Letter to the Editor: Defining Acute on Chronic Liver Failure: More Elusive Than Ever
Authors: Jasmohan S. Bajaj, Florence Wong, Patrick S. Kamath
Journal: Hepatology (2019)

Potential conflict of interest: Nothing to report. To the Editor: The onset of jaundice, ascites, hepatic encephalopathy, and variceal bleeding has traditionally been termed “decompensated cirrhosis,” which is associated with high mortality without liver transplantation. Decompensated cirrhosis is deemed to be distinct from acute‐on‐chronic liver failure (ACLF), a condition in which patients with chronic liver disease patients with/without cirrhosis have a rapid decline characterized by hepatic and extrahepatic organ failures, usually after a precipitating event.1 ACLF is associated with higher mortality and expenditure than decompensated cirrhosis. There are at least 10 different definitions of ACLF2; however, what makes ACLF unique has not been characterized. Despite this, the number of citations of ACLF increased from 2 in the year 2000 to 2,485 in 2018. Failing organ systems and abnormal laboratory data are currently required to define ACLF.1 Although predictive of short‐term mortality, as demonstrated by Mahmud et al., organ failure occurs at a late stage, and may be irreversible despite intensive therapy.1 Thus, current ACLF definitions may promote a passive, reactive approach.1 Moreover, none of the current organ‐failure scores has consistently demonstrated a C statistic of at least 0.8, the accepted threshold for an excellent model to predict mortality. Therefore, organ failure scores should not be used to define ACLF when the goal is to improve patient outcomes. The definitions of ACLF have resulted in substantial confusion among the multidisciplinary teams caring for these patients, especially regarding decisions to transplant early or to avoid transplant because of “futility.”3 There is also little evidence that an ACLF diagnosis using organ‐failure criteria has resulted in a meaningful management change or improved survival. Despite the shortcomings of the current ACLF definitions, worldwide interest sparked by ACLF‐related studies has demonstrated a major need to identify early which patient with chronic liver disease is at risk for preventable mortality. An optimal definition of ACLF requires understanding its unique pathophysiology, possibly using biomarkers related to inflammation, microbiota, and metabolomics (Table 1).4 Defining criteria should be delinked from prognostic criteria, so that patients can be identified early in their clinical course when interventions are likely to improve outcomes. A uniform definition of ACLF that can be applied worldwide is essential and should probably include hepatic encephalopathy and coagulation defects, which are required to diagnose acute liver failure.5 Table 1 - Components of an Ideal Definition for ACLF Components Positive Impact on the field Encompasses chronic liver disease through cirrhosis, is etiology‐agnostic, and is sensitive to local needs through subtypes Worldwide acceptance and shifting focus to improving outcomes Focuses on pathophysiological differences between decompensated cirrhosis and other critical illnesses, independent of cirrhosis and ACLF Differentiation between these conditions may lead to ACLF‐specific therapeutic measures Contains clinico‐pathophysiological hybrid elements that are not dependent on organ failure or situations in which organ failure is imminent Use of the definition to prevent ACLF development rather than focusing on extrahepatic organ failure; may identify patients who can benefit from liver‐support devices Clinical or simple, readily available, and inexpensive predictive biomarkers in the definition Acceptance in clinical practice beyond academic centers and in resource‐poor countries Prognostic element Assessment of response to therapies and help in decision making regarding liver transplant or futility