Liver societies agree on first global definition of acute-on-chronic liver failure

Clinical takeaway: Acute-on-chronic liver failure (ACLF) should now be diagnosed using a standardized framework centered on liver failure plus extrahepatic organ dysfunction or failure, allowing earlier recognition and more consistent risk stratification worldwide. Clinicians should prioritize prompt identification of precipitants such as infection, alcohol-related hepatitis, drug-induced liver injury, and viral hepatitis, while considering early transplant referral for patients with severe disease.

Five major liver societies have issued the first global consensus definition and management framework for ACLF, a syndrome marked by acute deterioration in patients with advanced chronic liver disease and high short-term mortality. The document aims to resolve longstanding differences among regional definitions that have complicated patient care, research, and clinical trial design.

The new framework defines ACLF as liver failure plus at least one extrahepatic organ dysfunction or failure. Liver failure is defined as bilirubin ≥5 mg/dL and INR ≥1.5, while the diagnosis applies to patients with advanced chronic liver disease, including those with compensated disease who develop new decompensation.

A new 3-grade system stratifies severity. Grade 1 consists of liver failure plus one extrahepatic organ dysfunction, grade 2 requires one extrahepatic organ failure, and grade 3 involves two or more extrahepatic organ failures. Renal failure is defined as KDIGO stage 2-3 acute kidney injury, while grade 3-4 hepatic encephalopathy is considered an organ failure.

Several practical treatment recommendations address common ACLF precipitants. For severe alcohol-associated hepatitis, corticosteroids are not recommended in ACLF grade 3 because response rates are very low. In treated patients, Lille scores should be assessed on days 4 and 7 to limit unnecessary steroid exposure. The panel also states that mandatory minimum abstinence periods should not be required before liver transplant listing in patients facing very high short-term mortality.

For drug- or herb-induced liver injury, immediate discontinuation of the offending agent is mandatory. The consensus supports use of cause-specific therapies when available, including N-acetylcysteine, corticosteroids for selected immune-mediated injury, and other antidote-based approaches, along with early transplant-center referral for high-risk patients.

For virus-triggered ACLF, the document recommends rapid virologic testing and initiation of antiviral therapy within 24 hours of confirming the cause whenever possible. Recommended therapies include entecavir or tenofovir for HBV-related disease, direct-acting antivirals for HCV, and ribavirin in selected hepatitis E cases.

Critical care recommendations include full sepsis evaluation, early appropriate antibiotics, balanced crystalloids rather than normal saline for initial fluid resuscitation, norepinephrine as the first-line vasopressor, and expedited transplant assessment for severe ACLF. The panel notes that mortality risk may exceed that predicted by MELD scores and argues for development of ACLF-specific transplant-prioritization policies.

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

Key recommendations

• Diagnose ACLF using liver failure (bilirubin ≥5 mg/dL and INR ≥1.5) plus at least one extrahepatic organ dysfunction or failure.
• Use the new 3-grade severity system based on the number of extrahepatic organ dysfunctions and failures.
• Do not use corticosteroids in ACLF grade 3 alcohol-associated hepatitis; reassess treated patients with Lille scores on days 4 and 7.
• Immediately stop suspected offending drugs in DILI-related ACLF and initiate cause-specific therapies when available.
• Start indicated antiviral therapy promptly in virus-related ACLF, ideally within 24 hours of etiologic confirmation.
• Perform full infectious workups and provide early appropriate antimicrobial therapy.
• Consider expedited liver transplant evaluation for severe ACLF because short-term mortality may exceed MELD-based estimates.

Source: Bajaj JS, et al. (2026 Oct 30) Hepatology. Acute-on-chronic liver failure: A global multisociety consensus on definitions