Tri-typing of hepatitis B-related acute-on-chronic liver failure defined by the World Gastroenterology Organization.

BACKGROUND AND AIM: Tri-typing of acute-on-chronic liver failure (ACLF), as proposed by the World Gastroenterology Organization (WGO), has not been validated in patients infected with hepatitis B virus (HBV). We aim to compare the three types of ACLF patients in clinic characteristics. METHODS: Hospitalized ACLF patients with chronic hepatitis B from five hepatology centers were retrospectively selected and grouped according to the WGO classification. For each group, we investigated laboratory tests, precipitating events, organ failure, and clinical outcome. RESULTS: Compared with type-B (n = 262, compensated cirrhosis) and type-C (n = 129, decompensated cirrhosis) ACLF, type-A patients (n = 195, non-cirrhosis) were associated with a younger age, the highest platelet counts, the highest aminotransferase levels, and the most active HBV replications. HBV reactivation were more predominant in type-A, while bacterial infections in type-B and type-C ACLF cases. Liver failure (97.4%) and coagulation failure (86.7%) were most common in type-A compared with type-B or type-C ACLF patients. Kidney failure was predominantly identified in type-C subjects (41.9%) and was highest (23/38, 60.5%) in grade 1 ACLF patients. Furthermore, type-C ACLF showed the highest 28-day (65.2%) and 90-day (75.3%) mortalities, compared with type-A (48.7% and 54.4%, respectively) and type-B (48.4% and 62.8%, respectively) ACLF cases. Compared with type-A (11.7%) ACLF patients, the increased mortality from 28 to 90 days was higher in type-B (31.6%) and type-C (37.5%). CONCLUSION: Tri-typing of HBV-related ACLF in accordance with the WGO definition was able to distinguish clinical characteristics, including precipitating events, organ failure, and short-term prognosis in ACLF patients.

The Use of NACSELD and EASL-CLIF Classification Systems of ACLF in the Prediction of Prognosis in Hospitalized Patients With Cirrhosis.

INTRODUCTION: Acute-on-chronic liver failure (ACLF) is defined by the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) consortium and the North American Consortium for the Study of End-Stage Liver Disease (NACSELD) as an acute deterioration of cirrhosis with multiple organ failures and high short-term mortality. However, their diagnostic criteria differ. We aimed to compare these 2 criteria in the prediction of prognosis in hospitalized cirrhosis. METHODS: This was a prospective study of nonelectively hospitalized patients with cirrhosis (N = 468) from a single tertiary hospital between 2016 and 2018. Baseline characteristics, incidence, and types of organ failure and survival data at 7, 28, and 90 days were collected. Prognostic utilities of the 2 criteria were compared. RESULTS: One hundred thirty-seven of 468 patients (29.3%) had EASL-CLIF ACLF, and 35 of 468 (7.4%) had NACSELD ACLF. The 28-day transplant-free survival of ACLF was 58.4% using EASL-CLIF and 37.1% using the NACSELD criteria. In predicting 28-day mortality, the NACSELD criteria demonstrated significantly higher overall accuracy (92.0% vs 85.3%, P < 0.01), specificity (99.7% vs 84.0%, P < 0.001), and positive predictive value (97.1% vs 50.4%, P < 0.001) but lower sensitivity (49.3% vs 92.5%, P < 0.001) and negative predictive value (91.6% vs 98.5%, P < 0.001) than those of EASL-CLIF. The results were similar in predicting 7-day outcome. However, the overall accuracy became similar between NACSELD and EASL-CLIF ACLF criteria in predicting 90-day mortality (86.3% vs 88.7%, P = 0.27) because of the decrease of sensitivity and negative predictive value of NACSELD ACLF criteria. The prognostic performance of these 2 ACLF criteria was similar when applied to patients with or without hepatitis B virus infection as an etiology of cirrhosis. DISCUSSION: There are both caveats and utilities of NACSELD and EASL-CLIF ACLF criteria in prognosis prediction in patients with cirrhosis. NACSED criteria is highly accurate in predicting morality, whereas the EASL-CLIF criteria is more sensitive to identify patients who would benefit from liver transplantation.

[A new perspective on acute-on-chronic liver failure based on clinical outcome of dynamic classification criteria].

Objective: To analyze the clinical characteristics among types of acute-on-chronic liver failure (ACLF) and explore the new classification criteria for judging the prognosis of acute-on-chronic liver failure, so as to provide a basis for the formulation of more precise therapeutic schedule. Methods: 388 cases with ACLF diagnosed in two tertiary level hospitals were included. Patients demographic characteristics, clinical examination information, diagnostic and treatment process information were collected. Laboratory examination data of day 1, 3, 7, 14, 21, 28 and of week 12 or prior to discharge after improvement and at 24 h prior to liver transplantation or death from the diagnosis of ACLF were collected. According to the change trend of the patient's prothrombin activity (PTA), the changes within 4 weeks and 12 weeks were divided into: increased to > 40 %, increase but still ≤ 40%, progressively decreasing or not continuously rising. Moreover, the change trend of total bilirubin (TBil) was divided into: decreasing degree≥50%, decreasing degree < 50%, progressively increasing or not decreasing. Patients meeting the requirements of dynamic classification were screened. PTA and TBil variation tendency of each patient at week 4 and 12 was synthesized, and prognostic condition for dynamic classification was formulated. The clinical characteristics of ACLF patients were analyzed by χ (2) test. Results: A total of 262 screened cases were enrolled. At the 4th week of the course of disease, 45% of the patients' PTA had increased to > 40%, and 40.8% of the patients' TBIL had decreased by 50%. When the course of disease was progressed to 12 weeks, 65.3% of the patients' PTA had increased to > 40%, and 63.4% of the patients' TBIL had decreased by 50%. Combined with the prognosis of the patients at the 4th and 12th week, the patients' disease evolution process was divided into five types: Type A: 60 cases (22.9%) of rapid progression; Type B: 82 cases (31.3%) of rapid recovery; Type C: 48 cases (18.3%) of slow progression; Type D: 43 cases (16.4%) of slow recovering; Type E: 29 cases (11.1%) of slow persistence. The proportions of patients with rapid progression combined with upper gastrointestinal hemorrhage, hepatic encephalopathy, and acute renal injury were 16.7%, 33.3%, and 33.3%, respectively; while the above-mentioned complications accounted for 3.7%, 7.3%, and 12.2% only in the rapid recovery type, χ (2) = 14.411, 20.060, 12.140, P < 0.05, and the differences were statistically significant. Fungal infection rates were 21.7%, and 10.4% in patients who died of disease or liver transplantation (i.e., patients with rapid progression and slow-progressing types), respectively, and 1.2%, 14%, and 6.9% in patients with rapid progression type, slow-recovering type, and slow persistence type, respectively, and the difference between the rapid progression type and the rapid recovery type was significant, χ (2) = 18.925, and the difference was statistically significant (P < 0.05). Conclusion: The course of disease progression in ACLF patients can be divided into rapid progression type, rapid recovery type, slow progression type, slow recovering type, and slow persistence type. The basis of liver disease, accompanied with fungal infection, gastrointestinal hemorrhage, hepatic encephalopathy and acute renal injury can affect the development of ACLF.

Evaluating the best empirical antibiotic therapy in patients with acute-on-chronic liver failure and spontaneous bacterial peritonitis.

BACKGROUND/AIMS: Spontaneous bacterial peritonitis (SBP) is a life-threatening complication of advanced cirrhosis. By studying the susceptibility of isolated organisms and analyzing empirical antibiotic therapy combined with clinical outcomes, we aimed to find an improved empirical antibiotic therapy by considering the individual acute-on-chronic liver failure (ACLF) grade for patients with or without sepsis. METHODS: Clinical outcomes of 182 patients were assessed retrospectively with multivariable regression analysis. Each of the 223 isolates was individually evaluated regarding susceptibility results and intrinsic resistances. RESULTS: Piperacillin/tazobactam had the highest antimicrobial susceptibility among monotherapies/fixed combinations, which was significantly lower than combination therapies such as meropenem-linezolid (75.3% vs. 98.5%, P < 0.001). The sensitivity of pathogens to empirical antibiotic therapy correlated with significantly lower inpatient mortality (18.9% vs. 37.0%, P = 0.018), shorter inpatient stay (16.3 ±â€¯10.2 vs. 26.4 ±â€¯21.0 days, P = 0.053) and shorter intensive care treatment (2.1 ±â€¯4.5 vs. 7.9 ±â€¯15.4 days, P = 0.016). The largest difference of mortality was observed in patients with ACLF grade 3 (54.5% vs. 73.1% [sensitive vs. non-sensitive]). CONCLUSION: All SBP patients benefited from efficient empirical antibiotic therapy, regarding the reduced inpatient mortality and complications. For SBP patients with ACLF grade 3 without sepsis, the combination therapy with meropenem-linezolid may be suitable considering the susceptibility results and the concentration in the peritoneal cavity.

Validation of CLIF-C ACLF score to define a threshold for futility of intensive care support for patients with acute-on-chronic liver failure.

BACKGROUND: Acute-on-chronic liver failure (ACLF) is a severe complication of cirrhosis and is defined by organ failure and high rates of short-term mortality. Patients with ACLF are managed with multiorgan support in the intensive care unit (ICU). Currently, it is unclear when this supportive care becomes futile, particularly in patients who are not candidates for liver transplant. The aim of this study was to determine whether the currently available prognostic scores can identify patients with ACLF in whom prolonged ICU care is likely to be futile despite maximal treatment efforts. METHODS: Data of 202 consecutive patients with ACLF admitted to the ICU at the Royal Free Hospital London between 2005 and 2012 were retrospectively analyzed. Prognostic scores for chronic liver diseases, such as Child-Pugh, Model for End-Stage Liver Disease (MELD), European Foundation for the study of chronic liver failure (CLIF-C) organ failure (OF), and CLIF-C ACLF, were calculated 48 hours after ICU admission and correlated with patient outcome after 28 days. RESULTS: The CLIF-C ACLF score, compared with all other scores, most accurately predicted 28-day mortality, with an area under the receiver operator characteristic of 0.8 (CLIF-C OF, 0.75; MELD, 0.68; Child-Pugh, 0.66). A CLIF-C ACLF score cutoff ≥ 70 identified patients with a 100% mortality within 28 days. These patients had elevated inflammatory parameters representing a systemic inflammatory response, most often renal failure, compared with patients below this cutoff. CONCLUSIONS: Patients with ACLF and high CLIF-C ACLF score (≥ 70) after 48 hours of intensive care may reach a threshold of futility for further ongoing intensive support. The best treatment options in this scenario remain to be determined but may include palliative care.

[Acute-on-chronic liver failure].

Acute-on-chronic liver failure (ACLF) is a clinical syndrome characterized by acute decompensation of liver cirrhosis, organ failure and high short-term mortality (20-80% at one month). The main precipitants are infections and excessive alcohol intake, and the mechanistic features include a high level of systemic inflammation, macrophage activation and liver injury. The severity of ACLF is graded according to the number and extent of organ failures. Prognostic scores help predict mortality and support decisions on intensive treatment or futility.

Molecular Adsorbent Recirculating System Can Reduce Short-Term Mortality Among Patients With Acute-on-Chronic Liver Failure-A Retrospective Analysis.

OBJECTIVES: Acute-on-chronic liver failure is associated with numerous consecutive organ failures and a high short-term mortality rate. Molecular adsorbent recirculating system therapy has demonstrated beneficial effects on the distinct symptoms, but the associated mortality data remain controversial. DESIGN: Retrospective analysis of acute-on-chronic liver failure patients receiving either standard medical treatment or standard medical treatment and molecular adsorbent recirculating system. Secondary analysis of data from the prospective randomized Recompensation of Exacerbated Liver Insufficiency with Hyperbilirubinemia and/or Encephalopathy and/or Renal Failure trial by applying the recently introduced Chronic Liver Failure-criteria. SETTING: Medical Departments of University Hospital Muenster (Germany). PATIENTS: This analysis was conducted in two parts. First, 101 patients with acute-on-chronic liver failure grades 1-3 and Chronic Liver Failure-C-Organ Failure liver subscore equals to 3 but stable pulmonary function were identified and received either standard medical treatment (standard medical treatment, n = 54) or standard medical treatment and molecular adsorbent recirculating system (n = 47) at the University Hospital Muenster. Second, the results of this retrospective analysis were tested against the Recompensation of Exacerbated Liver Insufficiency with Hyperbilirubinemia and/or Encephalopathy and/or Renal Failure trial. INTERVENTIONS: Standard medical treatment and molecular adsorbent recirculating system. MEASUREMENTS AND MAIN RESULTS: Additionally to improved laboratory variables (bilirubin and creatinine), the short-term mortality (up to day 14) of the molecular adsorbent recirculating system group was significantly reduced compared with standard medical treatment. A reduced 14-day mortality rate was observed in the molecular adsorbent recirculating system group (9.5% vs 50.0% with standard medical treatment; p = 0.004), especially in patients with multiple organ failure (acute-on-chronic liver failure grade 2-3). Concerning the affected organ system, this effect of molecular adsorbent recirculating system on mortality was particularly evident among patients with increased kidney, brain, or coagulation Chronic Liver Failure-C-Organ Failure subscores. Subsequent reanalysis of the Recompensation of Exacerbated Liver Insufficiency with Hyperbilirubinemia and/or Encephalopathy and/or Renal Failure dataset with adoption of the Chronic Liver Failure-classification resulted in similar findings. CONCLUSIONS: Molecular adsorbent recirculating system treatment was associated with an improved short-term survival of patients with acute-on-chronic liver failure and multiple organ failure. Among these high-risk patients, molecular adsorbent recirculating system treatment might bridge to liver recovery or liver transplantation.

Liver transplantation in the most severely ill cirrhotic patients: A multicenter study in acute-on-chronic liver failure grade 3.

BACKGROUND & AIMS: Liver transplantation (LT) for the most severely ill patients with cirrhosis, with multiple organ dysfunction (accurately assessed by the acute-on-chronic liver failure [ACLF] classification) remains controversial. We aimed to report the results of LT in patients with ACLF grade 3 and to compare these patients to non-transplanted patients with cirrhosis and multiple organ dysfunction as well as to patients transplanted with lower ACLF grade. METHODS: All patients with ACLF-3 transplanted in three liver intensive care units (ICUs) were retrospectively included. Each patient with ACLF-3 was matched to a) non-transplanted patients hospitalized in the ICU with multiple organ dysfunction, or b) control patients transplanted with each of the lower ACLF grades (three groups). RESULTS: Seventy-three patients were included. These severely ill patients were transplanted following management to stabilize their condition with a median of nine days after admission (progression of mean organ failure from 4.03 to 3.67, p=0.009). One-year survival of transplanted patients with ACLF-3 was higher than that of non-transplanted controls: 83.9 vs. 7.9%, p<0.0001. This high survival rate was not different from that of matched control patients with no ACLF (90%), ACLF-1 (82.3%) or ACLF-2 (86.2%). However, a higher rate of complications was observed (100 vs. 51.2 vs. 76.5 vs. 74.3%, respectively), with a longer hospital stay. The notion of a "transplantation window" is discussed. CONCLUSIONS: LT strongly influences the survival of patients with cirrhosis and ACLF-3 with a 1-year survival similar to that of patients with a lower grade of ACLF. A rapid decision-making process is needed because of the short "transplantation window" suggesting that patients with ACLF-3 should be rapidly referred to a specific liver ICU. Lay summary: Liver transplantation improves survival of patients with very severe cirrhosis. These patients must be carefully monitored and managed in a specialized unit. The decision to transplant a patient must be quick to avoid a high risk of mortality.

Reviewing the diagnostic criteria for acute-on-chronic liver failure.

INTRODUCTION: For over 20 years, acute-on-chronic liver failure (ACLF) has taken multiple definitions and/or classifications. The definition outlines the acute and chronic insults to include a homogenous patient group with liver failure and an expected outcome in a specific time frame. Early and accurate diagnosis is essential as this inflammation of the liver may tilt the balance of liver destruction and regeneration adversely. Various factors such as superadded systemic sepsis, liver reserve, cause of primary chronic liver disease, state of immune system or the state of gut microbial flora might determine the ultimate prognosis. Areas covered: To date, there has been no universally accepted definition of ACLF. In this review, we discuss the strengths and weaknesses, controversies and basis for early identification and accurate diagnosis of ACLF. PubMed and Google scholar database searches were conducted, search terms included 'acute on chronic liver failure,' 'ACLF,' and 'diagnostic criteria.' Expert commentary: With recent advances in the management of advanced cirrhosis, research will gradually shift towards ACLF in the near future, focusing on the pathogenesis, new treatment options and improving survival. Once we improve understanding of this syndrome, newer definitions will evolve, thereby enabling earlier diagnosis and novel therapeutic avenues.

[Acute-on-chronic liver failure - new Definition of a complex clinical picture]. / Akut-auf-chronisches Leberversagen: Neue Definition eines komplexen Krankheitsbildes.

Acute-on-chronic liver failure (ACLF) is characterized by a sudden onset of decompensation in patients with preexisting liver disease followed by subsequent organ failure and high short-term mortality. ACLF is extremely heterogeneous in terms of predisposing stage of liver disease, precipitating events, and the course of organ failure and has been defined differently by different medical associations in the East and in the West. A recent consensus working definition is the basis for further research in order to understand underlying pathophysiological mechanisms, to establish diagnostic and prognostic biomarkers, and to implement risk-adapted treatment strategies.

Acute kidney injury and acute-on-chronic liver failure classifications in prognosis assessment of patients with acute decompensation of cirrhosis.

OBJECTIVE: Prognostic stratification of patients with cirrhosis is common clinical practice. This study compares the prognostic accuracy (28-day and 90-day transplant-free mortality) of the acute-on-chronic liver failure (ACLF) classification (no ACLF, ACLF grades 1, 2 and 3) with that of acute kidney injury (AKI) classification (no AKI, AKI stages 1, 2 and 3). DESIGN: The study was performed in 510 patients with an acute decompensation of cirrhosis previously included in the European Association for the Study of the Liver-Chronic Liver Failure consortium CANONIC study. ACLF was evaluated at enrollment and 48 h after enrollment, and AKI was evaluated at 48 h according to Acute Kidney Injury Network criteria. RESULTS: 240 patients (47.1%) met the criteria of ACLF at enrollment, while 98 patients (19.2%) developed AKI. The presence of ACLF and AKI was strongly associated with mortality. 28-day transplant-free mortality and 90-day transplant-free mortality of patients with ACLF (32% and 49.8%, respectively) were significantly higher with respect to those of patients without ACLF (6.2% and 16.4%, respectively; both p<0.001). Corresponding values in patients with and without AKI were 46% and 59%, and 12% and 25.6%, respectively (p<0.0001 for both). ACLF classification was more accurate than AKI classification in predicting 90-day mortality (area under the receiving operating characteristic curve=0.72 vs 0.62; p<0.0001) in the whole series of patients. Moreover, assessment of ACLF classification at 48 h had significantly better prognostic accuracy compared with that of both AKI classification and ACLF classification at enrollment. CONCLUSIONS: ACLF stratification is more accurate than AKI stratification in the prediction of short-term mortality in patients with acute decompensation of cirrhosis.

Increased delayed mortality in patients with acute-on-chronic liver failure who have prior decompensation.

BACKGROUND AND AIM: Patients with acute-on-chronic liver failure (ACLF) represent a complex population with differential prognosis. The aim of the study was to categorize ACLF according to the severity of underlying chronic liver diseases. METHODS: A total of 540 ACLF patients were recruited, including 127 with prior decompensated cirrhosis and 413 without prior decompensation (PD) including 193 with underlying chronic hepatitis and 220 with prior compensated cirrhosis. The clinical characteristics and prognosis of subgroups were compared. Cox proportional hazard model and multinominal logistic regression analysis were performed to identify significant prognostic parameters. RESULTS: The 28-day, 3-month and 1-year survival of ACLF patients with or without PD were 58.9% versus 61.4%, 36.2 versus 52.5%, and 29.1% versus 49.6%, respectively. On multinominal logistic regression analysis or time-to-death analysis by Cox proportional hazard model, PD was significantly associated with post-28-day mortality but not within-28-day mortality. On multivariate time-to-death analysis, older age, high international normalized ratio (INR) and serum bilirubin, low levels of serum sodium and platelet count, and presence of hepatic encephalopathy (HE), upper gastrointestinal bleeding, and respiratory or circulation dysfunction were predictors of within-28-day mortality in patients without PD, whereas the risk factors in patients with PD were high INR, creatinine, presence of HE, and respiratory or circulation dysfunction. CONCLUSION: ACLF patients with or without PD had comparable short-term prognosis but differential 1-year mortality. ACLF patients with PD were distinct from those without PD in age, types of acute insults, severity of hepatic damage, and distribution of complications, and the former group was characterized by increased delayed mortality.

Acute liver failure and transplantation in children.

Acute liver failure (ALF) was relatively easy to recognise in the days before liver transplantation became available as rescue therapy, because the diagnosis was based on end-stage disease manifestations such as profound coagulopathy, jaundice, encephalopathy and cerebral oedema (in a patient with no history of chronic liver disease). These criteria no longer help us in an era in which we struggle to define which patients are going to progress to this end-stage picture in the time necessary for evaluation and listing for life-saving transplantation. Ideally, identifying which patients will recover spontaneously or with appropriate treatment would relieve the justifiable concern that some patients receive a transplant when, given time, they would have recovered. Currently, the data to guide us in avoiding death without transplantation and unnecessary transplantation remain elusive.