Patients with cirrhosis may develop acute complications such as ascites, hepatic encephalopathy, gastrointestinal hemorrhaging, and bacterial infections that lead to hospitalization.1 On admission, some of these patients will have mere decompensated cirrhosis, whereas others will exhibit decompensated cirrhosis associated with newly developed liver and/or extrahepatic organ failure.2 Patients with cirrhosis and acute organ failure are at high risk for short-term death.3, 4 It has become customary to refer to these individuals as patients with acute-on-chronic liver failure (ACLF).3, 4 ACLF episodes are responsible for a large proportion of the health care costs attributable to acute decompensation of cirrhosis.3 Consequently, the development of ACLF is an important outcome in clinical trials,3 and its prevention is a key component of cirrhosis management strategies.4
Despite the importance of ACLF, a universally accepted definition of ACLF is still lacking.5 In fact, the current definitions of ACLF differ greatly from one another, and they were developed on theoretical grounds rather than experimental grounds.5 Notably, there are regional differences in ACLF definitions. For example, ACLF has been defined as an acute hepatic insult manifesting as jaundice (serum bilirubin level ≥ 5 mg/dL) and coagulopathy (international normalized ratio ≥ 1.5) and complicated within 4 weeks by ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease.6 In Western countries, it has been suggested that ACLF be defined as an acute deterioration of liver function in patients with cirrhosis that is usually associated with a precipitating event and results in the failure of one or more organs and high short-term mortality.3 It has also been suggested that the Sequential Organ Failure Assessment (SOFA) score7 (Fig. 1) be used to diagnose organ failure in patients with cirrhosis admitted to the intensive care unit.8-10 In these patients, the SOFA score is a better predictor of in-hospital death than liver-specific prognostic scores such as the Child-Pugh and Model for End-Stage Liver Disease scores.9, 10 However, the components of the SOFA score do not take into account some specific pathophysiological and clinical features of cirrhosis.
ACLF, acute-on-chronic liver failure; CANONIC, CLIF Acute-on-Chronic Liver Failure in Cirrhosis; CLIF, Chronic Liver Failure; FiO2, fraction of inspired oxygen; PaO2, partial pressure of arterial oxygen; SOFA, Sequential Organ Failure Assessment.
Establishing the Definition of ACLF
In 2009, a group of European investigators decided to create the Chronic Liver Failure (CLIF) consortium, which was dedicated to the study of the complications of cirrhosis. This consortium was endorsed by the European Association for the Study of the Liver. The first study performed in the context of the CLIF consortium was the CLIF Acute-on-Chronic Liver Failure in Cirrhosis (CANONIC) study, whose major endpoint was to define ACLF. The CANONIC study enrolled 1343 patients hospitalized for an acute complication of cirrhosis in 29 liver units from 8 European countries between February and September 2011. For the diagnosis of organ failure, the investigators used a modified SOFA score, the so-called CLIF-SOFA score, which had been specifically developed before the onset of the study. Like the original score, the CLIF-SOFA score assessed six organ systems (liver, kidneys, brain, coagulation, circulation, and lungs), but it also took into account some specificities of cirrhosis. All variables included in the CLIF-SOFA score were clinical variables easy to obtain or biological variables routinely measured at every hospital. The definitions of organ failure according to the CLIF-SOFA score were as follows: (1) liver failure was defined as a serum bilirubin level of 12.0 mg/dL or more; (2) kidney failure was defined as a serum creatinine level of 2.0 mg/dL or more or as the use of renal replacement therapy; (3) cerebral failure was defined as grade III or IV hepatic encephalopathy according to the West Haven classification; (4) coagulation failure was defined as an international normalized ratio greater than 2.5 and/or a platelet count of 20 × 109/L or less; (5) circulatory failure was defined as the use of dopamine, dobutamine, or terlipressin; and (6) respiratory failure was defined as a partial pressure of arterial oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio of 200 or less or a pulse oximetry saturation/FiO2 ratio of 200 or less. The preliminary results of the CANONIC study were presented at the annual meeting of two major associations: the European Association for the Study of the Liver11 and the American Association for the Study of Liver Diseases.12 In summary, the investigators identified four groups of patients at enrollment: the first group did not have ACLF, whereas the three others had ACLF of increasing severity.
The first group was composed of the majority of the patients (77.5%); these did not have ACLF but had mere decompensated cirrhosis and were divided into three subgroups: (1) patients with no organ failure, (2) patients with a single nonkidney organ failure (i.e., a single failure of the liver, coagulation, circulation, or respiration) who had serum creatinine levels < 1.5 mg/dL and no hepatic encephalopathy, and (3) patients with a single cerebral failure who had serum creatinine levels < 1.5 mg/dL. The 28-day mortality rate for this group was very low (4.7%).
The second group included 11% of the enrolled patients and was called ACLF grade 1. This group was divided into three subgroups: (1) patients with a single kidney failure; (2) patients with a single failure of the liver, coagulation, circulation, or respiration who had serum creatinine levels ranging from 1.5 to 1.9 mg/dL, mild-to-moderate hepatic encephalopathy, or both; and (3) patients with a single cerebral failure who had serum creatinine levels ranging from 1.5 to 1.9 mg/dL. The 28-day mortality rate for this group was very significant (22.1%).
The third group included 8% of the enrolled patients and was called ACLF grade 2. This group included patients with two organ failures and was associated with high 28-day mortality (32%).
The fourth group included 3.5% of the enrolled patients and was called ACLF grade 3. This group included patients with three organ failures or more and was associated with very high 28-day mortality (76.7%).
It should be noted that this definition was obtained in Western countries; 60% of the patients had alcoholic cirrhosis, and 20% had hepatitis C virus–related cirrhosis. There were very few cases of hepatitis B virus–related liver disease. Therefore, the Western definition of ACLF should be evaluated in countries with a high prevalence of hepatitis B virus–related cirrhosis (particularly in Asia).
Taken together, the results of the CANONIC study indicate that simple and robust criteria allow us to distinguish among patients with cirrhosis admitted for an acute complication those who do not have ACLF and a good prognosis and those who have ACLF associated with a poor prognosis. Therefore, there is a definition of ACLF ready for prime time. The evidence-based definition of ACLF derived from the CANONIC study serves to identify patients who are at high risk for end-organ failure–related death and require specific treatments and/or intensive management. In addition, a robust definition of ACLF sets the stage for exploring important features of this syndrome that are still unknown, including its prevalence, the frequency of its precipitating factors, its natural history, and its pathogenic mechanisms.