A Validation Cohort for ACLF Diagnosis and Prognosis
Condition: Liver Failure, Acute on Chronic; Liver Dysfunction
MeSH terms: Liver Failure; Hepatic Insufficiency; Liver Diseases; Liver Failure, Acute; Acute-On-Chronic Liver Failure
Study type: Observational

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Standary therapy
Intervention type(s): Other
Intervention description(s): Standary therapy for chronic liver disease with ALI and/or AD
Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        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].
      
Biospecimen description: 
      whole blood, serum
    
Keywords: acute-on-chronic liver disease; acute decompensation; multiple organ failures; acute-on-chronic liver failure