Acute-on-chronic Liver Failure Grade Research Articles

Higher Frequency of Hospital-Acquired Infections but Similar In-Hospital Mortality Among Admissions With Alcoholic Hepatitis at Academic vs. Non-academic Centers.

BackgroundAlcoholic hepatitis (AH) is a unique syndrome characterized by high short-term mortality. The impact of the academic status of a hospital (urban and teaching) on outcomes in AH is unknown.MethodsNational Inpatient Sample dataset (2006–2014) on AH admissions stratified to academic center (AC) or non-academic center (NAC) and analyzed for in-hospital mortality (IHM), hospital resource use, length of stay in days (d), and total charges (TC) in United States dollars (USD). Admission year was stratified to 2006–2008 (TMI), 2009–2011 (TM2), and 2012–2014 (TM3).ResultsOf 62,136 AH admissions, the proportion at AC increased from 46% in TM1 to 57% in TM3, Armitage trend, p < 0.001. On logistic regression, TM3, younger age, black race, Medicaid and private insurance, and development of acute on chronic liver failure (ACLF) were associated with admission to an AC. Of 53,264 admissions propensity score matched for demographics, pay status, and disease severity, admissions to AC vs. NAC (26,622 each) were more likely to have liver disease complications (esophageal varices, ascites, and hepatic encephalopathy) and hospital-acquired infections (HAI), especially Clostridioides difficile and ventilator-associated pneumonia. Admissions to AC were more likely transfers from outside hospital (1.6% vs. 1.3%) and seen by palliative care (4.8% vs. 3.3%), p < 0.001. Use of endoscopy, dialysis, and mechanical ventilation were similar. With similar IHM comparing AC vs. NAC (7.7% vs. 7.8%, p = 0.93), average LOS and number of procedures were higher at AC (7.7 vs. 7.1 d and 2.3 vs. 1.9, respectively, p < 0.001) without difference on total charges ($52,821 vs. $52,067 USD, p = 0.28). On multivariable logistic regression model after controlling for demographics, ACLF grade, and calendar year, IHM was similar irrespective of academic status of the hospital, HR (95% CI): 1.01 (0.93–1.08, p = 0.70). IHM decreased over time, with ACLF as strongest predictor. A total of 63 and 22% were discharged to home and skilled nursing facility, respectively, without differences on academic status of the hospital.ConclusionAdmissions with AH to AC compared to NAC have higher frequency of liver disease complications and HAI, with longer duration of hospitalization. Prospective studies are needed to reduce HAI among hospitalized patients with AH.

Serum ammonia is a strong prognostic factor for patients with acute-on-chronic liver failure

Ammonia is thought to be central to the pathogenesis of hepatic encephalopathy (HE), but its prognostic role in acute-on-chronic liver failure (ACLF) is still unknown. We aimed to determine the association between serum ammonia level and short-term prognosis in ACLF. Furthermore, we performed an in-depth evaluation of the independent effect of serum ammonia level on the short-term prognosis of hepatitis B virus (HBV) reactivation-induced ACLF patients. We identified 174 patients as part of prospective observational studies in patients with ACLF. Plasma ammonia levels were measured on admission, and several prognostic scores were used to determine the prognostic effect of ammonia. The 28-day patient survival was determined. Receiver operating characteristic analysis was used to identify the cut-off points for ammonia values, and multivariable analysis was performed using the Cox proportional hazard regression model. Plasma ammonia was significantly higher in nonsurvivors (83.53 ± 43.78 versus 67.13 ± 41.77 µmol/L, P = 0.013), and ACLF patients with hyperammonemia had significantly higher 28-day mortality than those without hyperammonemia. Ammonia was also closely related to ACLF grade (P < 0.001) and organ failure, including liver (P = 0.048), coagulation (P < 0.001) and brain (P < 0.001). HBV reactivation serves as the main precipitating factor in the ACLF population. Subgroup analysis showed that ammonia is also a strong prognostic factor in the HBV reactivation-induced ACLF population. Ammonia level is closely correlated with failure of other organs and is an independent risk factor for mortality in ACLF and the special population defined as HBV reactivation-related ACLF. Based on the results from our study, we measured serum ammonia in the population with ACLF, which strongly indicates their prognosis. It serves as an important biomarker and a therapeutic target.

Acute-on-chronic liver failure as a major predictive factor for mortality in patients with variceal bleeding

Background/AimsThis study examined the risk factors associated with mortality in cirrhotic patients hospitalized with variceal bleeding, and evaluated the effects of acute-on-chronic liver failure (ACLF) on the prognosis of these patients.MethodsThis study was retrospectively conducted on patients registered in the Korean acute-on-chronic liver failure study cohort, and on 474 consecutive cirrhotic patients hospitalized with variceal bleeding from January 2013 to December 2013 at 21 university hospitals. ACLF was defined as described by the European Association for the Study of Liver-Chronic Liver Failure Consortium.ResultsAmong a total of 474 patients, 61 patients were diagnosed with ACLF. The cumulative overall survival (OS) rate was lower in the patients with ACLF than in those without (P<0.001), and patients with higher ACLF grades had a lower OS rate (P<0.001). The chronic liver failure-sequential organ failure assessment (CLIF-SOFA) score was identified as a significant prognostic factor in patients hospitalized with variceal bleeding (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.30–1.50; P<0.001), even in ACLF patients with variceal bleeding (HR, 1.32; 95% CI, 1.19–1.46, P<0.001). Concerning the prediction of the mortality risk at 28- and 90-day using CLIF-SOFA scores, c-statistics were 0.895 (95% CI, 0.829–0.962) and 0.897 (95% CI, 0.842–0.951), respectively, and the optimal cut-off values were 6.5 and 6.5, respectively.ConclusionsIn cirrhotic patients hospitalized with variceal bleeding, the prognosis was poor when accompanied by ACLF, especially depending upon CLIF-SOFA score. CLIF-SOFA model well predicted the 28-day or 90-day mortality for cirrhotic patients who experienced variceal bleeding.

Longterm Outcomes of Patients Undergoing Liver Transplantation for Acute-on-Chronic Liver Failure.

Recent data have demonstrated >80% 1-year survival probability after liver transplantation (LT) for patients with severe acute-on-chronic liver failure (ACLF). However, longterm outcomes and complications are still unknown for this population. Our aim was to compare longterm patient and graft survival among patients transplanted across all grades of ACLF. We analyzed the United Network for Organ Sharing database for the years 2004-2017. Patients with ACLF were identified using the European Association for the Study of the Liver-Chronic Liver Failure criteria. Kaplan-Meier and Cox regression methods were used to determine patient and graft survival and associated predictors of mortality in adjusted models. A total of 56,801 patients underwent transplantation of which 31,024 (54.6%) had no ACLF, 8757 (15.4%) had ACLF grade 1, 9039 (15.9%) had ACLF grade 2, and 7891 (14.1%) had ACLF grade 3. The 5-year patient survival after LT was lower in the ACLF grade 3 patients compared with the other groups (67.7%; P<0.001), although after year 1, the percentage decrease in survival was similar among all groups. Infection was the primary cause of death among all patient groups in the first year. Infection was the primary cause of death among all patient groups in the first year. After the first year, infection was the main cause of death in patients transplanted with ACLF grade 1 (32.1%), ACLF grade 2 (33.9%), and ACLF grade 3 (37.6%), whereas malignancy was the predominant cause of death in those transplanted with no ACLF (28.5%). In conclusion, patients transplanted with ACLF grade 3 had lower 5-year survival as compared with patients with ACLF grades 0-2, but mortality rates were not significantly different after the first year following LT. Graft survival was excellent across all ACLF groups.

Serum Sphingosine-1-Phosphate Is Decreased in Patients With Acute-on-Chronic Liver Failure and Predicts Early Mortality.

Sphingosine‐1‐phosphate (S1P) regulates pathophysiological processes, including liver regeneration, vascular tone control, and immune response. In patients with liver cirrhosis, acute deterioration of liver function is associated with high mortality rates. The present study investigated whether serum S1P concentrations are associated with disease severity in patients with chronic liver disease from compensated cirrhosis (CC), acute decompensation (AD), or acute‐on‐chronic liver failure (ACLF). From August 2013 to October 2017, patients who were admitted to the University Hospital Frankfurt with CC, AD, or ACLF were enrolled in our cirrhosis cohort study. Tandem mass spectrometry was performed on serum samples of 127 patients to assess S1P concentration. Our study comprised 19 patients with CC, 55 with AD, and 51 with ACLF, aged 29 to 76 years. We observed a significant decrease of S1P according to advanced liver injury from CC and AD up to ACLF (P < 0.001). S1P levels further decreased with progression to ACLF grade 3 (P < 0.05), and S1P highly inversely correlated with the Model for End‐Stage Liver Disease score (r = −0.508; P < 0.001). In multivariate analysis, S1P remained an independent predictor of 7‐day mortality with high diagnostic accuracy (area under the curve, 0.874; P < 0.001). Conclusion: In patients with chronic liver disease, serum S1P levels dramatically decreased with advanced stages of liver disease and were predictive of early mortality. Because S1P is a potent regulator of endothelial integrity and immune response, low S1P levels may significantly influence progressive multiorgan failure. Our data justify further elucidation of the diagnostic and therapeutic role of S1P in ACLF.

Patients with severe acute-on-chronic liver failure are disadvantaged by model for end-stage liver disease-based organ allocation policy.

Mortality for patients with acute-on-chronic liver failure (ACLF) may be underestimated by the model for end-stage liver disease-sodium (MELD-Na) score. To assess waitlist outcomes across varying grades of ACLF among a cohort of patients listed with a MELD-Na score ≥35, and therefore having similar priority for liver transplantation. We analysed the United Network for Organ Sharing (UNOS) database, years 2010-2017. Waitlist outcomes were evaluated using Fine and Gray's competing risks regression. We identified 6342 candidates at listing with a MELD-Na score ≥35, of whom 3122 had ACLF-3. Extra-hepatic organ failures were present primarily in patients with four to six organ failures. Competing risks regression revealed that candidates listed with ACLF-3 had a significantly higher risk for 90-day waitlist mortality (Sub-hazard ratio (SHR)=1.41; 95% confidence interval [CI] 1.12-1.78) relative to patients with lower ACLF grades. Subgroup analysis of ACLF-3 revealed that both the presence of three organ failures (SHR=1.40, 95% CI 1.20-1.63) or four to six organ failures at listing (SHR=3.01; 95% CI 2.54-3.58) was associated with increased waitlist mortality. Candidates with four to six organ failures also had the lowest likelihood of receiving liver transplantation (SHR=0.61, 95% CI 0.54-0.68). The Share 35 rule was associated with reduced 90-day waitlist mortality among the full cohort of patients listed with ACLF-3 and MELD-Na score ≥35 (SHR=0.59; 95% CI 0.49-0.70). However, Share 35 rule implementation was not associated with reduced waitlist mortality among patients with four to six organ failures (SHR=0.76; 95% CI 0.58-1.02). The MELD-Na score disadvantages patients with ACLF-3, both with and without extra-hepatic organ failures. Incorporation of organ failures into allocation policy warrants further exploration.

Strategies for liver transplantation during the SARS-CoV-2 outbreak: Preliminary experience from a single center in France.

Liver transplantation (LT) during the ongoing severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pandemic is challenging given the urgent need to reallocate resources to other areas of patient care. Available guidelines recommend reorganizing transplant care, but data on clinical experience in the context of SARS‐CoV‐2 pandemic are scarce. Thus, we report strategies and preliminary results in LT during the peak of the SARS‐CoV‐2 pandemic from a single center in France. Our strategy to reorganize the transplant program included 4 main steps: optimization of available resources, especially intensive care unit capacity; multidisciplinary risk stratification of LT candidates on the waiting list; implementation of a systematic SARS‐CoV‐2 screening strategy prior to transplantation; and definition of optimal recipient‐donor matching. After implementation of these 4 steps, we performed 10 successful LTs during the peak of the pandemic with a short median intensive care unit stay (2.5 days), benchmark posttransplant morbidity, and no occurrence of SARS‐CoV‐2 infection during follow‐up. From this preliminary experience we conclude that efforts in resource planning, optimal recipient selection, and organ allocation strategy are key to maintain a safe LT activity. Transplant centers should be ready to readapt their practices as the pandemic evolves.

Cystatin C and Sarcopenia Predict Acute on Chronic Liver Failure Development and Mortality in Patients on the Liver Transplant Waiting List.

Cystatin C (CysC) is an early biomarker of renal dysfunction scarcely studied in patients awaiting liver transplantation (LT). Sarcopenia is frequent in cirrhosis and impacts prognosis. We aimed to assess the capability of these factors to predict survival and acute-on-chronic liver failure (ACLF) in patients awaiting LT, as well as early post-LT outcomes. Single-center study that included all cirrhotic patients listed for LT between 2014 and 2017. Competing risk regression analysis was used to evaluate the capability of liver-, kidney-, and global status-related variables at waitlist (WL) inclusion to predict WL mortality and ACLF. Variables associated with post-LT outcomes were evaluated with logistic regression analysis. One-hundred-and-eighty patients were included. Fifty-six (31%) patients developed ACLF, 54 (30%) underwent LT and 35 (19%) died. In the adjusted competing risk regression analysis, CysC ≥ 1.5 mg/L, sarcopenia and MELD-Na were independent predictors of ACLF in the WL, while CysC ≥ 1.5 mg/L, sarcopenia and albumin were independent predictors of mortality. The cumulative incidence of ACLF and mortality at 12 months were 50% and 34% in patients with sarcopenia and CysC ≥1.5 mg/L. An estimated glomerular filtration rate by chronic kidney disease (CKD)-EPI-CysC-creatinine <60 mL/min/1.73 m at WL inclusion was an independent predictor of the need for renal replacement therapy (RRT) in the first month post-LT. Higher levels of CysC and sarcopenia are strongly associated with the ACLF and mortality in WL. The assessment of both risk factors may improve the prognostic evaluation and allow identifying a group of patients with a very high risk of poor outcomes while awaiting LT.

Model for end-stage liver disease-sodium underestimates 90-day mortality risk in patients with acute-on-chronic liver failure

It is unclear whether the model for end-stage liver disease-sodium (MELD-Na) score captures the clinical severity of acute-on-chronic liver failure (ACLF). We compared observed 90-day mortality in patients with ACLF with expected mortality based on the calculated MELD-Na and examined the consequences of underestimating clinical severity. We identified patients with ACLF during hospitalization for cirrhosis in 127 VA hospitals between 01/01/2004 and 12/31/2014. We examined MELD-Na scores by ACLF presence and grade. We used actual and observed 90-day mortality to estimate a standardized mortality ratio (SMR) by ACLF presence and grade. We used transplant center-specific median MELD-Na at transplantation (MMaT) to estimate the proportion likely to receive priority for liver transplantation (LT) based on MELD-Na alone. Of 71,894 patients hospitalized for decompensated cirrhosis, 18,979 (26.4%) patients met the criteria for ACLF on admission. The median (P25-P75) MELD-Na on admission was 26 (22-30) for ACLF compared to 15 (12-20) for patients without ACLF; it was 24 (21-27), 27 (23-31), and 32 (26-37) for ACLF-1, 2 and 3, respectively. At 90 days, 40.0% of patients with ACLF died (30.8%, 41.6% and 68.8% with ACLF-1, 2 and 3, respectively) compared to 21.3% of patients without ACLF. Compared to the expected death rate based on MELD-Na, mortality risk was higher for patients with ACLF, SMR (95% CI): 1.52 (1.48-1.52), 1.46 (1.41-1.51), 1.50 (1.44-1.55), 1.66 (1.58-1.74) for overall ACLF, ACLF-1, -2 and -3, respectively. Only 9.1% of patients with ACLF reached the national median MELD-Na of 35 and between 17.3% to 35.1% exceeded the MMaT at any center. During index admission, 589 (0.8%) patients with ACLF were considered for LT evaluation and 16 (0.1%) were listed for LT. In a US cohort of hospitalized patients with decompensated cirrhosis, MELD-Na did not capture 90-day mortality risk in patients with ACLF. Patients with ACLF are at a disadvantage in the current MELD-Na-based system. Acute-on-chronic liver failure (ACLF) is a condition marked by multiple organ failures in patients with cirrhosis and is associated with a high risk of death. Liver transplantation may be the only curative treatment for these patients. A score called model for end-stage liver disease-sodium (MELD-Na) helps guide donor liver allocation for transplantation in the United States. The higher the MELD-Na score in a patient, themore likely that a patient receives a liver transplant. Our study data showed that MELD-Na score underestimates the risk of dying at 90 days in patients with ACLF. Thus, physicians need to start liver transplant evaluation early instead of waiting for a high MELD-Na number.

Rebleeding and mortality risk are increased by ACLF but reduced by pre-emptive TIPS

The relationship between acute-on-chronic liver failure (ACLF) and acute variceal bleeding (AVB) is poorly understood. Specifically, the prevalence and prognosis of ACLF in the context of AVB is unclear, while the role of transjugular intrahepatic portosystemic shunt (TIPS) in the management in patients with ACLF has not been described to date. A multicenter, international, observational study was conducted in 2,138 patients from 34 centers between 2011 and 2015. ACLF was defined and graded according to the EASL-CLIF consortium definition. Placement of pre-emptive TIPS (pTIPS) was based on individual center policy. Patients were followed-up for 1 year, until death or liver transplantation. Cox regression and competing risk models (Gray's test) were used to identify independent predictors of rebleeding or mortality. At admission, 380/2,138 (17.8%) patients had ACLF according to EASL-CLIF criteria (grade 1: 38.7%; grade 2: 39.2%; grade 3: 22.1%). The 42-day rebleeding (19% vs. 10%; p <0.001) and mortality (47% vs. 10%; p <0.001) rates were higher in patients with ACLF and increased with ACLF grades. Of note, the presence of ACLF was independently associated with rebleeding and mortality. pTIPS placement improved survival in patients with ACLF at 42 days and 1 year. This effect was also observed in propensity score matching analysis of 66 patients with ACLF, of whom 44 received pTIPs and 22 did not. This large multicenter international real-life study identified ACLF at admission as an independent predictor of rebleeding and mortality in patients with AVB. Moreover, pTIPS was associated with improved survival in patients with ACLF and AVB. Acute variceal bleeding is a deadly complication of liver cirrhosis that results from severe portal hypertension. This study demonstrates that the presence of acute-on-chronic liver failure (ACLF) is the strongest predictor of mortality in patients with acute variceal bleeding. Importantly, patients with ACLF and acute variceal (re)bleeding benefit from pre-emptive (early) placement of a transjugular intrahepatic portosystemic shunt.

Targeted lipidomics reveals extensive changes in circulating lipid mediators in patients with acutely decompensated cirrhosis

Acute-on-chronic liver failure (ACLF) is a newly described syndrome, which develops in patients with acute decompensation of cirrhosis, and is characterized by intense systemic inflammation, multiple organ failures and high short-term mortality. The profile of circulating lipid mediators, which are endogenous signaling molecules that play a major role in inflammation and immunity, is poorly characterized in ACLF. In the current study, we assessed the profile of lipid mediators by liquid chromatography coupled to tandem mass spectrometry in plasma from patients with acute decompensation of cirrhosis, with (n= 119) and without (n= 127) ACLF, and from healthy controls (n= 18). Measurements were prospectively repeated in 191 patients with acute decompensation of cirrhosis during a 28-day follow-up period. Fifty-nine lipid mediators (out of 100) were detected in plasma from cirrhotic patients, of which 16 were significantly associated with disease status. Among these, 11 lipid mediators distinguished patients at any stage from healthy controls, whereas 2 lipid mediators (LTE4 and 12-HHT, both derived from arachidonic acid) shaped a minimal plasma fingerprint that discriminated patients with ACLF from those without. Levels of LTE4 distinguished ACLF grade 3 from ACLF grades 1 and 2, followed the clinical course of the disease (increased with worsening and decreased with improvement) and positively correlated with markers of inflammation and non-apoptotic cell death. Moreover, LTE4 together with LXA5 (derived from eicosapentaenoic acid) and EKODE (derived from linoleic acid) were associated with short-term mortality. LXA5 and EKODE formed a signature associated with coagulation and liver failures. Taken together, these findings uncover specific lipid mediator profiles associated with disease severity and prognosis in patients with acute decompensation of cirrhosis. Acute-on-chronic liver failure (ACLF) is characterized by intense systemic inflammation, multiple organ failures and high short-term mortality. In the current study, we assessed the plasma lipid profile of 100 bioactive lipid mediators in healthy controls, patients with decompensated cirrhosis, and those who had developed ACLF. We identified lipid mediator signatures associated with inflammation and non-apoptotic cell death that discriminate disease severity and evolution, short-term mortality and organ failures.

Outcomes of Liver Transplant Recipients With Acute-on-Chronic Liver Failure Based on EASL-CLIF Consortium Definition: A Single-center Study.

Eight hundred twenty-five consecutive LT patients (04/2006-03/2013) were included in a retrospective analysis. Of the 690 evaluable patients, 589 had no ACLF, and the remaining 101 were grouped into ACLF Grades 1-3 (ACLF Grade 1: 50 [49.5%], ACLF Grade 2: 32 [31.7%], and ACLF Grade 3: 19 [18.8%]). LT recipients transplanted in the context of ACLF had significantly increased serum creatinine (2.27 ± 1.16 versus 0.98 ± 0.32; P < 0.0001), and inferior 1-year graft (90% versus 78%; P < 0.0001) and patient survival (92% versus 82%; P = 0.0004) by Kaplan-Meier survival analysis; graft and patient survival correlated negatively with increasing severity of ACLF. One-year graft and patient survival were lower in those with high ACLF (Grade 2 and 3) irrespective of Model for End-Stage Liver Disease compared with other groups. The ACLF group had longer intensive care unit stays (10.6 ± 19.5 versus 4.2 ± 9; P < 0.0001), hospital stays (20.9 ± 25.9 versus 11.7 ± 11.4; P < 0.0001), and increased surgical re-exploration (26.7 % versus 14.6%, P = 0.002). Patients with ACLF undergoing LT have significantly higher resource utilization, inferior graft survival and patient survival, and renal dysfunction at 1 year. The combination of ACLF and Model for End-Stage Liver Disease can be considered when determining the suitability for potential transplantation.

Clinical characteristics and 28-d outcomes of bacterial infections in patients with hepatitis B virus-related acute-on-chronic liver failure.

BACKGROUNDAcute-on-chronic liver failure (ACLF), which includes hepatic and multiple extra-hepatic organ failure, is a severe emergency condition that has high mortality. ACLF can rapidly progress and requires an urgent assessment of condition and referral for liver transplantation. Bacterial infections (BIs) trigger ACLF and play pivotal roles in the deterioration of clinical course.AIMTo investigate the clinical characteristics and 28-d outcomes of first BIs either at admission or during hospitalization in patients with hepatitis B virus (HBV)-ACLF as defined by the Chinese Group on the Study of Severe Hepatitis B (COSSH).METHODSA total of 159 patients with HBV-ACLF and 40 patients with acute decompensation of HBV-related chronic liver disease combined with first BIs were selected for a retrospective analysis between October 2014 and March 2016. The characteristics of BIs, the 28-d transplant-free survival rates, and the independent predictors of the 28-d outcomes were evaluated.RESULTSA total of 194 episodes of BIs occurred in 159 patients with HBV-ACLF. Among the episodes, 13.4% were community-acquired, 46.4% were healthcare-associated, and 40.2% belonged to nosocomial BIs. Pneumonia (40.7%), spontaneous bacterial peritonitis (SBP) (34.5%), and bloodstream infection (BSI) (13.4%) were the most prevalent. As the ACLF grade increased, the incidence of SBP showed a downward trend (P = 0.021). Sixty-one strains of bacteria, including 83.6% Gram-negative bacteria and 29.5% multidrug-resistant organisms, were cultivated from 50 patients with ACLF. Escherichia coli (44.3%) and Klebsiella pneumoniae (23.0%) were the most common bacteria. As the ACLF grade increased, the 28-d transplant-free survival rates showed a downward trend (ACLF-1, 55.7%; ACLF-2, 29.3%; ACLF-3, 5.4%; P < 0.001). The independent predictors of the 28-d outcomes of patients with HBV-ACLF were COSSH-ACLF score (hazard ratio [HR] = 1.371), acute kidney injury (HR = 2.187), BSI (HR = 2.339), prothrombin activity (HR = 0.967), and invasive catheterization (HR = 2.173).CONCLUSIONFor patients with HBV-ACLF combined with first BIs, pneumonia is the most common form, and the incidence of SBP decreases with increasing ACLF grade. COSSH-ACLF score, acute kidney injury, BSI, prothrombin activity, and invasive catheterization are the independent predictors of 28-d outcomes.

From the Editor's Desk…

From the Editor's Desk…

Acute-on-chronic liver failure: a single-centre experience.

Aim of the studyWe set out to determine the applicability of acute-on-chronic liver failure (ACLF) diagnostic criteria and characteristics of thus defined ACLF sub-cohorts in a real-life clinical context.Material and methodsRetrospective charts’ analysis of consecutive patients hospitalized with decompensated liver disease. Inclusion criteria: acute decompensation, informed consent. Exclusion criteria: malignancy. Diagnostic tools: 1st phase – CLIF-SOFA score calculated manually; 2nd phase – CLIF-C ACLF score calculated at www.efclif.com.ResultsOf 432 hospitalized patients aged 52 years, 41% were female, with MELD 20, 32% patients had acute decompensation (AD); main triggers were alcoholic hepatitis (38%), infections (26%), and variceal bleeding (23%). Of patients with AD, ACLF grades 0-3 was present in 64%, 19%, 13%, and 4%, respectively. In hospital mortality according to final AD/ACLF grade in ACLF 0-3 was 7.5%, 42%, 47%, and 80%, respectively (p < 0.0001).ConclusionsDiagnosing ACLF is nowadays easy; it helps to stratify patients at admission, and refine risk stratification at day 7. The main trigger of AD/ACLF in this region is alcohol. Currently, there are no ACLF-specific treatments; however, timely intensive supportive care can influence the prognosis. Even though still elusive and controversial, the ACLF concept can help systematize management of patients admitted with acute decompensation of advanced chronic liver disease.

Von-Willebrand factor: A biomarker to predict in-hospital survival in patients with severe and very severe alcoholic hepatitis

Objectives: The aim of this study is to assess the utility of plasma von-Willebrand factor (VWF) levels in predicting in-hospital survival for patients with severe alcoholic hepatitis. Methods: From a prospectively collected database of acute-on-chronic liver failure (ACLF) patients, we retrospectively selected all severe alcoholic hepatitis (discriminant function [DF] ≥32) patients and correlated baseline plasma VWF (antigen, Ag and collagen-binding activity [CBA]) levels with disease severity. In-hospital survival was classified as discharged alive (or) died/discharged in a terminal condition (poor outcome). Results: Of 34 consecutive severe alcoholic hepatitis patients (age: 40.5, 30–63 years; median, range, hospital stay: 6, 2–15 days) studied, 15 had a poor outcome. Plasma VWF-CBA was higher in patients with poor outcome (736 [396–1157] IU/dL) as compared to patients discharged in stable state (492 [97–986] IU/dL; P = 0.03). VWF-CBA correlated well with VWF-Ag, model for end-stage liver disease (MELD) score, sequential organ failure assessment score and ACLF grades. AUROC to predict composite poor outcome was similar for plasma VWF-CBA (0.72, 0.54–0.89) and MELD score (0.71, 0.53–0.89). Plasma VWF-CBA was higher in 23 “very severe” alcoholic hepatitis (DF >60 or MELD >30) patients. Combining plasma VWF-CBA (>750 IU/dL) and criteria for “very severe” alcoholic hepatitis had a sensitivity of 100% (81%–100%) and negative predictive value of 100% (68%–100%) for predicting poor outcome. Conclusions: Plasma VWF levels are markedly elevated, correlate with organ failure, and predict in-hospital survival in severe alcoholic hepatitis, and also in “very severe” alcoholic hepatitis, patients.

Blood metabolomics uncovers inflammation-associated mitochondrial dysfunction as a potential mechanism underlying ACLF

Acute-on-chronic liver failure (ACLF), which develops in patients with cirrhosis, is characterized by intense systemic inflammation and organ failure(s). Because systemic inflammation is energetically expensive, its metabolic costs may result in organ dysfunction/failure. Therefore, we aimed to analyze the blood metabolome in patients with cirrhosis, with and without ACLF. We performed untargeted metabolomics using liquid chromatography coupled to high-resolution mass spectrometry in serum from 650 patients with AD (acute decompensation of cirrhosis, without ACLF), 181 with ACLF, 43 with compensated cirrhosis, and 29 healthy individuals. Of the 137 annotated metabolites identified, 100 were increased in patients with ACLF of any grade, relative to those with AD, and 38 comprised a distinctive blood metabolite fingerprint for ACLF. Among patients with ACLF, the intensity of the fingerprint increased across ACLF grades, and was similar in patients with kidney failure and in those without, indicating that the fingerprint reflected not only decreased kidney excretion but also altered cell metabolism. The higher the ACLF-associated fingerprint intensity, the higher the plasma levels of inflammatory markers, tumor necrosis factor α, soluble CD206, and soluble CD163. ACLF was characterized by intense proteolysis and lipolysis; amino acid catabolism; extra-mitochondrial glucose metabolism through glycolysis, pentose phosphate, and D-glucuronate pathways; depressed mitochondrial ATP-producing fatty acid β-oxidation; and extra-mitochondrial amino acid metabolism giving rise to metabotoxins. In ACLF, intense systemic inflammation is associated with blood metabolite accumulation and profound alterations in major metabolic pathways, in particular inhibition of mitochondrial energy production, which may contribute to the development of organ failures. Acute-on-chronic liver failure (ACLF), which develops in patients with cirrhosis, is characterized by intense systemic inflammation and organ failure(s). Because systemic inflammation is energetically expensive, its metabolic costs may result in organ dysfunction/failure. We identified a 38-metabolite blood fingerprint specific for ACLF that revealed mitochondrial dysfunction in peripheral organs. This may contribute to organ failures.

Effect of the clinical course of acute-on-chronic liver failure prior to liver transplantation on post-transplant survival

Patients with acute-on-chronic liver failure (ACLF) can be listed for liver transplantation (LT) because LT is the only curative treatment option. We evaluated whether the clinical course of ACLF, particularly ACLF-3, between the time of listing and LT affects 1-year post-transplant survival. We identified patients from the United Network for Organ Sharing database who were transplanted within 28days of listing and categorized them by ACLF grade at waitlist registration and LT, according to the EASL-CLIF definition. A total of 3,636 patients listed with ACLF-3 underwent LT within 28days. Among those transplanted, 892 (24.5%) recovered to no ACLF or ACLF grade 1 or 2 (ACLF 0-2) and 2,744 (75.5%) had ACLF-3 at transplantation. One-year survival was 82.0% among those transplanted with ACLF-3 vs. 88.2% among those improving to ACLF 0-2 (p<0.001). Conversely, the survival of patients listed with ACLF 0-2 who progressed to ACLF-3 at LT (n=2,265) was significantly lower than that of recipients who remained at ACLF 0-2 (n=17,631) at the time of LT (83.8% vs. 90.2%, p<0.001). Cox modeling demonstrated that recovery from ACLF-3 to ACLF 0-2 at LT was associated with reduced 1-year mortality after transplantation (hazard ratio0.65; 95% CI 0.53-0.78). Improvement in circulatory failure, brain failure, and removal from mechanical ventilation were also associated with reduced post-LT mortality. Among patients >60years of age, 1-year survival was significantly higher among those who improved from ACLF-3 to ACLF 0-2 than among those who did not. Improvement from ACLF-3 at listing to ACLF 0-2 at transplantation enhances post-LT survival, particularly in those who recovered from circulatory or brain failure, or were removed from the mechanical ventilator. The beneficial effect of improved ACLF on post-LT survival was also observed among patients >60years of age. Liver transplantation (LT) for patients with acute-on-chronic liver failure grade 3 (ACLF-3) significantly improves survival, but 1-year survival probability after LT remains lower than the expected outcomes for transplant centers. Our study reveals that among patients transplanted within 28days of waitlist registration, improvement of ACLF-3 at listing to a lower grade of ACLF at transplantation significantly enhances post-transplant survival, even among patients aged 60years or older. Subgroup analysis further demonstrates that improvement in circulatory failure, brain failure, or removal from mechanical ventilation have the strongest impact on post-transplant survival.

Combination and sequential evaluation of acute-on-chronic liver failure (ACLF) and hyponatremia and prognosis in cirrhotic patients

BackgroundFew studies have evaluated whether combination and sequential evaluation of ACLF (acute-on-chronic liver failure) and hyponatremia aids prognosis. AimsDescribe clinical course and determine prognostic capability of assessing ACLF and hyponatremia at specific time-points. MethodsProspective study with inclusion of 376 patients. ACLF and hyponatremia were evaluated at days 1 and 7 and classified as persistent, transient, de novo or absent. Follow-up was 90 days. ResultsAt inclusion, ACLF was diagnosed in 99 patients. Reversal was observed in 57 patients and was associated with lower creatinine and ACLF grade. De novo ACLF developed in 19 patients, and MELD (model of end-stage liver disease) score and lower albumin were predictive factors. Hyponatremia was present in 76 patients (persistent, transient and de novo in 27, 24 and 25 respectively). ACLF at D7 had the lowest survival compared to transient or no ACLF (21, 57 and 80%, p < 0.0001). Hyponatremia at admission was associated with low survival (35%) whereas survival was higher for de novo or absent cases (70%), p < 0.001. In multivariate analysis ACLF at D7 and hyponatremia at D1 were predictors of survival. ConclusionACLF and hyponatremia are dynamic and evaluation of both conditions at different time-points identifies patients at higher risk of short-term mortality.

P: 23 Prospective Study on Mortality of Acute on Chronic Liver Failure and Its Predictors

BACKGROUND: Acute on chronic liver failure (ACLF) is a well recognized entity, characterized by an acute liver insult in patients with underlying chronic liver disease leading to sudden deterioration of liver function and a high mortality. We aimed to determine hospital, 28 days and 12 weeks mortality of ACLF, its predictors and precipitating factors METHODS: We conducted a prospective descriptive study at AIMS (Asian institute of medical sciences, Hyderabad, Pak.) from January 2018 to December 2018. We enrolled patients of ACLF as defined by Asian Pacific Association for the Study of Liver (APASL, 2014) and collected data to determine cause, precipitating acute insult, organ failure, ACLF grade MELD, and CTP scores. Patients were followed to determine hospital, 28 days and 12 weeks mortality and its predictors. RESULTS: Total patients were 117 with mean age of 40.9 +- 13.9 years (range 12–85). Majority were males 86 (73.5%) and 31 (26.5%) were females. Majority of patients 55 (47%) were Hepatitis B Virus (HBV) positive, among them 24 (43.6%) were with HDV co-infection. The most common precipitating acute insult was SEPSIS 65 (55.6). Others were drug induce liver injury (DILI) 8 (6.8%), HEV acute hepatitis 7 (5.9), HDV superinfection 5 (4.3%), HBV flair 4 (3.4%), alcohol binge drinking 4 (3.4%), surgery 2 (1.7%), acute PVT 2 (1.7%), Upper GI Bleed 1 (0.9%) and 20 (17.1%) were unknown. Hospital mortality was 49 (41.9%), 28 days 71 (60.7%) and 12 weeks mortality was 103 (88.0%). Organ failure (P = 0.002), ACLF grade (P = 0.002), encephalopathy (P = 0.001), MELD (P = 0.01) and AKI (P = 0.02) were found to be predictors of mortality. CONCLUSIONS: Acute-on-chronic liver failure (ACLF) is an acute deterioration of liver function superimposed on Chronic Liver Disease with a high mortality. In our study HBV infection was the commonest cuase of CLD, and sepsis was the commonest acute insult. We found high hospital, 28 days and 12 weeks mortality. Organ failure, ACLF grade, encephalopathy, MELD score and AKI were found to be predictors of mortality of ACLF.