Acute-on-chronic Liver Failure Grade Research Articles

Hepatocytic Apoptosis and Immune Dysfunction in Decompensation of Alcoholic Liver Cirrhosis with Different Grades of Acute-on-Chronic Liver Failure.

Acute-on-chronic liver failure (ACLF) of varying grades was assessed in 110 patients with alcoholic liver cirrhosis using the on-line CLIF-C ACLF Calculator ( www.efclif.com/scientific-activity/score-calculators/clif-c-aclf ); fragments of cytokeratin-18, TNFα, IL-1β, IL-4, IL-6, and IL-8 were also assayed. As ACLF progressed from grade 0 to grade 3, the levels of cytokeratin-18 fragments, IL-6, and IL-8 significantly increased, while IL-4 decreased. TNFα peaked in ACLF grade 1, but decreased in grades 2 and 3. IL-1β did not depend on the ACLF grade. Thus, hepatic damage and immune dysfunction are implicated in the progression of ACLF.

Improved Survival With Higher-risk Donor Grafts in Liver Transplant With Acute-on-chronic Liver Failure.

Using the Organ Procurement and Transplantation Network and the United Network for Organ Sharing registry, 17 300 ACLF patients who underwent liver transplantation between 2002 and 2019 were evaluated. Based on DRI, adjusted hazard ratios for 1-y patient death were analyzed in 3 eras: Era 1 (2002-2007, n = 4032), Era 2 (2008-2013, n = 6130), and Era 3 (2014-2019, n = 7138). DRI groups were defined by DRI <1.2, 1.2-1.6, 1.6-2.0, and >2.0. ACLF patients had significantly lower risks of patient death within 1 y in Era 2 (adjusted hazard ratio, 0.69; 95% confidence interval, 0.61-0.78; P < 0.001) and Era 3 (adjusted hazard ratio, 0.48; 95% confidence interval, 0.42-0.55; P < 0.001) than in Era 1. All DRI groups showed lower hazards in Era 3 than in Era 1. Improvement of posttransplant outcomes were found both in ACLF-1/2 and ACLF-3 patients. In ACLF-1/2, DRI 1.2 to 1.6 and >2.0 had lower adjusted risk in Era 3 than in Era 1. In ACLF-3, DRI 1.2 to 2.0 had lower risk in Era 3. In the overall ACLF cohort, the 2 categories with DRI >1.6 had significantly higher adjusted risks of 1-y patient death than DRI <1.2. When analyzing hazards in each era, DRI > 2.0 carried significantly higher adjusted risks in Eras 1 and 3' whereas DRI 1.2 to 2.0 had similar adjusted risks throughout eras. Similar tendency was found in ACLF-1/2. In the non-ACLF cohort, steady improvement of posttransplant outcomes was obtained in all DRI categories. Similar results were obtained when only hepatitis C virus-uninfected ACLF patients were evaluated. In ACLF patients, posttransplant outcomes have significantly improved, and outcomes with higher-risk organs have improved in all ACLF grades. These results might encourage the use of higher-risk donors in ACLF patients and provide improved access to transplant.

Discordance in categorization of acute-on-chronic liver failure in the United Network for Organ Sharing database

Studies regarding acute-on-chronic liver failure (ACLF) among liver transplant (LT) candidates from the United Network for Organ Sharing (UNOS) database are being used to inform LT policy changes worldwide. We assessed the validity of identifying ACLF in UNOS. We performed stratified random sampling among 3 US LT centers between 2013-2019 to obtain a representative patient sample across ACLF grades. We compared the concordance of ACLF classification by UNOS vs. blinded manual chart review, according to EASL-CLIF. Among 481 sampled LT registrants, 250 (52%) had no ACLF, 75 (16%) had ACLF grade 1, 79 (16%) had ACLF grade 2, and 77 (16%) had ACLF grade 3 per UNOS categorization. Concordance of ACLF grade by UNOS vs. chart review was: 72%, 64%, 56%, and 64% for no ACLF, grade 1, grade 2, and grade 3, respectively, with an overall Cohen's kappa coefficient of 0.48 (95% CI 0.42-0.54). Absence of acute decompensation was the most common reason for overestimation, and discordant brain and respiratory failure categorization were the most common reasons for underestimation of ACLF by UNOS. In this retrospective multi-center study, ACLF categorization by UNOS showed weak agreement with manual chart review. These findings are informative for ongoing allocation policy discussions, highlight the importance of prospective studies regarding ACLF in LT, and should encourage UNOS reform. Acute-on-chronic-liver-failure (ACLF) is a specific and common form of liver failure associated with high death rates. Studies have been published using the United States transplant registry (UNOS) to identify and describe outcomes of transplant candidates and recipients with ACLF, and these data are driving policy changes for transplant allocation around the world, but nobody has shown whether these data are reliable. We found that UNOS was not categorizing ACLF in concordance or accurately when compared to chart review, which shows the need for UNOS reform and non-UNOS studies to appropriately inform policies regarding the transplantation of patients with ACLF.

Characteristics and predictors of short-term mortality in decompensated cirrhotic patients with acute-on-chronic liver failure.

We aimed to investigate the characteristics of acute-on-chronic liver failure (ACLF) and factors associated with 28-day mortality in patients with ACLF. This prospective study included ACLF patients based on the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) Consortium criteria, admitted between March 2021 and February 2022. We examined variables associated with 28-day mortality using multivariate Cox regression analysis. Of 326 patients admitted with acute decompensation (AD) of cirrhosis, 109 (33.44%) patients were diagnosed with ACLF (mean age 63.61 ±11.15 years, 65.14% males). Of these, 26.61%, 35.78%, and 37.61% of patients were in ACLF grades 1, 2, and 3 respectively. HCV (80.73%) was the main aetiology of cirrhosis. Upper gastrointestinal bleeding (25.69%) was the most common trigger. Kidney failure (73.39%) was the most common organ failure. The 28-day mortality rate was 66.97%. Cox regression analysis revealed that the existence of 2 (HR = 6.99, 95% CI: 2.68-18.25, p < 0.0001) or ≥ 3 (HR = 9.34, 95% CI: 3.6-24.74, p < 0.0001) organ failures, hepatic encephalopathy (HR = 2.96, 95% CI: 1.27-6.94, p = 0.01), and elevated serum bilirubin (HR = 1.03, 95% CI: 1.00-1.06, p = 0.04) were independent predictors for 28-day mortality, while shifting blood pH to the normal range was associated with a decrease in the HR of ACLF mortality (HR = 0.03, 95% CI: 0.002-0.44, p = 0.01). ACLF has a very high 28-day mortality, which is associated with the existence of 2 or more organ failures, hepatic encephalopathy, elevated serum bilirubin, and low blood pH.

A neutrophil-to-lymphocyte ratio-based prognostic model to predict mortality in patients with HBV-related acute-on-chronic liver failure

BackgroundAlthough the Asian Pacific Association for the Study of the Liver acute-on-chronic liver failure (ACLF) research consortium (AARC) ACLF score is easy to use in patients with hepatitis b virus-related ACLF (HBV-ACLF), serum lactate is not routinely tested in primary hospitals, and its value may be affected by some interference factors. Neutrophil-to-lymphocyte ratio (NLR) is used to assess the status of bacterial infection (BI) or outcomes in patients with various diseases. We developed an NLR-based AARC ACLF score and compared it with the existing model.MethodsA total of 494 HBV-ACLF patients, enrolled in four tertiary academic hospitals in China with 90-day follow-up, were analysed. Prognostic performance of baseline NLR and lactate were compared between cirrhotic and non-cirrhotic subgroups via the receiver operating curve and Kaplan–Meier analyses. A modified AARC ACLF (mAARC ACLF) score using NLR as a replacement for lactate was developed (n = 290) and validated (n = 204).ResultsThere were significantly higher baseline values of NLR in non-survivors, patients with admission BI, and those with higher grades of ACLF compared with the control groups. Compared with lactate, NLR better reflected BI status in the cirrhotic subgroup, and was more significantly correlated with CTP, MELD, MELD-Na, and the AARC score. NLR was an independent predictor of 90-day mortality, and was categorized into three risk grades (< 3.10, 3.10–4.78, and > 4.78) with 90-day cumulative mortalities of 8%, 21.2%, and 77.5% in the derivation cohort, respectively. The mAARC ACLF score, using the three grades of NLR instead of corresponding levels of lactate, was superior to the other four scores in predicting 90-day mortality in the derivation (AUROC 0.906, 95% CI 0.872–0.940, average P < 0.001) and validation cohorts (AUROC 0.913, 95% CI 0.876–0.950, average P < 0.01), with a considerable performance in predicting 28-day mortality in the two cohorts.ConclusionsThe prognostic value of NLR is superior to that of lactate in predicting short-term mortality risk in cirrhotic and non-cirrhotic patients with HBV-ACLF. NLR can be incorporated into the AARC ACLF scoring system for improving its prognostic accuracy and facilitating the management guidance in patients with HBV-ACLF in primary hospitals.

The Prediction of In-Hospital Mortality in Decompensated Cirrhosis with Acute-on-Chronic Liver Failure.

Acute-on-chronic liver failure (ACLF) is a condition in cirrhosis associated with organ failure (OF) and high short-term mortality. Both the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) and North American Consortium for the Study of End-Stage Liver Disease (NACSELD) ACLF definitions have been shown to predict ACLF prognosis. The aim of this study was to compare the ability of the EASL-CLIF versus NACSELD systems over baseline clinical and laboratory parameters in the prediction of in-hospital mortality in admitted patients with decompensated cirrhosis. Five NACSELD centers prospectively collected data to calculate EASL-CLIF and NACSELD-ACLF scores for admitted patients with cirrhosis who were followed for the development of OF, hospital course, and survival. Both the number of OFs and the ACLF grade or presence were used to determine the impact of NACSELD versus EASL-CLIF definitions of ACLF above baseline parameters on in-hospital mortality. A total of 1031 patients with decompensated cirrhosis (age, 57±11years; male, 66%; Child-Pugh-Turcotte score, 10±2; Model for End-Stage Liver Disease [MELD] score, 20±8) were enrolled. Renal failure prevalence (28% versus 9%, P<0.001) was more common using the EASL-CLIF versus NACSELD definition, but the prevalence rates for brain, circulatory, and respiratory failures were similar. Baseline parameters including age, white cell count on admission, and MELD score reasonably predicted in-hospital mortality (area under the curve, 0.76). The addition of number of OFs according to either system did not improve the predictive power of the baseline parameters for in-hospital mortality, but the presence of NACSELD-ACLF did. However, neither system was better than baseline parameters in the prediction of 30- or 90-day outcomes. The presence of NACSELD-ACLF is equally effective as the EASL-CLIF ACLF grade, and better than baseline parameters in the prediction of in-hospital mortality in patients with cirrhosis, but not superior in the prediction of longer-term 30- or 90-day outcomes.

From the Editor’s desk…

From the Editor’s desk…

HBV-related acute-on-chronic liver failure with underlying chronic hepatitis has superior survival compared to cirrhosis.

Acute-on-chronic liver failure (ACLF) is divided into three types according to the underlying liver disease: non-cirrhosis (type A), compensated cirrhosis (type B) and decompensated cirrhosis (type C). However, whether the underlying chronic liver diseases impact the ACLF prognosis is not clear. The present study aimed to compare the characteristics and outcomes of type A and type B hepatitis B virus (HBV)-ACLF patients. According to the European Association for the Study of Liver-Chronic Liver Failure (EASL-CLIF) diagnostic criteria, 86 type A HBV-ACLF and 71 type B HBV-ACLF were prospectively enrolled. The demography and laboratory data, organ failures, ACLF grades and prognosis were evaluated. Univariate and multivariate Cox regression analyses were performed to analyze the prognostic factors. The 28-day and 90-day mortality rates of type A and type B ACLF were 20.9 vs. 60.6% and 34.9 vs. 73.2%, respectively (both P < 0.001). Patients with type A ACLF were younger, had higher viral load and higher levels of alanine aminotransferase and aspartate aminotransferase, platelet count, serum albumin and sodium, international normalized ratio and alpha-fetoprotein, lower rate of ascites, lower Child-Pugh scores and CLIF sequential organ failure assessment scores, higher rate of coagulation failure. Type B ACLF had more renal and cerebral failure. Cirrhosis was one of the independent prognostic factors [hazard ratio, 2.4 (95% CI, 1.451-3.818) P < 0.001]. ACLF developing on noncirrhotic chronic hepatitis B had more serious liver inflammation but fewer extrahepatic organ failures and better outcome than ACLF developing from compensated HBV cirrhosis.

Bone Marrow Mesenchymal Stem Cells in Acute-on-Chronic Liver Failure Grades 2 and 3: A Phase I-II Randomized Clinical Trial.

Introduction Acute-on-chronic liver failure (ACLF) is an acute liver decompensation in cirrhotic patients, which leads to organ failures and high short-term mortality. The treatment is based on the management of complications and, in severe cases, liver transplantation. Since specific treatment is unavailable, we aimed to evaluate the safety and initial efficacy of bone marrow mesenchymal stem cells (BM-MSC) in patients with ACLF Grades 2 and 3, a population excluded from previous clinical trials. Methods This is a randomized placebo-controlled phase I-II single center study, which enrolled 9 cirrhotic patients from 2018 to 2020, regardless of the etiology. The control group (n = 5) was treated with standard medical therapy (SMT) and placebo infusion of saline. The intervention group (n = 4) received SMT plus 5 infusions of 1 × 106 cells/kg of BM-MSC for 3 weeks. Both groups were monitored for 90 days. A Chi-square test was used for qualitative variables, and the t-test and Mann–Whitney U test for quantitative variables. The Kaplan–Meier estimator was used to build survival curves. In this study, we followed the intention-to-treat analysis, with a significance of 5%. Results Nine patients with a mean Child–Pugh (CP) of 12.3, MELD of 38.4, and CLIF-C score of 50.7 were recruited. Hepatitis C and alcohol were the main etiologies. The average infusion per patient was 2.9 and only 3 patients (2 in control and 1 in the BM-MSC group) received all the protocol infusions. There were no infusion-related side effects, although one patient in the intervention group presented hypernatremia and a gastric ulcer, after the third and fifth infusions, respectively. The survival rate after 90 days was 20% (1/5) for placebo versus 25% (1/4) for the BM-MSC. The patient who completed the entire MSC protocol showed a significant improvement in CP (C-14 to B-9), MELD (32 to 22), and ACLF (grade 3 to 0). Conclusion BM-MSC infusion is safe and feasible in patients with ACLF Grades 2 and 3.

Serum CXCL1 Is a Prognostic Factor for Patients With Hepatitis B Virus-Related Acute-On-Chronic Liver Failure.

Purpose: Neutrophils and cytokines play a major role in the pathogenesis of acute-on-chronic liver failure (ACLF). We aimed to determine whether chemokine (CXC) ligand 1 (CXCL1), a key marker of neutrophil recruitment and activation, could predict the severity and prognosis of hepatitis B virus–related ACLF (HBV-ACLF).Methods: Hospitalized patients with HBV-ACLF were enrolled in a prospective study and stratified as survivors (alive at 28 days) and nonsurvivors (deceased at 28 days). Serum CXCL1 levels were measured in healthy controls, patients with chronic HBV, patients with HBV-related compensated cirrhosis, and patients with HBV-ACLF. Univariate and multivariable logistic analyses, Pearson correlation analysis, area under the receiver operating characteristic curve (AUROC), and Z tests were used to evaluate the performance of CXCL1 as a marker in HBV-ACLF.Results: Patients with HBV-ACLF had significantly higher serum levels of CXCL1 and neutrophil count than healthy controls and patients with chronic HBV or HBV-related compensated cirrhosis (P < 0.01, respectively). Among patients with HBV-ACLF, survivors had lower serum CXCL1 levels and neutrophil count than those of nonsurvivors (P < 0.001, P < 0.05, respectively). Serum CXCL1 level was positively correlated with neutrophil count (r = 0.256, P = 0.001), ACLF grade (r = 0.295, P < 0.001) and organ failure, including coagulation (r = 0.21, P = 0.005) and brain failure (r = 0.198, P = 0.008). Multivariable logistic analyses showed serum CXCL1 [OR (95% CI) = 1.017 (1.009–1.025), P < 0.001] was an independent risk factor for 28-day mortality in HBV-ACLF. Meanwhile, the AUROC analysis demonstrated that serum CXCL1 [0.741 (0.669–0.804)] might be a reliable prognostic biomarker for patients with HBV-ACLF.Conclusions: Overall, serum CXCL1 can serve as a biomarker indicating the severity of disease and prognosis for patients with HBV-ACLF. CXCL1 might also be a therapeutic target in this disease.

EASL-CLIF criteria outperform NACSELD criteria for diagnosis and prognostication in ACLF

There is no consensus on the best definition for acute-on-chronic liver failure (ACLF). In this study, we compared the prevalence and 30-day all-cause and transplant-free mortality of patients with ACLF identified by European Association for the Study of the Liver-Chronic Liver Failure Consortium (EASL-CLIF) and North American Consortium for the Study of End-stage Liver Disease (NACSELD) criteria. We performed this comparative analysis using the United Network for Organ Sharing (UNOS) data from January 11, 2016 to August 31,2020. A total of 10,198 (21%) adult patients had EASL-CLIF ACLF grade 1-3, but of these only 15.3% had ACLF by NACSELD. Of the 2,562 with EASL-CLIF ACLF grade 3, only 48.8% had NACSELD-ACLF, 16.8% had no organ failure (OF) and 34.4% had 1 OF. The 30-day all-cause mortality was 1.5%, 7.7%, 13.3% and 25.8% for EASL-CLIF grade 0-3, respectively, and it was 15.4% and 28.1% in those without and with NACSELD-ACLF. When EASL-CLIF grade 3 patients were stratified by NACSELD OF, the mortality ranged from 18.6% with no OF to 41.0% with 4 OFs. The 30-day transplant-free mortality in those with no OF by NACSELD was 2.7%, but when the same group is stratified by EASL-CLIF grades 0-3, the mortality rates were 1.5%, 10.5%, 43.5% and 86%, respectively; the mortality rates ranged from 3.0% to 75.7% in those with 1 OF by NACSELD. There is a clear discordance in the prevalence and 30-day mortality rates of patients with ACLF identified by the EASL-CLIF and NACSELD criteria. EASL-CLIF criteria have a better sensitivity to detect ACLF and have a better prognostic capability. There is no consensus on the definition of acute-on-chronic liver failure. European (EASL-CLIF) and North American (NACSELD) consortia have each proposed a commonly used definition. In this study, we compared the prevalence and short-term (30-day) mortality based on these definitions. Using a very large data set, we observed that there was a significant discordance in the prevalence and mortality based on these criteria. EASL-CLIF criteria appeared to be more sensitive to identify acute-on-chronic liver failure, and were better at predicting all-cause and short-term mortality.

Evaluation of prognostic value of neutrophil-to-lymphocyte ratio in patients with acute-on-chronic liver failure or severe liver injury from chronic HBV infection.

Acute-on-chronic liver failure (ACLF) is associated with bacterial infection and poor outcome. Neutrophil-to-lymphocyte ratio (NLR) is used to assess bacterial infection and immune dysfunction in numerous diseases. We aimed to evaluate NLR as a prognostic biomarker and to explore its combination with accepted prognostic models in ACLF patients. This retrospective study included patients with ACLF or severe liver injury from chronic HBV infection admitted to three tertiary academic hospitals in China from 2013 to 2019. Baseline NLR was correlated with ACLF grade, bacterial infection, survival and accepted ACLF scores. Baseline NLR values were significantly increased in nonsurvivors and patients with bacterial infection at or after admission and were unaffected by cirrhotic status in 412 transplant-free patients included in three cohorts. Compared with accepted scores, NLR showed moderate accuracy in predicting 28-day mortality and high accuracy in predicting 90-day mortality. Three levels of mortality risk were graded on the basis of NLR values (<3.10, 3.10-4.79 and >4.79), and NLR >4.79 was associated with 53.2-60.0% 28-day and 75.0-80.0% 90-day mortality in these cohorts. Multivariate analyses indicated that NLR retained statistical significance independently of CLIF consortium organ failure score (CLIF-C OFs). NLR-based CLIF-C ACLF score was primarily developed and showed excellent performance in predicting 28/90-day mortality. NLR is a dependable biomarker for bacterial infection assessment and short-term mortality prediction in ACLF patients and can be used jointly with CLIF-C OFs to improve the accuracy of mortality prediction in patients with the disease. NLR-based CLIF-C ACLF model needs further validation.

Predictors of early mortality among patients with acute-on-chronic liver failure.

Background and AimAcute‐on‐chronic liver failure (ACLF) is a transpiring entity, which possesses high short‐term/early mortality (28 days). Several mortality predictors have been studied, but none were proved reliable. Serum ferritin, an acute phase reactant and marker of hepatic necro‐inflammation, is found to predict mortality in multiple liver diseases. We aimed to evaluate the role of serum ferritin and other clinical features, biochemical parameters and conventional scoring systems in predicting early mortality among ACLF.MethodsA prospective cohort study was done from October 2017 to March 2019 at a tertiary care (non‐transplant) center in eastern India. A total of consecutive 50 ACLF patients diagnosed, based on Asia Pacific Association for the Study of liver disease definition, were investigated for ferritin and other laboratory parameters on day‐0, day‐7, and followed up for 28 days.ResultsAlthough the majority did not have organ failure (ACLF grade 0) according to European Association for Study of Liver‐chronic liver failure sequential organ failure assessment criteria, early mortality was high (56%). On undergoing univariate analysis, multiple variables (ascites, HE, creatinine, total leucocyte count (TLC), bilirubin, albumin) predicted mortality. However, on multivariate analysis, only total bilirubin independently predicted. None of the scores on day‐0 were predictive, while model for end‐stage liver disease [area under the receiver operating characteristics (AUROC)‐0.703, 95% confidence interval [CI]: 0.535–0.859] and Child–Turcotte–Pugh (AUROC‐0.697, 95% CI: 0.550–0.855) on day‐7 did.ConclusionACLF is a dynamic process; day‐7 assessment with above predictors, to be considered a milestone for prognostication and opting treatment modalities. Serum ferritin does not predict early mortality in ACLF.

Predictors and outcome of emergent Liver transplantation for patients with acute-on-chronic liver failure

Background and aimsControversy exists over whether emergent liver transplantation (LT) should be performed for patients with acute-on-chronic liver failure (ACLF), especially for patients with multiple organ failure. MethodsA total of 110 ACLF patients, defined by the European Association for the Study of the Liver (EASL) Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) criteria were analyzed. The primary outcome was overall survival after ACLF diagnosis. ResultsDuring follow-up, 76 patients received LT (59 received deceased-donor LT and 17 patients received living-donor LT). The overall survival was better for patients who received LT than patients who did not (82.9% vs. 17.6%, P < 0.001). Among the 76 patients who received LT, the overall survival was not different according to ACLF grade at diagnosis (70.0%, 85.3%, and 84.4% at one-year for ACLF grades 1, 2, and 3, respectively, P = 0.45). The baseline model for end-stage liver disease (MELD) score and progression of the ACLF grade during the pre-transplant period were independent factors for survival after LT. The one-year survival rate was 92.3% for patients with baseline MELD scores of ≤ 32 without ACLF grade progression, whereas it was 33.3% for those with baseline MELD scores of > 32 and ACLF grade progression. ConclusionsEmergent LT provided a significant survival benefit to ACLF patients, regardless of the baseline ACLF grade. Post-LT outcomes were associated with baseline MELD scores and ACLF progression during the pre-transplant period, which might be used in the emergent LT plan for patients presenting with ACLF.

Acute on Chronic Liver Failure From Nonalcoholic Fatty Liver Disease: A Growing and Aging Cohort With Rising Mortality.

We assessed the burden of nonalcoholic fatty liver disease (NAFLD)-related acute on chronic liver failure (ACLF) among transplant candidates in the United States, along with waitlist outcomes for this population. We analyzed the United Network for Organ Sharing registry from 2005 to 2017. Patients with ACLF were identified using the European Association for the Study of the Liver/Chronic Liver Failure criteria and categorized into NAFLD, alcohol-associated liver disease (ALD), and hepatitis C virus (HCV) infection. We used linear regression and Chow's test to determine significance in trends and evaluated waitlist outcomes using Fine and Gray's competing risks regression and Cox proportional hazards regression. Between 2005 and 2017, waitlist registrants for NAFLD-ACLF rose by 331.6% from 134 to 574 candidates (P<0.001), representing the largest percentage increase in the study population. ALD-ACLF also increased by 206.3% (348-1,066 registrants; P<0.001), whereas HCV-ACLF declined by 45.2% (P<0.001). As of 2017, the NAFLD-ACLF population consisted primarily of persons aged ≥60 years (54.1%), and linear regression demonstrated a significant rise in the proportion of patients aged ≥65 in this group (β=0.90; P=0.011). Since 2014, NAFLD-ACLF grade 1 was associated with a greater risk of waitlist mortality relative to ALD-ACLF (subhazard ratio [SHR]=1.24; 95% confidence interval [CI], 1.05-1.44) and HCV-ACLF (SHR=1.35; 95% CI, 1.08-1.71), among patients aged ≥60 years. Mortality was similar among the three groups for patients with ACLF grade 2 or 3. NAFLD is the fastest rising etiology of cirrhosis associated with ACLF among patients listed in the United States. As the NAFLD population continues to grow and age, patients with NAFLD-ACLF will likely have the highest risk of waitlist mortality.

Acute-on-chronic liver failure in Egypt: an underestimated complication of liver cirrhosis.

Acute-on-chronic liver failure (ACLF) is a severe liver cirrhosis complication with high mortality rates. Despite that chronic liver diseases are prevalent in Egypt, there is no available data about patients with ACLF. We aimed to evaluate the pattern of ACLF in Egypt. This prospective cohort study included all patients with ACLF, according to the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver, admitted to Al-Rajhi liver Hospital, Egypt, between November 2018 and October 2019. We recorded data at admission, days 3, 7, 14 and 28, and calculated ACLF grades and Chronic Liver Failure Consortium scores until discharge or death. Kaplan-Meier survival analysis was used for survival analysis. We analyzed 52 patients with ACLF. Liver cirrhosis was secondary to hepatitis C virus in 46 patients (88.9%), and hepatitis B virus in 4 (7.4%). The main ACLF precipitating factors were infection in 38 (73.1%) and variceal bleeding in 9 (17.3%). The most common infections were spontaneous bacterial peritonitis (44.7%) and chest infection (31.6%). The 28 and 90-day mortality rates were 86.5 and 96.2%. None of the patients who survived >28 days had ACLF 3 at admission or day 7. Among those who died <28 days, ACLF 3 was reported in 7 at admission and 19 on day 7. Living donor liver transplantation was not offered in any case. In this study, the 28-day mortality rate was higher than in the literature. Egypt urgently needs to develop specific protocols for the proper management of ACLF.

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.

Predictors of Outcomes of Patients Referred to a Transplant Center for Urgent Liver Transplantation Evaluation.

Liver transplantation (LT) is definitive treatment for end‐stage liver disease. This study evaluated factors predicting successful evaluation in patients transferred for urgent inpatient LT evaluation. Eighty‐two patients with cirrhosis were transferred for urgent LT evaluation from January 2016 to December 2018. Alcohol‐associated liver disease was the common etiology of liver disease (42/82). Of these 82 patients, 35 (43%) were declined for LT, 27 (33%) were wait‐listed for LT, 5 (6%) improved, and 15 (18%) died. Psychosocial factors were the most common reasons for being declined for LT (49%). Predictors for listing and receiving LT on multivariate analysis included Hispanic race (odds ratio [OR], 1.89; P = 0.003), Asian race (OR, 1.52; P = 0.02), non‐Hispanic ethnicity (OR, 1.49; P = 0.04), hyponatremia (OR, 1.38; P = 0.04), serum albumin (OR, 1.13; P = 0.01), and Model for End‐Stage Liver Disease (MELD)‐Na (OR, 1.02; P = 0.003). Public insurance (i.e., Medicaid) was a predictor of not being listed for LT on multivariate analysis (OR, 0.77; P = 0.02). Excluding patients declined for psychosocial reasons, predictors of being declined for LT on multivariate analysis included Chronic Liver Failure Consortium (CLIF‐C) score >51.5 (OR, 1.26; P = 0.03), acute‐on‐chronic liver failure (ACLF) grade 3 (OR, 1.41; P = 0.01), hepatorenal syndrome (HRS) (OR, 1.38; P = 0.01), and respiratory failure (OR, 1.51; P = 0.01). Predictors of 3‐month mortality included CLIF‐C score >51.5 (hazard ratio [HR], 2.52; P = 0.04) and intensive care unit (HR, 8.25; P < 0.001). Conclusion: MELD‐Na, albumin, hyponatremia, ACLF grade 3, HRS, respiratory failure, public insurance, Hispanic race, Asian race, and non‐Hispanic ethnicity predicted liver transplant outcome. Lack of psychosocial support was a major reason for being declined for LT. The CLIF‐C score predicted being declined for LT and mortality.

Validating a novel score based on interaction between ACLF grade and MELD score to predict waitlist mortality

Among candidates listed for liver transplant (LT), the model for end-stage liver disease (MELD) score may not capture acute-on-chronic liver failure (ACLF) severity. Data on the interaction between ACLF and MELD score in predicting waitlist mortality are scarce. We analyzed the UNOS database (01/2002 to 06/2018) for LT listings in adults with cirrhosis and ACLF (without hepatocellular carcinoma). ACLF grades 1, 2, 3a, and 3b- were defined using the modified EASL-CLIF criteria. Of 18,416 candidates with ACLF at listing (mean age 54 years, 69% males, 63% Caucasians), 90-day waitlist mortality (patient death or being too sick for LT) was 21.6% (18%, 20%, 25%, and 39% for ACLF grades 1, 2, 3a, and 3b, respectively). Using a Fine and Gray regression model, we identified an interaction between MELD and ACLF grade, with ACLF having a higher impact at lower MELD scores. Other variables included candidate's age, sex, liver disease etiology, listing MELD, ACLF grade, obesity, and performance status. A score developed using parameter estimates from the interaction model on the derivation cohort (n = 9,181) stratified the validation cohort (n= 9,235) into quartiles: Q1 (score <10.42), Q2 (10.42-12.81), Q3 (12.82-15.50), and Q4 (>15.50). Waitlist mortality increased with each quartile from 13%, 18%, 23%, and 36%, respectively. Observed vs. expected waitlist mortality deciles in the validation cohort showed good calibration (goodness of fit p= 0.98) and correlation (R= 0.99). Among selected candidates who have ACLF at listing, MELD score and ACLF interact in predicting cumulative risk of 90-day waitlist mortality, with higher impact of ACLF grade at lower listing MELD score. Validating these findings in large prospective studies will support consideration of both MELD and ACLF when prioritizing transplant candidates and allocating liver grafts. In patients with cirrhosis listed for liver transplantation, the presence of multiorgan failure, a condition referred to as acute-on-chronic liver failure, is associated with high waiting list mortality rates. Current organ allocation policy disadvantages patients with this condition. This study describes and validates a new scoring method that performs better than the currently available scoring systems. Further validation of this approach may reduce the deaths of patients with cirrhosis and acute-on-chronic liver failure on the transplant waiting list.

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.