Chinese CLIF-C Acute-on-Chronic Liver Disease and Liver Failure Study
Chinese CLIF-C Acute-on-Chronic Liver Disease and Liver Failure Study
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.
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.
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)>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].

 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