ACLF Needs One Language: Journal of Hepatology | August 2026

Introduction:

Acute-on-chronic liver failure (ACLF) is a high-mortality syndrome characterised by acute deterioration of chronic liver disease with organ dysfunction or failure. Yet, unlike conditions such as sepsis or myocardial infarction, ACLF still lacks a universally accepted definition. Different international consortia use different diagnostic criteria, creating substantial differences in which patients are labelled as having ACLF.

Why does harmonisation matter?

Different ACLF definitions identify different patient populations.

Variation in criteria makes epidemiological studies difficult to compare.

Incidence, severity grading and mortality can change depending on the definition applied.

Heterogeneous enrolment criteria complicate comparison and interpretation of clinical trials.

Biomarker, mechanistic and therapeutic studies cannot progress efficiently without agreement on what constitutes ACLF.

A common definition could also improve communication between clinicians, researchers, regulators and healthcare systems.

The Key Problem:

Major ACLF frameworks have evolved from different geographical and clinical contexts and therefore emphasize different components of the syndrome.

The resulting problem is fundamental:

Different definition → different patient selection → different prevalence → different prognosis → difficult trial comparison

Thus, disagreement over terminology is not merely academic—it directly affects the evidence generated about ACLF.

Lessons From Other Diseases:

The authors draw parallels with sepsis and myocardial infarction.

Sepsis evolved from the relatively nonspecific concept of infection plus SIRS toward a definition centred on life-threatening organ dysfunction caused by a dysregulated host response to infection.

Similarly, myocardial infarction definitions evolved from symptoms and ECG findings through CK-MB and ultimately to standardised cardiac troponin-based criteria.

In both cases, harmonisation allowed more consistent diagnosis, epidemiology, research and clinical-trial design.

Clinical & Research Impact:

A harmonised ACLF framework could provide a common foundation for:

Diagnosis → severity classification → prognostication → trial enrolment → therapeutic evaluation → comparison across regions

Importantly, harmonisation does not necessarily mean that every existing regional concept must simply be discarded. Rather, the goal should be to identify the core biological and clinical features shared across ACLF phenotypes and establish reproducible criteria that can function internationally.

Why This Is Particularly Important Now:

ACLF research is moving toward biomarkers, immune dysfunction, organ-support strategies and potential disease-modifying therapies. Without a common case definition, apparently conflicting studies may partly reflect different definitions rather than genuinely different biology or treatment effects.

A universally applicable framework would also make multinational ACLF trials substantially more interpretable and generalizable.

Bottom Line:

The absence of a universally accepted ACLF definition is now a barrier to scientific progress. Just as standardised definitions transformed research in sepsis and myocardial infarction, harmonising ACLF criteria is essential for comparable epidemiology, reliable prognostication, meaningful clinical trials and development of effective therapies. The field needs to move from competing definitions toward a shared international framework.