Foreword:
The "Acute-on-Chronic Liver Failure (ACLF) Monthly Review" is a scholarly column produced by the Chinese Acute-on-Chronic Liver Failure Consortium at the invitation of the editorial department of the journal Liver International. Each month, the column focuses on a specific area of ACLF to disseminate knowledge about the concept and significance of ACLF and to help readers stay updated on recent developments in the field. The aim is to benefit both liver disease specialists and researchers interested in field hotspots, as well as frontline clinical practitioners in need of practical knowledge.
In July 2023, Liver International invited Professor Ruben Hernaez from the USA, Professor Richard Moreau from France, and Professor Hai Li from China to publish a review titled “Definition, diagnosis, and epidemiology of acute-on-chronic liver failure” (Liver Int. 2023 Jul 9), which presents perspectives on the definition and diagnostic standards of ACLF from Asia, Europe, and North America. This month’s review focuses on the Eastern scholars’ understanding of ACLF as discussed in the review. Additionally, a brief review of significant ACLF-related literature updated on PubMed from March 21, 2024, to April 20, 2024, will be provided.
About the Authors:
The Chinese Acute-on-Chronic Liver Failure Consortium (Ch-CLIF-C) was initiated by Professor Hai Li from the Department of Gastroenterology at Renji Hospital, affiliated with Shanghai Jiao Tong University School of Medicine. It includes 15 top-tier hospitals’ infection and liver disease centers across China. The consortium is dedicated to exploring the pathogenesis of ACLF and establishing diagnostic criteria based on a high level of evidence for ACLF in regions with a high prevalence of hepatitis B. Currently, the team is conducting “CATCH LIFE” (Chinese AcuTe-on-CHronic LIver FailurE), the largest reported prospective multicenter cohort study on ACLF globally, which includes two major cohorts (an exploratory cohort with 2600 enrollees and a validation cohort with 1370 enrollees).
Editor-in-Chief for this Issue:
Dr. Hai Li is a Professor, doctoral supervisor, and the Chief Physician of the Department of Gastroenterology at Renji Hospital, affiliated with Shanghai Jiao Tong University School of Medicine. He is also a researcher at the Shanghai Institute of Digestive Disease and the Deputy Director of the Ministry of Health’s Key Laboratory of Digestive Diseases (Shanghai Jiao Tong University). As the leader of the Chinese Acute-on-Chronic Liver Failure Consortium (Chinese CLIF Consortium), he has spearheaded a multicenter study on the natural course of acute-on-chronic liver failure (CATCH-LIFE Study) across 15 top-tier hospitals in China, completing the prospective enrollment of an investigation cohort of 2600 cases and a validation cohort of 1370 cases. Currently, he also holds academic positions such as a member of the Severe Liver Disease Collaborative Group of the Chinese Medical Association and a member of the Evidence-Based Medicine Branch of the Chinese Medical Doctor Association.
Editorial by Zixuan Shen
PhD candidate under the supervision of Professor Hai Li in the Department of Gastroenterology at Renji Hospital, affiliated with Shanghai Jiao Tong University School of Medicine. Her research focuses on the clinical characteristics and early prediction of acute-on-chronic liver failure (ACLF). Her main responsibilities involve cleaning, verifying, and analyzing data from the CATCH-LIFE cohort.
Thematic Review
The concept of Acute-on-Chronic Liver Failure (ACLF) was first introduced in 1997 to describe hemodynamic changes following large-volume plasma exchange. In 2009, the Asian Pacific Association for the Study of the Liver (APASL) published the first consensus on ACLF. Subsequently, the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) and the North American Consortium for End-Stage Liver Disease (NACSELD) also provided their definitions. However, global consensus on ACLF diagnostic criteria has not been reached, and there are significant regional differences in perspectives. These differences mainly reflect the different stages of the ACLF disease process depicted in three main diagnostic criteria (Figure 1). This article will discuss the Eastern perspective on ACLF definitions and compare the differences between Eastern and Western ACLF diagnostic standards.
Evolution of APASL’s Diagnostic Criteria
In 2009, APASL first issued a consensus defining ACLF as liver failure manifested by jaundice (TB≥5 mg/dL) and coagulation dysfunction (INR>1.5 or prothrombin activity <40%) in patients with chronic liver disease, accompanied by ascites and/or hepatic encephalopathy within four weeks. APASL updated the definition of ACLF in 2014 and again in 2019. The 2014 definition emphasized the high mortality rate within 28 days for ACLF patients and added bacterial infection as a factor of acute injury. In 2019, APASL included vascular liver diseases such as portal vein thrombosis in the list of acute injuries.
According to APASL, liver failure is the only form of organ failure in the diagnostic criteria. Patients with non-cirrhotic or cirrhotic chronic liver disease (CLD) who develop liver failure following an acute injury are defined as ACLF. However, cirrhotic patients who develop complications after an acute injury, including gastrointestinal bleeding, ascites, sepsis, hepatic encephalopathy, and hepatorenal syndrome, are considered by APASL to have decompensated cirrhosis, not ACLF.
APASL’s criteria focus on liver damage, considering acute liver injury as the cause of liver failure, leading to subsequent extrahepatic organ failure. In APASL’s definition, extrahepatic organ failures are seen as complications of liver failure. As the number of dysfunctional or failing organs increases, mortality accumulates. From APASL’s perspective, Western criteria require failure of two organs or single non-hepatic organ failure (like renal failure), which is too late, contradicting the early identification of ACLF.
APASL’s criteria are relatively straightforward, facilitating the rapid identification of early, reversible ACLF in resource-limited settings. However, the patients identified by APASL represent a broad and heterogeneous group with mortalities ranging from 10% to 80%, thus not aiding clinicians in adapting treatment strategies according to different mortality rates.
Mechanism of ACLF in Hepatitis B Patients
Research on hepatitis B patients has corroborated that in patients with HBV reactivation, liver failure occurs before extrahepatic organ failure, supporting APASL’s understanding of the ACLF concept. In hepatitis B patients carrying the susceptible genotype rs3129859C and HLA-DRB1*12:02, reactivation of HBV can induce rapid proliferation of CD4+ T cells specific to the HBV core, producing significant amounts of TNF-α, which leads to hepatocellular necrosis. Extensive hepatocyte necrosis is a key histological feature of hepatitis B-related cirrhosis ACLF, triggering the release of numerous damage-associated molecular patterns (DAMPs). This enhances the innate immune response, causing systemic inflammation, ultimately leading to extrahepatic organ failure. Therefore, from APASL’s perspective, choosing isolated liver failure as a diagnostic criterion allows for the early identification of ACLF and excludes patients with cirrhosis who suffer from renal or circulatory failure caused by septic shock or hypovolemic shock due to esophageal-gastric variceal bleeding.
While the definition of ACLF is relatively clear in Asia, the diagnostic criteria for “liver failure” are still debated, with currently five definitions: APASL’s criteria (TB≥5 mg/dL and INR≥1.5), Japan’s criteria (TB ≥12 mg/dL or INR >2.5), China’s COSSH criteria (TB≥12 mg/dL and INR ≥1.5), the Chinese Medical Association’s criteria (TB ≥10 mg/dL and INR ≥1.5), and China’s CATCH-LIFE criteria (TB >18 mg/dL or INR >2). Although these standards vary, ACLF being associated with a greater than 15% 28-day mortality rate without transplantation is a global consensus. In APASL studies, the 28-day mortality rate for grade 1 ACLF patients is 12.7%, below the 15% threshold, indicating that APASL’s threshold might be set too low. Thus, groups like the Chinese Medical Association and COSSH opt for stricter liver failure criteria. To obtain a cutoff based on the 28-day transplantation-free mortality rate, the CATCH-LIFE study surveyed 3790 patients with cirrhotic and non-cirrhotic CLD, using multivariate Cox proportional hazard models to derive critical values for liver failure from TB (isolated TB >18 mg/dL) and coagulation failure from INR (isolated INR >2).
What about other organ failures? Some researchers in Asia use both hepatic and extrahepatic organ failure criteria to diagnose ACLF. For example, COSSH combines APASL and EASL-CLIF criteria, incorporating patients with chronic hepatitis B who have TB≥12 mg/dL and INR≥1.5 into EASL-CLIF’s criteria. COSSH’s diagnostic criteria address the shortcomings of EASL-CLIF’s criteria in diagnosing HBV patients and are applicable to a broader patient population.
The APASL cohort includes only patients who meet the APASL-ACLF criteria, hence it does not capture the overall incidence of ACLF. In contrast, 14 cohorts from Asia using various definitions provide data supporting the disease burden of ACLF in the East, including China (7037 cases), South Korea (1470 cases), India (1053 cases), Thailand (706 cases), and Japan (501 cases).
In three research cohorts, the prevalence of APASL-ACLF among hospital patients with cirrhotic or non-cirrhotic liver disease is 14.6% (713/4876), ranging from 9.5% to 26.2%, with prevalence rates using other definitions (Chinese and Japanese standards) being 19.8% (226/1144) and 36.5% (183/501) respectively. These figures represent the prevalence of ACLF diagnosed based on liver failure.
Additionally, multi-organ failure ACLF diagnostic criteria including EASL-CLIF, NACSELD, and COSSH are widely applied in Asia. The prevalence of EASL-ACLF and NACSELD-ACLF among hospital patients with cirrhosis is 25.3% (1308/5167) and 7.5% (35/468) respectively. The prevalence of COSSH-ACLF in non-cirrhotic or cirrhotic CLD patients is 29.6% (391/1322).
In the five cohorts including APASL, HBV (55.0%) and alcohol (29.3%) are the most common causes of ACLF. The cause varies by country, with alcohol being most common in South Korea (82.1%, 78/95) and India (70.4%, 247/351), while HBV is predominant in China (89.0%, 3469/3897) and Thailand (38.2%, 131/343).
In HBV-related ACLF patients, regardless of the definition used, liver failure is the predominant form of organ failure. In four Chinese cohorts using different standards to diagnose HBV-related ACLF, the proportion of liver failure is 80.9% in APASL-ACLF, 77.7% in EASL-ACLF, and 94.1% in COSSH-ACLF. In patients with alcohol-related EASL-ACLF, renal failure is the most common organ failure (70.2%, 379/540). However, APASL criteria may fail to identify these patients as its definition does not include extrahepatic failures.
Summary
Despite the lack of global consensus on the diagnostic criteria for Acute-on-Chronic Liver Failure (ACLF), there is a universal recognition that ACLF is a clinical syndrome associated with high short-term mortality and multi-organ failure. All definitions aim to rapidly identify high-risk patients in a clinical setting to facilitate timely treatment.
Each definition has its strengths and limitations. For researchers, the EASL-CLIF criteria provide an opportunity to test various hypotheses because they offer more detailed data and define a clear patient group—those with acutely decompensated cirrhosis. Conversely, if there is a need to quickly identify patients at high risk of poor outcomes, the NACSELD criteria provide a method for doing so. APASL’s criteria facilitate the early identification of reversible ACLF, giving clinicians the opportunity to intervene.
Recent Monthly ACLF Research Overview and Brief Review
From March 21, 2024, to April 20, 2024, a total of 12 reviews/commentaries and articles related to ACLF were updated on PubMed, covering aspects such as etiology, diagnosis, pathogenesis, treatment, and prognosis predictions.
01
Fernández J, Lozano M, Torres M, et al. Effect of plasma exchange with albumin replacement on albumin functionality and organ dysfunction in acute-on-chronic liver failure. JHEP Rep. 2024 Jan 22;6(4):101017.
Brief Description: This study was a phase II prospective, open-label, uncontrolled clinical trial conducted at a single center, involving ten adult patients. It aimed to validate the effectiveness and safety of plasma exchange with 5% albumin replacement (PE-A5%) in treating patients with ACLF. Patients underwent six sessions of PE-A5% treatment over ten days and were followed up for assessments of albumin functionality and various organ functions. The results showed significant improvements in patients’ albumin levels and functionality, including binding capacity and antioxidative properties. Additionally, systemic hemodynamics, renal, cerebral, and liver functions showed marked improvements post-treatment. PE-A5% also ameliorated some inflammatory parameters and was proven safe and tolerable for ACLF patients. The research team considers PE-A5% a promising strategy for treating ACLF, especially in situations where liver transplantation is not available due to organ unavailability.
Brief Review: This study explored a relatively new treatment approach—improving albumin functionality and organ dysfunction through PE-A5%. This method may offer a new treatment option for critically ill patients in the field of ACLF treatment, particularly for those for whom traditional treatments are ineffective. As a phase II, prospective, open-label, uncontrolled clinical trial, the study had a clear objective and a reasonable design. The detailed documentation of the treatment’s specific effects on albumin functionality and multi-organ function over a short period provides a foundation for further large-scale studies. Although the study had a small sample size and was not randomized, which limits the statistical power and general applicability of the results, it is commendable as exploratory work for future phase III clinical studies. If these preliminary findings are validated in larger, randomized controlled trials, PE-A5% could become an effective strategy for treating ACLF.
02
Song DS, Kim HY, Jung YK, et al. Dynamic Assessment of Modified Quick Sequential Organ Failure Assessment in Acutely Deteriorated Patients with Chronic Liver Disease. Clin Mol Hepatol. 2024 Apr 11. doi: 10.3350/cmh.2023.0563.
Brief Description: This study mainly investigated the ability of the modified quick Sequential Organ Failure Assessment (m-qSOFA) scoring system to identify high-risk patients among those with acutely deteriorated chronic liver disease, especially those with ACLF. Utilizing data from the KACLiF study and AARC, the study modified the qSOFA scoring system by replacing the Glasgow Coma Scale with hepatic encephalopathy assessment, considering m-qSOFA≥2 as high risk. The results indicated that patients with high m-qSOFA scores had significantly lower transplantation-free survival (TFS) compared to those with low m-qSOFA scores in both cohorts. When the AARC-ACLF diagnostic criteria were applied, there was no significant difference in TFS between high and low m-qSOFA scores among ACLF patients in the KACLiF cohort; however, in the AARC cohort, high m-qSOFA scores were associated with significantly lower TFS. After switching to EASL-ACLF diagnostic criteria, high m-qSOFA scores were associated with significantly lower TFS in the KACLiF cohort. Further analysis showed that the m-qSOFA score was an independent risk factor for one-month TFS in both cohorts. The study found that baseline and dynamic changes in m-qSOFA helped identify patients with organ failure development and high short-term mortality risk among CLD patients.
Brief Review: The study innovatively modified the qSOFA scoring system and utilized large datasets (KACLiF and AARC cohorts) to explore the efficacy of m-qSOFA scoring under different ACLF conditions, finding potential impacts on risk stratification and management of chronic liver disease patients. Notably, the study compared the efficacy of m-qSOFA scoring under two different ACLF diagnostic standards, revealing the value of m-qSOFA in different clinical contexts. As a dynamic assessment tool, m-qSOFA helps in timely identification of high-risk chronic liver disease patients, potentially facilitating more timely interventions. However, the study also has certain limitations. Firstly, it did not compare m-qSOFA scoring with other existing scoring systems, so the advancement of m-qSOFA could not be determined. Secondly, the study only used one-month TFS as an outcome, which is significant for ACLF patients, but 90-day TFS is also important and could be considered in future studies to further explore the score’s applicability in Western regions.
