Acute-on-chronic liver failure (ACLF) has been recognized for almost 30 years, but there is still no unified definition or diagnostic standard worldwide. Recently, the core clinical features used to describe ACLF have narrowed these differences and built a broader consensus. This review updates the latest changes in disease classification, summarizes the current understanding of ACLF pathogenesis, outlines new treatment targets, and presents a three-stage mouse model that supports testing of potential therapies.
Acute-on-chronic liver failure (ACLF) is widely recognized as a distinct clinical syndrome. However, major differences between Eastern and Western definitions still create barriers in practice and research. In Asia, criteria have often focused on early liver failure, partly because hepatitis B is a common background disease. In Europe and North America, definitions more strongly emphasize extrahepatic organ failure and short-term prognosis, reflecting different patient profiles such as alcoholic hepatitis and hepatitis C. These gaps lead to inconsistent case identification and heterogeneous case mixes. As a result, reported incidence, mortality, and disease severity may vary simply because different criteria are used. This also makes it difficult to compare studies, validate scoring systems across regions, and design clinical trials with similar patient groups.
A research team led by Dr. Xiaogang Xiang from Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, published a review in the Chinese Medical Journal on March 10, 2026, summarizing how ACLF definitions have evolved over time. With growing evidence, researchers now share several core elements. ACLF develops in patients with chronic liver disease. An acute intrahepatic or extrahepatic insult triggers it. Many patients develop extrahepatic organ failure, and short-term mortality is high. In some patients, reversal remains possible. In 2025, the Chinese Society of Hepatology of the Chinese Medical Association (CMA) released its first national guideline for ACLF and proposed a two-type classification at disease onset. Type I ACLF refers to acute severe liver injury on the background of chronic liver disease, without extrahepatic organ failure at onset. Type II ACLF refers to acute decompensation on the background of cirrhosis, with kidney dysfunction or extrahepatic organ failure developing over a short period. This approach aims to narrow gaps between Eastern and Western criteria and may support further alignment toward a unified global framework.
Despite differences in underlying liver diseases across regions, current research suggests a shared pathway of progression. Acute injury and bacterial infection can trigger systemic inflammation, which then drives organ dysfunction. Studies report that more than 66% of patients with ACLF have bacterial infection, including about 37% at admission and about 46% who develop new infection during hospitalization. Injured liver tissue and microbes release inflammatory signals, including damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), that activate innate immunity and amplify cytokine production, which can contribute to a cytokine storm and widespread tissue damage. Importantly, research has revealed a biphasic immune imbalance during the course of ACLF. The early stage is characterized by excessive immune activation, whereas the later stage progresses to immune exhaustion or immune paralysis, which markedly increases the risk of secondary infections. The PIRO framework, covering predisposition, insult, response, and organ failure, provides a clear way to describe this process and supports the development of anti-inflammatory and immune-modulating therapies.
Advances in treatment research have also relied on improved experimental models. Earlier animal models often reproduced only part of the disease and did not capture the full course from chronic injury to acute worsening and organ failure. A three-stage mouse model was developed by Dr. Xiang’s team by sequentially combining chronic liver injury, an acute hepatic insult, and bacterial infection, thereby recapitulating the clinically relevant trajectory of chronic injury, acute exacerbation, and infection. This model reproduces systemic inflammation and damage to organs outside the liver, and it offers a 5- to 7-day window for testing interventions. Using this model, researchers found that impaired liver regeneration is a key driver of disease progression and may be linked to an imbalance in STAT1 and STAT3 signaling. Based on these findings, IL-22-based therapies, including IL-22 fusion proteins (IL-22Fc), have advanced into multicenter phase II trials. The model has also supported other discoveries, pointing to additional pathways and immune targets for future study.
In clinical practice, ACLF management is still centered on organ support, control of the underlying cause, and management of major complications, including infection. Liver transplantation remains the most effective option for end-stage disease, but donor shortages and timing constraints limit access. For this reason, researchers continue to explore new therapies that may improve survival or serve as a bridge to transplantation. These include cell-based treatments, immune-regulating agents such as thymosin alpha 1, and cytokine-targeted therapies such as IL-22. Strategies that modulate the gut – liver axis, including engineered adsorbents, is also being studied for its potential to reduce systemic inflammation. Overall, the field is moving from supportive care alone toward more precise, mechanism-based interventions.
Dr. Xiang hopes this review will improve the understanding of ACLF among clinicians and researchers. Dr. Xiang said, “ Although a unified definition of ACLF has not yet been established and diagnostic criteria still vary across societies and organizations worldwide, clinical criteria are becoming clearer as research advances. A growing consensus has emerged regarding the core features of ACLF, which has substantially narrowed the gap between Eastern and Western perspectives. However, assessment standards for these key features remain inconsistent. There is a need for global, multicenter prospective studies with large sample sizes and diverse etiologies to harmonize diagnostic criteria and support the development of an international consensus. ”
About Dr. Xiaogang Xiang from Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
He is a Chief Physician and Principal Investigator at the Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. His research focuses on the pathogenesis and therapy of severe viral hepatitis and acute-on-chronic liver failure. His work has appeared in journals including Journal of Hepatology , Journal of Clinical Investigation , and Theranostics . He has received numerous national and municipal academic awards and honors, and serves on the committees of several key national and regional hepatology and infectious disease societies.
Funding information
This study was supported by grants from the National Natural Science Foundation of China (Nos. 82570730, 82170619, and 81970544), Shanghai Oriental Talents Program Top-notch Talent Project (No. BJJY2024072), Project for Discipline Leaders in the Three-year Action Plan (2023–2025) for Strengthening the Construction of Public Health System in Shanghai (No. GWVI-11.2-XD03), Program for young outstanding academic leaders (No. 20XD1422600), the Shanghai Rising Stars of Medical Talent Youth Development Program Outstanding Youth Medical Talents (No. SHWJRS [2021]-99), the Shanghai talent development fund (No. 2020097), and Shanghai Municipal Key Clinical Specialty (No. shslczdzk01103).
Chinese Medical Journal
Literature review
Animals
Acute-on-chronic liver failure (ACLF): From definition to pathogenesis and therapy
10-Mar-2026
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