ACLF - Nat.Rev.Gastro Hepato Jan 2026

Acute-on-Chronic Liver Failure (ACLF) is a severe and complex syndrome that occurs in patients with pre-existing chronic liver disease or cirrhosis. It is characterized by acute hepatic decompensation, which leads to worsening portal hypertension, systemic inflammation, a high risk of infection, organ dysfunction, and elevated short-term mortality.

### Key Features and Classification:

1. **Types of ACLF**:

• **Type A**: Primarily involves hepatic failure.
• **Type B**: Involves extrahepatic organ failure (EHOF).

2. **Pathophysiology**:

• Severe hepatic injury in ACLF triggers systemic inflammation driven by damage-associated molecular patterns (DAMPs), gut-derived microbial products, and immunometabolic dysregulation.
• Immune dysfunction may manifest either as hyperinflammation (hypercytokinaemia) or as immune paresis, which increases vulnerability to infections and organ failure.

3. **Determinants of Outcomes**:

• The outcome in ACLF is influenced by the nature and severity of the acute insult and the underlying hepatic functional reserve.

### Management and Treatment:

1. **Golden Window**:

• The first week of illness is critical for implementing interventions. Severity scores, such as those developed by the ACLF Research Consortium and the European Association for the Study of the Liver Chronic Liver Failure Consortium, guide therapeutic decisions during this period.

2. **Management Priorities**:

• Addressing the acute hepatic insult.
• Managing portal hypertension.
• Preventing and reversing organ failure.
• Optimizing patients for liver transplantation when necessary.

3. **Therapeutic Approaches**:

• Protocol-based critical care hepatology and multidisciplinary approaches have shown success in helping nearly 50% of ACLF patients survive with their native liver.
• Emerging therapies include immune modulation, liver regeneration strategies, therapeutic plasma exchange, and artificial liver support systems.

4. **Liver Transplantation**:

• Liver transplantation remains the definitive and life-saving therapy for patients with severe ACLF who do not respond to other treatments.

### Advances and Challenges:

• The Kyoto ACLF Consensus represents a global effort to standardize definitions, simplify treatment endpoints, and refine prediction tools for ACLF.
• Despite progress, significant knowledge gaps remain, particularly regarding targeted non-transplantation interventions. Further research is necessary to improve outcomes for ACLF patients.