Acute-on-Chronic Liver Failure Gets Unified Global Definition, Grading

Five international liver societies have published a unified definition of acute-on-chronic liver failure (ACLF). It anchors diagnosis to liver failure, defined as bilirubin ≥5 mg/dL and international normalized ratio (INR) ≥1.5, plus at least 1 extrahepatic organ dysfunction or failure.¹

The American Association for the Study of Liver Diseases (AASLD) announced the consensus on October 30, 2026, developed with the European Association for the Study of the Liver (EASL), the Asian Pacific Association for the Study of the Liver (APASL), the Latin American Association for the Study of the Liver (ALEH), and the Society on Liver Disease in Africa (SOLDA).¹,²

"This global collaboration represents an important step toward improving care for patients with ACLF," Jasmohan Bajaj, MD, MS, FAASLD, said in a statement.1 "By establishing a shared framework, we can strengthen clinical decision-making, accelerate research and advance the development of effective treatments worldwide."

The 81-statement position paper was published jointly in Hepatology, Journal of Hepatology, Annals of Hepatology, and Hepatology International.¹ According to the authors, differing diagnostic criteria, organ failure thresholds, and outcome measures across regional frameworks have limited comparison between studies. These differences have also complicated the design and regulatory evaluation of international trials.¹ The consensus builds on the APASL Kyoto Consensus and the 2025 organ failure definitions rather than replacing existing regional frameworks.¹

How Do the New ACLF Diagnostic Criteria Define Liver and Organ Failure?

Diagnosis requires advanced chronic liver disease (ACLD), defined as fibrosis stage F3 or higher, a threshold chosen to prevent overlap with acute liver failure.¹ ACLD may be established by biopsy, prior diagnosis, elastography, or clinical and imaging evidence of portal hypertension. The authors caution against relying on noninvasive tests alone, since acute liver injury can produce findings resembling ACLD.¹

Liver failure is the primary requisite condition for diagnosis. Type A ACLF develops in patients with compensated ACLD or cirrhosis without prior decompensation, while type B develops in patients with prior decompensated cirrhosis.¹ Type A may be diagnosed when liver failure accompanies new-onset ascites or hepatic encephalopathy (HE), present at initial presentation or developing within two to four weeks.¹

Extrahepatic organ failures are defined as follows:¹

• Kidney: acute kidney injury (AKI) stage 2 to 3 by Kidney Disease: Improving Global Outcomes (KDIGO) criteria, or new renal replacement therapy
• Brain: West Haven grade 3 to 4 HE, or mechanical ventilation for HE
• Circulatory: vasopressor use, excluding treatment of hepatorenal syndrome-AKI alone
• Respiratory: mechanical ventilation, PaO2/FiO2 ≤225, or SpO2/FiO2 ≤244 when PaO2/FiO2 is unavailable

How is ACLF Severity Graded Under the Global Consensus?

Severity is graded by the number of extrahepatic organ dysfunctions or failures accompanying liver failure. Grade 1 requires liver failure plus one extrahepatic organ dysfunction, such as KDIGO stage 1 AKI or West Haven grade 2 HE. Grade 2 requires liver failure plus one extrahepatic organ failure, and grade 3 requires two or more.¹

Circulatory and respiratory dysfunction count toward grade 1 only in a monitored high-dependency or intensive care setting. Adding organ dysfunction alongside organ failure is intended to support earlier recognition and intervention, according to the authors. They reported evidence from multiple prospectively collected international cohorts showing the framework and grading system independently predicted short-term mortality.¹

Each society nominated 2 chairs, 5 members, and 1 to 2 young investigators, and only statements reaching more than 70% agreement were adopted. Statements were presented at an open meeting before the EASL 2026 Congress in Barcelona, after which 12 revised statements passed a second Delphi round. Immune dysregulation and gut failure were flagged as candidate organ failures requiring further definition.¹

What Does the Consensus Recommend for ACLF Clinical Trials?

Endpoint recommendations were informed by discussions with the US Food and Drug Administration (FDA).¹,² Phase 1 and 2a trials should focus on safety, tolerability, target engagement, and organ function, with survival and liver transplantation (LT) collected as secondary or exploratory endpoints.¹ For phase 2b and 3 trials, survival with or without LT, assessed between day 30 and month 6 using competing-risk analysis, could serve as a major endpoint.¹

Listing for LT should not serve as a primary endpoint, given variation in organ access, listing delays, and donor availability. The authors recommend confirming changes in organ failure scores with at least two separate observations. They also describe the desirability of outcome ranking (DOOR) approach as an option for phase 2 through 4 trials.¹

The consensus also addresses etiology-specific management, critical care, and transplant candidacy. It recommends against corticosteroids in ACLF grade 3 and advises offering LT only to patients with an expected 1-year survival above 75% to 80%.¹ Results of the harmonization initiative will be presented at The Liver Meeting 2026 on November 7, 2026.²

References

1. American Association for the Study of Liver Diseases; European Association for the Study of the Liver; Asian Pacific Association for the Study of the Liver; Latin American Association for the Study of the Liver; Society on Liver Disease in Africa. Acute-on-chronic liver failure: a global multisociety consensus on definitions. Hepatology. Published online 2026. doi:10.1097/HEP.0000000000001891

2. American Association for the Study of Liver Diseases. AASLD joins global liver societies to establish unified definition of acute-on-chronic liver failure. Published October 30, 2026. Accessed October 30, 2026. https://www.aasld.org/aasld-joins-global-liver-societies-establish-unified-definition-acute-chronic-liver-failure