Acute-on-chronic Liver Failure Research Consortium Research Articles

Role of ammonia in predicting the outcome of patients with acute-on-chronic liver failure.

BACKGROUNDHigh venous ammonia (VA) values have been proven to be a part of the mechanism of hepatic encephalopathy in patients with liver cirrhosis (LC) as well as acute hepatitis. Moreover, VA has been associated with poor prognosis and high mortality in these clinical settings. However, the role of ammonia in acute-on-chronic liver failure (ACLF) has not yet been clearly established. AIMTo assess the role of VA in predicting the outcome of cirrhotic patients with ACLF in a tertiary care center.METHODSWe performed a retrospective observational study including consecutive patients with LC hospitalized for acute non-elective indications such as ascites, hepatic encephalopathy (HE), upper gastrointestinal bleeding, or bacterial infections that fulfilled the Asian Pacific Association for the Study of the Liver (APASL) criteria for ACLF. The study was conducted in “St. Spiridon” University Hospital, Iasi, Romania, a tertiary care center, between January 2017 and January 2019. The APASL ACLF Research Consortium (AARC) score was calculated and ACLF grade was established accordingly. West-haven classification was used for HE. Statistical analysis was performed using IBM SPSS version 22.0.RESULTSFour hundred and forty-six patients were included, aged 59 (50-65) years, 57.4% men. Child-Pugh, model for end-stage liver disease (MELD) and AARC scores were 11 (10-12), 19.13 ± 6.79, and 7 (6-8), respectively. 66.4% had ACLF grade I, 31.2% ACLF grade II, and 2.5% ACLF grade III. HE was diagnosed in 83.9%, 34% grade I, 37.2% grade II, 23.5% grade III, and 5.3% grade IV. Overall mortality was 7.8%. VA was 103 (78-148) μmol/L. Receiver operating characteristic analysis showed good accuracy for the prediction of in-hospital mortality for the AARC score [Area under the curve (AUC) = 0.886], MELD score (AUC = 0.816), VA (AUC = 0.812) and a fair accuracy for the Child-Pugh score (AUC = 0.799). Subsequently, a cut-off value for the prediction of mortality was identified for VA (152.5 μmol/L, sensitivity = 0.706, 1-specificity = 0.190). Univariate analysis found acute kidney injury, severe HE (grade III or IV), VA ≥ 152.5 μmol/L, MELD score ≥ 22.5, Child-Pugh score ≥ 12.5, and AARC score ≥ 8.5 to be associated with in-hospital mortality. Multivariate analysis identified AARC score ≥ 8.5 and venous ammonia ≥ 152 μmol/L to be independent predictors of in-hospital mortality.CONCLUSIONVA could be used as an inexpensive predictor of in-hospital mortality in patients with ACLF. Patients with both ACLF and VA > 152.5 μmol/L have a high risk for a poor outcome.

Dynamic Prognostication in Transplant Candidates with Acute-on-Chronic Liver Failure.

We aimed to extensively investigate clinical markers that are sufficiently dynamic for prognosis of acute-on-chronic liver failure (ACLF). Defined by the Asian Pacific Association for the Study of the Liver (APASL) criteria, patients with ACLF on the liver transplant waitlist in a tertiary center were retrospectively reviewed. Laboratory results and severity scores at three time points (days 1, 7, and 14 after admission) were analyzed. From 2015 to 2019, 64 patients with ACLF were enrolled, of which 24 received a liver transplant from 22 live donors. The hospital mortality rate was 31% (8% for transplant; 45% for nontransplant groups), and the 3-month survival was crucial for determining long-term outcomes. The number of significant variables for mortality, and, specifically, the hazards of international normalized ratio of prothrombin time (INR) and APASL ACLF Research Consortium (AARC) score were increased within two weeks. In multivariable analysis, INR and AARC score (D-14) were associated with poor survival and liver transplant was a protective factor in all patients, while AARC score (D-14) was significant in the nontransplant group. AARC score at day 14 is an independent risk factor for mortality in ACLF. Liver transplant from live donors reversed poor outcomes in patients with ACLF in a timely manner.

Prevalence, profile and predictors of invasive fungal infections in acute-on-chronic liver failure; analysis of Asia Pacific Association for Study of the Liver, Acute-on-Chronic Liver Failure Research Consortium (AARC) data base

Prevalence, profile and predictors of invasive fungal infections in acute-on-chronic liver failure; analysis of Asia Pacific Association for Study of the Liver, Acute-on-Chronic Liver Failure Research Consortium (AARC) data base

Adipocyte Fatty Acid–Binding Protein as a Predictor of Outcome in Alcohol-induced Acute-On-Chronic Liver Failure

Alcohol is the leading cause of acute-on-chronic liver failure (ACLF). Several severity scores predict the outcome of ACLF. However, there is a lack of simple biomarkers in predicting the outcome of these sick patients. Fatty acid-binding proteins (FABPs) are small cytosolic proteins that play a major role in lipid metabolism, energy homeostasis, and inflammation, but, have not been investigated in alcohol-induced ACLF (A-ACLF). The primary objective was to assess the correlation between serum adipocyte-FABP (A-FABP) and liver-FABP (L-FABP) levels on mortality at day 90. Secondary objectives were to compare the levels between controls and A-ACLF, correlate L-FABP, and A-FABP levels on the development of organ failure/sepsis at day 90. In this prospective observational pilot study, we included patients with A-ACLF and age-matched healthy controls. FABP's were analyzed by enzyme-linked immunosorbent assaymethod. The patients were followed up for 90 days. Twenty-five patients with A-ACLF (mean age: 40years; mean model for end-stage liver disease NA: 29.8; median Modified Maddrey's discriminant function [mDF]: 95) and 12 controls (mean age: 36.83yrs) were included in the study. A-FABP and L-FABP levels were significantly high in patients with A-ACLF than controls. Forty-four percent of patients with A-ACLF developed sepsis, 48% developed organ failure, and 44% expired by day 90. On multivariate Cox regression analysis, A-FABP (hazard ratio [HR]: 1.27 [1.08-1.5]; P = 0.003), Asian Pacific Association for the Study of Liver ACLF research consortium score (HR: 3.3[1.15-9.54]; P = 0.02), L-FABP (HR: 0.69 [0.52-0.91]; P = 0.009), and serum protein levels (HR: 0.03 [0.003-0.36]; P = 0.005) predicted mortality. A-FABP (1.17 [1.07-1.29]; P = 0.001), and serum bilirubin (1.05 [0.99-1.12]; P = 0.06) predicted development of organ failure, and only mDF (HR: 1.04 [1.01-1.07]; P = 0.009) predicted the development of sepsis on multivariate analysis. Fifteen patients received steroid therapy, of which 13.34% were nonresponders. In a selected group of patients with A-ACLF, A-FABP is highly sensitive at predicting mortality and outcome. If validated in a large, diverse sample, A-FABP can be used as a simple biomarker for prognostication in A-ACLF.

Models for acute on chronic liver failure development and mortality in a veterans affairs cohort.

The diagnosis of acute on chronic liver failure (ACLF) carries a high short-term mortality, making early identification of at-risk patients crucial. To date, there are no models that predict which patients with compensated cirrhosis will develop ACLF, and limited models exist to predict ACLF mortality. We sought to create novel risk prediction models using a large North American cohort. We performed a retrospective study of 75,922 patients with compensated cirrhosis from the Veterans Outcomes and Costs Associated with Liver Disease (VOCAL) dataset. Using 70% derivation/30% validation sets, we identified ACLF patients using the Asian Pacific Association of Liver (APASL) definition. Multivariable logistic regression was used to derive prediction models (called VOCAL-Penn) for developing ACLF at 3, 6, and 12months. We then created prediction models for ACLF mortality at 28 and 90days. The VOCAL-Penn models for ACLF development had very good discrimination [concordance (C) statistics of 0.93, 0.92, and 0.89 at 3, 6, and 12months, respectively] and calibration. The mortality models also had good discrimination at 28 and 90days (C statistics 0.89 and 0.88, respectively), outperforming the Model for End-stage Liver Disease (MELD), MELD-sodium, and the APASL ACLF Research Consortium ACLF scores. We have developed novel tools for predicting development of ACLF in compensated cirrhosis patients, as well as for ACLF mortality. These tools may be used to proactively guide patient follow-up, prognostication, escalation of care, and transplant evaluation. Receiver operating characteristic (ROC) curves for predicting development of APASL ACLF at 3months (a), 6months (b), and 1year (c).

1119 Assessment of Utility of Prognostic Models for Predicting Short-Term Mortality of Patients With Acute-on-Chronic Liver Failure

INTRODUCTION: Acute-on-chronic liver failure (ACLF) is a clinical syndrome associated with high short-term mortality. Numerous models have been proposed to predict outcomes in ACLF patients, including novel ones by Asian Pacific Association for the Study of the Liver (APASL) ACLF Research Consortium (AARC), but their utility in a heterogeneous population of ACLF patients remains inconclusive. The study aims to assess the performance of established and newer models for predicting mortality of ACLF patients. METHODS: A retrospective study of 96 patients fulfilling either APASL or European Association for the Study of the Liver (EASL) criteria for ACLF admitted to a tertiary hospital in Singapore between 2004 and 2018 was performed. Child-Turcotte-Pugh (CTP) score, Model for End-Stage Liver Disease (MELD)-Na, Chronic Liver Failure Consortium (CLIF)-SOFA, CLIF-C ACLF and AARC prognostic scores (MELD-lactate, AARC-ACLF) were calculated on days 1, 4, 7 of hospital admission and days 1, 4 of ICU admission. Outcomes assessed were survival to discharge without transplant, 30-day survival and 90-day survival. The scores were evaluated by measuring area under receiver operating characteristic (AUROC) curve at each time point and compared. RESULTS: 28 patients (29.2%) survived to discharge without transplant, 21 patients (21.9%) underwent urgent transplant and 47 patients (49%) died before discharge. 30-day transplant-free survival was 21.9% and 90-day survival was 19.8%. CTP, MELD-Na, MELD-lactate, CLIF-C ACLF and AARC-ACLF scores had high accuracy in predicting hospital mortality on day 4 admission (CTP D1 AUROC 0.642, D4 0.715; MELD-Na D1 0.607, D4 0.721; MELD-lactate D1 0.664, D4 0.861; CLIF-C ACLF D1 0.559, D4 0.697; AARC-ACLF D1 0.571, D4 0.747). CTP, MELD-Na and MELD-lactate scores also had good predictive utility on day 7 admission (CTP D7 0.684; MELD-Na 0.67; MELD-lactate 0.848). This held true regardless of whether APASL or EASL criteria was applied. In addition, the sequential change in CLIF-SOFA and CLIF-C ACLF scores from day 1 to day 4 was significantly associated with need for urgent transplant or death before discharge. CONCLUSION: CTP, MELD-Na and MELD-lactate scores are superior at prognosticating outcomes on day 4 and 7 of admission in our multi-ethnic Asian population. The trend of CLIF-SOFA and CLIF-C ACLF scores from day 1 to day 4 of admission may also contribute valuable information to our assessment of ACLF patients.

Drug-Induced Acute-on-Chronic Liver Failure in Asian Patients.

Acute insults from viruses, infections, or alcohol are established causes of decompensation leading to acute-on-chronic liver failure (ACLF). Information regarding drugs as triggers of ACLF is lacking. We examined data regarding drugs producing ACLF and analyzed clinical features, laboratory characteristics, outcome, and predictors of mortality in patients with drug-induced ACLF. We identified drugs as precipitants of ACLF among prospective cohort of patients with ACLF from the Asian Pacific Association of Study of Liver (APASL) ACLF Research Consortium (AARC) database. Drugs were considered precipitants after exclusion of known causes together with a temporal association between exposure and decompensation. Outcome was defined as death from decompensation. Of the 3,132 patients with ACLF, drugs were implicated as a cause in 329 (10.5%, mean age 47 years, 65% men) and other nondrug causes in 2,803 (89.5%) (group B). Complementary and alternative medications (71.7%) were the commonest insult, followed by combination antituberculosis therapy drugs (27.3%). Alcoholic liver disease (28.6%), cryptogenic liver disease (25.5%), and non-alcoholic steatohepatitis (NASH) (16.7%) were common causes of underlying liver diseases. Patients with drug-induced ACLF had jaundice (100%), ascites (88%), encephalopathy (46.5%), high Model for End-Stage Liver Disease (MELD) (30.2), and Child-Turcotte-Pugh score (12.1). The overall 90-day mortality was higher in drug-induced (46.5%) than in non-drug-induced ACLF (38.8%) (P = 0.007). The Cox regression model identified arterial lactate (P < 0.001) and total bilirubin (P = 0.008) as predictors of mortality. Drugs are important identifiable causes of ACLF in Asia-Pacific countries, predominantly from complementary and alternative medications, followed by antituberculosis drugs. Encephalopathy, bilirubin, blood urea, lactate, and international normalized ratio (INR) predict mortality in drug-induced ACLF.

THU-053-Usefulness of lactate-free Asian Pacific Association for The Study of Liver acute-on-chronic liver failure research consortium ACLF score for predicting short-term mortality in patient with alcoholic liver disease

Aims: Asian Pacific Association for the Study of Liver (APASL) acute-on-chronic liver failure (ACLF) Research Consortium (AARC) proposed new prognostic scoring system of ACLF in cluding lactate. However, lactate is not routinely checked in clinical practice of patient with ACLF in Korea. Therefore, we aimed to investigate the predictive accuracy of lactate-free AARC-ACLF score for predicting short-term mortality in patients with alcoholic liver disease. Methods: A total of 749 ALD patients who had liver failure (bilirubin≥5mg/dL and INR≥1.5) in AARC database were in vestigated. Diagnostic performances for short-term mortality were compared according to the area under receiver operating characteristic (AUROC) curve. Predictive accuracy of lactate-free AARC-ACLF score were compared with other prognostic scores in 143 ALD patients with liver failure and 60 ALD patients with ACLF according to AARC definition in Korean ACLF cohort. Results: Among 749 patients, 30-day and 90-day mortality were 40.3% and 51.5%. There were no significant differences in AUROC for predicting 30-day and 90-day mortality between AARC-ACLF score and lactate-free AARC-ACLF score (30-day mortality: 0.752 vs. 0.751, P=0.918, 90-day mortality: 0.728 vs. 0.736, P=0.346). In Korean ACLF cohort, the AUROCs of lactate-free AARC-ACLF score for predicting 28-day and 90- day mortality were 0.861 and 0.846 in ALD with liver failure, and 0.884 and 0.874 in ALD patients with ACLF according to AARC definition, respectively. In Korean ALD patients with liver failure and ACLF according to AARC definition, diagnostic per formance of lactate-free AARC-ACLF score for predicting 28- day and 90-day mortality was comparable to those of Model for End-stage Liver Disease (MELD), MELD-Na, Chronic Liver Failure-Sequential Organ Failure Assessment score. Conclusions: Lactate-free AARC-ACLF score is as excellent as AARC-ACLF score in predicting short-term mortality in ALD patients with liver failure of AARC database and Korean ACLF cohort.

Flare of Autoimmune Hepatitis Causing Acute on Chronic Liver Failure: Diagnosis and Response to Corticosteroid Therapy.

Autoimmune hepatitis (AIH) is considered less common in the Asia Pacific region. Due to this, AIH flare as a cause of acute on chronic liver failure (ACLF) is often overlooked and treatment delayed. We aimed at the defining clinical and histopathological spectrum and role of steroid therapy in AIH-ACLF. Patients with AIH-ACLF, prospectively recruited and followed between 2012 and 2017, were analyzed from the Asian Pacific Association for the Study of the Liver ACLF Research Consortium (AARC) data base. Diagnosis of AIH was confirmed using International Autoimmune Hepatitis Group score or simplified AIH score with histopathological evidence. Of 2,825 ACLF patients, 82 (2.9%) fulfilled criteria of AIH (age 42.1 ± 18.1 years, 70% female). At baseline, mean bilirubin was 18.6 ± 8.2 mg/dL, Child-Turcotte-Pugh score was 11.7 ± 1.4, and Model for End-Stage Liver Disease (MELD) score was 27.6 ± 6.5. Mean immunoglobulin G was 21.61 ± 7.32 g/dL, and this was elevated ≥1.1 times in 97% of cases; 49% were seronegative. Liver histology was available in 90%, with median histological activity index of 10 (interquartile range, 7-12); 90% with moderate to severe interface activity; 56% showing significant parenchymal necrosis (bridging and confluent necrosis); and cirrhosis in 42%. Twenty-eight (34%) patients received steroid therapy and showed shorter intensive care unit (ICU) stay (median 1.5 versus 4 days, P < 0.001) and improved 90-day survival (75% versus 48.1%, P = 0.02) with comparable incidence of sepsis (P = 0.32) compared to those who did not. Patients of advanced age, more severe liver disease (MELD >27; 83.3% sensitivity, 78.9% specificity, area under the receiver operating characteristic curve 0.86), presence of hepatic encephalopathy, and fibrosis grade ≥F3 had an unfavorable response to corticosteroid therapy. Conclusion: AIH presenting as ACLF is not uncommon in Asian patients; a low threshold for liver biopsy is needed to confirm the diagnosis as nearly half the patients are seronegative; early stratification to steroid therapy or liver transplantation (MELD >27, hepatic encephalopathy in ≥F3) would reduce ICU stay and improve outcomes.

Management of acute-on-chronic liver failure: an algorithmic approach.

Acute-on-chronic liver failure (ACLF) is a distinct syndrome of liver failure in a patient with chronic liver disease presenting with jaundice, coagulopathy and ascites and/or hepatic encephalopathy, developing following an acute hepatic insult and associated with high 28-day mortality. The definition though lacks global consensus, excludes patients with known distinct entities such as acute liver failure and those with end-stage liver disease. The initial Systemic Inflammatory Response Syndrome (SIRS) because of cytokine storm in relation to acute insult and/or subsequent development of sepsis due to immunoparalysis leads to extrahepatic organ failure. These cascades of events progress through a 'Golden Window' period of about 7days, subsequent to which majority of the patients develop complications, such as sepsis and extrahepatic organ failure. Prevention of sepsis, support of organs and management of organ failure (commonly hepatic, renal, cerebral, coagulation) and early referral for transplant is crucial. The APASL ACLF research consortium (AARC) liver failure score is a dynamic prognostic model for management decisions and is superior to existing models. Aggressive multidisciplinary approach can lead to a transplant-free survival in nearly half of the cases. The present review provides an algorithmic approach to management of organ failure, sepsis prevention, use of dynamic prognostic models for management decision and is aimed to improve the skills for managing and improving the outcomes of such critically ill patients.

7. AARC-ACLF score: best predictor of outcome in children and adolescents with decompensated Wilson's disease

Background and Aims: At present, there is an urgent need to identify ideal prognostic markers, in order to consider LT early in the course for decompensated Wilson's disease (WD) subjects, for best results. Recently, doubts have been raised about the universal application and efficacy of New Wilson's index (NWI) in predicting Liver Transplant (LT) or mortality in such cases. APASL (Asian Pacific Association for the Study of the Liver) ACLF (Acute on Chronic Liver Failure) Research Consortium (AARC) has introduced a new score (AARC-ACLF score) which has not been studied in these children. This work was thus planned to study the predictive risk factors or scores for mortality at 90 days in decompensated WD in children and adolescents. Methods: Data of all pediatric WD cases was prospectively collected and analyzed. Cox regression and Area under Receiver Operative Curve (AUROC) analysis were used to identify best predictive score for mortality at 90 days. Results: Sixty confirmed cases of decompensated WD, 35 (58.3%) improved on medical management and 25 (41.7%) either died (20) or were transplanted (5). Among those with NWI ≥ 11 (34/60 cases) 17 survived versus those with NWI < 11 (21/61), 3 died. NWI (HR 1.299, 95%CI 1.118–1.508, p = 0.001), AARC ACLF (HR 1.45, 95%CI 1.21–1.75, p = 0.001) and Chronic liver failure Sequential Organ failure Assessment score also known as CLIF SOFA (HR 1.26, 95%CI 1.11–1.49, p = 0.004) were all significantly associated with death on univariate Cox regression analysis. On comparative evaluation of the predictive scores in the present cohort, the highest positive (5.25) and lowest negative (0.12) likelihood ratios as well as highest accuracy (85.25%) revealed AARC ACLF as the best predictor of mortality. AARC ACLF had the best predictability with AUROC of 0.90 and the minimum standard error of 0.042 (Fig. 1). For every unit increase in AARC ACLF score, there is likelihood of 45% increase in 90 day mortality. The optimal cut off for the AARC ACLF was ≥11 with significantly better survival. Conclusions: AARC ACLF is the best score for the prediction of mortality at 90 days in decompensated WD cases. NWI has lower sensitivity and accuracy as a predictive tool for death in this cohort. While all patients’ with decompensated WD should be listed for LT, but an immediate LT is indicated if AARC ACLF ≥11 is present in the patient. The authors have none to declare.

Acute-on-Chronic Liver Failure

Acute-on-chronic liver failure (ACLF) is increasingly recognized as a distinct disease entity associated with acute deterioration of liver function in patients with chronic liver disease. Although no widely accepted diagnostic criteria for ACLF are yet available, the definitions of the Asian-Pacific Association for the Study of the Liver (APASL) ACLF Research Consortium (AARC) and the European Association for the Study of the Liver (EASL) Chronic Liver Failure Consortium (CLIF-C) are commonly employed. However, the AARC and CLIF-C criteria are based on fundamentally different features, rendering among-study comparisons difficult. The areas of uncertainty include the definition and extent of heterogeneity of ACLF, ambiguities in terms of the underlying liver disease, and whether infection or sepsis may precipitate the condition. Although the detailed pathogenesis of ACLF remains to be elucidated, changes in host responses to injury, infection, and uncontrolled inflammation play important roles. The “predisposition, infection/inflammation, response, organ failure” (PIRO) concept used to evaluate sepsis may be valuable when it is sought to describe the pathophysiology and clinical features of ACLF. Currently, treatment is limited to organ support but a better understanding of the pathophysiology is likely to lead, in future, to the discovery of novel biomarkers and the development of new therapeutic strategies. (Korean J Med 2017;92:118-123)

PS033 - The Decision for Liver Transplant in Acute on Chronic Liver Failure (ACLF) - First Week is the Crucial Period - Analysis of the Apasl ACLF Research Consortium (AARC) Prospective Data of 1021 Patients

PS033 - The Decision for Liver Transplant in Acute on Chronic Liver Failure (ACLF) - First Week is the Crucial Period - Analysis of the Apasl ACLF Research Consortium (AARC) Prospective Data of 1021 Patients

Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL) 2014.

The first consensus report of the working party of the Asian Pacific Association for the Study of the Liver (APASL) set up in 2004 on acute-on-chronic liver failure (ACLF) was published in 2009. Due to the rapid advancements in the knowledge and available information, a consortium of members from countries across Asia Pacific, "APASL ACLF Research Consortium (AARC)," was formed in 2012. A large cohort of retrospective and prospective data of ACLF patients was collated and followed up in this data base. The current ACLF definition was reassessed based on the new AARC data base. These initiatives were concluded on a 2-day meeting in February 2014 at New Delhi and led to the development of the final AARC consensus. Only those statements which were based on the evidence and were unanimously recommended were accepted. These statements were circulated again to all the experts and subsequently presented at the annual conference of the APASL at Brisbane, on March 14, 2014. The suggestions from the delegates were analyzed by the expert panel, and the modifications in the consensus were made. The final consensus and guidelines document was prepared. After detailed deliberations and data analysis, the original proposed definition was found to withstand the test of time and identify a homogenous group of patients presenting with liver failure. Based on the AARC data, liver failure grading, and its impact on the "Golden therapeutic Window," extra-hepatic organ failure and development of sepsis were analyzed. New management options including the algorithms for the management of coagulation disorders, renal replacement therapy, sepsis, variceal bleed, antivirals, and criteria for liver transplantation for ACLF patients were proposed. The final consensus statements along with the relevant background information are presented here.