The aim of this study is to assess prospectively the critical period prior to the development of Acute-on-Chronic Liver Failure (ACLF) (1), to uncover mechanistic and pathophysiological processes associated with the development and clinical course of ACLF (2) and to identify the precipitating events of ACLF (3).

1. This International-European, investigator-initiated, multicenter, prospective, observational study will be performed in centers that belong to the European Foundation for the Study of Chronic Liver failure (EF-CLIF)-European Association for Study of the Liver (EASL)-EASL-CLIF Consortium.
2. The population of patients would include ca. 1,200 cirrhotic patients over a twelve-months period. These patients will be admitted/referred to the study center because of acute decompensation (AD) of cirrhosis (ascites, overt encephalopathy, GI-hemorrhage, new onset of non-obstructive jaundice and/or bacterial infections), without ACLF (as defined according to the Canonic study ) at hospitalization.
3. After the enrolment visit, the patients will be stratified into two groups: Group 1 patients with high risk of ACLF development (CLIF-C AD score ≥ 50) and in Group 2 patients with low risk of ACLF (CLIF-C AD score <50). The whole cohort will be followed for 3 months, while Group 1 will be followed more closely. Development of ACLF is an end-point and in this case a final visit 7-10 days after ACLF development is planned. Data on liver transplantation, mortality and causes of mortality 3 months, 6 months and 12 months will be collected in the whole cohort.
4. Prospective collection of biological material and performance of ancillary studies investigating predictors for development and pathogenesis of ACLF.

Specific goals of the study:

• To identify early clinical predictors, biomarkers, mechanisms and precipitating events during the critical period prior to and involved in the development and clinical course of ACLF (with special emphasis to medical trajectory and drug history) in patients admitted/referred to study center with acute decompensation of cirrhosis (ascites, GI-hemorrhage, overt encephalopathy, new onset of non-obstructive jaundice and/or bacterial infections) and the chronological relationship of the events with occurrence and dynamics of ACLF development.
• To develop a score predicting ACLF development (CLIF-PREDICT score) and assess 28-day, 90-day, 6-month and 1-year all-cause mortality in cirrhotic patients with acute AD, but without ACLF.
• To serve as a core (hub) study for prospective ancillary studies regarding diagnosis, prognosis and pathogenesis of AD and ACLF.

Main endpoints

• Assessment of the critical period prior to ACLF development

  • Characterization of mechanisms responsible for ACLF development
  • Predictors of clinical course dynamics of ACLF evolution and mortality.
  • Identification and role of precipitating events for ACLF development.

• To elaborate a CLIF-PREDICT score 2. Secondary endpoints

• Prospective core ancillary studies to investigate the pathogenesis of ACLF.

Inclusion Criteria:

The patients admitted/referred to study center with AD of cirrhosis (ascites, overt encephalopathy, new onset of non-obstructive jaundice, GI-hemorrhage and/or bacterial infections), but without ACLF (as defined according to the CANONIC study) at study inclusion.

Exclusion Criteria:

1. Presence of ACLF at inclusion;
2. Pregnancy;
3. Age <18 years;
4. Patients with acute or subacute liver failure without underlying cirrhosis;
5. Patients with cirrhosis who develop decompensation in the postoperative period following partial hepatectomy;
6. Evidence of current malignancy except for non-melanocytic skin cancer and hepatocellular carcinoma within Milan criteria;
7. Presence or history of severe extra-hepatic diseases (e.g., chronic renal failure requiring hemodialysis, severe heart disease (NYHA > II); severe chronic pulmonary disease (GOLD > III), severe neurological and psychiatric disorders);
8. HIV-positive patients
9. Previous liver or other transplantation
10. Admission/referral of more than 72 hours before inclusion
11. Patients who decline to participate or who cannot provide prior written informed consent and when there is documented evidence that the patient has no legal surrogate decision maker and it appears unlikely that the patient will regain consciousness or sufficient ability to provide delayed informed consent;
12. Physician´s denial (e.g. the investigator considers that the patient will not follow the protocol scheduled).

The population of patients would include ca. 1,200 cirrhotic patients over a twelve-months period. These patients will be admitted/referred to the study center because of acute decompensation of cirrhosis (ascites, overt encephalopathy, GI-hemorrhage, new onset of non-obstructive jaundice and/or bacterial infections), without ACLF (as defined according to the CANONIC study ) at hospitalization.