**1. Definition of Acute-on-Chronic Liver Failure**

Acute decompensation (AD) of cirrhosis refers to the development of ascites, gastrointestinal haemorrhage, hepatic encephalopathy or any combination of these, which leads to hospital admission [1]. Acute-on-chronic liver failure (ACLF) is a distinct syndrome that develops in patients with acutely decompensated chronic liver disease and is characterised by high 28-day mortality. Other major features of ACLF are the strong association with one or more precipitating factor(s), the development of single- or multiple organ failures (OFs) and a severe degree of systemic inflammation [2–4]. International scientific societies have proposed different definitions of ACLF in recent years; they differ from each other mainly in the type of precipitant (hepatic or extrahepatic), the stage of underlying liver disease (chronic hepatitis or cirrhosis) and the inclusion or not of extra-hepatic OFs. In spite of these differences, each of them recognizes ACLF as a definite clinical entity. Table 1 summarizes definitions, diagnostic criteria and stratification of ACLF used by the four major international consortia [2,5–9].

The definition proposed by the European Association for the Study of the Liver— Chronic Liver Failure (EASL-CLIF) Consortium is based on the results of the CANONIC study, a multi-center prospective investigation in which 1343 patients non-electively hospitalized for AD of cirrhosis were enrolled, irrespective of prior episode(s) of AD [2]. This definition considers both hepatic and extra-hepatic precipitants and both liver and extra-hepatic OFs. The diagnosis of OFs is based on a modified Sequential Organ Failure Assessment (SOFA) score, called CLIF-C organ failure (CLIF-C OF), which considers the function of six organ systems (liver, kidney, brain, coagulation, circulation and respiration) [2]. According to the number of OFs, patients with ACLF were stratified into three groups: (I) patients with a single kidney failure or another single OF if associated with brain or kidney disfunction (ACLF grade 1); (II) patients with two OFs (ACLF grade 2); (III) patients with three or more OFs (ACLF grade 3) [2]. We contributed to the development of this definition, which nowadays is the most studied. Thus, we currently use it in our center.


The definition proposed by the North American Consortium for the Study of Endstage Liver Disease (NACSELD) is based on an investigation involving 507 patients with AD of cirrhosis non electively hospitalised for infection [5]. Like the European one, the North American definition considers extra-hepatic OFs as part of the syndrome but does not include liver and coagulation. It defines ACLF by the presence of two or more OFs among kidney, brain, circulation and respiration and stratifies patients according to the number of organ failures [5]. The Chinese Group on the Study of Severe Hepatitis B (COSSH) developed a definition for hepatitis B virus (HBV)-related ACLF by using data from a large cohort of 1202 patients with HBV-related AD, with or without cirrhosis. The CLIF-C OF scoring system was used to define OFs; so, this definition and the consequent stratification of patients are quite similar to the European ones. The only difference is that, in the Chinese classification, a patient with single liver failure with INR ≥ 1.5 is considered as having ACLF grade 1 [6]. The Asian Pacific Association for the Study of the Liver (APASL) proposed a definition of ACLF in 2009 which was based on an expert opinion. This definition was updated by the APASL ACLF Research Consortium (AARC) in 2014 and then in 2019, using the results of the AARC database (5228 patients collected at that time) [7–9]. Unlike the above definitions, AARC investigators consider extra-hepatic OFs as manifestations but not as components of the syndrome, and extrahepatic insults (for example, bacterial infections) as complications, but not triggers, of ACLF. So, ACLF is considered as an acute hepatic insult (for example, HBV reactivation or acute alcoholic hepatitis), manifested as jaundice (total bilirubin levels ≥ 5 mg/dL) and coagulation failure (INR ≥ 1.5 or prothrombin activity < 40%) and complicated by clinical ascites, encephalopathy or both within 4 weeks in patients with chronic liver disease or compensated cirrhosis without prior decompensation and with no AD [9]. Thus, AARC investigators consider ACLF to be totally distinct from acutely decompensated cirrhosis. The severity of ACLF is assessed using a grading system based on the AARC score [9].
