Acute on chronic liver failure (ACLF) is a distinct entity encompassing the acute deterioration of liver function, culminating in multiple organs failure and high short-term mortality. Definitions and descriptions of ACLF vary between Western and Eastern types, and alcoholism and hepatitis B virus (HBV) are the main etiologies, respectively. To determine whether there are unified diagnostic criteria, severity classification and prognostic model for different etiologies of ACLF. Investigators had launched a multicenter prospective cohort with the same inclusion criteria and disease indicators as those used in the European CANONIC (Chronic liver failure-ACLF in Cirrhosis) study in China，the Ch-CANONIC study(NCT02457637). From Jan 2015 to Dec 2016, 2,600 inpatients with chronic liver disease complicated with ALI and/or AD were recruited. Data were collected during a 28-day hospitalization and continuous follow-ups were performed once a month until 36 months after hospitalization (at least 18 months up to now). Of these patients, 71.5% had HBV-related disease, 1833 had cirrhotic disease, and 767 had non-cirrhotic disease diagnosed by CT scan.

Due to the lack of pathological gold standards, the diagnosis of ACLF is based on the clinical assessment of short-term mortality from organ functional parameters. In subsequent statistics and data analysis, investigators focused on (but not limit in) the relationship between short-term mortality and 6 parameters (bilirubin, INR, Creatinine, SpO2/FiO2, mean arterial pressure and West-Haven grade) from CLIF-C OFs (Chronic liver failure-Consortium Organ Failure score). And then a specific mathematical model has been constructed to obtain the available organ failure cutoff values. Subsequently, investigators carried out a diagnostical criteria for ACLF based on the results obtained from the model and get a good internal-validation result through risk ratio. Meanwhile, investigators conducted a precise prediction model for patients' prognosis and achieved a good predictive effect with consistency by AUC internal-validation. In addition, investigators summarized the course and some characteristics of ACLF.

Therefore, investigators hope to launch another prospective multi-center cohort study with the same inclusion and exclusion criteria, and continue to recruit 800 to 900 patients (about 30% of the previous cohort) as the external validation cohort for the preliminary results mentioned above.

Acute-on chronic liver failure (ACLF) was first described by Japanese researchers in 1995. In 2011, the American Association for the Study of Liver Disease (AASLD) and the European Association for the Study of the Liver (EASL) concluded that the core characteristics of ACLF were multiple organ failures and high short-term mortality. In 2013, the EASL-CLIF (the European Association for the Study of The Liver-chronic liver failure) established the CLIF-SOFA (chronic liver failure-sequential organ failure assessment) criteria of ACLF through a prospective multicenter study at 29 liver units in eight European countries for 1 year, with a focus on patients with alcoholic cirrhosis with acute decompensation (AD). In the Asia-Pacific region, the majority of liver disease is viral hepatitis, while in western countries, it is alcoholic liver disease. There is a sharp east-west divide with respect to the definition of ACLF, especially in the definition of chronic liver disease and related organ failure.

In 2014, investigators had analyzed 6 years' data of hepatitis B virus (HBV)-related chronic liver disease in patients with AD in two affiliated hospitals of Shanghai Jiao Tong University School of Medicine. These data were also quantified and sent to the EASL-CLIF center for analysis. 80% of whole patients were clinically diagnosed with cirrhosis, 30% of which had pathological diagnosis. Through analysis of the liver tissues of the liver transplantation (LT) patients, 95% had pseudo-lobules. The residual 5% of liver tissues were in the S3 stage of progressive liver fibrosis. Moreover, the research also demonstrated that the pathological characteristics of ACLF may be MHN/SMHN (massive hepatic necrosis/submassive hepatic necrosis) in the background of liver pseudo-lobules. Regeneration of hepatic progenitor cells, cholestasis, and sepsis are other possible pathological features of ACLF.

Compared with the CANONIC (EASL-CLIF Acute-on-Chronic Liver Failure in Cirrhosis), there are many similarities between ACLF patients with alcoholic cirrhosis or HBV induced cirrhosis.But ACLF patients with cirrhosis induced by HBV or alcoholism differ in main types of organ failure. According to CLIF-C OFs (CLIF-C organ failure score), the incidence of 6 organ failures is not exactly the same in the two types of ACLF. Even for the same type of organ failure, the short-term mortality of patients is different.

To determine whether there are unified diagnostic criteria, disease grades classification and prognostic model for different etiologies of ACLF, Investigators had launched a multicenter prospective cohort with the same inclusion criteria and disease indicators as those used in the European CANONIC study in China，the Ch-CANONIC study (NCT02457637). The research was carried out in 14 Chinese national wide liver centers each of whose total beds are around 500. From Jan 2015 to Dec 2016, 2600 inpatients with chronic liver disease (including chronic liver hepatitis patients without cirrhosis, compensated cirrhosis patients, decompensated cirrhosis, non-alcoholic fatty liver disease or alcoholic liver disease patients) complicated with AD [acute decompensation): including [(having ascites, hepatic encephalopathy, bacterial infection, gastrointestinal bleeding or jaundice (TB>5NL) within 1 month before enrollment] and/or ALI [acute liver injury: including ALT>3NL (normal level), AST>3NL or TB>2NL within 1 week before enrollment] were recruited. Data were collected during a 28-day hospitalization and continuous follow-ups were performed once a month until 36 months after hospital discharge. Of these patients, 71.5% (1859/2600) had HBV-related disease,71.5% (1833/2600) had cirrhotic disease, and 28.5% (767/2600) had non-cirrhotic disease.

Up to now, every recruited patient has been followed-up for at least 18 months. Thus, a large amount of data has been collected for analysis. The preliminary results of our research are as follows (As the relevant papers are being reviewed, the detailed data will be updated in subsequent protocols):

1. Investigators explored the epidemiology of inpatients with severe chronic liver disease and the risk of high short-term mortality in nationwide hospitals, including the prevalence of acute deterioration, the disease burden and the clinical features of patients with short-term mortality.
2. Investigators had got some conclusions from many observations of the clinical course of patients with short-term mortality. The time interval from acute insults to different endpoints, including AD, organ failure and death was carefully evaluated. Moreover, the distribution and regularity of mortality within a one-year follow-up had also been plotted.
3. Due to the lack of pathological gold standards, the diagnosis of ACLF is based on the clinical assessment of short-term mortality from organ functional parameters. Investigators implemented a statistical approach to determine cut-off values for vital organ damage and failure. In subsequent statistics and data analysis, refer to the CANONIC study, at the beginning investigators focused on (but not limit in) the relationship between short-term mortality and 6 parameters (bilirubin, International Normalized Ratio, Creatinine, SpO2/FiO2, mean arterial pressure and West-Haven grade) from CLIF-C OFs. And then a specific an evidence-based model has been constructed to obtain the available organ failure cutoff values. Subsequently, investigators established a diagnostical criteria for ACLF based on the results obtained from the model to quantify the severity of the disease.
4. A prognosis model was established to define high disease risk patients to distinguish early-stage ACLF patients (pre-ACLF) from non-ACLF patients with AD or ALI. Investigators achieved a good predictive effect with consistency by AUC internal-validation.
5. Implementation of high-throughput screening by proteomic and metabolomic studies to screen and validate biomarkers for the prediction of ACLF in the early stage and establish a prognostic evaluation for ACLF using plasma from a biobank; execution of a Genome-wide Association Study (GWAS) using DNA samples extracted from peripheral blood mononuclear cells; and exploration of the mechanism of ACLF disease progression by studying DNA levels (GWAS), protein levels (proteomic analysis) and metabolite levels (metabolomic analysis). This part of work is in progress.

Therefore, investigators hope to launch another cohort study with the same inclusion/exclusion criteria and recruit 800-900 patients (about 30% of the previous cohort) as the external validation cohort for the preliminary results (1~4) mentioned above.

Overall, 800-900 inpatients will be enrolled continuously from Sep. 2018 to Mar. 2019(anticipated). The research will be carried out in about 12 Chinese national wide liver centers each of whose total beds are around 500. Every patient will have a unique number. Cirrhosis or non-cirrhosis will be diagnosed by CT, FibroScan and FIB-4 index. The investigators will take the note of the history of their liver disease and find the etiology of their liver disease, such as hepatitis B, NAFLD, alcoholic liver disease, and autoimmune liver disease. For viral hepatitis, the investigators will ask how antiviral therapy is conducted. The investigators will ascertain if the patients have a history of cirrhosis and for how long. The investigators will ascertain if the patients have any of the following predisposing factors: HBV reactivation, bacterial infection, active alcohol intake, HBV superimposed by other hepatitis viruses, gastrointestinal bleeding, portal vein thrombosis, surgery, intake of hepatotoxic drugs or herbs, or physiological exhaustion. The investigators will establish the main cause of admission: gastrointestinal bleeding, hepatic encephalopathy, ascites, bacterial infection, jaundice or ALI. The investigators will determine whether the patients have chronic disease such as hypertension, coronary heart disease, diabetes, chronic renal disease, or connective tissue disease.

During hospitalization, data will be collected at 1, 7,14, 21 and 28 days (or last visit date, if the patient is hospitalized less than 28 days), and 24h prior to death or LT (if the patient dies or has LT) and focus on the following three aspects.

The first aspect is evaluation of organ failure. The circulatory system will be evaluated by measuring heart rate and blood pressure and use of vasopressors. Renal function will be evaluated by serum creatinine or renal replacement therapy. Coagulation function will be evaluated by INR (international normalized ratio of prothrombin time). Liver function will be evaluated by serum total bilirubin. The respiratory system will be evaluated by the oxygenation index (SpO2/FiO2), and whether the patient needs nasal catheter oxygen and artificial ventilation will also be recorded. The nervous system will be evaluated by the West-Haven grade of hepatic encephalopathy. Bacterial infection, including pneumonia, urinary tract infection, spontaneous bacterial peritonitis, spontaneous bacteremia, and cellulitis will be evaluated by positive culture results or imaging findings.The investigators will establish whether ascites and hepatic encephalopathy can be medically controlled.

The second aspect is laboratory examinations. Tests at admission will include routine blood, urine and stool tests, liver and renal function tests, blood electrolytes, blood-gas analysis, blood glucose, coagulation test, C-reactive protein (CRP), procalcitonin (PCT), HBV antibodies and antigens, anti-hepatitis A (IgM), HBV-DNA, anti-hepatitis E (IgM), anti-hepatitis C, and immunoglobulins (IgA, IgG, IgM and IgM-4). Tests at other times will include blood, urine and stool routine tests, liver and renal function tests, blood electrolytes, blood glucose, coagulation test, CRP (C-reactive protein) and PCT (procalcitonin). Tests optionally done during hospitalization will include autoantibody measurement. Blood，sputum，ascites culture or middle urine cultivation will be taken if a patient is suspected of having a relevant infection.

The third aspect is imaging. During hospitalization, thoracic X ray or computed tomography (CT) will be done to diagnose pulmonary infection. Abdominal CT (enhanced when necessary), B ultrasound and FibroScan or other elastography will be done to diagnose cirrhosis (or fibrosis), portal thrombosis, esophageal and gastric varices and hepatocellular carcinoma.

Follow-up will be clinical visiting, but telephone call will be acceptable for patients unable to attend. Clinical follow-up is once a month for 3 months adding to 3 visits. Laboratory tests should be taken at least once (the last visit is perferred) including routine blood tests, liver and renal function test, coagulation test, CRP and PCT. B ultrasound will be done to monitor cirrhosis (or fibrosis) , complications and hepatocellular carcinoma. During follow-up, patients will be hospitalized again whenever they have new ALI or AD. Similar data will be collected reference to their prior admission and follow-up will restart. If the patients die during follow-up, the time of death and main cause of death will be noted. When the patients undergo LT during follow-up, the time of LT and the results of hepatic pathology will be noted.

Demographic data, disease history, baseline data after admission and follow-up data after discharge will be recorded in a similar process and quality control. But investigators plan to simplify some data collection work. Concretely, (1) During hospitalization, data will be recorded and followed up once a week (but must include the first and last day's data of hospitalization).(2) Samples of feces and urine are no longer collected. (3) The duration of follow-up for each discharged patient will be shorten from 36 months to 3 months.](streamdown:incomplete-link)

Inclusion Criteria:

• inpatient (hospitalization >1 days)(including patient in emergency observation wards)chronic liver disease patients including non-alcoholic fatty liver disease patients,chronic liver hepatitis patients without cirrhosis, compensated cirrhosis patients and decompensated cirrhosis patients
• having acute liver injury [ALT(alanine aminotransferase)>3ULN,AST(aspartate aminotransferase)>3ULN or TB(total bilirubin)>2 ULN within 1 week before enrollment] or acute decompensation[having ascites, hepatic encephalopathy, bacterial infection ,gastrointestinal bleeding or jaundice(TB>5NL)within 1 month before enrollment].

Exclusion Criteria:

• pregnancy
• hepatocellular carcinoma or other liver malignancies
• malignancy of other organs
• severe chronic extrahepatic disease including chronic obstructive pulmonary disease combined with respiratory failure, coronary heart disease with cardiac function level 3 (NYHA), myocardial infarction in the 3 months before admission, diabetes with severe complications and chronic kidney disease with end-stage renal failure receiving immunosuppressive drugs for reasons other than chronic liver disease

chronic liver disease patients（with liver dysfunction more than 6 months） with acute liver injury[with ALT>3 ULN),AST>3NL or TB>2 ULN within 1 week before enrollment] or acute decompensation[having ascites, hepatic encephalopathy, bacterial infection ,gastrointestinal bleeding or jaundice(TB > 5ULN)within 1 month before enrollment].