Simone I. Strasser

Description:Background: Larsucosterol is a DNA methyltransferase inhibitor in development for alcohol-associated hepatitis (AH), a disease for which there is no approved therapy. Methods: In this phase 2b trial, patients with severe AH were randomly assigned 1:1:1 to receive 30 mg or 90 mg of larsucosterol or placebo; a second dose was administered after 72 hours if the patient remained hospitalized. All patients received supportive care as determined by investigators. Patients in the placebo group, if prescribed, received 32 mg of methylprednisolone, while patients in the larsucosterol groups received matching placebo capsules. The primary end point was 90-day mortality or liver transplant (LT) rate. The key secondary end point was 90-day mortality. We prespecified the reporting of U.S. results separately. Results: Among 307 enrolled patients, 301 received at least one treatment dose. The difference in 90-day mortality or LT between the 30-mg or 90-mg larsucosterol and placebo groups did not reach statistical significance. Ninety-day mortality in the placebo and the 30-mg and 90-mg groups was 25 out of 103, 15 out of 102, and 17 out of 102, respectively. Among U.S. patients (76% of all enrolled patients), there were 21 deaths and 4 LTs among 77 patients in the placebo group, 8 deaths and 5 LTs among 73 patients in the 30-mg larsucosterol group, and 10 deaths and 8 LTs among 77 patients in the 90-mg larsucosterol group. In patients who were treated within less than 10 days of hospitalization (75%), mortality in the placebo group was 20 out of 79 (U.S. patients 17/57), mortality in the 30-mg larsucosterol group was 7 out of 74 (U.S. patients 4/57), and mortality in the 90-mg larsucosterol group was 13 out of 77 (U.S. patients 9/66). Most adverse events arising during treatment were attributable to hepatic disease, and there was no imbalance in adverse events that could not be ascribed to liver disease. Conclusions: The trial did not meet the primary end point of showing a beneficial effect of larsucosterol on 90-day mortality or LT in patients with severe AH. Equipoise has been established for a further trial of larsucosterol on AH survival. (The trial was funded by the DURECT Corporation; its ClinicalTrials.gov number is NCT04563026.).

Description:Despite significant benefit, the substantial economic cost has prevented the widespread adoption of Hypothermic Oxygenated machine PErfusion (HOPE) globally. Currently, HOPE is primarily utilised by liver transplantation (LT) units within high-income countries, leading to disparities in access for units operating within lower-resource settings. To address this, the Centre for Organ Assessment, Repair and Optimisation (COARO) has developed a low-cost HOPE system for clinical use. The aim of this paper was to assess the feasibility of translating the COARO system into routine clinical practice for all LT procedures at an Australian LT unit. The COARO system comprises readily available components and is built upon institutionally developed electrical and software architecture. Pre-clinical testing was conducted by sequentially perfusing human livers using HOPE followed by long-term normothermic machine perfusion. Following clinical introduction, all LT recipients at Royal Prince Alfred Hospital in Sydney, Australia were eligible to receive a graft perfused using the COARO system. Primary endpoints were measured perfusion dynamics and secondary endpoints were system costs and early graft and patient outcomes. Forty-five LT have been performed using the COARO system. No instances of device failure or unsafe perfusion have occurred. Seven patients developed early allograft dysfunction (15.6%) and the 3-month graft failure risk was 2.7% (1.8-3.9) based on the Liver Graft Assessment Following Transplantation (L-GrAFT7) score. Thirteen patients (28.9%) developed a Clavien-Dindo ≥IIIb complication. One patient developed primary non-function considered unrelated to HOPE. The total cost of the COARO system is US$1,494.87 per LT, 80% cheaper than a commercial equivalent. The COARO system is safe and presents significant economic advantage over commercial systems, allowing universal implementation of HOPE for all LT procedures in under resourced units.

Description:Acute-on-chronic liver failure (ACLF) represents a critical condition that may develop in patients with cirrhosis after an acute insult that is either hepatic or extrahepatic, and is characterized by infection risk, systemic inflammation, rapid clinical deterioration and high mortality.1 The criteria for diagnosis of ACLF vary due to differing definitions of organ failures (OFs) (Table 1). Because these patients are largely managed by intensive care physicians, OF definitions need to be consistent with intensive care literature. This is essential to identify “at-risk” populations, standardize management, define criteria for intervention, and determine entry and end points in clinical trials, drug development, and transplant priority. Toward this end, a panel of global experts, who previously authored ACLF guidance and consensus documents for the major liver societies, was convened to standardize OF definitions, building on recent consensus efforts2 (Supplementary Material). In general, OF indicates a risk for mortality, need for critical care, and requirement for early liver transplantation. Definitions were proposed to inform entry and end points for future studies and standardize management with statements with substantial agreement and those needing further study (Tables 2–4). Organ system EASL-CLIF AASLD/NACSELD APASL Liver Bilirubin >6 mg/dL or >12 mg/dL Not defined specifically Bilirubin >5 mg/dL with elevated INR (see below) Brain Grade 3–4 HE Grade 3–4 HE Grade 3–4 HE Coagulation ≥2.5 Not included INR >1.5 or prothrombin activity <40% (not separated but included in liver failure) Circulatory Vasopressor use for shock Vasopressors Not defined Respiratory PO2/FiO2 <200 or SaO2/FiO2 <214 Mechanical ventilation Not defined Renal sCr ≥2.0 mg/dL Need for RRT Not defined Immune system None None None GI failure None None None Table 1 Current Definitions of Organ Failures Based on Legacy Definitions of Liver Societies AASLD, American Association for the Study of Liver Disease; APASL, Asia Pacific Association for the Study of the Liver; EASL-CLIF, European Association for the Study of the Liver and European Foundation for the Study of Chronic Liver Failure consortium; GI, gastrointestinal; NACSELD, North American Consortium for the Study of End-Stage Liver Disease; PO2, partial pressure of oxygen; RRT, renal replacement therapy; SaO2, oxygen saturation. Open table in a new tab Liver Dysfunction vs failure Dysfunction: Total serum bilirubin ≥3 mg/dL but <7.5 mg/dL and INR ≥1.3 and <1.5 Failure: Total serum bilirubin ≥7.5 mg/dL and INR ≥1.5 Dynamic criteria A rise in serum bilirubin of 3.0 mg/dL from baseline in 3 d but <7.5 mg/dL, may be considered as failure, but requires validation Grading of liver failure in cirrhosis using well-established scores of liver failure, such as the MELD score and its iterations needs development and validation Impact of pre-existing chronic conditions The prognosis likely depends on whether the cirrhosis is compensated or decompensated with worse outcomes in the background of decompensated cirrhosis. Superimposed liver insults such as alcohol-related hepatitis, post-surgical or drug-induced injury can result in progression of liver dysfunction to liver failure Immune system and infections Severity Score Clinical presentation Dysfunction CSPH with no history of infections, and NLR ≤9 Failure (most relevant for inpatients) Cirrhosis with CSPH and 1 or more of the following: (1) invasive fungal infection, (2) SBP, (3) spontaneous bacteremia, (4) Vibrio infections, and (5) severe sepsis or septic shocka Dynamic criteria Worsening Septic shock; secondary infections; progression of NLR to > 9 Improvement Decreases in NLR to ≤3 Impact of pre-existing chronic conditions and repeated episodes Pre-existing and concomitant conditions Long-term antibiotic prophylaxis, Healthcare associated infection, Nosocomial infection, Diabetes, immunosuppressive therapies Repeated infectious episodes Immunosuppression Brain Dysfunction vs failure Clinical criteria West Haven criteria Clinical features Glasgow Coma Scale score Dysfunction: less relevant in inpatient settings 0 (could have minimal if tested; also part of covert) No abnormality apparent on clinical examination 15 1 (Covert HE, including the erstwhile grade 1 HE) Short-term memory loss, difficulty in concentrating and reverse of sleep–wake cycle 15 OF: acute encephalopathy, very relevant in inpatient settings. 2 Lethargy, apathy, drowsiness, flapping tremor (asterixis), disorientation, confusion, inappropriate behavior 12 and can be up to 15 (verbal response or obeying command typically impaired) 3 Stuporous but easily rousable, marked confusion, incoherent speech 6–12 4 Coma, unresponsive 3–6 (may respond to painful stimuli) Dynamic criteria Worsening Progression from normal mental status to dysfunction or OF Improvement Reversibility of mental status to normal (in inpatient settings) or cognitive performance to normal (for outpatients) Impact of pre-existing chronic conditions and repeated episodes Concomitant conditions Comorbid conditions, medications that lower threshold for confusion or induce withdrawal, substance abuse or withdrawal, or can be mistaken for HE. Repeated episodes Persistent cognitive impairment with repeated episodes and poor cognitive reserve. Kidney Phenotype Diagnostic criteria Clinical features FAKI ↑sCr by ≥0.3 mg/dL in <48 h, or ↑sCr by >1.5× from baseline Urine volume <0.5 mL/kg/h for ≥6 h Baseline sCr Stable sCr in ≤3 mo If not available, a stable sCr closest to the current one If no previous sCr at all, use admission sCr Stage 1 is usually treated in the outpatient setting Stages 2 and 3 are usually seen with liver failure or in patients with severe ascites and requires inpatient management. Vasoconstrictors are the treatment of choice for stages 2/3 AKI Liver transplant assessment is recommended. In selected patients kidney transplant needs consideration AKD ↑sCr by 50% from baseline for <3 mo or GFR for <60 mL/min/1.73m2 for <3 mo, or ↓GFR by >35% for <3 mo Can be slow deterioration of renal function over months (NAKI-AKD) Can be sequalae of unresolved AKI (AKI-AKD) Usually managed as outpatients CKD GFR <60 mL/min/1.73 m2 for ≥3 mo May be functional related to hemodynamic changes; seen in patients with ascites May be structural related to comorbid conditions, such as diabetes, obesity or hypertension. In selected patients, simultaneous liver- kidney transplant needs consideration Staging of AKI Stage 1 ↑sCr by ≥0.3mg/dL (26.4μmol/L) in <48 hours, or ↑sCr ≥1.5-2.0 times from baseline Stage 2 ↑sCr >2.0-3.0 times from baseline Stage 3 ↑sCr >3.0 times from baseline, or sCr >4 mg/dl (352 μmol/L) with an acute increase of ≥0.3 mg/dL (26.4 μmol/L), or Initiation of RRT Renal failure Stage ≥2 AKI ± RRT Dynamic criteria Progression Progression of AKI to a higher stage or need for RRT Regression Regression of AKI to a lower stage Response of AKI to treatment None No regression of AKI Partial Regression of AKI stage with final sCr ≥0.3 mg/dL (26.4 μmol/L) from baseline Complete Regression of AKI stage with final sCr <0.3 mg/dL (26.4 μmol/L) from baseline Impact of pre-existing chronic conditions and repeated episodes AoCKD Occurs in approximately 70% of patients with CKD Both AKI and AKD can be superimposed on CKD Definition is not set and staging of the superimposed AKI not well defined Mostly stage 1 AKI superimposed on CKD Clinical impact unclear Repeat episodes Unresolved AKI can evolve into AKD Repeat episodes of AKI can result in CKD Cardiorespiratory Circulatory Severity MAP <65 mm Hg Requirement for Vasopressors <0.1 norepinephrine ug/kg/min equivalent (early) Requirement for Vasopressors ≥0.1 ug/kg/min norepinephrine equivalent (late) Dynamic criteria Worsening Increasing vasopressor requirements Improvement Weaning of vasopressors Impact of pre-existing chronic conditions and repeated episodes Concomitant condition Cirrhotic cardiomyopathy, portopulmonary hypertension, HFrEF (no change in definition similar to general critical care/cardiology literature) Respiratory Definition and severity Nonintubated ARDS Intubated ARDS PaO2:FiO2 ≤300 mm Hg or SpO2:FiO2 ≤315 (if SpO2 ≤97%) on HFNO with flow of ≥30 L/min or NIV/CPAP with at least 5 cm H2O end-expiratory pressure Mild: 200 < PaO2:FiO2 ≤300 mm Hg or 235 < SpO2:FiO2 ≤315 (if SpO2 ≤97%) Moderate: 100 < PaO2:FiO2 ≤200 mm Hg or 148 < SpO2:FiO2 ≤235 (if SpO2 ≤97%) Severe: PaO2:FiO2 ≤100 mm Hg or SpO2:FiO2 ≤148 (if SpO2 ≤97%) Dynamic criteria Worsening Requirement for intubation if documented hypoxemia, worsening PaO2/FiO2 Improvement Extubation, improving PaO2/FiO2 Impact of pre-existing chronic conditions and repeated episodes Concomitant condition COPD, interstitial lung disease, hepatopulmonary syndrome (no change in definition similar to general critical care/respirology literature) Gastrointestinal Severity Dysfunction Gastrointestinal symptoms (nausea, vomiting, constipation, diarrhea, dysmotility and altered intestinal permeability) directly related to cirrhosis and hospitalization that makes it unable to perform digestion or absorption adequately but without systemic consequences. Failure Inability to meet nutritional needs by mouth or the enteral route and restoration is not achieved despite intervention to use the enteral route. Table 2 Proposed Diagnostic Criteria for Individual Organ Failures in Cirrhosis in the Setting of Chronic Disease ARDS, acute respiratory distress syndrome; COPD, chronic obstructive pulmonary disease; CPAP, continuous positive airway pressure; CSPH, clinically significant portal hypertension; FAKI, functional acute kidney injury; HFNO, high flow nasal oxygen; HFrPE, heart failure with reduced ejection fraction; SaO2, oxygen saturation. a Infections such as urinary tract infection, cellulitis, soft-tissue infections, and pneumonia may not necessarily constitute immune failure due to differences in prognosis. Open table in a new tab Statement Agree/strongly agree, n (%) Liver Liver dysfunction and liver failure are defined by the presence of elevated bilirubin and INR and a change from baseline levels. 29 (83) Liver dysfunction is already present in cirrhosis reinforcing its centrality and as a prerequisite for the definition of ACLF. 30 (86) Baseline liver function, as captured by bilirubin and INR, should be established in all patients presenting with ACLF. The lowest stable bilirubin and INR (without anticoagulant use) in the previous 3 mo should be used. If no values are available, then admission bilirubin and INR may be used as baseline. 31 (89) Progression from liver dysfunction to liver failure is often rapid in ACLF. High levels of serum bilirubin or a rapid change in bilirubin are an indicator of failure. The optimal cutoffs of serum bilirubin and INR to define grades of liver failure need validation. 34 (97) Brain Encephalopathy in inpatients with cirrhosis should be investigated for other causes of delirium before making a diagnosis of HE. 33 (94) Progression from HE ≤2 on West-Haven compared with grade 3 or 4 is a major sentinel event that needs to be prevented. 35 (100) Airway protection is important to prevent aspiration pneumonia in those with grades 2–4 HE. 27 (77) Advanced care planning is challenging in grade 3–4 HE and should preferably be carried out before this stage is reached. 35 (100) A normal blood ammonia level has negative predictive value, and normal ammonia in a patient with cirrhosis and delirium should prompt renewed or further differential diagnostic workup for other causes of delirium. 30 (86) Comorbid conditions, such as age, alcohol use, pre-existing mild cognitive impairment, Parkinson’s disease, and diabetes can reduce the threshold for overt HE development and should be addressed during the hospitalization. 32 (91) Opioids, benzodiazepines, and other sedative medications can precipitate or worsen acute encephalopathy through their overuse or following withdrawal. 35 (100) Persistent HE despite optimized therapy should raise the possibility of refractory HE, shunt-related HE, undiagnosed or untreated precipitants, or an alternative diagnosis. 35 (100) Kidney The definitions of AKD, AKI, and CKD, staging of AKI are based on KDIGO criteria and modified by ICA. 34 (97) Terlipressin is the recommended vasoconstrictor of choice management of stages 2 and 3 AKI. 34 (97) All patients with stage 2 or 3 AKI should be referred for evaluation for liver transplant. 20 (57)a AKD is a newly recognized condition in cirrhosis associated with increased morbidity and mortality. 33 (94) Both AKI and AKD can progress to CKD. 29 (83) Structural CKD is characterized by biomarkers of renal parenchymal damage, whereas functional CKD is characterized by severe renal sodium retention as indicated by low urinary Na+. 31 (89) Separating functional vs structural CKD may be difficult especially in longstanding CKD. 35 (100) CKD management should focus on associated conditions: ascites; fluid and electrolytes management; and comorbid conditions, such as diabetes, hypertension, and obesity. 34 (97) AoCKD is defined as acute deterioration of kidney function superimposed on an elevated sCr. To date, the data on this condition are limited. 31 (89) Patients with AoCKD and liver dysfunction will likely need simultaneous liver kidney transplantation. 24 (69)a Prevention of AKI or AoCKD include: avoidance of NSAID and other nephrotoxins, judicious early use of antibiotics in infections, close monitoring of electrolytes and volume status of patients with ascites, prompt treatment of early stage of AKI to prevent progression, and use of albumin where indicated. 35 (100) Immune system Systemic immune deficiency may result from impairment of circulating innate and adaptive immune cells whose effector functions are reduced. The functional defects in immune cells are a major contributor to the inability to appropriately clear pathogens from the bloodstream, allowing them to disseminate. 35 (100) Unlike patients with AIDS, in whom the risk of opportunistic infections can be assessed by counting CD4 T cells in blood, there is no established biomarker of immune deficiency in cirrhosis that could be used to evaluate the risk of infection. 33 (94) Parenchymal or systemic fungal infection is a hallmark of immune system failure. 33 (94) Understanding the dynamics of alterations in immunity in blood, barrier tissues, and internal borders during the progression of cirrhosis is an urgent and unmet medical need. 32 (91) Cardiorespiratory Circulatory Point-of-care ultrasound/bedside echocardiography should be performed early for assessment of volume status, ventricular function and guide fluid resuscitation in patients with ACLF even before the development of circulatory failure. 35 (100) Deviation from current definitions of circulatory failure (MAP < 65 mm Hg or requirement for vasopressors) is not backed by evidence in ACLF. However, management should be personalized for ACLF patients with cardiac dysfunction, hypertension and AKI. 32 (91) The specific role of albumin in resuscitation strategies in cirrhosis/ACLF patients with circulatory failure is unclear and warrants further investigation. 32 (91) Cirrhosis/ACLF patients with cirrhotic cardiomyopathy or a history of heart failure (HFrEF/HFpEF) warrant personalized/individualized care based on perfusion markers optimizing flow and pressure. 34 (97) Respiratory Definitions of respiratory failure/acute lung injury in ACLF should be based on critical care definitions (ie, revised 2023 Berlin Criteria) and be the same irrespective of whether the patient has underlying chronic lung disease or not. 34 (97) Terlipressin should be avoided in patients with ACLF 3 or patients with significant hypoxemia if safer alternative therapies available. 30 (86) Noninvasive respiratory strategies (ie, HFNC and noninvasive ventilation) should be used in a similar fashion compared with general critical care patients irrespective of evidence of underlying pulmonary comorbidity. 34 (97) Mechanical ventilation strategies in patients with ACLF with moderate/severe ARDS (PaO2 / FiO2 < 200) should be based on general critical care/acute lung injury literature with special considerations for high positive end expiratory pressure to avoid compromising venous return. 34 (97) Gastrointestinal failure Inability to use the gut as a viable alternative for nutrition is gut failure. 34 (97) Table 3 Consensus Statements Selected During the In-Person Meeting and Received ≥70% Final Agreement (n = 35 Panelists, 100% Response Rate) ARDS, acute respiratory distress syndrome; HFrEF, heart failure with ejection fraction; HFpEF, heart failure with preserved ejection fraction; ICA, International Club of Ascites; KDIGO, Kidney Disease: Improving Global Outcomes; NSAID, nonsteroidal anti-inflammatory drug. a Did not reach ≥70% agreement. Open table in a new tab Organ system Agreement, n (%) Liver A dynamic scoring system, using both bilirubin and INR over time, can reliably represent on-going injury and transition from hepatic dysfunction to liver failure or vice versa. 14 (40) Clearance of lactate has a role in prognosis and disease severity in patients with ACLF. Serial measurements of scores using lactate with indicators of liver injury, such as AARC score or MELD-Lactate may be useful to assess progression or regression of liver failure in patients with cirrhosis. 13 (37) Primary and secondary end points in clinical trials for liver failure in patients with ACLF should include 90-d survival. 14 (40) A reduction in MELD by 5 points as approved by FDA for alcohol-associated hepatitis can be accepted for assessing response to a therapy. 16 (46) Brain Transplant eligibility needs to be re-evaluated for patients whose brain function does not recover despite maximal therapy. 16 (46) Scales such as Hepatic Encephalopathy Grading Index and Hepatic Encephalopathy Staging Tool can be used to grade inpatient HE without dependence on the semi-quantitative West Haven Criteria. 16 (46) Serum admission thyroxine levels can predict the development of grade 3–4 HE. 11 (31) Prophylaxis using lactulose to prevent overt HE is not recommended for all patients but could have a role in those with upper GI bleeding. 13 (37) Initiation of rifaximin does not prevent HE development or progression in the acute inpatient setting. 13 (37) Cognitive testing and subsequent referral as needed to ensure risk stratification and diagnosis of overlapping conditions should ideally be performed at least once in patients with cirrhosis. 10 (29) Cognitive testing to diagnose covert HE should be standard within 2 wk of discharge for OHE in all patients. 10 (29) Given the distractions in the inpatient setting, covert HE testing should be avoided in hospitalized patients unless a quiet environment can be ensured. 11 (31) As part of OF, grade 3 should be separated from grade 4 and progression from grade 3–4 and vice versa should be documented as worsening/improving. 7 (20) Ammonia levels in inpatients may have prognostic value but have to be interpreted in context and logistic circumstances. 13 (37) Immune/infections Immune failure may be defined by the recurrence of infection in a separate organ with a different organism leading to readmission. 13 (37) Kidney Definition of kidney failure was briefly discussed but not agreed on: Should it be stage 2 AKI; a certain sCr, such as 2 mg/dL or 1.5 mg/dL? 13 (37) Definition and staging of AoCKD was discussed. Propose to use the AKI definition and staging superimposed on CKD. 11 (31) Management of AKD is not defined. 15 (43) The possible phenotypes of AoCKD: Functional AKI on functional/structural CKD or structural AKI on functional/structural CKD. Are biomarkers helpful or add to the confusion? 12 (34) Management of AoCKD has not been studied, and the definition of response to treatment needs to be defined. 11 (31) Table 4 Consensus Statements According to Organ Systems With <50% Agreement During the Selection In-Person Meeting (n = 35 Panelists, 100% Response Rate) FDA, US Food and Drug Administration; GI, gastrointestinal; OHE, overt hepatic encephalopathy.

Description:Objective: Cure of hepatitis C virus (HCV) infection decreases liver- and all-cause mortality. However, the risk of early mortality after HCV cure remains. We examined factors associated with cause-specific mortality after direct-acting antiviral (DAA) therapy. Methods: DAA-treated adults (recruited 2016-2021) were followed up to September 2023. Medication, health-service use, and deaths were obtained from population databases. The primary outcome was all-cause and cause-specific mortality. Results: Among 3619 patients (average 52.0 years (SD = 10.5), 66.0% male, 33.6% with cirrhosis) followed for a median of 6.8 years (IQR 5.5-7.4), 423 (11.7%) died (40.6% due to liver disease, 13.2% self-harm/accidental poisoning and 12.3% respiratory disease/lung cancer). Cirrhosis (adjusted hazard ratio (adj-HR) = 14.51, 95% CI 6.87-30.64), FIB4 > 3.25 (adj-HR = 4.22, 95% CI 2.63-6.80), nonsustained virological response (SVR) (adj-HR = 3.94, 95% CI 2.64-5.88) and age ≥ 60 years (adj-HR = 1.88, 95% CI 1.32-2.69) increased liver-related mortality risk. Mortality was threefold higher in non-SVR (32.4% of 210 patients vs. 10.2% of 2894 with SVR, p < 0.001). Non-SVR increased risk of liver mortality (adj-HR = 4.30, 95% CI 2.90-6.37). Mental health medication use (adj-HR = 2.82, 95% CI 1.40-5.67), loss to clinical follow-up (adj-HR = 2.61, 95% CI 1.31-5.21) and injection drug use/opioid replacement therapy (adj-HR = 2.26, 95% CI 1.23-4.14) increased risk of self-harm/accidental poisoning-related mortality. Age ≥ 60 years and diabetes increased mortality risk from other extrahepatic cancer (adj-HR = 2.68, 95% CI 1.31-5.51 and adj-HR = 2.57, 95% CI 1.15-5.72) and cardiovascular disease (adj-HR = 2.71, 95% CI 1.06-4.19 and adj-HR = 2.28, 95% CI 1.03-5.05). Conclusions: Liver-related death drives mortality for cirrhotic patients. Curing HCV remains critical. Holistic HCV care, with attention to mental health illnesses in younger patients, metabolic comorbidities, and better cancer screening for older patients may reduce excess mortality.

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