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.

Acute-on-chronic liver failure (ACLF) is a severe clinical syndrome characterized by high morbidity and mortality rates. Bacterial infection is a frequent precipitating factor and complication in ACLF patients, significantly worsening patient outcomes. Elucidating the mechanisms underlying bacterial infections and their impact on ACLF pathophysiology is crucial for developing effective therapies to reduce infection rates and mortality. Current research highlights that immune suppression in ACLF increases susceptibility to bacterial infections, which in turn exacerbate immune dysfunction. However, a comprehensive review summarizing the emerging mechanisms underlying this immunosuppression is currently lacking. This review aims to provide an overview of the latest research, focusing on alterations in the immune responses of innate immune cells-including monocytes, macrophages, and neutrophils-as well as adaptive immune cells such as T and B lymphocytes during the onset and progression of bacterial infections in ACLF. In addition, recent advances in immunomodulatory therapies, including stem cell-based interventions, will also be discussed.

Sarcopenia is prevalent in patients with chronic liver diseases, especially in cirrhosis patients. While sarcopenia is identified as a predictor of mortality in cirrhosis, its influence on acute-on-chronic liver failure (ACLF) remains unclear. This systematic review with meta-analysis aimed to explore the prognostic value of sarcopenia in ACLF patients.

A comprehensive online literature search was performed in Medline (via PubMed), Web of Science, Embase, and Cochrane Library, and eligible studies were screened according to the predetermined criteria. The quality of the included studies was assessed by using the revised Cochrane Collaboration Risk of Bias Tool for randomized-control studies and the Newcastle-Ottawa Quality Assessment Scale for observational studies. Available outcomes measured by odds ratio (OR), hazard ratio (HR), and risk ratio (RR) with a 95% confidence interval (CI) were extracted and further included in the meta-analysis. Stata (version 18.0) was used for all statistical analyses.

Nine studies were included in further analysis. The pooled prevalence of sarcopenia was 53.3% (95% CI: 53.26 - 71.23%). The presence of sarcopenia was positively associated with 28-day mortality (HR = 2.11, 95% CI: 1.50-2.95, p < 0.001, I2 = 0.0%; OR = 2.73, 95% CI: 1.37-5.42, p = 0.004, I2 = 0.0%), 90-day mortality (HR = 1.66, 95% CI: 1.13-2.46, p = 0.01, I2 = 72.3%), and overall mortality (HR = 1.81, 95% CI: 1.30-2.51, p < 0.01, I2 = 0.0%). When using continuous variables to describe sarcopenia, a 1-unit increase in these indicators was almost significantly related to reduced 90-day mortality (HR = 0.98, 95% CI: 0.95-1.00, p = 0.052, I2 = 0.0%) and significantly associated with lower 1-year post-transplantation mortality (HR = 0.91, 95% CI: 0.85-0.98, p = 0.012, I2 = 32.7%).

Current evidence illustrates that sarcopenia is an unfavorable factor for both short- and long-term prognosis. More studies are needed to validate these findings in the future.

To explore the role of age at listing on outcomes for patients with acute-on-chronic liver failure (ACLF) awaiting liver transplantation (LT).

We assessed adult candidates listed for LT in the Scientific Registry of Transplant Recipients database from January 1, 2007 to June 30, 2018. Patients were divided into four groups based on age at listing: I (≤34), II (35-49), III (50-64), and IV (≥65). The ACLF grade was estimated (est-ACLF), and intent-to-treat survival, overall survival (OS), as well as potential predictors for OS was evaluated.

Est-ACLF-3 was associated with a higher 30-d cumulative dropout rate and inferior intent-to-treat survival across age groups. No difference was observed in OS among ACLF grades in group I, but significantly inferior OS was observed in higher ACLF grades in groups II-IV. Multivariate analysis showed age (P < 0.001, ref. group I; hazard ratio 0.995 for group II, P = 0.936; 1.196 for group III, P = 0.002; 1.651 for group IV, P < 0.001) and est-ACLF grade (P < 0.001, ref. est-ACLF-0; 1.214 for est-ACLF-1, P < 0.001; 1.246 for est-ACLF-2, P < 0.001; 1.578 for est-ACLF-3, P < 0.001) were independent predictors for OS. Generalized additive model showed different association between age and OS among different ACLF grades.

Young patients with high ACLF grades could achieve similar OS compared with those with low grades. Elderly patients with higher ACLF grades were associated with inferior outcomes after LT.

Acute decompensation of cirrhosis is associated with high mortality, and acute-on-chronic liver failure is at the extreme of its spectrum of severity. This study aimed to evaluate the incidence and risk factors for the development of acute-on-chronic liver failure in outpatients with cirrhosis.

This is a retrospective cohort study of consecutive patients with cirrhosis attending an outpatient clinic at a referral hospital in southern Brazil. Clinical, laboratory, and imaging data at the first outpatient visit were collected. The primary outcome of interest was the development of acute-on-chronic liver failure.

Three hundred patients with cirrhosis were included in the study. During a median follow-up of 56.5 months, 41 developed acute-on-chronic liver failure. The incidence of acute-on-chronic liver failure was 3.9% at 12 months, 7.0% at 24 months, 8.8% at 36 months, and 12.7% at 60 months. The cumulative incidence of acute-on-chronic liver failure was 23.0% at 84 months. Multivariate Cox regression analysis showed that baseline hemoglobin (hazard ratio of 0.78, 95% confidence interval: 0.67-0.90) and Child-Pugh score (hazard ratio of 1.70, 95% confidence interval: 1.44-2.00) were independently associated with the development of acute-on-chronic liver failure.

Nearly one-fourth of outpatients with cirrhosis developed acute-on-chronic liver failure during follow-up, which was independently associated with low hemoglobin levels and poor liver function according to the Child-Pugh score at baseline.

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

This narrative review addresses the definition of acute-on-chronic liver failure, a condition associated with high short-term mortality in patients with chronic liver disease and/or cirrhosis. We provide two major points of view: the East and the West perspective. Both definitions vary regarding the underlying patient population and organ failure(s) definition. Nevertheless, all the definitions have their clinical utility: from the core concept of having the "liver" as a conditio sine qua non, the syndrome cannot exist (Asian Pacific Association for the Study of the Liver); a data-driven, robust definition (European Association for the Study of the Liver); a bedside tool that can quickly identify patients at high risk of dying (North American Consortium for the Study of End-stage Liver Disease [NACSELD]). In each section, we provide the overall definitions, the criteria of organ failure(s), and some epidemiological data illustrating how these apply in each area of the world.

Morbidity and mortality from cirrhosis are substantial and increasing. Health disparities in cirrhosis and liver transplantation are reflective of inequities along the entire spectrum of chronic liver disease care, from screening and diagnosis to prevention and treatment of liver-related complications. The key populations experiencing disparities in health status and healthcare delivery include racial and ethnic minority groups, sexual and gender minorities, people of lower socioeconomic status and underserved rural communities. These disparities lead to delayed diagnosis of chronic liver disease and complications of cirrhosis (for example, hepatocellular carcinoma), to differences in treatment of chronic liver disease and its complications, and ultimately to unequal access to transplantation for those with end-stage liver disease. Calling out these disparities is only the first step towards implementing solutions that can improve health equity and clinical outcomes for everyone. Multi-level interventions along the care continuum for chronic liver disease are needed to mitigate these disparities and provide equitable access to care.

The July effect in US teaching hospitals has been studied with conflicting results. We aimed to evaluate the effect of physician turnover in July on the clinical outcomes of patients hospitalized with cirrhosis.

We utilized the Nationwide Inpatient Sample database (2016-2019) to identify patients hospitalized with cirrhosis and liver-related complications (variceal bleeding, hepatorenal syndrome, acute-on-chronic liver failure). We used difference-in-differences analysis to compare teaching and non-teaching hospital differences in mortality and length of stay (LOS) in May and July, and trends in outcomes in other months before and after July.

We included 78,371 hospitalizations in teaching and 23,518 in non-teaching hospitals in May and July. Teaching hospital admissions had overall higher complication rates and mortality compared to non-teaching hospitals. We did not find a difference in mortality between teaching and non-teaching hospitals in all cirrhotic patients (adjusted odds ratio 1.01, 95%CI [0.88-1.16]) or in those with severe complications (0.87, [0.72-1.06]). There was greater LOS in July vs. May in teaching hospitals relative to non-teaching hospitals for all patients with cirrhosis (adjusted rate ratio 1.03, 95%CI [1.02-1.05]) and for those with severe complications (1.19, [1.17-1.21]). The months after July were associated with longer LOS in teaching hospitals, with the effect gradually diminishing over the subsequent months.

Our study suggests trainee turnover in July did not affect mortality, but lengthened hospital stays for patients with cirrhosis, highlighting the need for effective supervision of new trainees and strategies to mitigate operational disruptions for improved clinical management.

Acute-on-chronic liver failure (ACLF) is a syndrome of patients with chronic liver disease presenting with multiple organ failures. Recently, Sundaram-ACLF-LT Mortality (SALT-M) score has been developed to predict 1-year post-liver transplantation mortality. We validated the SALT-M score in a large-volume, Asian single-centre cohort.

We validated the SALT-M score in a large-volume, Asian single-centre cohort.

We analysed 224 patients of ACLF grade 2-3. Area under the receiver operating characteristic curve (AUROC) and concordance index (c-index) were used to assess and compare the predictability of posttransplant mortality of SALT-M and other scores. Moreover, we compared the survivals of patients with high and low SALT-M, in conjunction with MELD score and ACLF grade.

The AUROC for prediction of 1-year post-LT survival was higher in SALT-M (0.691) than in MELD, MELD-Na, MELD 3.0 and delta-MELD. Similarly, the c-index of the SALT-M (0.650) was higher than aforementioned MELD systems. When categorised by the cut-off of SALT-M ≥ 20 and MELD ≥ 30, patients with high SALT-M exhibited lower post-LT survival than those with low SALT-M scores regardless of high or low MELD (40.0% for high SALT-M/high MELD vs. 42.9% for high SALT-M/low MELD vs. 73.8% for low SALT-M/high MELD vs. 63.7% for low SALT-M/low MELD, p < 0.001). In patients with ACLF grade 3, SALT-M effectively stratified the posttransplant mortality (39.4% for high SALT-M vs. 63.1% for low SALT-M, p = 0.018).

SALT-M outperformed previous MELD systems for predicting posttransplant mortality in Asian LT cohort with severe ACLF. Transplantability for patients with severe ACLF could be determined based on SALT-M.

Acute-on-chronic liver failure (ACLF) is a major public health concern. We aimed to assess the definitions, etiologic spectrum, organ failure (OF), and outcomes of ACLF globally.

Three databases were searched for studies on ACLF from 1990 until September 2022. Information regarding definitions, acute precipitants, underlying chronic liver disease (CLD), OF, and mortality were extracted. Meta-analyses were performed for pooled prevalence rates (95% confidence interval [CI]) using random-effects model for each definition of ACLF.

Of the 11,451 studies identified, 114 articles (142 cohorts encompassing 210,239 patients) met the eligibility criteria. Most studies (53.2%) used the European Association for the Study of the Liver (EASL) definition, followed by Asia-Pacific Association for the Study of the Liver (APASL) (33.3%). Systemic infection was the major acute precipitant, and alcohol use was the major cause of CLD in EASL-defined studies, whereas alcohol was both the major acute precipitant and cause of CLD in APASL-defined studies. Liver failure was the major OF in APASL-based studies, whereas renal failure was predominant in EASL-based studies. Thirty-day mortality varied across definitions: APASL: 38.9%, 95% CI, 31.2%-46.9%; EASL: 47.9%, 95% CI, 42.2%-53.5%; and NACSELD: 52.2%, 95% CI, 51.9%-52.5%. Diagnostic overlap between definitions ranged from 7.7% to 80.2%. Meta-regression suggested that the World Health Organization region influenced 30-day mortality in studies using EASL definition.

Heterogeneity in the definition of ACLF proposed by different expert societies and regional preferences in its use result in differences in clinical phenotype and outcomes. A uniform definition would enhance the comparability and interpretation of global data.

Acute-on-chronic liver failure (ACLF) has a 22%-74% 28-day mortality rate and 30%-40% 30-day readmission rate. We investigated the acceptability and feasibility of a multimodal community intervention for ACLF.

A single-arm nonrandomized pilot study of consecutive participants with ACLF was conducted in a tertiary health service. Participants received weekly medical and nursing reviews, dietetics, physiotherapy, pharmacy, social work, addiction medicine, and neuropsychiatry, where indicated. A digital platform included remote weight monitoring and online surveys. The primary outcome was acceptability/feasibility. Secondary outcomes included safety, mortality, readmission, liver disease severity, and costs.

Fifty-nine patients were enrolled with median age 51 years (interquartile range (IQR): 45-59); majority alcohol etiology (74%),and median Model for End-Stage Liver Disease Sodium score 16 (IQR: 12-21). LivR Well was acceptable with low attrition (8 of 59), adherence to the program including home visits (mean 8.4 ± 4.2) and consultations (mean 2.4 ± 1.5) per patient. This was supported by positive feedback and themes identified through a qualitative subanalysis. Feasibility was demonstrated by recruitment rate of 4.94 patients/month and 86% completion. Mortality was lower than expected at 3%, 30-day readmission rate was 15%, and median Model for End-Stage Liver Disease Sodium score reduced to 15 (P = .01). Median 6-month costs reduced from $30,454 (IQR: $21,953-$65,657) to $17,657 ($4249-$42,876) (P = .009). The total 6-month health-care cost was $1,868,859 (95% confidence interval 1,081,821-2,655,897) compared to $2,518,227 (95% confidence interval 1,959,610-3,076,844).

LivR Well was acceptable, feasible, and safe with low short-term mortality and readmission rates. Health-care costs were reduced by 26% driven by a 40% reduction in 30-day readmission. Further evaluation includes a randomized controlled trial of LivR Well compared to standard care.

Cirrhosis represents a significant global health challenge, characterized by high morbidity and mortality rates that severely impact human health. Timely and precise prognostic assessments of liver cirrhosis are crucial for improving patient outcomes and reducing mortality rates as they enable physicians to identify high-risk patients and implement early interventions. This paper features a thorough literature review on the prognostic assessment of liver cirrhosis, aiming to summarize and delineate the present status and constraints associated with the application of traditional prognostic tools in clinical settings. Among these tools, the Child-Pugh and Model for End-Stage Liver Disease (MELD) scoring systems are predominantly utilized. However, their accuracy varies significantly. These systems are generally suitable for broad assessments but lack condition-specific applicability and fail to capture the risks associated with dynamic changes in patient conditions. Future research in this field is poised for deep exploration into the integration of artificial intelligence (AI) with routine clinical and multi-omics data in patients with cirrhosis. The goal is to transition from static, unimodal assessment models to dynamic, multimodal frameworks. Such advancements will not only improve the precision of prognostic tools but also facilitate personalized medicine approaches, potentially revolutionizing clinical outcomes.

The incidence of hospitalisations related to acute-on-chronic liver failure (ACLF) is increasing. Liver transplantation (LT) remains the definitive treatment for the condition.

To evaluate the influence of race and ethnicity on LT outcomes in ACLF.

We conducted a retrospective analysis utilising LT data from the United Network for Organ Sharing (UNOS) database. White patients served as the control group and patients of other races were compared at each ACLF grade. The primary outcomes assessed were graft failure and all-cause mortality.

Blacks exhibited a higher all-cause mortality (Grade 1: aHR 1.36, 95% CI 1.18-1.57, p < 0.001; Grade 2: aHR 1.27, 95% CI 1.08-1.48, p = 0.003; Grade 3: aHR 1.19, 95% CI 1.04-1.37, p = 0.01) and graft failure (Grade 1: aHR 2.05, 95% CI 1.58-2.67, p < 0.001; Grade 2: aHR 1.91, 95% CI 1.43-2.54, p < 0.001; Grade 3: aHR 1.50, 95% CI 1.15-1.96, p = 0.002). Hispanics experienced a lower all-cause mortality at grades 1 and 3 (Grade 1: aHR 0.83, 95% CI 0.72-0.96, p = 0.01; Grade 3: aHR 0.80, 95% CI 0.70-0.91, p < 0.001) and Asians with severe ACLF demonstrated decreased all-cause mortality (Grade 3: aHR 0.55, 95% CI 0.42-0.73, p < 0.001).

Black patients experienced the poorest outcomes and Hispanic and Asian patients demonstrated more favourable outcomes compared to Whites.

In this editorial, we comment on the article by Zhou et al. The study reveals the connection between ferroptosis and pyroptosis and the effect of silent information regulator sirtuin 1 (SIRT1) activation in acute liver failure (ALF). ALF is characterized by a sudden and severe liver injury resulting in significant hepatocyte damage, often posing a high risk of mortality. The predominant form of hepatic cell death in ALF involves apoptosis, ferroptosis, autophagy, pyroptosis, and necroptosis. Glutathione peroxidase 4 (GPX4) inhibition sensitizes the cell to ferroptosis and triggers cell death, while Gasdermin D (GSDMD) is a mediator of pyroptosis. The study showed that ferroptosis and pyroptosis in ALF are regulated by blocking the p53/GPX4/GSDMD pathway, bridging the gap between the two processes. The inhibition of p53 elevates the levels of GPX4, reducing the levels of inflammatory and liver injury markers, ferroptotic events, and GSDMD-N protein levels. Reduced p53 expression and increased GPX4 on deletion of GSDMD indicated ferroptosis and pyroptosis interaction. SIRT1 is a NAD-dependent deacetylase, and its activation attenuates liver injury and inflammation, accompanied by reduced ferroptosis and pyroptosis-related proteins in ALF. SIRT1 activation also inhibits the p53/GPX4/GSDMD axis by inducing p53 acetylation, attenuating LPS/D-GalN-induced ALF.

Liver failure profoundly affects the immune system, leading to dysregulation of innate and adaptive immune response. This review explores the intricate relationship between liver function and immune homeostasis. The role of the liver as a central hub in immune response initiation is elucidated, emphasizing its involvement in hepatic inflammation induction and subsequent systemic inflammation. Cytokines, chemokines, growth factors, and lipid mediators orchestrate these immune processes, serving as both prognostic biomarkers and potential therapeutic targets in liver failure-associated immune dysregulation, which might result from acute-on-chronic liver failure (ACLF) and cirrhosis. Furthermore, the review delves into the mechanisms underlying immunosuppression in liver failure, encompassing alterations in innate immune cell functions such as neutrophils, macrophages, and natural killer cells (NK cells), as well as perturbations in adaptive immune responses mediated by B and T cells. Conclusion: Understanding the immunological consequences of liver failure is crucial for developing targeted therapeutic interventions and improving patient outcomes in liver disease management.

Since the first liver transplant was performed over six decades ago, the landscape of liver transplantation in the US has seen dramatic evolution. Numerous advancements in perioperative and operative techniques have resulted in major improvements in graft and patient survival rates. Despite the increase in transplants performed over the years, the waitlist mortality rate continues to remain high. The obesity epidemic and the resultant metabolic sequelae continue to result in more marginal donors and challenging recipients. In this review, we aim to highlight the changing characteristics of liver transplant recipients and liver allograft donors. We focus on issues relevant in successfully transplanting a high model for end stage liver disease recipient. We provide insights into the current use of terms and definitions utilized to discuss marginal allografts, discuss the need to look into more consistent ways to describe these organs and propose two new concepts we coin as "Liver Allograft Variables" (LAV) and "Liver Allograft Composite Score" (LACS) for this. We discuss the development of spectrum of risk indexes as a dynamic tool to characterize an allograft in real time. We believe that this concept has the potential to optimize the way we allocate, utilize and transplant livers across the US.

Patients with acute decompensation of cirrhosis or acute-on-chronic liver failure (ACLF) often require intensive care unit (ICU) admission for organ support. Existing research, mostly from specialized liver transplant centers, largely addresses short-term outcomes. Our aim was to evaluate in-hospital mortality and 1-year transplant-free survival after hospital discharge in the Netherlands.

We conducted a nationwide observational cohort study, including patients with a history of cirrhosis or first complications of cirrhotic portal hypertension admitted to ICUs in the Netherlands between 2012 and 2020. The influence of ACLF grade at ICU admission on 1-year transplant-free survival after hospital discharge among hospital survivors was evaluated using unadjusted Kaplan-Meier survival curves and an adjusted Cox proportional hazard model.

Out of the 3,035 patients, 1,819 (59.9%) had ACLF-3. 1,420 patients (46.8%) survived hospitalization after ICU admission. The overall probability of 1-year transplant-free survival after hospital discharge was 0.61 (95% CI 0.59-0.64). This rate varied with ACLF grade at ICU admission, being highest in patients without ACLF (0.71; 95% CI 0.66-0.76) and lowest in those with ACLF-3 (0.53 [95% CI 0.49-0.58]) (log-rank p <0.0001). However, after adjusting for age, malignancy status and MELD score, ACLF grade at ICU admission was not associated with an increased risk of liver transplantation or death within 1 year after hospital discharge.

In this nationwide cohort study, ACLF grade at ICU admission did not independently affect 1-year transplant-free survival after hospital discharge. Instead, age, presence of malignancy and the severity of liver disease played a more prominent role in influencing transplant-free survival after hospital discharge.

Patients with acute-on-chronic liver failure often require intensive care unit (ICU) admission for organ support. In these patients, short-term mortality is high, but long-term outcomes of survivors remain unknown. Using a large nationwide cohort of ICU patients, we discovered that the severity of acute-on-chronic liver failure at ICU admission does not influence 1-year transplant-free survival after hospital discharge. Instead, age, malignancy status and overall severity of liver disease are more critical factors in determining their long-term survival.

Traditional herbal pair Paeoniae Radix Rubra (roots of Paeonia lactiflora Pall., Chishao in Chinese) and Aconiti Lateralis Radix Praeparata (lateral roots of Aconitum carmichaelii Debeaux, Fuzi in Chinese) are widely used for the treatment of liver diseases, demonstrating clinical efficacy against acute-on-chronic liver failure (ACLF). As the core drug pair representing the "clearing method" and "warming method" in traditional Chinese medicine (TCM), they align with the TCM syndromic characteristics of ACLF, characterized by a mixture of deficiencies and realities. However, the molecular mechanisms underlying the anti-ACLF effects of Chishao - Fuzi herbal pair remain unclear.

To reveal the immunoinflammatory status of patients with hepatitis B virus-related ACLF (HBV-ACLF) based on macrophage polarization and to explore the mechanism of action of Chishao - Fuzi herbal pair in regulating macrophage polarization against ACLF.

Peripheral blood samples were prospectively obtained from patients with HBV-ACLF, patients with chronic hepatitis B (CHB) in the immunoactive phase and healthy individuals. Flow cytometry, qRT-qPCR, and ELISA were used to reveal the activation status of monocyte-macrophages and the expression differences in related cytokines in the peripheral blood of patients with HBV-ACLF. Then, an ACLF rat model and a macrophage inflammation model in vitro were established. Hematoxylin-eosin staining, immunohistochemical staining, transmission electron microscopy, flow cytometry, western blotting, RT-qPCR, and ELISA were used to observe changes in the expression of M1/M2 macrophage markers and related inflammatory factors after Chishao - Fuzi herbal pair intervention, both in vivo and in vitro.

Patients with HBV-ACLF exhibited an imbalance in M1/M2 macrophage polarization, showing a tendency to activate M1 macrophages with high expression of CD86 and iNOS. This imbalance led to an increase in relevant pro-inflammatory factors (IL-1β, IL-6, TNF-α) and a decrease in anti-inflammatory factors (IL-10, TGF-β, VEGF), exacerbating the uncontrolled immune-inflammatory response. Chishao - Fuzi herbal pair intervention improved liver function, coagulation function, and histopathological injury in ACLF rats. It also partially ameliorated endotoxemia and inflammatory injury in ACLF. The mechanism was to restore the immune-inflammatory imbalance and prevent the exacerbation of inflammatory response to liver failure by promoting macrophage polarization toward M2 anti-inflammatory direction, inhibiting M1 macrophage activation, and increasing the levels of anti-inflammatory factors and decreasing pro-inflammatory factors.

Chishao - Fuzi herbal pair can reduce the systemic inflammatory burden of liver failure by modulating macrophage polarization and restoring ACLF immune-inflammatory imbalance. This study provides new perspectives and strategies for studying HBV-ACLF immune reconstitution and inflammatory response control.

Complications of acute-on-chronic liver failure (ACLF) include increased short-term mortality. Extrahepatic organ failures result from chronic liver disease and acute hepatic injury. This combination characterizes end-stage liver disease. Its rapid progression makes it challenging for hepatologists and intensivists to treat. The varied definitions of this condition lead to varied clinical presentations. Hepatic or extrahepatic failures are more prevalent in chronic hepatitis B or cirrhosis patients who receive an additional injury. Numerous intensity parameters and prognosis ratings, including those for hepatitis B virus (HBV), have been developed and verified for various patients and causes of the disease. Liver regeneration, liver transplantation (LT), or antiviral therapy for HBV-related ACLF are the main treatment aims for various organ failures. LT is the best treatment for HBV-ACLF. In some HBV-related ACLF patients, nucleos(t)ide analogs and artificial liver assistance may enhance survival. Combining epidemiological and clinical studies, this review updates our understanding of HBV-ACLF's definition, diagnosis, epidemiology, etiology, therapy, and prognosis.

Cirrhotic patients with acute-on-chronic liver failure (ACLF) in the intensive care unit (ICU) have a poor but variable prognoses. Accurate prognosis evaluation can guide the rational management of patients with ACLF. However, existing prognostic scores for ACLF in the ICU environment lack sufficient accuracy.

To develop a new prognostic model for patients with ACLF in ICU.

Data from 938 ACLF patients in the Medical Information Mart for Intensive Care (MIMIC) database were used to develop a new prognostic model (MIMIC ACLF) for ACLF. Discrimination, calibration and clinical utility of MIMIC ACLF were assessed by area under receiver operating characteristic curve (AUROC), calibration curve and decision curve analysis (DCA), respectively. MIMIC ACLF was then externally validated in a multiple-center cohort, the Electronic Intensive Care Collaborative Research Database and a single-center cohort from the Second Hospital of Hebei Medical University in China.

The MIMIC ACLF score was determined using nine variables: ln (age) × 2.2 + ln (white blood cell count) × 0.22 - ln (mean arterial pressure) × 2.7 + respiratory failure × 0.6 + renal failure × 0.51 + cerebral failure × 0.31 + ln (total bilirubin) × 0.44 + ln (internationalized normal ratio) × 0.59 + ln (serum potassium) × 0.59. In MIMIC cohort, the AUROC (0.81/0.79) for MIMIC ACLF for 28/90-day ACLF mortality were significantly greater than those of Chronic Liver Failure Consortium ACLF (0.76/0.74), Model for End-stage Liver Disease (MELD; 0.73/0.71) and MELD-Na (0.72/0.70) (all P < 0.001). The consistency between actual and predicted 28/90-day survival rates of patients according to MIMIC ACLF score was excellent and superior to that of existing scores. The net benefit of MIMIC ACLF was greater than that achieved using existing scores within the 50% threshold probability. The superior predictive accuracy and clinical utility of MIMIC ACLF were validated in the external cohorts.

We developed and validated a new prognostic model with satisfactory accuracy for cirrhotic patients with ACLF hospitalized in the ICU. The model-based risk stratification and online calculator might facilitate the rational management of patients with ACLF.

Alcoholic hepatitis (AH) is a frequent precipitating event for the development of acute-on-chronic liver failure (ACLF), a syndrome characterised by organ failures due to immune dysfunction. The histological features of this complication are not well characterized. We investigated whether ACLF has specific histological characteristics.

Prospective cohort study in consecutive adult patients admitted between 03-2008 and 04-2021 to a tertiary referral centre with suspected AH. Diagnosis of AH was based on clinical presentation and confirmed by transjugular liver biopsy. All biopsies were assessed by a dedicated liver pathologist, blinded for clinical data and outcome. Diagnosis of ACLF was based on EASL-CLIF criteria. Histological and clinical characteristics of patients with and without ACLF at baseline were compared.

184 patients with biopsy-proven AH were enrolled. Median time from hospital admission to transjugular biopsy was 4.5 days (IQR 2-8). At baseline, ACLF was present in 73 patients (39.7%). Out of the 110 patients without ACLF at baseline, 30 (27.3%) developed ACLF within 28 days (median 7.5 days (IQR 2-20)). At baseline, ductular bilirubinostasis (DB) was the only histological feature significantly more frequently present in patients with ACLF compared to patients without ACLF (50.7% vs. 30.6%, p = 0.003). No clear association between histological features and the development of ACLF later on could be demonstrated.

In this well-defined cohort of patients with biopsy-proven AH, DB was associated with the presence of ACLF. This finding fits with the pathophysiology of this syndrome, which is characterized by systemic inflammation and an increased risk of infections.

Previous studies have shown that hepatocyte-like cells can be generated from fibroblasts using either lineage-specific transcription factors or chemical induction methods. However, these methods have their own deficiencies that restrict the therapeutic applications of such induced hepatocytes. In this study, we present a transgene-free, highly efficient chemical-induced direct reprogramming approach to generate hepatocyte-like cells from mouse embryonic fibroblasts (MEFs). Using a small molecule cocktail (SMC) as an inducer, MEFs can be directly reprogrammed into hepatocyte-like cells, bypassing the intermediate stages of pluripotent and immature hepatoblasts. These chemical-induced hepatocyte-like cells (ciHeps) closely resemble mature primary hepatocytes in terms of morphology, biological behavior, gene expression patterns, marker expression levels, and hepatic functions. Furthermore, transplanted ciHeps can integrate into the liver, promote liver regeneration, and improve survival rates in mice with acute liver damage. ciHeps can also ameliorate liver fibrosis caused by chronic injuries and enhance liver function. Notably, ciHeps exhibit no tumorigenic potential either in vitro or in vivo. Mechanistically, SMC-induced mesenchymal-to-epithelial transition and suppression of SNAI1 contribute to the fate conversion of fibroblasts into ciHeps. These results indicate that this transgene-free, chemical-induced direct reprogramming technique has the potential to serve as a valuable means of producing alternative hepatocytes for both research and therapeutic purposes. Additionally, this method also sheds light on the direct reprogramming of other cell types under chemical induction.

Acute-on-chronic liver failure (ACLF) has a high mortality rate, and liver transplantation is considered a definite treatment for patients with this condition. This study aims to evaluate the outcomes of living donor liver transplantation (LDLT) in ACLF patients in a single centre in a lower middle-income country, Vietnam.

This was a retrospective study at the 108 Military Central Hospital (Hanoi, Vietnam), enroling 51 patients diagnosed with ACLF based on Asian Pacific Association for the Study of the Liver (APASL) criteria who underwent LDLT with a right lobe graft from December 2019 to December 2022. The authors utilize the model for end-stage liver disease (MELD) and APASL ACLF Research Consortium (AARC) scores to evaluate and stratify the severity of ACLF.

The average age of all patients was 47.27±13.61, with 88.24% being male. The average BMI was 22.78±2.61. The most common underlying liver disease was chronic viral hepatitis B (88.2%). The average MELD score of the patients was 34.90±5.61, with 33.3% having MELD score greater than or equal to 40. In terms of ACLF severity, five patients (9.8%) had grade I ACLF, 35 patients (68.6%) had grade II ACLF, and 11 patients (21.6%) had grade III ACLF. The average AARC score was 9.43±1.68. The duration of treatment in the ICU was 8.59±7.27 days, and the length of hospital stay was 28.02±13.45 days. The most common post-transplant complication was biliary complication (19.61%). Death occurred in 7 patients (13.7%). The survival rates at 6 months, 1 year, and 3 years were 84%, 81.7%, and 81.7%, respectively.

Living donor liver transplantation for ACLF patients is safe and has a high post-transplant survival rate. Multidisciplinary care before, during, and after surgery, and the decision to do a liver transplant early, is essential in saving the lives of ACLF patients.

It is essential to identify the subgroup of patients who experience poorer outcomes in order to adapt clinical management effectively. In the context of liver disease, the earlier the identification occurs, the greater the range of therapeutic options that can be offered to patients. In the past, patients with acute decompensation (AD) of chronic liver disease were treated as a homogeneous group, with emphasis on identifying those at the highest risk of death. In the last 15 years, a differentiation has emerged between acute-on-chronic liver failure syndrome (ACLF) and AD, primarily due to indications that the latter is linked to a less favorable short-term prognosis. Nevertheless, the definition of ACLF varies among the different knowledge societies, making it challenging to assess its true impact compared with AD. Therefore, the purpose of this review is to provide a detailed analysis emphasizing the critical importance of identifying ACLF in the field of advanced liver disease. We will discuss the differences between Eastern and Western approaches, particularly in relation to the occurrence of liver failure and disease onset. Common characteristics, such as the dynamic nature of the disease course, will be highlighted. Finally, we will focus on two key clinical implications arising from these considerations: the prevention of ACLF before its onset and the clinical management strategies once it develops, including liver transplantation and withdrawal of care.

There is growing acceptance that principles of palliative care should be integrated into the management of serious illnesses affecting the liver, such as acute-on-chronic liver failure (ACLF). However, rates, patterns, and predictors of specialty palliative care consultation among patients with ACLF have not been well-described.

We performed a retrospective cohort study of patients hospitalized with ACLF between 1/1/2008 and 12/31/2018 using the VOCAL cohort. Patients were followed until 6/2021. We used mixed-effects regression analyses to identify significant patient and facility factors associated with palliative care consultation. We examined timing of consultation, the influence of ACLF characteristics, and facility-level variation on receipt of palliative care consultation.

We identified 21,987 patients hospitalized with ACLF, of whom 30.5% received specialty palliative care consultation. Higher ACLF grade (ACLF-2 [odds ratio (OR) 1.82, 95% CI 1.67-1.99], ACLF-3 [OR 3.06, 95% CI 2.76-3.40]), prior specialty palliative care consultation (OR 2.62, 95% CI 2.36-2.91), and hepatocellular carcinoma (OR 2.10, 95% CI 1.89-2.33) were associated with consultation. Consultation occurred latest and closest to the time of death for patients with ACLF-3 compared to ACLF-1 and ACLF-2. Significant facility-level variation in consultation persisted among patients with ACLF-3, despite adjusting for multiple patient and facility factors.

In this large cohort of hospitalized patients with ACLF, specialty palliative care consultation was rare, more common in patients with higher grade ACLF, and tended to occur closer to the time of death for the sickest patients. Greater attention should be placed on earlier integration of palliative care during acute hospitalizations in patients with ACLF.

Though palliative care consultation is recommended for patients with acute-on-chronic liver failure, there is no data demonstrating how often this occurs during hospitalizations, on a population level. We found that consultation occurs in only 30.5% of patients and occurs later for patients with grade 3 acute-on-chronic liver failure. Our data should provoke clinicians to urgently consider quality improvement efforts to integrate palliative care into the management of these seriously ill patients.

Infection is a major cause of increased mortality in patients with acute-on-chronic liver failure (ACLF). This study aims to examine the potential correlation of the skeletal muscle index at the third lumbar vertebra (L3-SMI) with infections among ACLF patients and to evaluate its impact on the long-term survival.

This retrospective study included 126 patients who underwent abdominal computed tomography (CT) and were diagnosed with ACLF at our center between December 2017 and December 2021. L3-SMI was calculated using CT, and the clinical and biochemical data as well as MELD scores were also collected, so as to analyze the relationship between L3-SMI and infections in ACLF patients and the impact on long-term prognosis.

Of the 126 ACLF patients enrolled, 50 had infections. In the multivariate logistic regression analysis, both L3-SMI [odds ratio (OR) = 0.89, 95% confidence interval (CI) = 0.81 - 0.97, P = 0.011] and hepatic encephalopathy (OR = 8.20, 95% CI = 1.70 - 39.59, P = 0.009) were independently associated with the risk of infection development. The overall survival (OS) estimates were obtained using Kaplan-Meier curves, and it was found that patients in the lowest tertile of L3-SMI had significantly lower 3-month, 6-month, 1-year, and 2-year survival rates than those in the highest tertile (P = 0.014; log-rank test).

Low L3-SMI is an independent risk factor for the development of infections and significantly influences the long-term survival in ACLF patients.

Acute-on-chronic liver failure (ACLF), a clinical syndrome that can develop at any stage in the progression of cirrhotic liver disease, is characterized by an acute decompensation in liver function with associated multiorgan failure and high short-term mortality. Current evidence points to ACLF being reversible, particularly in those at the lower end of the severity spectrum. However, there are no specific treatments for ACLF, and overall outcomes remain poor. Expedited liver transplantation as a treatment option is limited by organ shortage and a lack of priority allocation for this indication. Other options are therefore urgently needed, and our improved understanding of the condition has led to significant efforts to develop novel therapies. In conclusion, this review aims to summarize the current understanding of the pathophysiological processes involved in the onset, progression, and recovery of ACLF and discuss novel therapies under development.

Acute-on-chronic liver failure (ACLF) is a clinically and pathophysiologically distinct condition from acutely decompensated cirrhosis and is characterised by systemic inflammation, extrahepatic organ failure, and high short-term mortality.

To provide a narrative review of the diagnostic criteria, prognosis, epidemiology, and general management principles of ACLF. Four specific interventions that are explored in detail are intravenous albumin, extracorporeal liver assist devices, granulocyte-colony stimulating factor, and liver transplantation.

We searched PubMed and Cochrane databases for articles published up to July 2023.

Approximately 35% of hospital inpatients with decompensated cirrhosis have ACLF. There is significant heterogeneity in the criteria used to diagnose ACLF; different definitions identify different phenotypes with varying mortality. Criteria established by the European Association for the Study of the Liver were developed in prospective patient cohorts and are, to-date, the most well validated internationally. Systemic haemodynamic instability, renal dysfunction, coagulopathy, neurological dysfunction, and respiratory failure are key considerations when managing ACLF in the intensive care unit. Apart from liver transplantation, there are no accepted evidence-based treatments for ACLF, but several different approaches are under investigation.

The recognition of ACLF as a distinct entity from acutely decompensated cirrhosis has allowed for better patient stratification in clinical settings, facilitating earlier engagement with the intensive care unit and liver transplantation teams. Research priorities over the next decade should focus on exploring novel treatment strategies with a particular focus on which, when, and how patients with ACLF should be treated.

Acute on chronic liver failure (ACLF) is a clinical syndrome described in patients with acute decompensation (AD) of cirrhosis, characterized by organ failures and high mortality. Intensive management, including liver transplantation (LT), has been shown to improve survival. To address the limited Australian data on ACLF, we describe the prevalence, clinical profile, and outcome of ACLF in an Australian cohort of hospitalized patients.

A retrospective review of hepatology admissions in a tertiary hospital from 1 January 2017 to 31 December 2019 identified AD and ACLF cohorts, as defined by the European Association for Study of the Liver definition. Patient characteristics, clinical course, survival at 28- and 90-day survival, and feasibility of LT were analyzed.

Among the 192 admissions with AD, 74 admissions (39%) met ACLF criteria. A prior diagnosis of alcohol-related cirrhosis was highly prevalent in both cohorts. Grade-1 ACLF was the most frequent (60%), with renal failure being the commonest organ failure; 28-day (23% vs 2%, P = <0.001) and 90-day mortality (36% vs 16%, P = 0.002) were higher in ACLF than AD. Due to ongoing alcohol use disorder (AUD), only six patients underwent LT assessment during ACLF admission.

ACLF was common in our cohort of cirrhosis with AD and was associated with high mortality. AUD despite prior cirrhosis diagnosis was a barrier to LT. Prioritization of ACLF patients for LT after addressing AUD and relaxation of the 6-month abstinence rule may improve ACLF survival and should be addressed in prospective studies.

Genetic ancestry or racial differences in health outcomes exist in diseases associated with systemic inflammation (eg, COVID-19). This study aimed to investigate the association of genetic ancestry and race with acute-on-chronic liver failure (ACLF), which is characterized by acute systemic inflammation, multi-organ failure, and high risk of short-term death.

This prospective cohort study analyzed a comprehensive set of data, including genetic ancestry and race among several others, in 1274 patients with acutely decompensated cirrhosis who were nonelectively admitted to 44 hospitals from 7 Latin American countries.

Three hundred ninety-five patients (31.0%) had ACLF of any grade at enrollment. Patients with ACLF had a higher median percentage of Native American genetic ancestry and lower median percentage of European ancestry than patients without ACLF (22.6% vs 12.9% and 53.4% vs 59.6%, respectively). The median percentage of African genetic ancestry was low among patients with ACLF and among those without ACLF. In terms of race, a higher percentage of patients with ACLF than patients without ACLF were Native American and a lower percentage of patients with ACLF than patients without ACLF were European American or African American. In multivariable analyses that adjusted for differences in sociodemographic and clinical characteristics, the odds ratio for ACLF at enrollment was 1.08 (95% CI, 1.03-1.13) with Native American genetic ancestry and 2.57 (95% CI, 1.84-3.58) for Native American race vs European American race CONCLUSIONS: In a large cohort of Latin American patients with acutely decompensated cirrhosis, increasing percentages of Native American ancestry and Native American race were factors independently associated with ACLF at enrollment.

Acute-on-chronic liver failure (ACLF) is a clinical syndrome characterized by severe hepatic dysfunction leading to multiorgan failure in patients with end-stage liver disease. ACLF is a challenging clinical syndrome with a rapid clinical course and high short-term mortality. There is no single uniform definition of ACLF or consensus in predicting ACLF-related outcomes, which makes comparing studies difficult and standardizing management protocols challenging. This review aims to provide insights into the common prognostic models that define and grade ACLF.

Acute-on-chronic liver failure (ACLF) is a fatal complication of cirrhosis. Hence, identification of risk factors for ACLF is crucial. Previous studies have linked proton pump inhibitor (PPI) treatment to complications of cirrhosis, however, a possible effect of PPI treatment on the risk of ACLF has not been investigated yet. Therefore, the present study aimed to characterize the impact of PPI treatment on ACLF development.

A total of 642 patients hospitalized due to complications of cirrhosis were retrospectively identified, and PPI treatment during an observation period of 3 years following the hospitalization was reviewed. Subsequently, 74 patients with newly initiated PPI treatment at the time of hospitalization (PPI group) were 1:1 propensity score matched to 74 patients who received no PPI treatment (no-PPI group). Primary end point was the development of ACLF during the observation period, and secondary endpoints were mortality and upper gastrointestinal bleeding.

PPI and no-PPI groups had comparably severe chronic liver disease at baseline. Nevertheless, the cumulative incidence of ACLF in the presence of death as competing risk was markedly higher in the PPI group compared with the no-PPI group. ACLF-related deaths contributed significantly to a higher 3-year mortality in the PPI group. Uni and multivariable competing risk regression models confirmed that PPI treatment was an independent predictor of ACLF in the study collective (subdistribution HR: 1.892, 95% CI: 1.092-3.281, p = 0.023). The impact of PPI treatment on ACLF development was particularly strong in patients with a model for end-stage liver disease score >12. Upper gastrointestinal bleeding was slightly less frequent in the PPI group.

The present results indicate that PPI treatment could be a risk factor for ACLF in patients with advanced cirrhosis.

Acute-on-chronic liver failure (ACLF) carries a high short-term mortality for patients with cirrhosis. Prior literature suggests that statin exposure may reduce the likelihood of ACLF events. However, it is unclear if statin exposure is associated with ACLF-related mortality. This study sought to determine the association between statin use and short-term mortality among patients hospitalised with ACLF.

This was a retrospective cohort study of Veterans Health Administration (VHA) patients diagnosed with cirrhosis between 2008 and 2021 and hospitalised with high-grade (2 or 3) ACLF. Patients were stratified into those with and without continuous statin exposure for at least 90 days prior to hospitalisation. Multivariable logistic regression models were created to determine the adjusted association between statin exposure and 28-day and 90-day mortality. Categorical statin dose exposure, converted to simvastatin equivalents, was also explored.

A total of 11,731 patients with cirrhosis hospitalised with Grade 2 or 3 ACLF were included in the analytic cohort, 26% of whom had statin exposure. In adjusted logistic regression models, statin use was associated with 18% lower odds of ACLF-related 28-day mortality (odds ratio [OR] 0.82, 95% CI 0.73-0.93, p = 0.001) and 24% lower odds of 90-day mortality (OR 0.76, 95% CI 0.68-0.86, p <0.001). Increasing statin dose exposure was also associated with further reductions in 90-day mortality (e.g. OR 0.81, 95% CI 0.70-0.93 for 10-40 mg vs. 0 mg and OR 0.72, 95% CI 0.60-0.87 for 80 mg vs. 0 mg, p <0.001).

In this large, retrospective cohort study, statin exposure before high-grade ACLF hospitalisation was associated with reduced odds of 28-day and 90-day mortality in patients with cirrhosis. A statin dose-dependent reduction in 90-day ACLF-related mortality was also observed.

Statins have been identified as a class of medications with potential beneficial effects for patients with cirrhosis. In this large, retrospective cohort study of patients with cirrhosis who seek care at the Veterans Health Administration, statin use was associated with a decrease in short term (28-day and 90-day) mortality as a result of acute-on-chronic liver failure. Future prospective studies are needed to further clarify the relative safety and efficacy of statin therapy in reducing morbidity and mortality associated with acute-on-chronic liver failure in patients with cirrhosis.

Variceal bleeding is a consequence of severe portal hypertension in patients with liver cirrhosis. Although the rate of bleeding has decreased over time, variceal bleeding in the presence of acute-on-chronic liver failure (ACLF) carries a high risk of treatment failure and short-term mortality. Treatment and/or removal of precipitating events (mainly bacterial infection and alcoholic hepatitis) and decrease of portal pressure may improve outcome of patients with acute decompensation or ACLF. Transjugular intrahepatic portosystemic shunts (TIPSs), especially in the preemptive situation, have been found to efficiently control bleeding, prevent rebleeding, and reduce short-term mortality. Therefore, TIPS placement should be considered as an option in the management of ACLF patients with variceal bleeding.

Acute-on-chronic liver failure (ACLF) is a syndrome in patients with cirrhosis with high short-term mortality. Infection is a frequent precipitant of ACLF; however, it is unclear if prognosis varies by difference infectious sources. To address this knowledge gap, we utilized a large national database of patients with cirrhosis.

This was a retrospective cohort study of patients with cirrhosis in the Veterans Health Administration between 2008 and 2016. First ACLF hospitalizations were identified and infections were classified using validated algorithms, categorized as bacteremia, fungal, spontaneous bacterial peritonitis (SBP), pyelonephritis/urinary tract infection, or skin and soft tissue/musculoskeletal infection (SST/MSK). Inverse probability treatment weighing for infection-associated ACLF followed by multivariable logistic regression was used to evaluate the association between infection type and 90-day mortality.

A total 22,589 ACLF hospitalizations were included, 3998 (17.7%) of which had ACLF grade 3. Infection was associated with 12,405 (54.9%) of ACLF hospitalizations. In regression models, SBP was associated with a 1.79-fold increased odds of 90-day mortality vs. no infection (95% confidence interval [CI] 1.58-2.02, p < 0.001), whereas SST/MSK infections had a lower relative odds of mortality (odds ratio 0.48, 95% CI 0.42-0.53, p < 0.001). There was a significant interaction between infection category and ACLF grade on the outcome of 90-day mortality (p < 0.001).

The impact of infection on short-term mortality in ACLF varies depending on the source of infection. This has relevance for ACLF prognostication and challenges previous notions that bacterial infection invariably worsens prognosis among all patients with ACLF.

Changes in outcomes of cirrhotic patients admitted to intensive care units (ICUs) with infections are poorly understood. We aimed to describe changes over time in outcomes for such patients and to compare them to other ICU admissions.

Analysis of consecutive admissions to 188 ICUs between 2005 and 2017 as recorded in the Australian and New Zealand Intensive Care Society Centre for Outcome and Research Evaluation Adult Patient Database.

Admissions for cirrhotic patients with infections accounted for 4645 (0.6%) of 813 189 non-elective ICU admissions. Hospital mortality rate (35.5%) was significantly higher compared with other cirrhotic patients' admissions (28.5%), and other ICU admissions for infection (17.1%, p < .0001), and increased to 52.2% in the presence of acute-on-chronic liver failure (ACLF). Hospital mortality in cirrhotic patients' ICU admissions for infection decreased significantly over time (annual decline odds ratio, 0.97; 95% CI, 0.95-0.99, p = .002). There was a comparable reduction in-hospital mortality rates over time in other ICU admissions for infections and other cirrhotic patients' ICU admissions. However, mortality rates did not change over time in the ACLF subgroup. Median hospital and ICU length of stays for cirrhotic patients' ICU admissions for infections were 12.1 and 3.5 days, respectively, and decreased significantly by 1 day every 4 years in-hospital survivors(p < .0001).

Hospital mortality in ICU admissions for cirrhotic patients with infection is double that of non-cirrhotic patients with infection but has declined significantly over time. Outcomes in the subgroup with ACLF remained poor without significant improvement over the study period.