Five liver societies from around the world have agreed upon a single definition of acute-on-chronic liver failure (ACLF), resolving longstanding regional differences in how ACLF is defined, experts said. 

The consensus is a "historic milestone in hepatology," said Debbie Shawcross, MBBS, PhD, of King's College London, United Kingdom, who introduced the consensus in a session at The Liver Meeting 2026: American Association for the Study of Liver Diseases (AASLD).

"This is the foundation that we can [use to] improve clinical care for patients with ACLF, we can accelerate research, we can develop urgently needed therapies, and we can improve outcomes for patients worldwide," Shawcross explained.

The consensus was published in Hepatologyand presented at the meeting by representatives from each working group.

Different Definitions 

The international societies previously had differing definitions of ACLF, said Shawcross. 

The European Association for the Study of the Liver definition was based on organ failures and an associated score; the North American Consortium for the Study of End-Stage Liver Disease definition focused on extrahepatic organ failures, such as hepatic encephalopathy and the need for vasopressors or renal replacement therapy; and the Asian Pacific Association for the Study of the Liver definition centered on liver failure, including elevated bilirubin, encephalopathy, and coagulopathy.

"This was not good for science," said Paolo Angeli, MD, PhD, of the University of Padua, Italy, who presented the new definition and grading system on behalf of the data working group. 

"It was a cause of fragmentation, politicization of science, and at the end, loss of credibility of science." 

Consensus Details 

Under the new consensus, ACLF requires advanced chronic liver disease (fibrosis stage F3 or higher), liver failure (bilirubin level of at least 5 mg/dL plus an international normalized ratio of at least 1.5), and dysfunction or failure of at least one other organ.

Severity of ACLF is then graded by involvement of other organs. 

Grade 1 ACLF is liver failure plus dysfunction of one extrahepatic organ (circulatory/respiratory only if in a monitored high dependency/intensive care setting); grade 2 is liver failure plus failure of any one extrahepatic organ; and grade 3 is liver failure plus failure of two or more extrahepatic organs. 

Organ dysfunction is a new category intended to identify patients earlier. For example, stage 1 acute kidney injury counts as kidney dysfunction, whereas stage 2 or 3 acute kidney injury, or new renal replacement therapy, is considered kidney failure.

Implications for Research and Clinical Practice 

"Achieving consensus on the definition of ACLF improves the generalizability of research across the globe," said Elliot B. Tapper, MD, of the University of Michigan, Ann Arbor. "Instead of ACLF meaning one thing in the US and another in Europe or Asia, this creates harmony."

Still, Tapper suggested that the immediate impact will be on research rather than patient care.

"Is it important for patients? No, or at least not yet. Is it important for researchers and journals? Yes, and very," Tapper told Medscape Medical News. "The hope is that harmonized definitions allow for larger studies which can impact patient care globally, and then we will see our patients benefit."

Kavish R. Patidar, DO, of Houston Methodist Hospital, who was not involved in the consensus, said the new category of organ dysfunction could be clinically meaningful.

"From a clinical perspective, recognizing organ dysfunction before progression to organ failure may allow earlier intervention and more timely consideration for liver transplantation," Patidar told Medscape Medical News.

The consensus also provides a framework for future clinical trials, developed with input from the FDA, according to Jasmohan S. Bajaj, MD, of Virginia Commonwealth University, Richmond, who co-chaired the effort. 

Specifically, primary endpoints for phase 1 and 2a trials are safety, tolerability, target engagement, and organ function. For phase 2b and 3, the primary endpoints are survival, with and without liver transplant.

Listing for transplant cannot be a primary endpoint, Bajaj added, because "access to liver transplant [depends on] where you are, how much you can afford, and whether you have a donor. … Many patients become ineligible during their illness, introducing a selection bias."

During the question-and-answer session, Alberto Farias, MD, PhD, of the University of São Paulo, Brazil, raised concerns about patients with isolated liver failure, who have high mortality but do not meet the new definition because they lack extrahepatic organ involvement.

Angeli acknowledged that the definition has limitations but said that patients excluded from it are not excluded from optimal management, including priority for liver transplant.

Next Steps 

Patidar said the new criteria still need to be validated across diverse patient populations and healthcare settings.

"We need to determine whether it adequately captures patients at high risk of short-term mortality, particularly those with severe extrahepatic organ failure who do not meet the proposed liver failure criteria," he said.

Anna M. Banc-Husu, MD, a pediatric hepatologist at Texas Children's Hospital and Baylor College of Medicine, Houston, urged the societies to include children in future work. "Children are not little adults," she said. 

"This bread has barely come out of the oven," Bajaj replied. "Let us eat this first, and then we will do this. We won't forget."

Mark Sonderup, MBChB, PhD, of the University of Cape Town, South Africa, who presented on behalf of the critical care working group, said few disciplines had achieved this kind of global harmonization.

"We've actually de-Babelized ourselves," he said. "And so suddenly the world is speaking the same language, and that means you can actually now get out of the starting blocks."

Shawcross reported relationships with Genfit, Alfa Sigma, Apollo Therapeutics, Norgine, and EnteroBiotix. Angeli reported relationships with CSL Behring, Grifols, Jafron Biomedical, Biovie, and Kedrion. Bajaj reported relationships with Merz, Sequana, Bausch, Grifols, Boehringer Ingelheim, and Genfit. Farias and Sonderup reported no relevant financial relationships. Tapper reported relationships with Novartis, Axcella, Allergan, Mallinckrodt, Bausch Health, Kaleido, Novo Nordisk, Gilead, and Valeant. Patidar reported relationships with Madrigal Pharmaceuticals, Keenova Therapeutics, Novo Nordisk, and HepQuant. Disclosure information for Banc-Husu was not available.