Chinese CLIF-C Acute-on-Chronic Liver Disease and Liver Failure Study
Condition: Liver Failure, Acute on Chronic
MeSH terms: Liver Diseases; Liver Failure; Hepatic Insufficiency; 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. Currently, there are differences in definitions and descriptions between western
      and eastern types of ACLF, especially in the definition of chronic liver disease and its
      precipitating events. The CANONIC (EASL-CLIF ACLF in Cirrhosis) study put forward CLIF-SOFA
      (chronic liver failure-sequential organ failure assessment) scores as the clinical diagnostic
      criteria of ACLF in 2013. Although the Asian Pacific Association for the Study of the Liver
      (APASL) reached a consensus for diagnostic criteria of ACLF in 2008, it is based on expert
      opinion. This prospective multicenter clinical trial is launched to clarify the eastern type
      of ACLF (HBV related) and estimate whether the eastern and western (alcoholic related) types
      are homogenous. 3 key points of concern are: (1) Whether HBV and non-HBV ACLFs are belonged
      to a homogenous disease entity which share the same diagnostic criteria, disease grades
      classification and prognostic model? (2) Whether acute deteriorating patients from cirrhosis
      or from mild fibrosis (S1-S2) belong to a homogenous entity? (3) To clarify if there are
      heterogenous groups in APASL criteria diagnosed ACLF patients.

      14 Chinese national wide liver centers have been included. Continuous hospitalized chronic
      liver disease patients of various etiologies (including both cirrhotic and non-cirrhotic)
      with acute decompensation (AD) or acute hepatic injury (ALI) (aminotransferase > 3NL(normal
      level)) will be recruited from January to December 2015. Biochemical parameters, organ
      failure will be collected and evaluated at day 1,4,7,14,21 and 28 after enrollment.
      Patients'death and LT (liver transplantation) are the primary and secondary endpoints of
      observation. Mortality and LT rate will be calculated at 28 days,90 days,180 days,1 year and
      2 years after enrollment. Considering there will lack of liver biopsy in most of the
      patients, both CT and FibroScan as supplementary methods to differentiate non-cirrhotic
      patients. The patients will be continuously followed up once a month until the 24th month
      after hospital discharging and follow similar hospitalization process again whenever they
      have new ALI or AD. Data about the patients from stable chronic liver disease to
      deterioration will be acquired analyzed according to the questions hoped to resolve.
    

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
      China, patients with acute deterioration of previously chronic liver disease were diagnosed
      with chronic severe hepatitis, until 2008 these patients had been termed "ACLF", due to the
      APASL reached a consensus of diagnostic criteria of ACLF. 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 its precipitating events.

      The investigators 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 centre 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 pseudolobules. The residual 5% of liver tissues were in the S3 stage
      of progressive liver fibrosis. 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: (1)The age of ACLF patients is younger than that of
      cirrhotic patients with AD. (2)ACLF is exist at any stage of liver fibrosis. (3)The number of
      organ failures decides the severity of the disease and is related to mortality of the
      patient. (4) Predisposition to acute liver injury (ALI) does not correlate with the history
      of the disease and outcome of the patient. (5)The 90-day mortality rate of ACLF is 45-50%,
      which is obviously higher than that of non-ACLF patients (5%). (6)Eastern and western types
      of ACLF can have similar SOFA scores as a diagnostic criterion (CLIF-OF or CLIF-SOFA), and a
      similar prognostic model to predict the outcomes of ACLF and non-ACLF patients. ACLF patients
      with cirrhosis induced by HBV or alcoholism differ in main types of organ failure. The former
      group is liver failure (total bilirubin≥12mg/dl) and coagulation failure(international
      normalized ratio; INR≥2.5), whereas the latter group is renal failure(creatinine≥2mg/dl or
      use of renal replacement therapy) and nervous system failure(hepatic encephalopathy; HE≥III
      grade).

      Research on hepatic pathology in HBV-induced ACLF patients after LT in RenJi Hospital
      demonstrated that the pathological characteristics of ACLF may be MHN/SMHN (massive hepatic
      necrosis/submassive hepatic necrosis) in the background of liver pseudolobules. Regeneration
      of hepatic progenitor cells, cholestasis, and sepsis are other possible pathological features
      of ACLF.

      It is necessary to conduct a prospective multicentre study to clarify the eastern type of
      ACLF and the differences between the eastern and western types of ACLF. The investigators are
      going to identify three key points: (1)Whether HBV and non-HBV ACLFs are belong to a
      homogenous disease entity which share the same diagnostic criteria, disease grades
      classification and prognostic model; (2) Whether acute deteriorating patients from cirrhosis
      or from mild fibrosis (S1-S2) belong to a homogenous entity? (3)To clarify if there are
      heterogenous groups in APASL criteria diagnosed ACLF patients.

      The investigators plan to enroll 2000-3000 consecutive patients from January to December
      2015. The research will be carried out in about 14 Chinese national wide liver centers each
      of whose total beds are around 500.

      The research has two stages. The first stage will be enrollment of 2000-3000 consecutive
      patients from January to December 2015. Only chronic liver disease patients of various
      etiologies with AD or ALI will be enrolled. Biochemical parameters, organ failure evaluation,
      imaging test results treatment therapies will be recorded at day 1,4,7,14,21 and 28 (or last
      visit date) after enrollment according to case report form. If the patients die or undergo
      LT, the data at the 24h prior to death or LT will be also recorded. The second stage will be
      follow-up from January 2016 to December 2017. If the patients improve and are discharged, 24
      months' follow-up should be conducted. Whenever the patients die or have LT, the study will
      be end. Follow-up will be clinical visiting, but telephone call will be acceptable for
      patients unable to attend. 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.

      Every patient will have a unique number. As soon as they are hospitalized, name, age, sex,
      ID(identification) number, telephone number, e-mail address, WeChat(a popular mobile phone
      text and voice messaging communication service) number, family address, and degree of
      education will be collected. The investigators will get the history and etiology of their
      liver disease, such as hepatitis B, 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 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, 4, 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 ratio of
      oxyhemoglobin saturation and fraction of inspired oxygen. The nervous system will be
      evaluated by the 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. Systemic
      inflammatory reactive syndrome, sepsis, severe sepsis and septic shock will also be assessed.
      Gastrointestinal bleeding before and after admission, treatment with diuretics, and
      paracentesis will be recorded. 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 and PCT (procalcitonin). Tests optionally
      done during hospitalization will include autoantibody measurement, blood culture(if the
      patients have fever and shivering), sputum culture(if there is suspicion of pulmonary
      infection),middle urine cultivation(when there is suspicion of urinary tract infection) and
      ascites culture(when there is suspicion of spontaneous bacterial peritonitis).

      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.

      Patients will be followed up regularly after discharge. When 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.

      Follow-up is by clinical visiting or telephone call depending on whether the patient can
      attend the clinic. Clinical follow-up is once a month for 2 years adding to 24 visits. The
      time of visit will be recorded. Antiviral therapy and alcohol intake will be monitored(if the
      patient has). Laboratory tests include routine blood tests, liver and renal function test,
      coagulation test, CRP and PCT. B ultrasound will be done to monitor cirrhosis (or fibrosis)
      and hepatocellular carcinoma. Telephone follow-up will be at 28 days, 3, 6,9, 12, 15, 18, 21
      and 24 months. The investigators will determine whether there are new complications (e.g.
      gastrointestinal bleeding, hepatic encephalopathy, ascites, bacterial infection) and
      hepatocellular carcinoma.

      Referring to the structure of the clinical research of CANONIC study, the investigators will
      meet every three months to exchange results and ideas. All young committee members from
      Chinese Society of Hepatology can campaign for joining in this research. There will be a core
      group with 3-4 members comprising experts with an interest in ACLF. These core members will
      be responsible for making policies. Members of core group are flexible. Monopolizing and
      arbitrariness should be forbidden.

      Independent departments of gastroenterology, hepatology or infectious diseases are a
      requirement of the hospitals. Every hospital should have only one principal investigator (PI)
      as their representative. The PI should be the head of the department and involved in clinical
      work. The PI should make ward rounds at least twice weekly and evaluate the patients beside
      the bed. Young members of Chinese Society of Hepatology will be prioritized for the PI. If
      the young members do not undertake clinical work, they can recommend an eligible attending
      physician.

      There are some measures to guarantee the quality of follow-up. First, set up fast-track
      follow-up cards for each patient. These patients have priority to make an appointment and see
      a doctor. Second, every PI should have their assistants. Every assistant is equipped with a
      cellphone so that patients can call to visit a doctor immediately or be hospitalized in an
      emergency. Third, set up a WeChat group for patients to inform them about follow-up 1 week in
      advance. Fourth, every assistant should master the follow-up strategies.
    

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（having liver dysfunction more than 6 months） with acute
        liver injury[having ALT(alanine aminotransferase)>3NL(normal level),AST(aspartate
        aminotransferase)>3NL or TB(total bilirubin)>2NL 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].
      
Biospecimen description: 
      whole blood, serum, urine, stool, liver tissue
    
Keywords: acute-on-chronic liver disease; acute decompensation; multiple organ failures; acute on chronic liver failure