The concept of acute-on-chronic liver failure (ACLF) has been widely accepted around the world since it was proposed nearly 30 years ago, but there are still no universal criteria for the definition and diagnosis of ACLF worldwide. In recent years, the key clinical features for describing ACLF, such as the underlying chronic liver diseases, acute intrahepatic or extrahepatic insults, acute hepatic decompensation, extrahepatic organ failure, short-term high mortality, and the reversible course of the disease, have gradually narrowed the differences and reached a consensus. The pathogenesis of ACLF has not been fully elucidated, and most relevant studies focus on systemic inflammation and immune dysfunction. In this review, we discuss the evolution in the clinical definition of ACLF during the last few years and suggest clear criteria for ACLF diagnostics. In addition, we summarize the current understanding of ACLF pathogenesis and review the latest therapeutic targets against this condition. Lastly, we present a novel experimental mouse model that has been proven to be instrumental for the assessment of novel potential therapies for ACLF.

Acute-on-chronic liver failure (ACLF) is characterised by systemic inflammation and organ failures in patients with decompensated liver cirrhosis. In the absence of specific approved treatments, ACLF is associated with a high short-term mortality. In this study, we aimed to evaluate the investigational drug VS-01, a liposomal formulation for intraperitoneal infusion, in patients with decompensated liver cirrhosis, ascites, and covert hepatic encephalopathy, to inform further studies in patients with more advanced disease (eg, overt hepatic encephalopathy and ACLF). This phase 1b, first-in-human, open-label, non-randomised, single ascending and multiple dose study was conducted at the Hospital of the Goethe University Frankfurt in Germany. Eligible patients had decompensated liver cirrhosis, ascites requiring paracentesis, and covert hepatic encephalopathy (ie, minimal or grade 1 according to West Haven criteria) and were aged 18-60 years in part A of the study and 18-64 years in part B. The main exclusion criterion was organ failures meeting the definition of ACLF. Patients received single ascending doses of VS-01 (15 mL/kg, 30 mL/kg, and 45 mL/kg) in part A and multiple doses (34-42 mL/kg per day on 4 consecutive days) in part B, in addition to standard care. VS-01 was administered intraperitoneally over 60 min using a standard paracentesis catheter, with a dwell time of 2 h in part A and on days 2 and 3 of part B and a dwell time of 3 h on days 1 and 4 of part B. At the end of the dwell time, VS-01 was passively drained and the peritoneal cavity was washed. Patients were followed up in hospital for 7 days after the last dose. The primary endpoint was the safety and tolerability of VS-01, including the incidence and severity of treatment-related adverse events (TEAEs) and serious adverse events, vital signs, electrocardiograms (ECGs), and laboratory abnormalities. Safety was analysed in the safety analysis set, defined as all patients who received at least one dose of VS-01. This study was registered with EudraCT, 2018-004606-25, and is complete. Patients were recruited between Sept 23, 2019, and Dec 18, 2020. Of 15 patients screened, nine were assigned to part A (n=3 per dose level; male:female=7:2) and three were assigned to part B (male:female=1:2). No serious adverse events were reported. 20 TEAEs were reported in seven (58%) of 12 patients (four events in part A; 16 in part B). Most TEAEs were mild (14) and short in duration (19 resolved during follow-up). One TEAE-an overdose of VS-01 (26·4 mL/kg instead of 15 mL/kg; CTCAE grade 1) in part A-was considered to be definitely related to VS-01. Two (10%) of 20 TEAEs were judged to be possibly related to VS-01: one episode of grade 1 extravasation at the infusion site (part A, 45 mL/kg), which resolved within 3 days, and one episode of grade 2 pleural effusion on day 11 (part B, 41·8 mL/kg), which required no therapeutic procedure. Six (30%) of 20 TEAEs (reported in three [25%] patients) were of grade 3 but none were deemed to be treatment-related. No patients discontinued the study or VS-01 due to adverse events. The most common TEAEs were gastrointestinal disorders (seven [35%] of 20 events, reported in four [33%] of 12 patients). No clinically significant changes in vital signs, ECGs, or laboratory values were noted in any patient. VS-01 was generally well tolerated with a favourable safety profile in patients with decompensated liver cirrhosis, ascites, and covert hepatic encephalopathy. The results of this study supported the initiation of proof-of-concept studies in larger cohorts of patients with decompensated cirrhosis and ACLF. Versantis AG.

Acute-on-chronic liver failure (ACLF) is a distinct clinical syndrome characterized by an acute decompensation of chronic liver disease in association with extrahepatic organ failure(s) and a high short-term mortality. Despite its increasing clinical relevance, there is no internationally standardized definition of ACLF to date. This review provides a comprehensive overview of current ACLF definitions, underlying pathogenic mechanisms, frequent precipitating events, and current treatment strategies. While liver transplantation remains the only curative treatment option, its role in the setting of ACLF is controversially debated, and patient selection remains complex due to high perioperative risk. Thus, the review article describes the current role of liver transplantation in patients with ACLF and describes novel prognostic scoring systems (e.g., TAM core, SALT-M model) that may be helpful in selecting suitable transplant candidates. Further emerging treatment options for ACLF include extracorporeal liver support systems, therapeutic plasma exchange, and immune-modulating approaches targeting toll-like receptor signaling that offer promising adjunctive strategies, though clinical evidence remains limited. Given the high burden and complexity of ACLF, harmonized definitions and evidence-based therapeutic frameworks are urgently needed to improve patient care and optimize transplant prioritization.

Acute-on-chronic liver failure (ACLF) is a complicated syndrome associated with high short-term mortality and reversibility. Whether the prior decompensation should be included in the definition of ACLF is controversial. A total of 532 patients with decompensation (prior or first) of chronic liver disease were retrospectively enrolled and analyzed from January 2018 to June 2023. Clinical data were used to identify the characteristics and determine prognosis. Of the 532 patients, 99 patients did not meet APASL-ACLF criteria due to the existence of prior decompensation and 433 patients met the Asian Pacific Association for the Study of the Liver (APASL)-ACLF criteria. The two groups had similar characteristics including prognosis scores (Chinese Group on the Study of Severe Hepatitis B (COSSH)-ACLF II score: 7.59 vs. 7.67, p = 0.934; Chronic Liver Failure (CLIF) Consortium ACLF score: 42.90 vs. 44.81, p = 0.273), the distribution of patients with APASL ACLF research consortium score (AARC score) (5-7: 19.2%/12.0%; 8-10: 56.6%/55.0%; 11-15: 24.2%/33.0%, p > 0.05) and the 28-/90-day mortality rates (30.5%/43.2% vs. 36.3%/43.1%, p = 0.267/0.978). In all integrated ACLF patients, Receiver Operating Characteristic (ROC) curve analysis and decision curve analysis (DCA) showed that COSSH-ACLF IIs had higher prognostic efficiency and clinical net benefit than AARC score and CLIF-C ACLFs for 28-/90-day mortality. Prior decompensated patients exhibited clinical characteristics and high short-term mortality similar to those of first decompensated patients. The COSSH-ACLF IIs demonstrated the highest prognostic efficiency for all integrated ACLF patients. Including prior decompensation in the ACLF definition can help to simplify and improve clinical management.

We aimed to study the etiologies and clinical profile and to describe the factors associated with mortality in acute-on-chronic liver failure(ACLF)patients at our center. Patients meeting the Asian Pacific Association for the Study of the Liver (APASL)definition of ACLF were included. We studied etiologies and clinical profile and analyzed the factors associated with mortality in patients with ACLF. We also analyzed the mortality rates based on the number of organ failures and the grade of ACLF. 114 patients were included. Alcohol (82, 71.9%), drugs (22, 19.3%), and viral hepatitis (17, 14.9%) were the commonest precipitating factors of ACLF. The commonest cause of chronic disease was alcohol (83, 72.8%). Fifty-three (46.5%), 60 (52.6%), 44 (38.6%), 32 (28.1%), and 24 (21.1%) experienced renal, coagulation, cerebral, respiratory, and circulation failures, respectively. Overall, the in-hospital mortality rate stood at 54 (48.6%), with a median stay of eight days. Advanced hepatic encephalopathy and ventilator support independently predicted mortality.The Sequential Organ Failure Assessment (SOFA) score outperformed all other prognostic scores in predicting mortality in ACLF. Alcohol was themost commonprecipitating factor for ACLF. The in-hospital mortality rate was 48.6%. Advanced hepatic encephalopathy and ventilator support independently predicted mortality.The SOFA score is a more accurate predictor of mortality in ACLF when compared to other prognostic scores.

Combining albumin dialysis for the removal of hydrophobic substances with classical haemodialysis in the treatment of acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) has a strong theoretical rational and clinical data showed a positive effect on laboratory and partly clinical characteristics of ALF and ACLF. However, neither the MARS nor the Prometheus System has so far been able to demonstrate a mortality benefit in ALF or ACLF patients. To date, only the use of therapeutic plasma exchange (TPE) has demonstrated significant removal of pathogen-associated (PAMPs), damage-associated molecular patterns (DAMPs) and pro-inflammatory cytokines. In addition, TPE also acts simultaneously by replacing protective but depleted mediators, thus improving multiple key pathophysiological principles of both ALF and ACLF. In ALF, both high-volume and standard-volume TPE showed a significant improvement in survival. The data on the use of TPE in ACLF is still sparse, with only two Chinese monocentric studies in patients with exclusively hepatitis B-associated ACLF suggesting potentially improved survival with TPE. The currently recruiting APACHE study will include patients with the modern EASL-CLIF definition of ACLF.

Acute-on-chronic liver failure (ACLF) is a clinical syndrome of acute decompensation accompanied by organ failure that occurs on the basis of chronic liver disease and has a high short-term mortality rate. Currently, there are still differences in relation to the definition of ACLF; thus, baseline characteristics and dynamic changes are important bases for clinical decision-making in patients with liver transplantation and others. The basic strategies for treating ACLF currently include internal medicine treatment, artificial liver support systems, and liver transplantation. Multidisciplinary active collaborative management throughout the whole course is of great significance for further improving the survival rate in patients with ACLF.

An Observational Study to Determine the Combination of Precipitating Factors Predicting 30-Day Mortality in Acute-On-Chronic Liver Failure (ACLF), With Respect to Underlying Disease Etiology and definition of ACLF

Background &Aim: The prognostic factors determining the outcome of patients with cirrhosis and multi-organ failure are currently under evaluation. Reversal of organ failure pattern in response to Liver Transplant has not been studied much. It is an understood phenomenon that different organs that failed as consequence of ACLF will ultimately recover from injury upon liver transplantation. The aim of the study was to determine the mean number of days a failing organ in a pre-transplanted patient will take to recover after liver transplantation. Methods: Data was collected from April 2013 till February 2020 in the department of Liver Transplantation, Hepatobiliary and Pancreatic Services, Shifa International Hospital, Islamabad. In this cross-sectional retrospective study, 82 ACLF patients of both genders of age >15 years who fulfilled EASL-AASLD definition and underwent liver transplantation were included in the study. And patients who fulfilled APASL criteria but did not fulfilled EASL-AASLD criteria of definition of ACLF or those who required ventilator support or triple inotropic support before surgery were excluded. Patients with serum creatinine level >1.5mg/dl were labeled as having renal failure. Those with total bilirubin level of >12 mg/dl were labeled as hepatic failure and those with INR >2.5 were having coagulation failure.

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Acute-on-chronic liver failure (ACLF) is defined by the rapid development of organ(s) failure(s) associated with high rates of early (28-day) mortality in patients with cirrhosis. ACLF has been categorized into three grades of increasing severity according to the nature and number of organ failures. In patients with grade 3 ACLF, 28-day mortality is >70%. While the definition of ACLF has been endorsed by European scientific societies, North American and Asian Pacific associations have proposed alternative definitions. A prognostic score called the CLIF-C ACLF score provides a more precise assessment of the prognosis of patients with ACLF. Although bacterial infections and variceal bleeding are common precipitating factors, no precipitating factor can be identified in almost 60% of patients with ACLF. There is increasing evidence that cirrhosis is a condition characterized by a systemic inflammatory state and occult infections or translocation of bacteria or bacterial products from the lumen of the GUT to the systemic circulation which could play a role in the development of ACLF. Simple and readily available variables to predict the occurrence of ACLF in patients with cirrhosis have been identified and high-risk patients need careful management. Whether prolonged administration of statins, rifaximin or albumin can prevent ACLF requires further study. Patients with organ(s) failure(s) may needed to be admitted to the ICU and there should be no hesitation in admitting patients with cirrhosis to the ICU. No benefit to survival was observed with albumin dialysis and rescue transplantation is the best option in the most severe patients. One-year post-transplant survival rates exceeding 70%-75% have been reported, including in patients with grade 3 ACLF but these patients were highly selected. Criteria have been proposed to define futile transplantation (too ill to be transplanted), but these criteria need to be refined to include age, comorbidities and frailty in addition to markers of disease severity.

Acute-on-chronic liver failure (ACLF) is relatively recent entity and is not well described in the literature. The term acute-on-chronic liver failure was first used in 1995 to describe a condition in which two insults to the liver are operating simultaneously, one of them being ongoing and chronic and the other one acute. However, a clear definition of ACLF is still lacking, and this term is being used to mean different entities by different clinicians. Any patient who had underlying chronic liver disease with superimposed acute insult is being labeled as having ACLF. Whatsoever may be the case the most important is the denominator, the presence or absence of underlying liver disease. Prospectively collected data of all patients included demographics, clinical presentation, course in hospital and outcome. All patients had routine hematological biochemical and liver function tests. The etiology of superimposed acute event and chronic liver disease was investigated in detail and prognostic scores were calculated within 24hrs of admission. 60 patients included in our study were followed up for next three months, of which 30 patients died and 30 patients survived. All patients were classified in Child- Pugh class based on CTP score. There were only three patients Child-Pugh class A and none of them died. Child- Pugh class B had 10 patients, out of these 2 patients died & 8 patients survived. Total 47 patients were classified in Child-Pugh class C and 28 (59.57%) & this difference was statistically significant (p=0.013). According EASL-CLIF consortium grading, 23 out of 30 patients of Grade 3 ACLF, 5 out of 16 Grade 2 ACLF, 2 out of 11 Grade 1 ACLF & none of the Grade 0 ACLF patients died. These findings are statistically very much significant (P=0.0001). Even MELD score was significantly high among Non survivors when compared to the Survivors. (30.04 ± 2.37 Vs 25.53 ± 1.81) (p=0.0001).

Acute-on-chronic liver failure: Definitions, pathophysiology and principles of treatment.

We aimed to evaluate the effect of acute-on-chronic liver failure (ACLF) on patients' 1-year post-liver transplant (LT) survival. In addition, we evaluated the effect of ACLF on the development of post-LT chronic kidney disease (CKD) and early allograft dysfunction (EAD). A retrospective cohort of patients who underwent transplantation from 2010 to 2016 was studied. EASL-CLIF's definition of ACLF was used. The risk of post-LT death, CKD, and EAD was estimated with regression models weighted by inverse probability weighting considering the recipients' characteristics. Donor's BMI and donor risk index were included in the models as well. A total of 185 patients were included: 125 (67.6%) without ACLF and 60 (32.4%) with ACLF. The 1-year post-LT survival rate was 91.2% [95% confidence interval (CI): 84.6-95.1%] in patients without ACLF versus 84.9% (95% CI: 73.1-91.9%) in patients with ACLF. Post-LT CKD occurred in 43 (38.7%) patients without ACLF versus 26 (52.0%) patients with ACLF. EAD occurred in 40 (32.3%) patients without ACLF versus 15 (28.8%) patients with ACLF. No effect of ACLF was found on survival (hazard ratio 1.75; 95% CI: 0.64-4.75, P = 0.272), CKD (odds ratio: 1.31; 95% CI: 0.60-2.86; P = 0.491), or EAD (odds ratio: 0.74; 95% CI: 0.38-1.66, P = 0.473). In this study, which included mainly patients with grade 1 ACLF at the time of LT, its presence had no impact on post-LT survival or on the occurrence of CKD or EAD.

Acute on Chronic Liver Failure—In-Hospital Predictors of Mortality in ICU

Acute-on-chronic liver failure (ACLF) is characterized by an acute deterioration of liver function in patients with cirrhosis in combination with recently defined organ failures. Our aim was to independently validate the prognostic value of the recently established EASL-CLIF-Consortium definition of ACLF and to identify new predictors of short-term mortality. Patients with cirrhosis and the International Classification of Diseases, Tenth Revision diagnosis of (sub)acute liver failure were retrospectively categorized according to the EASL-CLIF-Consortium definition. Logistic regression analyses were performed to identify clinical and epidemiological predictors of 30- and 90-day mortality. From 2008 to 2015, 257 patients were included. Overall, 173 (67%) patients met the EASL criteria for ACLF (grade 1: n=43 [25%], grade 2: n=52 [30%], grade 3: n=79 [45%]). Mortality within 30days in patients without ACLF was 3.6%, and 18.6%, 37.3% and 62.0% in patients with ACLF grades 1, 2 and 3 respectively. Outcome of patients with bacterial infection-triggered ACLF was distinct from non-infection-triggered ACLF (71.6% vs 33.8% 30-day survival, P<.001), and infection-triggered ACLF was independently associated with increased mortality (odds ratio [OR]=4.28, P<.001). Pneumonia was a particularly frequent infection and burdened with high mortality. In addition, infections with multidrug-resistant organisms were frequent and independently associated with mortality (P=.030, OR=4.41), as was glycopeptide antibiotic therapy as initial empirical antibiotic therapy (P=.005). This study confirmed the EASL-CLIF-Consortium definition of ACLF as strong predictor of mortality in patients with acute decompensation of cirrhosis. However, we have observed a remarkably higher mortality in infection-triggered ACLF compared to other precipitating events.

FRI-421 - Acute on chronic liver failure (ACLF) – combining CLIF-SOFA criteria with APASL definition of ACLF enhances prediction of mortality at 1, 3 and 6 months

The aim of the study was to assess the prevalence, profile, outcome, and predictive factors of pediatric acute-on-chronic liver failure (ACLF). All children 3 months to 18 years satisfying the Asia Pacific Association for the Study of Liver Diseases definition of ACLF were included. Data were both extracted from records (January 2011 to December 2014) and prospectively collected (January to October 2015). Successful outcome was defined as survival with native liver at 90 days, whereas poor outcome included those who died or received liver transplantation. Of the 499 children with chronic liver disease (CLD), 56 (11.2%) presented as ACLF, with a mean age of 9.35 (±4.39) years. Wilson disease and autoimmune hepatitis were the commonest underlying CLDs accounting for 24 (42.8%) and 18 (32.1%) cases, respectively. The most frequent events precipitating ACLF were a flare up of the underlying disease in 27 (48.2%) and acute viral hepatitis in 17 (30%). Poor outcome occurred in 22 (39.3%) children: 17 (30.4%) died and 5 (8.9%) received liver transplantation. Poor outcome was associated with grades 3 to 4 hepatic encephalopathy, bilirubin ≥17.5, international normalized ratio ≥3.5, and presence of 2 or more organ failures. On multivariate analysis, a Chronic Liver Failure-Sequential Organ Failure Assessment score ≥10 best predicted mortality (odds ratio 20.45, 95% confidence interval 3.9-106.7). ACLF is present in 11.2% of childhood CLD, with a 90-day native liver survival of 61%. A Chronic Liver Failure-Sequential Organ Failure Assessment score of ≥10 best predicts mortality at day 90.

The aim of this study was to analyze etiologies and frequency of hepatic and extrahepatic organ failures (OFs) and outcome of acute-on-chronic liver failure (ACLF) at 10 tertiary centers in India. In this retrospective study (2011-2014), patients satisfying Asian Pacific Association for the Study of the Liver definition of ACLF were included. Etiology of acute precipitating insult and chronic liver disease and outcomes were assessed. Occurrence and severity of OF were assessed by chronic liver failure-sequential organ failure assessment score. The mean (±SD) age of 1049 consecutive ACLF patients was 44.7 ± 12.2 years; Eighty-two percent were men. Etiology of acute precipitants included alcohol 35.7%, hepatitis viruses (hepatitis A, hepatitis B, and hepatitis E) 21.4%, sepsis 16.6%, variceal bleeding 8.4%, drugs 5.7%, and cryptogenic 9.9%. Among causes of chronic liver disease, alcohol was commonest 56.7%, followed by cryptogenic and hepatitis viruses. Predictors of survival were analyzed for a subset of 381 ACLF patients; OF's liver, renal, coagulation, cerebral, respiratory, and failure were seen in 68%, 32%, 31.5%, 22.6%, 14.5%, and 15%, respectively. Fifty-seven patients had no OF, whereas 1, 2, 3, 4, and 5 OFs were recorded in 126, 86, 72, 28, and 12 patients, respectively. The mortality increased progressively with increasing number of OFs (12.3% with no OF, 83.3% with five OFs). During a median hospital stay of 8 days, 42.6% (447/1049) of patients died. On multivariate analysis by Cox proportional hazard model, elevated serum creatinine (hazard ratio [HR] 1.176), advanced hepatic encephalopathy (HR 2.698), and requirement of ventilator support (HR 2.484) were independent predictors of mortality. Alcohol was the commonest etiology of ACLF. Within a mean hospital stay of 8 days, 42% patients died. OFs independently predicted survival.

Acute-on-chronic liver failure (ACLF) is a syndrome with high short-term mortality in patients with chronic liver disease. The definition of ACLF has been addressed recently in many publications, and despite regional differences the number and severity of organ failures are decisive for the presence and severity of ACLF. However, the predisposition of patients to develop ACLF has not been addressed in prospective studies. Several predisposing factors for ACLF have been mentioned, but still clear-cut analysis and the sequential processes have not been explored. One reason is that different factors might predispose in one setting and might be the precipitating event in another, thus rendering the generalization of predisposing factors difficult. However, genetic factors, lifestyle, past medical history, aging, latent chronic infections, and the severity of the liver disease and portal hypertension might predispose for the development of ACLF after proper injury and response.