Zhejiang University analysis maps the burden of acute-on-chronic liver failure in compensated liver disease

Acute-on-chronic liver failure (ACLF) is a rapidly progressive syndrome characterized by acute liver injury occurring in the setting of chronic liver disease and is associated with poor short-term outcomes. While ACLF is often linked to decompensated cirrhosis, it can also arise in patients with previously compensated liver disease. A new systematic review and meta-analysis provides a comprehensive assessment of the epidemiological features, causes, and outcomes of ACLF in this population, offering insights into how the disease burden has evolved over the past decade.

A research team led by Associate Professor Yu Shi, Deputy Director in the Department of Infectious Diseases at Zhejiang University, China, along with other researchers, analyzed cohort studies reporting ACLF defined according to the Asia-Pacific Association for the Study of the Liver (APASL) criteria. The study, available online on August 31 2025, and published in Volume 4, Issue 3 of the journal Portal Hypertension & Cirrhosis, provides a synthesis of data from 24 studies involving 4,398 patients with ACLF and compensated liver disease. Most of the included studies were conducted in Asia, reflecting regions where APASL-defined ACLF is most commonly encountered in clinical practice.

The analysis highlights the persistently high mortality associated with ACLF, even among patients without prior liver decompensation. The pooled mortality rate was 38.6% at 28 days and increased to 45.8% at 90 days, indicating that nearly half of the affected patients die within three months of ACLF onset. Importantly, temporal analyses showed no significant improvement in short-term mortality when comparing studies conducted before and after 2014, despite advances in antiviral therapies and supportive care.

“These findings demonstrate that compensated liver disease does not confer protection once ACLF develops,” said Dr. Shi. “Short-term mortality remains high, underscoring the limitations of current treatment strategies.”

Beyond outcomes, the study documents a marked shift in the etiological landscape of ACLF. Viral hepatitis and alcohol-related liver disease were the two most common underlying causes across all studies. However, when data were stratified by time period, the proportion of virus-related ACLF declined from 42.4% in the pre-2014 period to 28.2% after 2014, while alcohol-related ACLF increased from 31.7% to 48.2% over the same period. This transition parallels the expanded implementation of hepatitis B vaccination programs and antiviral therapies, alongside a growing global burden of alcohol-related liver disease.

The analysis also reveals substantial regional variation. Studies from China reported viral hepatitis as the predominant underlying etiology, whereas alcohol-related liver disease was more frequently observed in studies from India. Correspondingly, alcohol consumption emerged as a leading acute precipitating factor for ACLF in several regions, highlighting the role of modifiable behavioral risk factors in disease onset.

“The increasing contribution of alcohol-related liver disease represents a critical challenge for prevention,” Dr. Shi noted. “Unlike viral hepatitis, alcohol-related ACLF cannot be prevented through vaccination or short-term antiviral treatment.”

The study further assessed commonly used prognostic models and found that the Model for End-Stage Liver Disease (MELD) score remained the most frequently reported tool across studies. However, newer scoring systems incorporating multiple organ failures showed stronger discriminatory performance where data were available, suggesting a need for broader validation and adoption of more ACLF-specific prognostic tools.

Looking ahead, the findings have important implications for both clinical care and public health. Over the next five to ten years, the continued rise of alcohol-related ACLF may lead to increasing healthcare utilization and preventable mortality, particularly among middle-aged adults. The authors emphasize that effective prevention strategies, early identification of high-risk patients, and improved access to advanced therapies such as liver transplantation will be essential to reducing the burden of ACLF.

By systematically summarizing data from more than a decade of research, this study underscores a central message: although the causes of ACLF are changing, outcomes remain poor. Addressing this gap will require coordinated efforts across prevention, clinical management, and translational research.

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Reference
DOI: 10.1002/poh2.70018

About Zhejiang University
Zhejiang University is one of China’s oldest and most prestigious universities, internationally recognized for excellence in education, research, and innovation. Based in Hangzhou, the university is a member of China’s C9 League and consistently ranks among the world’s leading academic institutions. Zhejiang University is committed to advancing scientific discovery, improving human health, and addressing global challenges through interdisciplinary research and clinical translation. Its medical schools and affiliated hospitals play a leading role in biomedical research and patient care in China and globally.

Website: https://www.zju.edu.cn/english/

About Associate Professor Shi Yu from Zhejiang University
Dr. Shi Yu is an Associate Professor and physician in the Department of Infectious Diseases at the First Affiliated Hospital of Zhejiang University School of Medicine, China. He completed his medical training at Zhejiang University and holds a doctoral degree in medicine. His research focuses on clinical and basic studies of chronic liver disease, liver failure, and end-stage liver disease. Dr. Shi has published extensively in peer-reviewed international journals, including leading journals in the field of hepatology.

Funding Information
The study was supported by the National Key Research and Development Program of China (No. 2022YFC2304500, No. 2021YFC2301800), the National Natural Science Foundation of China (No. 81870425), the Fundamental Research Funds for the Central Universities (2023QZJH50), and the Medical and Health Research Project of Zhejiang Province (2022RC141).