Mortality In Acute-on-chronic Liver Failure Research Articles

Development and validation of a new prognostic model for patients with acute-on-chronic liver failure in intensive care unit.

Cirrhotic patients with acute-on-chronic liver failure (ACLF) in the intensive care unit (ICU) have a poor but variable prognoses. Accurate prognosis evaluation can guide the rational management of patients with ACLF. However, existing prognostic scores for ACLF in the ICU environment lack sufficient accuracy. To develop a new prognostic model for patients with ACLF in ICU. Data from 938 ACLF patients in the Medical Information Mart for Intensive Care (MIMIC) database were used to develop a new prognostic model (MIMIC ACLF) for ACLF. Discrimination, calibration and clinical utility of MIMIC ACLF were assessed by area under receiver operating characteristic curve (AUROC), calibration curve and decision curve analysis (DCA), respectively. MIMIC ACLF was then externally validated in a multiple-center cohort, the Electronic Intensive Care Collaborative Research Database and a single-center cohort from the Second Hospital of Hebei Medical University in China. The MIMIC ACLF score was determined using nine variables: ln (age) × 2.2 + ln (white blood cell count) × 0.22 - ln (mean arterial pressure) × 2.7 + respiratory failure × 0.6 + renal failure × 0.51 + cerebral failure × 0.31 + ln (total bilirubin) × 0.44 + ln (internationalized normal ratio) × 0.59 + ln (serum potassium) × 0.59. In MIMIC cohort, the AUROC (0.81/0.79) for MIMIC ACLF for 28/90-day ACLF mortality were significantly greater than those of Chronic Liver Failure Consortium ACLF (0.76/0.74), Model for End-stage Liver Disease (MELD; 0.73/0.71) and MELD-Na (0.72/0.70) (all P < 0.001). The consistency between actual and predicted 28/90-day survival rates of patients according to MIMIC ACLF score was excellent and superior to that of existing scores. The net benefit of MIMIC ACLF was greater than that achieved using existing scores within the 50% threshold probability. The superior predictive accuracy and clinical utility of MIMIC ACLF were validated in the external cohorts. We developed and validated a new prognostic model with satisfactory accuracy for cirrhotic patients with ACLF hospitalized in the ICU. The model-based risk stratification and online calculator might facilitate the rational management of patients with ACLF.

Assessing the predictive value of serum phosphate for short-term mortality in acute-on-chronic liver failure patients: An observational study at a non-transplant tertiary care centre.

The gradual clinical worsening of acute-on-chronic liver failure (ACLF) leads to a high 28-day mortality rate. There are several prognostication scores for predicting early mortality in ACLF. Serum phosphate, which is the main component of adenosine tri-phosphate (ATP) synthesis, is utilized for liver synthetic functions, leading to subnormal or decreased serum phosphate levels. Hence more than normal levels of serum phosphate can be used as a marker of decreased liver cell reserve. Hence, we aimed to compare serum phosphate levels with available prognostic scores to assess mortality among ACLF patients. 100 consecutive ACLF patients according to the Asia Pacific Association for Study of the Liver (APASL) definition were studied. The baseline blood workups and determination of viral bio-markers, serum phosphate, and lactate levels on days 1, 3, and 7 were carried out and prospectively followed up, and the baseline serum phosphate levels were compared with the usual scores to predict the 28-day mortality. CLIF-SOFA (accuracy 76-91%) followed by CLIF-C score (accuracy 73-84%) and AARC score (accuracy 70-85%) had the statistically significantly highest accuracy as compared with CTP, MELD, and MELD-Na on all three days. Serum phosphate values (accuracy 69-86%) on all three days were not better than the CLIF-SOFA score but better than all other prognostic scores on days 3 and 7. The high serum phosphate levels on day 3 with a value of more than 6.4 mg/dl showed almost comparable accuracy with CLIF-SOFA for screening short-term mortality. Hence serum phosphate measurement can be used as a simple bedside laboratory investigation to predict mortality in ACLF patients and early interventions in low-resource settings.

Cirrhotic cardiomyopathy influences clinical outcomes and enhances performance of conventional risk prediction models in acute-on-chronic liver failure with severe sepsis.

Point-of-care echocardiography (POC-Echo) is an essential intensive care hemodynamic monitoring tool. To assess POC-Echo parameters [i.e., cardiac index (CI), systemic vascular resistance index (SVRI) and cirrhotic cardiomyopathy (CCM) markers] and serum biomarkers in predicting circulatory failure (need for vasopressors) and mortality in patients with acute-on-chronic liver failure (ACLF) having sepsis-induced hypotension. We performed serial POC-Echo within 6 hours (h)of presentation and subsequently at 24, 48 and 72 h in patients with ACLF and sepsis-induced hypotension admitted to our liver intensive care unit. Clinical data, POC-Echo data and serum biomarkers were collected prospectively. We enrolled 120 patients [59% men, aged 49 ± 12 years, 56% alcohol-related disease and median MELDNa of 30 (27-32)], of whom 68 (56.6%) had circulatory failure, with overall mortality of 60%. CCM was present in 52.5%. The predictors of circulatory failure were CI (aHR -1.5; p = 0.021), N-terminal brain natriuretic peptide (aHR -1.1; p = 0.007) and CCM markers; e' septal mitral velocity (aHR -0.5; p = 0.039) and E/e' ratio (aHR -1.2; p = 0.045). Reduction in CI by 20% and SVRI by 15% at 72 h predicted mortality with a sensitivity of 84% and 72%, and specificity 76% and 65%, respectively (p < 0.001). The MELD-CCM model and CLIF-CCM model were computed as MELDNa + 1.815 × E/e' (septal) + 0.402 × e' (septal) and CLIF-C ACLF + 1.815 × E/e' (septal) + 0.402 × e' (septal), respectively, based on multivariable logistic regression. Both scores outperformed MELDNa (z-score = -2.073, p = 0.038) and CLIF-C ACLF score (z score = -2.683, p-value = 0.007), respectively, in predicting 90-day mortality. POC-Echo measurements such as CCM markers (E/e' and e' velocity) and change in CI reliably predict circulatory failure and mortality in ACLF with severe sepsis. CCM markers significantly enhanced the CLIF-C ACLF and MELDNa predictive performance.

Mechanisms of immunity in acutely decompensated cirrhosis and acute-on-chronic liver failure.

The identification of systemic inflammation (SI) as a central player in the orchestration of acute-on-chronic liver failure (ACLF) has opened new avenues for the understanding of the pathophysiological mechanisms underlying this disease condition. ACLF, which develops in patients with acute decompensation of cirrhosis, is characterized by single or multiple organ failure and high risk of short-term (28-day) mortality. Its poor outcome is closely associated with the severity of the systemic inflammatory response. In this review, we describe the key features of SI in patients with acutely decompensated cirrhosis and ACLF, including the presence of a high blood white cell count and increased levels of inflammatory mediators in systemic circulation. We also discuss the main triggers (i.e. pathogen- and damage-associated molecular patterns), the cell effectors (i.e. neutrophils, monocytes and lymphocytes), the humoral mediators (acute phase proteins, cytokines, chemokines, growth factors and bioactive lipid mediators) and the factors that influence the systemic inflammatory response that drive organ failure and mortality in ACLF. The role of immunological exhaustion and/or immunoparalysis in the context of exacerbated inflammatory responses that predispose ACLF patients to secondary infections and re-escalation of end-organ dysfunction and mortality are also reviewed. Finally, several new potential immunogenic therapeutic targets are debated.

Utility of Lactate to Bilirubin Index in Predicting Short-Term Mortality in Acute on Chronic Liver Failure: A Single Centered Study

Introduction: Most of the lactate in the body is cleared in the liver. Tissue hypoxia results in increased production of lactate and decreased utility of it. Hepatic insult results not only an increase in the blood lactate levels but also is an independent prognostic marker in critically ill cirrhotic patients. Alteration of liver function is indicated by rise in serum bilirubin. The aim of this study was to therefore to assess the utility of blood lactate to Bilirubin index (LBi) in predicting mortality in patients with acute on chronic liver failure (ACLF).&#x0D; Methods: This prospective observational study was conducted from January 2019 to June 2021 at the Department of Hepatogastroenterology, Sindh Institute of Urology and Transplantation. Patients aged &gt; 12 years and presenting ACLF were included and their baseline characteristics were recorded. Primary outcome was observed in terms of 30-days mortality and secondary outcome was six months mortality. These indices were then used to calculate the lactate to bilirubin index (LBi) as [1000 × lactate (mmol/L) × bilirubin (µmol/L)]/2. Area under Receiver operating curves (AUROC) for LBi, Child Turcotte Pugh score(CTP) and Model for End-stage Liver Disease score (MELD) were obtained in predicting both 30 days and six months mortality and at an optimal cutoff sensitivity, specificity and diagnostic accuracy for these scores were calculated.&#x0D; Results: A total number 159 patients with ACLF were included in the study. Most of the patients were young with mean age of 35.1 ±16.8 years. Males were 97(61%). Hepatitis C was the most common cause of chronic liver disease followed by hepatitis B and autoimmune hepatitis seen in 41 (25.8%), 39(24.5%) and 36 (22.6%) respectively. Hepatitis E was the most common cause of acute injury noted in 60 (37.7%) patients. The baseline characteristics showed mean serum lactate levels of 0.93±1.33 mmol/L, bilirubin levels of 258.5 ± 155.3 µmol/L, CTP score of 10.7 ± 1.8 and MELD score of 26 ±7.6. Out of 159 patients, 26 (16.4%) patients died within 30 days due to ACLF related complicaitons while 133 (83.6%) were discharged. AUROC obtained for LBi, CTP score and MELD score in predicting 30-day mortality in ACLF was 0.98, 0.79 and 0.78 respectively. A cut off of ≥11.8 for LBi Index, ≥30 for MELD score and ≥13 for CTP score were significantly associated with increased risk of 30-day mortality in ACLF patients in our population. However, the sensitivity, specificity, PPV, NPV and diagnostic accuracy of LBi in predicting 30-day mortality was significantly higher than that of CTP and MELD score. The diagnostic accuracy of LBi in predicting 30 days mortality was 87.5%. Similarly, AUROC obtained for LBi, CTP score and MELD score in predicting 6-month mortality in ACLF was 0.89, 0.72 and 0.66 respectively and the diagnostic accuracy of LBi dropped down to 76.6% with a sensitivity of 49.28%, specificity of 97.28%, PPV of 94.4% and NPV of 71.54%. &#x0D; Conclusion: Our results showed that LBi score of &gt;11.8 had an excellent sensitivity and specificity in predicting mortality in ACLF with an excellent diagnostic accuracy in predicting one month mortality as compared to the other scores. However, its utility in predicting long term mortality is yet to be proven. Further studies are needed to validate this index.

Comparison of Different Scores in Predicting Mortality in Patients with Acute on Chronic Liver Failure Admitted to the Intensive Care Unit of a Tertiary Care Hospital

Background: The illness known as acute-on-chronic liver failure (ACLF) was just recently identified and characterized which is linked to morbidity and deaths. Several prognostic models are available to stratify these patients. Objective: The objective was to compare the performance of different non-invasive available models in predicting one-month and six months mortality in ACLF. Methods: This retrospective study included patients of age range 8-70 years of any gender having liver cirrhosis and fulfilling the criteria of ACLF from January 2019 to December 2022. The predesigned formula was used to calculate scores based on different models. The outcome was noted in terms of one month and six months of mortality in each patient. The receiver operative curve was constructed for six prognostic models available for predicting 30-day and six months mortality in ACLF patients. These scores were subjected to multivariable cox-regression analysis to determine the independent determinants of both short- and long-term mortality in ACLF patients. Results: A total of 235 patients were studied in this retrospective investigation. A one-month mortality rate of 78 patients (33.2%) and a six-month mortality rate of 155 patients (66%) were recorded, respectively. CTP score, MELD score, LBi, CLIF-SOFA, and CLIF-ACLF were independent predictors of one-month mortality on multivariate cox-regression analysis, but only CTP score, MELD score, and LBi were independent predictors of mortality at six months. Conclusion: Among the six prognostic scores used for the ICU-admitted ACLF patients, LBi was the most efficient predictor of both one-month and six months mortality while CLIF-C SOFA and CLIF ACLF were good predictors of both mortalities. CTP and MELD scores were useful in forecasting six months' mortality.

Platelet to White Blood Cell Ratio (PWR) to Predict Mortality in Acute on Chronic Liver Failure of Cirrhosis Patient: A Systematic Review

Background: Liver cirrhosis (LC) is still being important public health concern, due to the rising of global incidence and mortality. There is risk progression in LC patients to acute-on-chronic liver failure (ACLF) patients with high incidence of complication and high short-term mortality rate. It needs rapid and simpler predictor to immediate and accurate triage of the patient. The aim of this study is to review systematically the role of PWR to predict the mortality in ACLF cirrhosis patient.Method: This systematic review study was identified by searching Pub-Med, Cochrane library, and EMBASE database (2016-2022). Only observational studies were included. ACLF patient was selected as the main subject in each study, and PWR was added as short-term mortality predictor. The Cochran seven step model was used to perform the review.Results: Six cohort retrospective studies met inclusion criteria, including total 1,348 patient ACLF. Half of studies included had high level of evidence. The non-survivor ACLF patient had significantly lower PWR values than survivor. The range of HR of PWR to predict mortality in ACLF was 0.665-0.995, with p value 0.0001. Whereas the cutoff range of PWR value to predict non survivor in ACLF patient was 7.83-14.2.Conclusion: PWR had a predictive efficacy, similar to CLIF-SOFA and MELD score in terms of predicting short-term mortality in ACLF patients. PWR showed significantly independent risk factor of short term mortality in ACLF cirrhotic patient.

Type of Infection Is Associated with Prognosis in Acute-on-Chronic Liver Failure: A National Veterans Health Administration Study.

Acute-on-chronic liver failure (ACLF) is a syndrome in patients with cirrhosis with high short-term mortality. Infection is a frequent precipitant of ACLF; however, it is unclear if prognosis varies by difference infectious sources. To address this knowledge gap, we utilized a large national database of patients with cirrhosis. This was a retrospective cohort study of patients with cirrhosis in the Veterans Health Administration between 2008 and 2016. First ACLF hospitalizations were identified and infections were classified using validated algorithms, categorized as bacteremia, fungal, spontaneous bacterial peritonitis (SBP), pyelonephritis/urinary tract infection, or skin and soft tissue/musculoskeletal infection (SST/MSK). Inverse probability treatment weighing for infection-associated ACLF followed by multivariable logistic regression was used to evaluate the association between infection type and 90-day mortality. A total 22,589 ACLF hospitalizations were included, 3998 (17.7%) of which had ACLF grade 3. Infection was associated with 12,405 (54.9%) of ACLF hospitalizations. In regression models, SBP was associated with a 1.79-fold increased odds of 90-day mortality vs. no infection (95% confidence interval [CI] 1.58-2.02, p < 0.001), whereas SST/MSK infections had a lower relative odds of mortality (odds ratio 0.48, 95% CI 0.42-0.53, p < 0.001). There was a significant interaction between infection category and ACLF grade on the outcome of 90-day mortality (p < 0.001). The impact of infection on short-term mortality in ACLF varies depending on the source of infection. This has relevance for ACLF prognostication and challenges previous notions that bacterial infection invariably worsens prognosis among all 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.

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.

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.

Patient Frailty Is Independently Associated With the Risk of Hospitalization for Acute-on-Chronic Liver Failure.

There is significant interest in identifying risk factors associated with acute-on-chronic liver failure (ACLF). In transplant candidates, frailty predicts wait-list mortality and posttransplant outcomes. However, the impact of frailty on ACLF development and mortality is unknown. This was a retrospective study of US veterans with cirrhosis identified between 2008 and 2016. First hospitalizations were characterized as ACLF or non-ACLF admissions. Prehospitalization patient frailty was ascertained using a validated score based on administrative coding data. We used logistic regression to investigate the impact of an increasing frailty score on the odds of ACLF hospitalization and short-term ACLF mortality. Cox regression was used to analyze the association between frailty and longterm survival from hospitalization. We identified 16,561 cirrhosis hospitalizations over a median follow-up of 4.19years (interquartile range, 2.47-6.34 years). In adjusted models, increasing frailty score was associated with significantly increased odds of ACLF hospitalization versus non-ACLF hospitalization (odds ratio, 1.03 per point; 95% CI 1.02-1.03; P<0.001). By contrast, frailty score was not associated with ACLF 28- or 90-day mortality (P=0.13 and P=0.33, respectively). In an adjusted Cox analysis of all hospitalizations, increasing frailty scores were associated with poorer longterm survival from the time of hospitalization (hazard ratio, 1.02 per 5 points; 95% confidence interval, 1.01-1.03; P=0.004). Frailty increases the likelihood of ACLF hospitalization among patients with cirrhosis, but it does not impact short-term ACLF mortality. These findings have implications for clinicians caring for frail outpatients with cirrhosis, including tailored follow-up, risk mitigation strategies, and possible expedited transplant evaluation.

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.

Abnormal Innate Immunity in Acute-on-Chronic Liver Failure: Immunotargets for Therapeutics.

Acute-on-chronic liver failure (ACLF) is a severe life-threatening condition with high risk of multiorgan failure, sepsis, and mortality. ACLF activates a multifaceted interplay of both innate and adaptive immune response in the host which governs the overall outcome. Innate immune cells recognize the conserved elements of microbial and viral origin, both to extort instant defense by transforming into diverse modules of effector responses and to generate long-lasting immunity but can also trigger a massive intrahepatic immune inflammatory response. Acute insult results in the activation of innate immune cells which provokes cytokine and chemokine cascade and subsequently initiates aggressive systemic inflammatory response syndrome, hepatic damage, and high mortality in ACLF. Dysregulated innate immune response not only plays a critical role in disease progression but also potentially correlates with clinical disease severity indices including Child-Turcotte-Pugh, a model for end-stage liver disease, and sequential organ failure assessment score. A better understanding of the pathophysiological basis of the disease and precise immune mechanisms associated with liver injury offers a novel approach for the development of new and efficient therapies to treat this severely ill entity. Immunotherapies could be helpful in targeting immune-mediated organ damage which may constrain progression toward liver failure and eventually reduce the requirement for liver transplantation. Here, in this review we discuss the defects of different innate immune cells in ACLF which updates the current knowledge of innate immune response and provide potential targets for new therapeutic interventions.

Higher Waitlist Mortality in Pediatric Acute-on-chronic Liver Failure in the UNOS Database.

Acute-on-chronic liver failure (ACLF), whereas increasingly well-defined in adults, has been poorly characterized in pediatric patients other than having a poor prognosis. This study aimed to identify ACLF and evaluate prognosis in the American pediatric population. Modified ACLF definitions (p-CLIF) were applied to 11,300 children listed for liver transplantation from March 2002 through 2017 in the Organ Procurement and Transplantation Network (OPTN) database. Pediatric ACLF patients have greater mortality within 90 days from listing (46.6% by p-CLIF) than other types of failure (<30%), including acute liver failure, as well as greater mortality within the first 30 and 90 days after transplantation than all other types of liver failure, but do not have increased mortality rates relative to other groups between 90 and 365 days from transplant. Although some ACLF listings also received 1B status, ACLF mortality at 90 days was greater than the general 1B population (50 vs 29.4%). Model for End-Stage Liver Disease/Pediatric End-Stage Liver Disease scores of ACLF patients are lower than 1B listings, and do not predict waitlist or posttransplant death. Greater number of organ failures does correlate with increased mortality. Biliary atresia is the leading etiology of pediatric chronic liver disease, accounting for over 30% of chronic and 45% of ACLF listings, yet is protective against mortality (hazard ratio [HR] = 0.142 for ACLF). Receiving exception approval is independently but similarly protective in ACLF (HR = 0.145). These findings pose a challenge for allocation decisions but indicate greater attention to ACLF is needed, as scoring systems may not capture these children's risk of early death, which appears to currently be mitigated by exceptions. Multicenter, clinical, preferably prospective study of ACLF is necessary to determine how to prioritize ACLF relative to other liver failure types to address its relatively higher early mortality.

Early Transplantation in Acute on Chronic Liver Failure: Who and When.

Acute on chronic liver failure (ACLF) is a unique syndrome that afflicts patients with chronic liver disease and results in high short-term mortality, > 50% at 28 days in patients with severe ACLF (grade 3, ACLF-3). Given this prognosis, there is an urgent need to understand risk factors for this condition, as well as selection criteria for patients who may benefit from liver transplantation (LT). Several studies have identified risk factors for developing ACLF, including higher model for end-stage liver disease score, anemia, and morbid obesity, as well ACLF mortality, such as infection, increasing organ failures, and higher white blood cell count. Prognostic tools are now available as online calculators. Regarding LT in ACLF, data suggest that even patients with ACLF-3 may do well after LT, with 1-year survival > 80% in several studies. Improvement in organ failures prior to LT, higher donor quality, and lack of mechanical ventilation further improve outcomes. Importantly, ACLF-3 patients may have higher short-term wait list mortality than patients listed status-1a, suggesting that increased LT prioritization may be warranted. ACLF is a high-mortality condition that frequently responds well to LT. Ongoing efforts to understand the natural history of ACLF and predictors of improved post-LT survival will facilitate LT criteria for this condition, which may ultimately include increased LT prioritization for selected patients.

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).

Coagulation failure is associated with bleeding events and clinical outcome during systemic inflammatory response and sepsis in acute-on-chronic liver failure: An observational cohort study.

Patients with acute-on-chronic liver failure (ACLF) have coagulation failure in the setting of systemic inflammatory syndrome (SIRS), sepsis and extra-hepatic organ failures. Consecutive ACLF patients without sepsis at baseline were assessed at days 0, 3 and 7 with thromboelastography (TEG) and specific assays (Factor VIII, von Willebrand factor [vWF], protein C and antithrombin III [ATIII]) and followed for development of sepsis, bleeding and outcome. Of 243 patients, 114 (63% ethanol related; mean age 44.3±11.7years; 90% male) were recruited. SIRS was noted in 39 (34.2%), 45 (39.5%) and 46 (40%) patients at days 0, 3 and 7 and sepsis in 28 (24%) and 52 (56.1%) patients at days 3 and 7 respectively. The 28- and 90-day survivals were 62% and 51% respectively. A hypocoagulable TEG at baseline was a predictor of bleeding (hazard ratio [HR] 2.1; CI 1.6-4.9; P=0.050) and mortality (HR 1.9; CI 1.3-7.9; P=0.043). ACLF patients had increased Factor VIII, vWF, tissue factor levels and tissue plasminogen activator (tPA) activity with reduced protein C and ATIII. Coagulation parameters like Coagulation Index (HR 2.1; CI 1.1-4.5; P=0.044),clot lysis (HR 3.2; CI 1.9-3.4; P=0.033), low protein C<30% (HR 2.1; CI 1.5-2.8; P=0.017), ATIII (HR 1.4; CI 1.7-3.1; P=0.052) and tPA (HR 1.5; CI 1.1-2.4; P=0.052) were predictors of mortality at day 28. Protein C activity <30% (HR 1.3; CI 1.0-2.9; P=0.042) and tPA >20ng/mL (HR 1.2; CI 1.1-2.1; P=0.040) predicted mortality when adjusted for age, gender and baseline MELD. Dynamic coagulation derangements, measured by TEG, determine the likelihood of bleeding and mortality in ACLF.

Prevalence and short-term mortality of acute-on-chronic liver failure: A national cohort study from the USA

Acute-on-chronic liver failure (ACLF) is characterised by the presence of organ failure in patients with decompensated cirrhosis and is associated with high short-term mortality. However, there are limited data on the prevalence and short-term outcomes of ACLF in patients with cirrhosis seen in the US. We aimed to study the prevalence and risk factors associated with the development and short term mortality in a large cohort of patients in the US. Using the US Department of Veterans Affairs (VA) Corporate Data Warehouse, we identified patients with ACLF during hospitalisation for decompensated cirrhosis at any of the 127 VA hospitals between January 1, 2004, and December 31, 2014. We examined the prevalence of ACLF and variables associated with 28- and 90-day mortality in ACLF, and trends in prevalence and survival over time. Of 72,316 patients hospitalised for decompensated cirrhosis, 19,082 (26.4%) patients met the criteria of ACLF on admission. Of these, 12.8% had 1, 10.1% had 2, and 3.5% had 3 or more organ failures. Overall, 25.5% and 40.0% of ACLF patients died within 28 days and 90 days of admission, respectively. Older age, White race, liver cancer, higher model for end-stage liver disease sodium corrected score, and non-liver transplant centre were associated with increased risk of death in ACLF. Over the study period, the prevalence of ACLF decreased, and all grades but ACLF-3 had improvement in survival. In a US cohort of hospitalised patients with decompensated cirrhosis, ACLF was common and associated with high short-term mortality. Over a decade, ACLF prevalence decreased but survival improvement of ACLF-3 was not seen. Early recognition and aggressive management including timely referral to transplant centres may lead to improved outcomes in ACLF. Acute-on-chronic liver failure (ACLF) is a condition marked by multiple organ failures in patients with cirrhosis and associated with a high risk of death. In this study of US patients hospitalised with cirrhosis, 1 in 4 patients developed ACLF. In total, 25% of patients with ACLF died within 1 month and 40% died within 3 months. Thus, early recognition of ACLF is important for the initiation of aggressive management, which is required to save these patients' lives.

Serum Urea at Admission Is a Predictor of Mortality in Patients With Acute on Chronic Liver Failure

Introduction: Occurrence of acute kidney injury [AKI] in Acute on chronic liver failure (ACLF) negatively impacts their survival. Only elevated serum creatinine is used to assess AKI and predict survival in ACLF. There is little data on impact of serum urea on outcome; serum urea values are ignored for prognostication. We performed a prospective study to evaluate the impact of serum urea on survival in ACLF. Methods: This study was conducted in ACLF patients hospitalised in Gastroenterology Department of SCB Medical College in India from October 2016 to March 2018. Demographic, clinical, laboratory parameters were recorded and outcome compared in patients with special reference to admission serum urea level. Results: Consecutive decompensated cirrhosis (DC) patients (n=439) were screened for ACLF as per The Asian Pacific Association for the Study of the Liver (APASL) criteria. 113 (25.7%) of them had ACLF. Out of the 113 ACLF cases, 78 (69%) had AKI as per AKIN (Acute Kidney Injury Network) criteria. Alcohol was the commonest underlying cause of CLD (74.3%) and continued alcohol intake (61%) was the commonest precipitant of ACLF. On multivariate analysis, admission serum urea (not serum creatinine) was found to be an independent predictor of mortality in ACLF both at 28 days; p=.001, AHR 1.014(1.006-1.023) and 90 days; p<.001, AHR 1.016(1.008-1.024) and also in ACLF patients with AKI, both at 28 days; p=0.002, AHR 1.014 (1.005-1.023) and 90 days; p=.001, AHR 1.016 (1.007-1.025). The discrimination ability between survivors and deceased is higher with serum urea [AUROC 28 days; 0.772 (0.686-0.859), 90 days; 0.780(0.695-0.866); 95% CI] than with serum creatinine [AUROC 28 days; 0.760(0.669-0.850), 90 days; 0.768(0.680-0.856); 95% CI]. Conclusion: In our institution, about one fourth of decompensated cirrhotic patients had ACLF, and more than two thirds of them were associated with AKI. Admission serum urea was found to be a better predictor of mortality than serum creatinine. Hence serum creatinine can be replaced by serum urea as a better predictor of mortality [both 28 and 90 days' mortality] in ACLF patients.