatory myeloid cells that permit microbial colonization and infection. This review addresses key evidence supporting the paradigm of immune dysfunction as a risk for microbial infections and identifies potential therapeutic targets for intervention. The primary focus is on cirrhosis-associated immune dysfunction and alcohol-associated liver disease, because the bulk of available data are from these 2 conditions.

There have been no studies evaluating how body mass index (BMI) impacts on waitlist and post-liver transplant (LT) mortality in acute-on-chronic liver failure (ACLF) by sex. We aimed to determine these impacts using the United Network for Organ Sharing (UNOS) database.

Adults listed for LT with estimated ACLF (Est-ACLF) (2005-2023) were identified and subdivided by sex and BMI (high/middle/low). Competing-risk analyses evaluated impacts on waitlist mortality. Kaplan-Meier analyses assessed post-LT survival. Multivariable Cox regression identified risk factors.

Of 37 251 Est-ACLF patients, 14 534 (39.0%) were female. Females had higher 90-day waitlist mortality than males (subhazard ratio [sHR]: 1.20, p < .01). High/low BMI patients had higher mortality than middle (sHR: 1.08/1.11, p < .01). In females, high BMI was associated with higher mortality than low (sHR: 1.10, p = .02); in males, low BMI was associated with higher mortality than high/middle (sHR: 1.16/1.16 vs. high/middle, p < .01). Multivariable analyses showed in females, high BMI was a significant risk factor for waitlist mortality (sHR:1.21, p < .01), while low was not; in males, high/low BMI was significant, with low having higher sHR (1.17) than high (1.09). Post-LT survival showed no significant difference in females; in males, low BMI showed worse post-3-/5-year-LT survival (p < .01). Multivariable Cox regression showed for females, neither low nor high BMI was significant for post-LT survival; for males, low BMI was significant for 1-/3-/5-year-LT survival (HR: 1.30/1.30/1.22, p < .01).

Our analysis of BMI's impact on LT outcomes in ACLF by sex enables risk stratification and provides a basis for adjusting BMI.

Cirrhosis is associated with a proinflammatory environment.

To analyse aetiology-specific inflammation patterns in compensated cirrhosis in animal models and patients.

Portal pressure (PP), fibrosis (collagen proportionate area [CPA]) and hepatic inflammation were measured in cirrhotic rat models (thioacetamide [TAA;n = 12]; choline-deficient high-fat diet [CDHFD;n = 12]; bile duct ligation [BDL;n = 16]). Compensated cirrhotic patients (alcohol-related liver disease [ALD;n = 67]; metabolic dysfunction-associated steatohepatitis [MASH;n = 50]; cholestatic liver disease [primary biliary cholangitis [PBC]/primary sclerosing cholangitis [PSC];n = 22]) undergoing hepatic venous pressure gradient (HVPG) measurement were included.

In rats, hepatic proinflammatory gene expression was highest in CDHFD and lowest in TAA, despite comparable PP levels. Across all animal models, Tnfa/Il6 correlated positively with CPA, and Mcp1 with elevated PP. Mcp1 was also associated with increased CPA in TAA/CDHFD. Mcp1/Cxcl1 showed a model-independent positive correlation to transaminases. Il1b correlated positively with CPA/PP in BDL and with transaminases in CDHFD. In patients, CRP/IL-6 were lower in MASH compared to ALD or PBC/PSC, regardless of hepatic function. IgA/IgG were highest and complement factors lowest in ALD. More pronounced systemic inflammation was linked to higher HVPG primarily in ALD/MASH.

Proinflammatory pathways are upregulated across all liver disease aetiologies, yet their association with fibrosis and portal hypertension can vary.

In cirrhotic patients, portal hypertension increases mortality after surgery. We evaluated the impact of pre-operative transjugular intrahepatic portosystemic shunt (TIPS) on the outcomes of bariatric surgery in cirrhosis.

Multicentric retrospective cohort. The decision for TIPS placement has been made according to hepatic venous pressure gradient (HVPG) values and centers' policy. The primary outcome: 1-year decompensation-free survival; secondary outcomes: 1-year acute-on-chronic liver failure (ACLF) and survival.

Fifty-three patients were included (2010-2022): 92% Child-Pugh A, MELD score 8, age 55 years, BMI 38.3 ± 13 kg/m2, 9 (18%) had TIPS. At baseline, patients with TIPS had more esophageal varices (89% vs 10%, p < 0.001), more previous decompensations (22% vs 0%, p = 0.002), and a higher HVPG (14 vs 7 mmHg, p < 0.001). All patients in the TIPS group had clinically significant portal hypertension vs 11% of patients without TIPS, p < 0.001. One-year decompensation-free survival was 77.8% and 93.2% in patients with and without TIPS, p = 0.064. ALCF occurred in 3 patients (6.8%) without TIPS and none with TIPS. All patients were alive 1 year after surgery.

In patients with cirrhosis and clinically significant portal hypertension (CSPH) undergoing bariatric surgery, TIPS placement was safe and had similar outcomes after surgery as patients without TIPS.

Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is linked to dyslipidemia and inflammatory responses. This study aimed to investigate the correlation between high-density lipoprotein cholesterol (HDL-C) levels and 90-day transplant-free (TF) mortality in patients with HBV-ACLF.

A prospective cohort of 287 patients with HBV-ACLF from Beijing Ditan Hospital was enrolled between January 2016 and December 2019. The prognostic accuracy of lipid profile parameters was evaluated by the area under the receiver operating characteristic curve (AUC), and the association between HDL-C levels and mortality was assessed using a restricted cubic spline analysis. Correlations between lipid profile parameters and inflammatory factors were analyzed. Kaplan-Meier curves were used to assess 90-day TF mortality, and log-rank tests were used for comparison analysis. These results were internally validated between January 2020 and December 2023 (n=125).

Patients with lower HDL-C levels exhibited higher mortality rates (adjusted hazard ratio for HDL-C < 0.13 mmol/L: 4.04, 95% confidence interval: 1.35-11.85) compared with those in the reference group (with HDL-C levels above 0.36 mmol/L). An "L-shaped" association was observed between HDL-C levels and TF mortality. The prognostic value of HDL-C (AUC at day 90: 0.732) was comparable to the model for end-stage liver disease score of 0.729. Additionally, HDL-C levels were inversely correlated with interleukin (IL)-4, IL-6, and tumor necrosis factor-α (all P<0.05). In the training cohort, the 90-day TF mortality rates were 8.3%, 15.2%, 24.0%, and 43.2% for the extremely low, low, medium, and high-risk subgroups, respectively, while in the validation cohort, they were 4.5%, 18.5%, 31.2%, and 44.7%, respectively.

HDL-C levels < 0.13 mmol/L were associated with increased 90-day transplant-free mortality in patients with HBV-ACLF. An inverse correlation was found between HDL-C levels and inflammatory markers.

The prognostic value of neutrophil-to-lymphocyte ratio (NLR) combined with Model for End-Stage Liver Disease (MELD) score was evaluated for hepatitis B virus-associated decompensated cirrhosis (HBV-DeCi).

The 30-day mortality of 166 hBV-DeCi patients was examined. Receiver operating characteristic curve analysis and multivariate regression analysis were used to assess the performance of NLR for prediction of poor outcomes.

The 30-day mortality rate was 10.2% (17/166). NLR was significantly lower in survivors than in non-survivors, and could be used for prognosis prediction in HBV-DeCi patients. Area under the curve was higher for NLR combined with MELD score than for each factor alone. (MELD score, AUC:0.864、NLR, AUC:0.781, Combined, AUC:0.920) The Odds ratio of MELD score is lower than NLR.(MELD score:1.447&NLR:1.745).

The findings demonstrate that NLR combined with MELD score has a high prognostic value for HBV-DeCi patients.

Hepatorenal syndrome-acute kidney injury (HRS-AKI) occurs in the setting of advanced chronic liver disease, portal hypertension, and ascites. HRS-AKI is found in ∼20% of patients presenting to the hospital with AKI, but it may coexist with other causes of AKI and/or with preexisting chronic kidney disease, thereby making the diagnosis challenging. Novel biomarkers such as urinary neutrophil gelatinase-associated lipocalin may be useful. While HRS-AKI is a functional form of AKI related to circulatory and neurohormonal dysfunction, there is increasing recognition of the importance of systemic inflammation and the renal microenvironment. Early diagnosis and initiation of HRS-AKI-specific treatment can improve outcomes. The mainstay of therapy is a vasoconstrictor (terlipressin or norepinephrine) combined with albumin, which achieves resolution of HRS in 40-50% of cases. Liver transplantation is the only option for patients failing to respond to medical therapies.

Acute kidney injury (AKI) in patients with acute-on-chronic liver failure (ACLF) is driven by the severity of systemic inflammation, acute portal hypertension driving circulatory dysfunction, hyperbilirubinemia, and toxicity of bile acids. The spectrum is mostly structural, associated with reduced response to vasoconstrictors. The progression is rapid, and need of renal replacement therapy and extracorporeal therapies may be required for the management. The development of renal failure is usually considered when defining the syndrome of ACLF.

In the current review we discuss the pathophysiological basis, natural course, and response to the current therapeutic modalities and challenges in assessing and managing AKI in patients with ACLF. We conducted a comprehensive search of electronic databases such as PubMed, Web of Science, and Scopus using keywords like lactate, NGAL, and PHTN, as well as CRRT, PLEX, ACLF, and AKI phases for our review. Peer-reviewed English papers that addressed our issue were considered.

The difficulties and specific management strategies for AKI in ACLF patients are discussed emphasizing the importance of customized protocols, risk assessment guided by biomarkers, and investigation of extracorporeal therapies that target bile acids.

Cirrhosis-associated immune dysfunction refers to the concurrent systemic inflammation and immunoparesis evident across the disease spectrum of chronic liver disease, ranging from the low-grade inflammatory plasma milieu that accompanies compensated disease to the intense high-grade inflammatory state with coexistent severe immune paralysis that defines acute decompensation and acute-on-chronic liver failure. Systemic inflammation plays a crucial role in the disease course of cirrhosis and is a key driver for acute decompensation and the progression from compensated to decompensated cirrhosis. Severe systemic inflammation is fundamental to the development of organ dysfunction and failure and, in its most extreme form, acute-on-chronic liver failure. Systemic inflammation propagates the development of hepatic encephalopathy and hepatorenal syndrome-acute kidney injury. It may also be involved in the pathogenesis of further complications such as hepatocellular carcinoma and mental illness. Those patients with the most profound systemic inflammation have the worst prognosis. Systemic inflammation exerts its negative clinical effects through a number of mechanisms including nitric oxide-mediated increased splanchnic vasodilation, immunopathology, and metabolic reallocation.

Neuroglia contribute to the pathophysiology of hepatic encephalopathy (HE) either beneficially or detrimentally. Pathogenesis of HE is linked to damage triggered by blood-derived toxins, with ammonia being the main causative factor. Neuroglial cells, especially astrocytes and microglia, respond to HE-associated systemic and central signals and undergo complex and variable changes in their metabolism, morphology, and function, which include ion and water dyshomeostasis in conjunction with neurotransmission imbalance and neuroinflammation. HE-induced alterations of astrocytes are defined as astrocytopathy, with aberrant astrocytes resulting in either gain or loss of functions. In the chronic HE, the presence of Alzheimer type II cells is a histologic hallmark, with asthenic astrocytes emerging as a newcomer. In acute HE, rapid swelling of astrocytes is a primary cause of cerebral edema and mortality. This chapter reviews the dominant role of astrocytes in the pathogenesis of HE resulting from acute and chronic liver failure, mainly in experimental models. The focus is on the loss of homeostatic function bearing upon the functioning of the glymphatic system, aberrant neurotransmission as a consequence of astrocyte-neuron miscommunication, and the concordant neuroinflammatory response of astrocytes and microglia. The chapter concludes with a delineation of concepts for future research.

Patients with cirrhosis have high systemic inflammation (TNFα, CRP, and IL-6) that is associated with poor outcomes. These biomarkers need continuous non-invasive monitoring, which is difficult with blood. We studied the AWARE sweat-sensor to measure these in passively expressed sweat in healthy people (N = 12) and cirrhosis (N = 32, 10 outpatients/22 inpatients) for 3 days. Blood CRP, TNFα, IL6, levels, and liver function and quality of life were measured. We found that CRP, TNFα, and IL6 were correlated in sweat and serum among both groups and were evaluated in inpatients versus outpatients/controls. IL6 is associated with lower transplant-free survival. Sweat monitoring nocturnal CRP/IL6 elevations in cirrhosis versus controls. Outpatients with cirrhosis had inflammation levels that elevated during the evening and peaked towards the early night periods. The levels start to fall much later at night and early morning. These data suggest that further investigation of continuous measurement of sweat biomarkers in cirrhosis is warranted.

Background: The prognosis of patients with liver failure (LF) depends significantly on the etiology and clinical indicators. This analysis of these basic indicators can help provide a basis for the study of predictive outcome indicators. Methods: We collected the data from multiple centers in Southeast China, including subclasses of acute liver failure (ALF), subacute liver failure (SLF), acute-on-chronic liver failure (ACLF), subacute-on-chronic liver failure (SALF), and chronic liver failure (CLF). Multivariate logistic regression analysis was used to screen for clinical indicators of nonsurvivors. We analyzed receiver operating characteristic (ROC) curves and cutoff values to assess the prognostic criteria. Results: Hepatitis B virus (HBV) infection is the leading etiology of patients with LF (64.52% (411/637)). SALF (41.36%) and CLF (32.30%) are the main subclasses of the hepatitis B virus-related liver failure (HBV-LF) group and the non-HBV-related LF group in Southeast China, respectively. Between 2018 and 2020, the incidence of HBV-LF decreased significantly, ranging from 72.36% to 59.74%, and the spontaneous survival rates of patients with HBV-LF were substantially lower than those of non-HBV-LF patients (36.43%~44.93% vs. 58.97%~63.64%). Infection and cirrhosis were the leading causes of death in both groups. The age and total bilirubin value of the nonsurvivors with HBV-LF were significantly higher, and the number of days of hospitalization was significantly shorter than that of the survivors. The ages of the nonsurvivors in the non-HBV-LF group were significantly higher than those of the survivors. The prothrombin time-international normalized ratio (PT-INR) is 2.05, 1.92, or 2.11, and antithrombin III (AT III) is 24.50%, which are proposed as prognostic criteria for the HBV-SALF (hepatitis B virus-related subacute-on-chronic liver failure), non-HBV-SLF (non-hepatitis B virus-related subacute liver failure), non-HBV-ACLF (non-hepatitis B virus-related acute-on-chronic liver failure), and HBV-ALF (hepatitis B virus-related acute liver failure) subclasses, respectively. Conclusions: The incidence of HBV-LF is decreasing annually. AT III, as an independent prognostic criterion, has excellent discriminative ability for the outcomes of the HBV-ALF subclass.

Acute-on-chronic liver failure (ACLF) and decompensated cirrhosis (DC) are life-threatening syndromes that can develop at the end-stage of chronic hepatitis B virus (HBV) infection. Both ACLF and DC are complicated by hepatic and extrahepatic pathogeneses. To better understand the compartment-specific metabolic modulations related to their pathogenesis, HBV-DC, HBV-ACLF patients, and controls (30 each) were analyzed by metabolomics using portal (Port), hepatic vein (Hep), and peripheral (Peri) serum. Compartment ratios of metabolites (RatioHep/Port, RatioPeri/Hep, and RatioPort/Peri) were calculated. The liver tissues (10 per group) were analyzed using transcriptomics and metabolomics. An additional 75 patients with ACLF, 20 with DC, and 20 with liver cirrhosis (LC) were used to confirm oxlipid dysregulation. Both multi-omics datasets suggest suppressed energy, amino acid, and pyrimidine metabolism in the ACLF/DC liver. The serum metabolomic variations were contributed primarily by disease rather than sampling compartments, as both HBV-ACLF and HBV-DC patients demonstrated abnormal profiles of amino acids and peptides, indoles, purines, steroids, and benzimidazoles. In ACLF/DC patients, impaired hepatic metabolism resulted in a highly correlated hepatic and portal vein serum metabolome and release of inflammatory lipids and heme metabolites from the liver. HBV-ACLF showed higher RatioPeri/Hep of extrahepatic inflammatory oxlipids, while HBV-DC patients showed higher RatioPort/Peri of gut microbial metabolites. An inflammatory oxlipid outburst was confirmed in the early stages of HBV-ACLF. The inflammatory effects of the selected oxlipids were confirmed in monocytes. These findings support a synergy between liver-specific mechanisms and systemic inflammation in ACLF/DC development, and that pro-inflammatory oxlipids are metabolic signatures of early HBV-ACLF.