Acute-on-Chronic Liver Failure in China: Rationale for Developing a Patient Registry and Baseline Characteristics

Acute-on-Chronic Liver Failure in China: Rationale for Developing a Patient Registry and Baseline... Abstract Definitions and descriptions of acute-on-chronic liver failure (ACLF) vary between Western and Eastern types, and alcoholism and hepatitis B virus (HBV) are, respectively, the main etiologies. To determine whether there are unified diagnostic criteria and common treatment programs for different etiologies of ACLF, a multicenter prospective cohort with the same inclusion criteria and disease indicators as those used in the European Consortium Acute-on-Chronic Liver Failure in Cirrhosis Study is urgently needed in Asia, where the prevalence of HBV is high. A multicenter prospective cohort of 2,600 patients was designed, drawing from 14 nationwide liver centers from tertiary university hospitals in China, and 2,600 hospitalized patients with chronic liver disease (both cirrhotic and noncirrhotic) of various etiologies with acute decompensation or acute hepatic injury were continuously recruited from January 2015 to December 2016. Data were collected during hospitalization, and follow-ups were performed once a month, with plans to follow all patients until 36 months after hospital discharge. Of these patients, 1,859 (71.5%) had HBV-related disease, 1,833 had cirrhotic disease, and 767 had noncirrhotic disease. The numbers and proportions of enrolled patients from each participating center and the baseline characteristics of the patients with or without cirrhosis are presented. acute decompensation, acute liver injury, acute-on-chronic liver failure, cirrhosis, noncirrhotic chronic liver disease, outcome, protocol design Acute-on-chronic liver failure (ACLF) is a distinct condition characterized by acute deterioration of liver function in both cirrhotic and noncirrhotic patients, successive multiple-organ failure, and high short-term (28-day) mortality (15%) (1, 2). Alcoholism is the main etiology of Western-type ACLF, with cirrhosis as the primary cause of almost all alcoholism-related ACLF (3). However, hepatitis B virus (HBV) is the main cause of Eastern-type ACLF (4, 5). The predisposition to HBV-related ACLF may affect both cirrhotic and noncirrhotic patients. The prevalence of ACLF has increased in recent decades. For instance, in the United States, it increased from 1.5% of hospitalizations for cirrhosis in 2001 to 5% in 2011 (6), and ACLF inpatient costs increased 5-fold from 2001 to 2011 (6). The economic burden of the treatment of this disease is very high, exceeding £50,000 (US $67,000) per patient in the United Kingdom (7) and over $3 billion in the United States annually (8). Liver transplantation (LT) is the only curative treatment for ACLF (9, 10). In 2013, the European Association for the Study of the Liver–Chronic Liver Failure (EASL-CLIF) Consortium conducted the prospective multicenter EASL-CLIF Acute-on-Chronic Liver Failure in Cirrhosis (CANONIC) Study at 29 liver units in 8 European countries, and they proposed the Chronic Liver Failure–Sequential Organ Failure Assessment (CLIF-SOFA) score as a clinical diagnostic criterion for alcoholism- and HBV-related ACLF. The 90-day mortality of ACLF patients according to CLIF-SOFA scores was as high as 51%, compared with 10% for non-ACLF patients (3). The European CANONIC study also identified systemic inflammatory responses as the primary drivers of multiple-organ failure, which is a typical pathogenesis in Western cirrhotic ACLF patients (3, 11). Submassive hepatic necrosis, as a critical histological feature, has recently been identified in HBV-related cirrhotic ACLF patients, and systemic inflammatory responses by necrotic parenchymal hepatocytes, which cause multiple-organ failure in HBV patients, have a mechanism similar to that in alcoholism-related ACLF (4, 12). However, the lack of multicenter, prospective studies on HBV-related ACLF in Asia has slowed the development of evidence-based diagnostic criteria for Eastern ACLF patients. The current Asian ACLF diagnostic criteria are the Asian Pacific Association for the Study of the Liver (APASL) criteria, which were created by consensus in 2009. The content was improved in 2014 (13, 14), but the criteria are still not supported by multicenter, prospective evidence-based data. The current APASL criteria (also known as the APASL ACLF research consortium (AARC) criteria) for ACLF are based on total bilirubin and the international normalized ratio of prothrombin time, which represent acute liver deterioration or single-organ liver failure (15–17). There is a sharp East-West divide with respect to the definition and diagnostic criteria for ACLF, and the key point is whether ACLF is acute, deteriorated, hepatic single-organ failure, or multiple-organ failure. In addition, the East and West are divided on some key elements of ACLF, such as the exact duration between acute insult and ACLF, what qualifies as the underlying chronic liver disease, organ failure in the definition of ACLF, and how to use mortality to define ACLF (18). Due to the current lack of universally accepted diagnostic criteria for ACLF of distinct etiologies and because the potential risk factors that affect its prognosis remain unclear, the optimal treatment for patients cannot be determined (19). Therefore, a prospective, multicenter study must be conducted to clarify the Eastern type of ACLF and the differences between the Eastern and Western types. Moreover, the inclusion criteria for the Eastern prospective study should be similar to those in the European CANONIC study, to allow comparison and validation of the data (20). Above all, data from a prospective, multicenter cohort in the East and exploration of the characteristics of the disease are urgently required, and the findings will facilitate the development of unified global diagnostic criteria through collaboration with a Western cohort to identify predisposing conditions, identify potential risk factors or biomarkers, and ultimately prevent ACLF. Finally, uniform diagnostic criteria could be used to develop and validate new treatments for ACLF. MATERIALS Aim and study protocol The overall aim was to build a prospective, multicenter, clinical patient cohort representing Eastern-type ACLF in patients with chronic liver disease (cirrhotic and noncirrhotic) of various etiologies, accompanied by acute decompensation (AD) or acute liver injury (ALI), to characterize disease progression and establish appropriate diagnostic criteria. The protocol included the following: Exploration of the epidemiology of inpatients with severe chronic liver disease and a high short-term risk of mortality in hospitals nationwide, including the prevalence of acute deterioration, the disease burden, and the clinical features of patients with short-term mortality. Exploration of the clinical course of patients with short-term mortality, determination of the time interval from acute insults to different endpoints (including AD, organ failure, and death), and identification of the distribution and regularity of mortality within a 1-year follow-up. Implementation of a statistical approach to determine cutoff values for vital organ dysfunction and failure, to establish diagnostic criteria for ACLF patients based on an evidence-based definition of organ failure, to quantify the severity of the disease and establish a prognosis model, to define high–disease risk patients, to determine whether there are universally accepted diagnostic criteria for both Eastern and Western types of the disease, and to distinguish early-stage ACLF patients (pre-ACLF) from non-ACLF patients with AD or ALI. 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 using DNA samples extracted from peripheral blood mononuclear cells; and exploration of the mechanism of ACLF disease progression by studying DNA levels (genome-wide association study), protein levels (proteomic analysis), and metabolite levels (metabolomic analysis). Overview A multicenter, prospective cohort design was used to observe hospitalized patients with AD or ALI at risk of developing ACLF, which leads to rapid deterioration and high mortality. Liver-cirrhotic or noncirrhotic patients with AD or ALI were consecutively recruited from 14 tertiary university hospitals in China. Data were collected according to case-report forms. The follow-up is ongoing and will last for 36 months. Death from any cause is considered the endpoint, and LT is considered a censoring event. Figure 1 shows a flow chart of the study design. Figure 1. View largeDownload slide Flow chart of the study design, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, 2015–2019. In the first stage, chronic liver disease patients with acute hepatic injury (alanine aminotransferase or aspartate aminotransferase >3 × upper limit of normal or total bilirubin >2 × upper limit of normal within 1 week before enrollment) or acute decompensation (ascites, hepatic encephalopathy, bacterial infection, or gastrointestinal bleeding within 1 month before enrollment) were chosen as candidates. In the enrollment stage, we collected measurements and biospecimens for days 1, 4, 7, 14, 21, and 28 as well as 24 hours before death or liver transplantation. Final number for each outcome or censored data will not be available until 2019, when monthly follow-up by clinic visit or phone call is completed. Figure 1. View largeDownload slide Flow chart of the study design, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, 2015–2019. In the first stage, chronic liver disease patients with acute hepatic injury (alanine aminotransferase or aspartate aminotransferase >3 × upper limit of normal or total bilirubin >2 × upper limit of normal within 1 week before enrollment) or acute decompensation (ascites, hepatic encephalopathy, bacterial infection, or gastrointestinal bleeding within 1 month before enrollment) were chosen as candidates. In the enrollment stage, we collected measurements and biospecimens for days 1, 4, 7, 14, 21, and 28 as well as 24 hours before death or liver transplantation. Final number for each outcome or censored data will not be available until 2019, when monthly follow-up by clinic visit or phone call is completed. The study initiated enrollment in January 2015, and enrollment ended in December 2016. Eligibility criteria The inclusion criteria included the following (Web Appendix 1, available at https://academic.oup.com/aje): Inpatients (hospitalization >1 day), including patients in emergency observation wards; and Chronic liver disease patients, including non–alcoholism-related fatty-liver disease patients, chronic liver hepatitis patients without cirrhosis, compensated cirrhosis patients, and decompensated cirrhosis patients; or Patients with ALI (alanine aminotransferase or aspartate aminotransferase >3 × upper limit of normal or total bilirubin >2 × upper limit of normal within 1 week before enrollment) or AD (ascites, hepatic encephalopathy, bacterial infection, or gastrointestinal bleeding within 1 month before enrollment). Patients were excluded if any of the following criteria were met: pregnancy, hepatocellular carcinoma or other liver malignancies, malignancy of other organs, severe chronic extrahepatic disease, and receipt of immunosuppressive drugs for reasons other than chronic liver disease Selection of centers The centers participating in this study met all qualifications (Web Appendix 2). Ultimately, 14 centers from 12 different provinces (Shanghai, Chongqing, Hubei, Beijing, Guangdong, Hunan, Jilin, Fujian, Tianjin, Shandong, Henan, and Xinjiang) participated; their locations are shown in Figure 2. Of the 14 centers, 13 are located in eastern China, in which 94% of the Chinese population resides. One liver center is in western China, in which 6% of the population resides. Figure 2. View largeDownload slide The 14 recruitment centers, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, 2015–2019. Approximately 6% of the total population in China resides west of the dividing line in the figure, and 94% of the total population in China resides east of the line; 13 centers are located in Eastern China, and 1 is located in Western China. Figure 2. View largeDownload slide The 14 recruitment centers, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, 2015–2019. Approximately 6% of the total population in China resides west of the dividing line in the figure, and 94% of the total population in China resides east of the line; 13 centers are located in Eastern China, and 1 is located in Western China. Follow-up The patients were followed for 28 days during hospitalization and regularly after discharge. All-cause mortality was considered the endpoint. LT and loss to follow-up were considered censoring events. During hospitalization, data were collected at 1, 4, 7, 14, 21, and 28 days (or the last day if the patient was hospitalized for less than 28 days) as well as 24 hours prior to death or LT (if the patient died or had LT), with a focus on the following aspects: evaluation of organ failure, laboratory examinations, and biospecimen retention. The status of patient discharge was then recorded, and the recorded information included whether the patient was discharged, died, or had LT, and whether the patient died within 28 days of admission. The time of death and the main cause of death or the time of LT and the results of hepatic pathology were also noted. Any other information considered important for the patient, particularly hospitalization expenses and duration, was also noted. After discharge, follow-up was performed by clinical visit or telephone call depending on whether the patient could attend the clinic. All patients had a home phone, mobile phone, or WeChat number (a popular mobile phone texting and voice messaging communication service; Tencent Inc., Shenzhen, China). To date, we have been unable to contact only approximately 5% of patients by phone, for reasons including not answering the phone, wrong number, refusal to answer questions, a number not in service, and other reasons. Telephone follow-ups were performed at 28 days and monthly, with a planned follow-up of 3 years, and then every 6 months to reinforce telephone follow-ups. At the follow-up contact, if the patient has died, then the time of death and the main cause of death are recorded. If the patient is alive, then the manifestation of new complications (e.g., gastrointestinal bleeding, hepatic encephalopathy, ascites, or bacterial infection) or hepatocellular carcinoma is determined. Antiviral therapy and alcohol intake are monitored (if applicable). If a patient has undergone LT, then the LT time, results of hepatic pathology, and hospital name are recorded. If a patient is lost to follow-up, then the day and reason are noted. Data collection Clinical data All measures for the study are listed in Table 1. The research included hospitalized patients’ data and outpatients’ follow-up data. Overall, 2,600 inpatients were enrolled continuously during January 2015 to December 2016 (ClinicalTrials.gov: NCT02457637). Only cirrhotic or noncirrhotic patients, of various etiologies, with AD or ALI were enrolled. Cirrhosis or absence of cirrhosis was then diagnosed by imaging according to the definition published in Aubé et al. (21). Demographic data, disease history, baseline data, follow-up data after admission, and follow-up data after discharge were recorded. During hospitalization, biochemical parameters, organ failure evaluation, imaging results, and applied treatments were recorded and followed up at days 1, 4, 7, 14, 21, and 28 (or the last day, if hospitalized for less than 28 days) after enrollment, according to the case report forms (Web Appendix 3–5 and Web Table 1). If patients died or underwent LT, then their data at 24 hours prior to death or LT were also recorded. After discharge, the patients were followed. For each discharged patient, a 36-month follow-up is conducted (ongoing) (Web Appendix 6). Table 1. Broad Categories for Each Follow-up Phase, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, 2015–2019 Phase Measurements Demographic data Name, age, sex, identification number, telephone number, e-mail address, WeChata (similar to WhatsAppb) number, family address, and degree of education. History of disease Etiology of liver disease, antiviral therapy, history of cirrhosis and previous acute decompensation, predisposing factors, main cause of admission, and other chronic disease. Baseline (day 1) Organ failure; bacterial infection, systemic inflammatory reactive syndrome, sepsis, severe sepsis, and septic shock; laboratory examinations: routine blood, urine, and stool tests; liver and renal function tests; blood electrolytes; blood-gas analysis; blood glucose; coagulation test; CRP; PCT; HBV antibodies and antigens; antihepatitis A (IgM); HBV-DNA, antihepatitis E (IgM); antihepatitis C; immunoglobulins (IgA, IgG, IgM, and IgG-4); autoantibody measurement; blood culture (if a patient exhibited fever and shivering), sputum culture (for suspected pulmonary infection), middle urine culture (for suspected urinary tract infection), and ascites culture (for suspected spontaneous bacterial peritonitis); imaging: thoracic x-ray or CT; MRI; B-ultrasound, and FibroScanc or other elastography; treatment with diuretics and paracentesis; whether ascites and hepatic encephalopathy could be medically controlled; plasma, PBMC DNA, urine, and liver tissues stored at −80°C. Follow-up after admission (4, 7, 14, 21, and 28 days (or the last day if the patient was hospitalized for less than 28 days) and 24 hours prior to death or LT (if the patient died or had LT)) Organ failure; bacterial infection, systemic inflammatory reactive syndrome, sepsis, severe sepsis, and septic shock; laboratory examinations: routine blood, urine, and stool tests; liver and renal function tests; blood electrolytes; blood glucose; coagulation test; and CRP and PCT. Optional tests during hospitalization included autoantibody measurement, blood culture (if a patient exhibited fever and shivering), sputum culture (for suspected pulmonary infection), middle urine culture (for suspected urinary tract infection), and ascites culture (for suspected spontaneous bacterial peritonitis); treatment with diuretics and paracentesis; whether ascites and hepatic encephalopathy could be medically controlled; status upon discharge.Plasma, PBMC DNA, urine, and liver tissues were stored at −80°C. Follow-up after discharge (monthly for 36 months) Death: the time of death and the main cause of death;Alive: new complications and hepatocellular carcinoma identification; LT: time of LT and hospital name; or loss to follow-up: the time and reason for loss to follow-up. Phase Measurements Demographic data Name, age, sex, identification number, telephone number, e-mail address, WeChata (similar to WhatsAppb) number, family address, and degree of education. History of disease Etiology of liver disease, antiviral therapy, history of cirrhosis and previous acute decompensation, predisposing factors, main cause of admission, and other chronic disease. Baseline (day 1) Organ failure; bacterial infection, systemic inflammatory reactive syndrome, sepsis, severe sepsis, and septic shock; laboratory examinations: routine blood, urine, and stool tests; liver and renal function tests; blood electrolytes; blood-gas analysis; blood glucose; coagulation test; CRP; PCT; HBV antibodies and antigens; antihepatitis A (IgM); HBV-DNA, antihepatitis E (IgM); antihepatitis C; immunoglobulins (IgA, IgG, IgM, and IgG-4); autoantibody measurement; blood culture (if a patient exhibited fever and shivering), sputum culture (for suspected pulmonary infection), middle urine culture (for suspected urinary tract infection), and ascites culture (for suspected spontaneous bacterial peritonitis); imaging: thoracic x-ray or CT; MRI; B-ultrasound, and FibroScanc or other elastography; treatment with diuretics and paracentesis; whether ascites and hepatic encephalopathy could be medically controlled; plasma, PBMC DNA, urine, and liver tissues stored at −80°C. Follow-up after admission (4, 7, 14, 21, and 28 days (or the last day if the patient was hospitalized for less than 28 days) and 24 hours prior to death or LT (if the patient died or had LT)) Organ failure; bacterial infection, systemic inflammatory reactive syndrome, sepsis, severe sepsis, and septic shock; laboratory examinations: routine blood, urine, and stool tests; liver and renal function tests; blood electrolytes; blood glucose; coagulation test; and CRP and PCT. Optional tests during hospitalization included autoantibody measurement, blood culture (if a patient exhibited fever and shivering), sputum culture (for suspected pulmonary infection), middle urine culture (for suspected urinary tract infection), and ascites culture (for suspected spontaneous bacterial peritonitis); treatment with diuretics and paracentesis; whether ascites and hepatic encephalopathy could be medically controlled; status upon discharge.Plasma, PBMC DNA, urine, and liver tissues were stored at −80°C. Follow-up after discharge (monthly for 36 months) Death: the time of death and the main cause of death;Alive: new complications and hepatocellular carcinoma identification; LT: time of LT and hospital name; or loss to follow-up: the time and reason for loss to follow-up. Abbreviations: CRP, C-reactive protein; CT, computed tomography; HBV, hepatitis B virus; IgA, immunoglobulin A; IgG, immunoglobulin G; IgG-4, immunoglobulin G4; IgM, immunoglobulin M; LT, liver transplantation; MRI, magnetic resonance imaging; PBMC, peripheral blood mononuclear cells; PCT, procalcitonin. a Wechat (Tencent Inc., Shenzhen, China). b WhatsApp (WhatsApp Inc., Mountain View, California). c Fibroscan (Echosens Inc., Paris, France). Table 1. Broad Categories for Each Follow-up Phase, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, 2015–2019 Phase Measurements Demographic data Name, age, sex, identification number, telephone number, e-mail address, WeChata (similar to WhatsAppb) number, family address, and degree of education. History of disease Etiology of liver disease, antiviral therapy, history of cirrhosis and previous acute decompensation, predisposing factors, main cause of admission, and other chronic disease. Baseline (day 1) Organ failure; bacterial infection, systemic inflammatory reactive syndrome, sepsis, severe sepsis, and septic shock; laboratory examinations: routine blood, urine, and stool tests; liver and renal function tests; blood electrolytes; blood-gas analysis; blood glucose; coagulation test; CRP; PCT; HBV antibodies and antigens; antihepatitis A (IgM); HBV-DNA, antihepatitis E (IgM); antihepatitis C; immunoglobulins (IgA, IgG, IgM, and IgG-4); autoantibody measurement; blood culture (if a patient exhibited fever and shivering), sputum culture (for suspected pulmonary infection), middle urine culture (for suspected urinary tract infection), and ascites culture (for suspected spontaneous bacterial peritonitis); imaging: thoracic x-ray or CT; MRI; B-ultrasound, and FibroScanc or other elastography; treatment with diuretics and paracentesis; whether ascites and hepatic encephalopathy could be medically controlled; plasma, PBMC DNA, urine, and liver tissues stored at −80°C. Follow-up after admission (4, 7, 14, 21, and 28 days (or the last day if the patient was hospitalized for less than 28 days) and 24 hours prior to death or LT (if the patient died or had LT)) Organ failure; bacterial infection, systemic inflammatory reactive syndrome, sepsis, severe sepsis, and septic shock; laboratory examinations: routine blood, urine, and stool tests; liver and renal function tests; blood electrolytes; blood glucose; coagulation test; and CRP and PCT. Optional tests during hospitalization included autoantibody measurement, blood culture (if a patient exhibited fever and shivering), sputum culture (for suspected pulmonary infection), middle urine culture (for suspected urinary tract infection), and ascites culture (for suspected spontaneous bacterial peritonitis); treatment with diuretics and paracentesis; whether ascites and hepatic encephalopathy could be medically controlled; status upon discharge.Plasma, PBMC DNA, urine, and liver tissues were stored at −80°C. Follow-up after discharge (monthly for 36 months) Death: the time of death and the main cause of death;Alive: new complications and hepatocellular carcinoma identification; LT: time of LT and hospital name; or loss to follow-up: the time and reason for loss to follow-up. Phase Measurements Demographic data Name, age, sex, identification number, telephone number, e-mail address, WeChata (similar to WhatsAppb) number, family address, and degree of education. History of disease Etiology of liver disease, antiviral therapy, history of cirrhosis and previous acute decompensation, predisposing factors, main cause of admission, and other chronic disease. Baseline (day 1) Organ failure; bacterial infection, systemic inflammatory reactive syndrome, sepsis, severe sepsis, and septic shock; laboratory examinations: routine blood, urine, and stool tests; liver and renal function tests; blood electrolytes; blood-gas analysis; blood glucose; coagulation test; CRP; PCT; HBV antibodies and antigens; antihepatitis A (IgM); HBV-DNA, antihepatitis E (IgM); antihepatitis C; immunoglobulins (IgA, IgG, IgM, and IgG-4); autoantibody measurement; blood culture (if a patient exhibited fever and shivering), sputum culture (for suspected pulmonary infection), middle urine culture (for suspected urinary tract infection), and ascites culture (for suspected spontaneous bacterial peritonitis); imaging: thoracic x-ray or CT; MRI; B-ultrasound, and FibroScanc or other elastography; treatment with diuretics and paracentesis; whether ascites and hepatic encephalopathy could be medically controlled; plasma, PBMC DNA, urine, and liver tissues stored at −80°C. Follow-up after admission (4, 7, 14, 21, and 28 days (or the last day if the patient was hospitalized for less than 28 days) and 24 hours prior to death or LT (if the patient died or had LT)) Organ failure; bacterial infection, systemic inflammatory reactive syndrome, sepsis, severe sepsis, and septic shock; laboratory examinations: routine blood, urine, and stool tests; liver and renal function tests; blood electrolytes; blood glucose; coagulation test; and CRP and PCT. Optional tests during hospitalization included autoantibody measurement, blood culture (if a patient exhibited fever and shivering), sputum culture (for suspected pulmonary infection), middle urine culture (for suspected urinary tract infection), and ascites culture (for suspected spontaneous bacterial peritonitis); treatment with diuretics and paracentesis; whether ascites and hepatic encephalopathy could be medically controlled; status upon discharge.Plasma, PBMC DNA, urine, and liver tissues were stored at −80°C. Follow-up after discharge (monthly for 36 months) Death: the time of death and the main cause of death;Alive: new complications and hepatocellular carcinoma identification; LT: time of LT and hospital name; or loss to follow-up: the time and reason for loss to follow-up. Abbreviations: CRP, C-reactive protein; CT, computed tomography; HBV, hepatitis B virus; IgA, immunoglobulin A; IgG, immunoglobulin G; IgG-4, immunoglobulin G4; IgM, immunoglobulin M; LT, liver transplantation; MRI, magnetic resonance imaging; PBMC, peripheral blood mononuclear cells; PCT, procalcitonin. a Wechat (Tencent Inc., Shenzhen, China). b WhatsApp (WhatsApp Inc., Mountain View, California). c Fibroscan (Echosens Inc., Paris, France). Biospecimens All biospecimens containing DNA, including plasma (1 mL–1.5 mL in total) and urine (1 mL–1.5 mL in total), were collected during hospitalization for as long as possible. All samples were stored at −80°C. Quality control Electronic data-capture functions Electronic data-capture functions included electronic case-report form development, data retention and audit trails, logical verification, management of data-related questions, source data validation, database locking, and data storage and export. Personnel training Before the electronic data-capture system was implemented, complete and timely training of personnel was carried out, and then access to the corresponding system rights was granted. Verification by regulatory authorities Internal verification: 1) A telephone check-in was conducted weekly. 2) A principal investigator meeting was conducted every 4 months. 3) Annual on-site verification of the criteria for inclusion, extreme value verification, logical verification, review of critical medical records (such as records regarding infection and hepatitis B reactivation), and verification of critical missing values was performed. External verification: 1) A third-party biological company (BC-BIOSTAT Co. Ltd., Beijing, China) was responsible for data management and data inventory. 2) A statistical plan was developed before the study. 3) The database was sent to the European CLIF data center for third-party quality verification. Archiving of traceable raw data Copies were made of medical records, including medical history records, physical examination data, clinical laboratory examination data, imaging pathology, medication orders. All data were stored on a hard disk and were sent to all the managing centers quarterly, and 3 copies were retained. Cold chain (−70°C) transport Cold chain (−70°C) transport of biochemical samples to the oversight center was carried out to ensure quality and unified management. RESULTS In total, 2,600 patients, including 1,833 patients with cirrhosis and 767 noncirrhotic patients, were enrolled from 14 centers based on imaging tests according to the study design shown in the flow chart (Figure 3). The numbers and proportions of patients from each center are presented in Figure 4. The top 6 centers with the largest numbers of enrolled patients were Ren Ji Hospital, Southwest Hospital, Wuhan Union Hospital, Nanfang Hospital, Beijing Ditan Hospital, and Xiangya Hospital. The numbers of patients enrolled, according to month, in 2015 and 2016 are shown in Figure 5A and 5B. On average, 90 patients per month were enrolled in 2015, and 127 patients per month were enrolled in 2016. Figure 3. View largeDownload slide Enrollment campaign flow diagram, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, 2015–2019. Phase I: recruitment; phase II: hospitalization follow-up at days 1, 4, 7, 14, 21, and 28 as well as 24 hours before death or liver transplantation (LT); phase III: outpatient follow-up every month for 36 months. For phase III, data will not be available until 2019, when monthly follow-up by clinic visit or phone call is completed. Figure 3. View largeDownload slide Enrollment campaign flow diagram, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, 2015–2019. Phase I: recruitment; phase II: hospitalization follow-up at days 1, 4, 7, 14, 21, and 28 as well as 24 hours before death or liver transplantation (LT); phase III: outpatient follow-up every month for 36 months. For phase III, data will not be available until 2019, when monthly follow-up by clinic visit or phone call is completed. Figure 4. View largeDownload slide The number of patients enrolled from each of the 14 centers, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, 2015–2019. Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai; Southwest Hospital, Third Military Medical University, Chongqing; Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei; Nanfang Hospital, Southern Medical University, Guangzhou; Beijing Ditan Hospital, Capital Medical University, Beijing; Xiangya Hospital, Central South University, Hunan; First Hospital of Jilin University (JU), Jilin; Taihe Hospital, Hubei University of Medicine, Hubei; Shanghai Public Health Clinical Centre (SPHCC), Fudan University, Shanghai; Second Hospital of Shandong University (SDU), Shandong; First Affiliated Hospital of Xinjiang Medical University (XMU), Xinjiang; Henan Provincial People’s Hospital, Henan; Tianjin, Affiliated Hospital of Logistics University of People’s Armed Police Force, Tianjin; and Fuzhou General Hospital of Nanjing Military Command, Fujian. Figure 4. View largeDownload slide The number of patients enrolled from each of the 14 centers, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, 2015–2019. Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai; Southwest Hospital, Third Military Medical University, Chongqing; Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei; Nanfang Hospital, Southern Medical University, Guangzhou; Beijing Ditan Hospital, Capital Medical University, Beijing; Xiangya Hospital, Central South University, Hunan; First Hospital of Jilin University (JU), Jilin; Taihe Hospital, Hubei University of Medicine, Hubei; Shanghai Public Health Clinical Centre (SPHCC), Fudan University, Shanghai; Second Hospital of Shandong University (SDU), Shandong; First Affiliated Hospital of Xinjiang Medical University (XMU), Xinjiang; Henan Provincial People’s Hospital, Henan; Tianjin, Affiliated Hospital of Logistics University of People’s Armed Police Force, Tianjin; and Fuzhou General Hospital of Nanjing Military Command, Fujian. Figure 5. View largeDownload slide The number of patients enrolled from each of the 14 centers, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, in 2015 (A) and in 2016 (B). Figure 5. View largeDownload slide The number of patients enrolled from each of the 14 centers, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, in 2015 (A) and in 2016 (B). We collected the patients’ plasma, urine, and peripheral blood mononuclear cell DNA and stored these samples at −80°C. Of the 2,600 patients enrolled, plasma samples were obtained at least once from 1,992 patients, and 2 or more samples were obtained from 692 patients; peripheral blood mononuclear cell DNA was obtained from 2,077 patients. The baseline clinical characteristics on the first day of admission for all enrolled patients with or without cirrhosis are summarized in Table 2. Overall, 74% of the patients were male, and the mean age of the patients was 48 years. In addition, 1,859 patients had HBV-associated ACLF (71.5%), accounting for the vast majority of the etiologies, and only 741 (28.50%) patients had other etiologies. The rates of loss to follow-up at 28, 90, and 180 days and at 1 year were 0.81%, 1.35%, 1.85%, and 5.12%, respectively (Table 3). The numbers of patients lost to follow-up at each center are shown in Table 3. The numbers of patients who underwent transplantation at 28, 90, and 180 days were 131, 171, and 177, respectively, as shown in Table 2. Table 2. Baseline Characteristics and Liver Transplantation Rates of Patients With and Without Cirrhosis on Admission (Day 1) and During Follow-up, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, 2015–2016a Characteristic Enrolled Patients (n = 2,600) Mean (SD) No. % Male sex 1,915 73.65 Age, years 48.34 (12.28) Etiology  Related to HBV 1,859 71.50  Not related to HBV 741 28.50 Laboratory data  Leukocyte count (× 109/L) 5.90 (4.64)  Platelet count (× 109/L) 109 (78)  Serum bilirubin, mg/dL 9.30 (10.32)  INR 1.64 (0.78)  Alanine aminotransferase, U/L 328.21 (515.93)  Aspartate aminotransferase, U/L 262.07 (98.69)  γ-Glutamyltransferase, U/L 127.78 (182.83)  Alkaline phosphatase, U/L 153.13 (126.70)  Serum creatinine, mg/dL 0.87 (0.63)  Serum sodium, mmol/L 137.38 (5.94) Liver transplantation, days  28 131 5.0  90 171 6.5  180 177 6.8 Characteristic Enrolled Patients (n = 2,600) Mean (SD) No. % Male sex 1,915 73.65 Age, years 48.34 (12.28) Etiology  Related to HBV 1,859 71.50  Not related to HBV 741 28.50 Laboratory data  Leukocyte count (× 109/L) 5.90 (4.64)  Platelet count (× 109/L) 109 (78)  Serum bilirubin, mg/dL 9.30 (10.32)  INR 1.64 (0.78)  Alanine aminotransferase, U/L 328.21 (515.93)  Aspartate aminotransferase, U/L 262.07 (98.69)  γ-Glutamyltransferase, U/L 127.78 (182.83)  Alkaline phosphatase, U/L 153.13 (126.70)  Serum creatinine, mg/dL 0.87 (0.63)  Serum sodium, mmol/L 137.38 (5.94) Liver transplantation, days  28 131 5.0  90 171 6.5  180 177 6.8 Abbreviations: HBV, hepatitis B virus; INR, international normalized ratio; SD, standard deviation. a The planned study completion date is 2019. Enrollment took place during 2015–2016. Table 2. Baseline Characteristics and Liver Transplantation Rates of Patients With and Without Cirrhosis on Admission (Day 1) and During Follow-up, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, 2015–2016a Characteristic Enrolled Patients (n = 2,600) Mean (SD) No. % Male sex 1,915 73.65 Age, years 48.34 (12.28) Etiology  Related to HBV 1,859 71.50  Not related to HBV 741 28.50 Laboratory data  Leukocyte count (× 109/L) 5.90 (4.64)  Platelet count (× 109/L) 109 (78)  Serum bilirubin, mg/dL 9.30 (10.32)  INR 1.64 (0.78)  Alanine aminotransferase, U/L 328.21 (515.93)  Aspartate aminotransferase, U/L 262.07 (98.69)  γ-Glutamyltransferase, U/L 127.78 (182.83)  Alkaline phosphatase, U/L 153.13 (126.70)  Serum creatinine, mg/dL 0.87 (0.63)  Serum sodium, mmol/L 137.38 (5.94) Liver transplantation, days  28 131 5.0  90 171 6.5  180 177 6.8 Characteristic Enrolled Patients (n = 2,600) Mean (SD) No. % Male sex 1,915 73.65 Age, years 48.34 (12.28) Etiology  Related to HBV 1,859 71.50  Not related to HBV 741 28.50 Laboratory data  Leukocyte count (× 109/L) 5.90 (4.64)  Platelet count (× 109/L) 109 (78)  Serum bilirubin, mg/dL 9.30 (10.32)  INR 1.64 (0.78)  Alanine aminotransferase, U/L 328.21 (515.93)  Aspartate aminotransferase, U/L 262.07 (98.69)  γ-Glutamyltransferase, U/L 127.78 (182.83)  Alkaline phosphatase, U/L 153.13 (126.70)  Serum creatinine, mg/dL 0.87 (0.63)  Serum sodium, mmol/L 137.38 (5.94) Liver transplantation, days  28 131 5.0  90 171 6.5  180 177 6.8 Abbreviations: HBV, hepatitis B virus; INR, international normalized ratio; SD, standard deviation. a The planned study completion date is 2019. Enrollment took place during 2015–2016. Table 3. Enrolled Number and Percentages of Patients Lost to Follow-up at 28 Days, 90 Days, and 180 Days in Total and at Each Center, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, 2015–2017 Center No. of Patients Enrolled Lost to Follow-up 28 Days, % 90 Days, % 180 Days, % 1 Year, % Total 2,600 0.81 1.35 1.85 5.12 Centera  Ren Ji Hospital 487 0.21 0.21 0.41 1.44  Southwest Hospital 348 0.00 1.15 2.01 7.47  Wuhan Union Hospital 326 2.15 2.76 2.76 5.83  Nanfang Hospital 291 0.00 0.00 0.34 5.15  Beijing Ditan Hospital 281 2.85 4.27 5.69 12.81  Xiangya Hospital 255 0.39 0.39 1.18 4.70  First Hospital of JU 146 0.00 0.68 2.05 4.12  Taihe Hospital 131 0.00 0.00 0.00 0.76  SPHCC 97 0.00 0.00 0.00 0.00  Second Hospital of SDU 76 2.63 3.95 3.95 5.26  First Hospital of XMU 68 0.00 0.00 0.00 0.00  Henan 48 2.08 4.17 4.17 6.25  Tianjin 27 0.00 3.70 3.70 3.70  Fuzhou 19 5.26 5.26 5.26 15.79 Center No. of Patients Enrolled Lost to Follow-up 28 Days, % 90 Days, % 180 Days, % 1 Year, % Total 2,600 0.81 1.35 1.85 5.12 Centera  Ren Ji Hospital 487 0.21 0.21 0.41 1.44  Southwest Hospital 348 0.00 1.15 2.01 7.47  Wuhan Union Hospital 326 2.15 2.76 2.76 5.83  Nanfang Hospital 291 0.00 0.00 0.34 5.15  Beijing Ditan Hospital 281 2.85 4.27 5.69 12.81  Xiangya Hospital 255 0.39 0.39 1.18 4.70  First Hospital of JU 146 0.00 0.68 2.05 4.12  Taihe Hospital 131 0.00 0.00 0.00 0.76  SPHCC 97 0.00 0.00 0.00 0.00  Second Hospital of SDU 76 2.63 3.95 3.95 5.26  First Hospital of XMU 68 0.00 0.00 0.00 0.00  Henan 48 2.08 4.17 4.17 6.25  Tianjin 27 0.00 3.70 3.70 3.70  Fuzhou 19 5.26 5.26 5.26 15.79 Abbreviations: JU, Jilin University; SDU, Shandong University; SPHCC, Shanghai Public Health Clinical Centre; XMU, Xinjiang Medical University. a The full names and locations of the centers are as follows: Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai; Southwest Hospital, Third Military Medical University, Chongqing; Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei; Nanfang Hospital, Southern Medical University, Guangzhou; Beijing Ditan Hospital, Capital Medical University, Beijing; Xiangya Hospital, Central South University, Hunan; First Hospital of Jilin University, Jilin; Taihe Hospital, Hubei University of Medicine, Hubei; Shanghai Public Health Clinical Centre, Fudan University, Shanghai; Second Hospital of Shandong University, Shandong; First Affiliated Hospital of Xinjiang Medical University, Xinjiang; Henan Provincial People’s Hospital, Henan; Tianjin, Affiliated Hospital of Logistics University of People’s Armed Police Force, Tianjin; and Fuzhou General Hospital of Nanjing Military Command, Fujian. Table 3. Enrolled Number and Percentages of Patients Lost to Follow-up at 28 Days, 90 Days, and 180 Days in Total and at Each Center, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, 2015–2017 Center No. of Patients Enrolled Lost to Follow-up 28 Days, % 90 Days, % 180 Days, % 1 Year, % Total 2,600 0.81 1.35 1.85 5.12 Centera  Ren Ji Hospital 487 0.21 0.21 0.41 1.44  Southwest Hospital 348 0.00 1.15 2.01 7.47  Wuhan Union Hospital 326 2.15 2.76 2.76 5.83  Nanfang Hospital 291 0.00 0.00 0.34 5.15  Beijing Ditan Hospital 281 2.85 4.27 5.69 12.81  Xiangya Hospital 255 0.39 0.39 1.18 4.70  First Hospital of JU 146 0.00 0.68 2.05 4.12  Taihe Hospital 131 0.00 0.00 0.00 0.76  SPHCC 97 0.00 0.00 0.00 0.00  Second Hospital of SDU 76 2.63 3.95 3.95 5.26  First Hospital of XMU 68 0.00 0.00 0.00 0.00  Henan 48 2.08 4.17 4.17 6.25  Tianjin 27 0.00 3.70 3.70 3.70  Fuzhou 19 5.26 5.26 5.26 15.79 Center No. of Patients Enrolled Lost to Follow-up 28 Days, % 90 Days, % 180 Days, % 1 Year, % Total 2,600 0.81 1.35 1.85 5.12 Centera  Ren Ji Hospital 487 0.21 0.21 0.41 1.44  Southwest Hospital 348 0.00 1.15 2.01 7.47  Wuhan Union Hospital 326 2.15 2.76 2.76 5.83  Nanfang Hospital 291 0.00 0.00 0.34 5.15  Beijing Ditan Hospital 281 2.85 4.27 5.69 12.81  Xiangya Hospital 255 0.39 0.39 1.18 4.70  First Hospital of JU 146 0.00 0.68 2.05 4.12  Taihe Hospital 131 0.00 0.00 0.00 0.76  SPHCC 97 0.00 0.00 0.00 0.00  Second Hospital of SDU 76 2.63 3.95 3.95 5.26  First Hospital of XMU 68 0.00 0.00 0.00 0.00  Henan 48 2.08 4.17 4.17 6.25  Tianjin 27 0.00 3.70 3.70 3.70  Fuzhou 19 5.26 5.26 5.26 15.79 Abbreviations: JU, Jilin University; SDU, Shandong University; SPHCC, Shanghai Public Health Clinical Centre; XMU, Xinjiang Medical University. a The full names and locations of the centers are as follows: Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai; Southwest Hospital, Third Military Medical University, Chongqing; Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei; Nanfang Hospital, Southern Medical University, Guangzhou; Beijing Ditan Hospital, Capital Medical University, Beijing; Xiangya Hospital, Central South University, Hunan; First Hospital of Jilin University, Jilin; Taihe Hospital, Hubei University of Medicine, Hubei; Shanghai Public Health Clinical Centre, Fudan University, Shanghai; Second Hospital of Shandong University, Shandong; First Affiliated Hospital of Xinjiang Medical University, Xinjiang; Henan Provincial People’s Hospital, Henan; Tianjin, Affiliated Hospital of Logistics University of People’s Armed Police Force, Tianjin; and Fuzhou General Hospital of Nanjing Military Command, Fujian. DISCUSSION Although investigators in 2 Asian countries, South Korea and India (16, 22, 23), have published prospective studies on ACLF, more than 50% of the patients in those studies had alcoholism-related ACLF and could not represent Eastern-type ACLF. Because China has a high prevalence of HBV, a Chinese cohort is more representative of the Eastern type of ACLF. In 2017, Wu et al. (24) published a multicenter study on HBV-related ACLF, but the inclusion criteria for the study were predefined as severe liver injury (total bilirubin ≥5 mg/dL and international normalized ratio ≥1.5) or AD of cirrhosis in chronic HBV-infected patients. Consequently, those whose disease was less severe (total bilirubin <5 mg/dL or international normalized ratio <1.5) at admission but who progressed rapidly and had transitioned into the progressive phase of ACLF within 28 days were likely to be missed. The same inclusion bias might be seen in patients who had extrahepatic organ failure at admission but without liver or coagulation failure. In our study, there was no prior definition of ACLF, allowing more accurate descriptions of the disease, which includes all the chronic liver-disease inpatients at high risk of death. The present study includes the largest multicenter, prospective cohort for investigating ACLF patients in China. This is also, to our knowledge, the first study of a high-risk population of ACLF patients with eligibility criteria and natural disease courses similar to those of the European CANONIC study. This cohort is also the largest cohort of Eastern-type (HBV) ACLF cases in the world, and the data collection has been designed to enable results to be compared with those from European studies to determine the similarities and differences between these types of ACLF. Fourteen Chinese liver centers were included nationwide; all but 1 were located in eastern China, a region representing 94% of the Chinese population, and 1 was in western China, which represents approximately 6% of the total population. In this cohort, 71.5% of the patients had HBV-related ACLF, which is typically representative of Eastern-type ACLF. The patient registry has several methodological strengths. First, compared with the European CANONIC Study and Chinese Group on the Study of Severe Hepatitis B (COSSH) from China, both of which included about 1,300 patients, this registry represents the largest multicenter, prospective cohort of ACLF patients in the world (3, 9, 24). Second, we used rigorous methods for the patient registry, including the registration of the study protocol at ClinicalTrials.gov, prespecification of data items, the use of central and electronic data collection through an electronic data capture system, annual on-site data verification, and archiving of traceable raw data through central storage to ensure quality control in various ways. This approach enabled us to maintain adherence to the study protocol and achieve a relatively high quality of data collection. Moreover, we have accomplished adequate and timely follow-up via active patient follow-up and physician-oriented outpatient on-site visits. The availability of good follow-up data can empower us to address varieties of clinical questions, not just the diagnostic issues. To our knowledge, this is the first large-scale study in China to explore the burden of chronic liver disease in terms of disease progression and deterioration. In addition to addressing the diagnostic criteria of ACLF and disease prediction through biomarkers, new biomarkers of the disease can be explored through multiomics to identify potential intervention targets. Most European studies of ACLF are based on cirrhosis patients. As demonstrated in clinical work conducted in China, researchers agree that noncirrhotic chronic liver disease patients can also develop ACLF despite the absence of supporting evidence. In our cohort, noncirrhotic HBV patients (who are common in Asia) and patients with liver cirrhosis (who are common in Western countries) were included. Therefore, these data can be used to investigate whether ACLF can develop in noncirrhotic patients and whether the disease characteristics of noncirrhotic ACLF patients are consistent with those of cirrhosis patients. European ACLF occurs mainly in patients with decompensated alcoholism-related cirrhosis combined with bacterial infection. These patients’ characteristics and disease durations are very similar to those of severe sepsis patients; thus, the course of the disease is complete in 28 days or less (25, 26). However, the pathology of HBV-related ACLF includes submassive hepatic necrosis (4) or sterile inflammation, both of which are considerable contributors to clinical death later than 28 days. Therefore, this study provides an opportunity to compare the different pathophysiological characteristics of the Eastern and Western types of ACLF to determine their respective natural courses. The present prospective, multicenter clinical patient cohort was developed to establish diagnostic criteria for Eastern-type ACLF by observing and exploring the early characteristics of the disease. More importantly, the study aims to distinguish pre-ACLF patients from non-ACLF patients with AD or ALI, thus providing evidence for timely intervention and improved survival of ACLF patients. This study further focuses on collaborating with the European Association for the Study of the Liver–Chronic Liver Failure Consortium to validate the results of both studies to achieve globally standardized diagnostic criteria, to identify important factors that influence prognosis and to manage them consistently. In the published European CANONIC Study and other Western ACLF studies, the etiology of ACLF is clearly different from that in our study cohort. The main cause of ACLF in the European CANONIC study patients was alcoholism-related liver disease, whereas hepatitis B patients accounted for approximately 70% of our cohort (1, 3, 27). In addition, the European CANONIC Study of multiple organ failure mainly evaluated renal failure, whereas in our cohort, the baseline data analysis showed that liver failure and coagulation abnormalities accounted for most cases (3). Moreover, due to the distinct etiology and characteristics of ACLF, the definitions and thresholds of liver, kidney, and coagulation system damage and failure in the Eastern and Western types of ACLF are not exactly the same. These criteria will need to be reevaluated in a follow-up study. Compared with Western-type ACLF, respiratory failure and circulatory failure are relatively rare in Eastern-type ACLF. Consequently, due to the different proportions of organ failure, 4 of these organs (excluding the respiratory and circulatory systems) can be used as standards for diagnosing ACLF in our subsequent analysis. Nevertheless, the main distinguishing features of Eastern and Western ACLF—namely, failure of different organs due to multiple organ failure and high mortality—are basically the same. The present study lacked liver biopsy specimens, and the diagnosis of cirrhosis was based on both clinical data and imaging. Although FibroScan (Echosens Inc., Paris, France) examination is disturbed by high levels of bilirubin and transaminase and therefore cannot accurately determine cirrhosis, patients without cirrhosis as diagnosed by computed tomography may be found to have early cirrhosis by pathology. In the future, the diagnosis of these noncirrhotic patients will involve the “FIB4” index for estimating hepatic fibrosis, aspartate aminotransferase-to-platelet ratio index (28), and other noninvasive indicators to qualify the disease. Second, it has been reported that hyperbilirubinemia affects the determination of serum creatinine values (29). To minimize this impact, we retested the patients with suspect creatinine levels and calibrated samples using reagents from Roche Diagnostics (Risch-Rotkreuz, Switzerland) (30, 31). Moreover, some data has supported the notion that systemic inflammation may be the primary driver of ACLF pathogenesis in cirrhosis (11, 32). Therefore, in cases of infection, which played a vital role in this study, the presence of bacterial DNA in peripheral blood will be analyzed through next-generation sequencing to identify infection in patients with clinically suspected infection but without a diagnosis of infection or a clear infection site. In summary, our Chinese cohort is the largest multicenter, prospective cohort for investigating ACLF patients in China. This study aims to build a prospective, multicenter clinical patient registry representative of Eastern-type ACLF in patients with chronic liver disease (cirrhotic and noncirrhotic) of various etiologies, accompanied by AD or ALI, to characterize disease progression and establish appropriate diagnostic criteria. ACKNOWLEDGMENTS Author affiliations: Department of Gastroenterology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China (Wen-yi Gu, Hai Li); Shanghai Institute of Digestive Disease, Shanghai, China (Wen-yi Gu, Hai Li); Key Laboratory of Gastroenterology and Hepatology, Chinese Ministry of Health (Shanghai Jiao Tong University), Shanghai, China (Wen-yi Gu, Hai Li); Department of Infectious Diseases, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China (Bao-yan Xu); Chinese Chronic Liver Failure Consortium, China (Bao-yan Xu, Xin Zheng, Jinjun Chen, Xian-bo Wang, Yan Huang, Yan-hang Gao, Zhong-ji Meng, Zhi-ping Qian, Feng Liu, Xiao-bo Lu, Hai Li); Department of Infectious Diseases, Institute of Infection and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (Xin Zheng); Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China (Jinjun Chen); Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China (Xian-bo Wang); Department of Infectious Disease, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Hunan, China (Yan Huang); Department of Hepatology, First Hospital of Jilin University, Jilin, China (Yan-hang Gao); Department of Infectious Disease, Taihe Hospital, Hubei University of Medicine, Hubei, China (Zhong-ji Meng); Department of Liver Intensive Care Unit, Shanghai Public Health Clinical Centre, Fudan University, Shanghai, China (Zhi-ping Qian); Department of Infectious Diseases and Hepatology, Second Hospital of Shandong University, Shandong, China (Feng Liu); Liver Disease Center, First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China (Xiao-bo Lu); Department of Infectious Disease, Henan Provincial People’s Hospital, Henan, China (Jia Shang); Infectious Disease Center, Affiliated Hospital of Logistics University of People’s Armed Police Force, Tianjin, China (Hai Li); Department of Infectious Disease, Fuzhou General Hospital of Nanjing Military Command, Fujian, China (Shao-yang Wang); and Chinese Evidence-Based Medicine Center and Clinical Research, Evaluation and Translation Group (CREAT) Group, West China Hospital, Sichuan University, Sichuan, China (Xin Sun). W.-Y.G., B.-Y.X., X.Z., J.C., X.-B.W., Y.H., contributed equally and share first authorship. This work was supported by the National Science and Technology Major Project (grants 2018ZX10723203 and 2018ZX10302206) and Shanghai Municipal Education Commission–Gaofeng Clinical Medicine and Shanghai Municipal Government Funding (grant 16CR1024B). This study was partly supported by the National Natural Science Foundation of China (grants GZ1263, 81470869, 81670576, 81330038, 81401665, 81270533, 81470038, 81271884, and 81461130019) and the Chongqing Natural Science Foundation (grant cstc2014jcyjA10118). We thank the Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis members and participants for the contributions to this study: Department of Gastroenterology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University—Zeng Bo, Chen Liuying, Yin Shan, Wang Shijin, Zhang Yan; Department of Infectious Diseases, Southwest Hospital, Third Military Medical University (Army Medical University)—Deng Guohong, Sun Shuning, Tan Wenting, Xiang Xiaomei, Dan Yunjie; Department of Infectious Diseases, Institute of Infection and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology—Xiong Shue, Xiong Yan, Zou Congcong; Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University—Li Beiling, Zhu Congyan; Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University—Zhang Qun, Hou Yixin, Li Yuxin, Huang Yunyi; Department of Infectious Disease, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University—Liu Xiaoxiao, Chen Jun; Department of Hepatology, First Hospital of Jilin University—Wen Xiaoyu, Gao Na, Liu Chunyan; Department of Infectious Disease, Taihe Hospital, Hubei University of Medicine—Lei Qing, Luo Sen; Department of Liver Intensive Care Unit, Shanghai Public Health Clinical Centre, Fudan University—Wang Jiefei, Ji Liujuan; Department of Infectious Diseases and Hepatology, Second Hospital of Shandong University—Li Jing, Wang Ziyu; Liver Disease Center, First Affiliated Hospital of Xinjiang Medical University—Jie Fangrong, Li Nan; Department of Infectious Disease, Henan Provincial People’s Hospital—Liu Junping; Infectious Disease Center, Affiliated Hospital of Logistics University of People’s Armed Police Force—Zhang Qing, Zheng Xuequn; and Department of Infectious Disease, Fuzhou General Hospital of Nanjing Military Command—Lin Taofa. Conflict of interest: none declared. Abbreviations ACLF acute-on-chronic liver failure AD acute decompensation ALI acute hepatic injury APASL Asian Pacific Association for the Study of the Liver CANONIC European Association for the Study of the Liver–Chronic Liver Failure Consortium Acute-on-Chronic Liver Failure in Cirrhosis HBV hepatitis B virus LT liver transplantation. REFERENCES 1 Bernal W , Jalan R , Quaglia A , et al. . Acute-on-chronic liver failure . Lancet . 2015 ; 386 ( 10003 ): 1576 – 1587 . Google Scholar CrossRef Search ADS PubMed 2 Arroyo V , Moreau R , Jalan R , et al. . Acute-on-chronic liver failure: a new syndrome that will re-classify cirrhosis . J Hepatol . 2015 ; 62 ( 1 suppl ): S131 – S143 . Google Scholar CrossRef Search ADS PubMed 3 Moreau R , Jalan R , Gines P , et al. . Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis . Gastroenterology . 2013 ; 144 ( 7 ): 1426 – 1437 . Google Scholar CrossRef Search ADS PubMed 4 Li H , Xia Q , Zeng B , et al. . Submassive hepatic necrosis distinguishes HBV-associated acute on chronic liver failure from cirrhotic patients with acute decompensation . J Hepatol . 2015 ; 63 ( 1 ): 50 – 59 . Google Scholar CrossRef Search ADS PubMed 5 Shi Y , Yang Y , Hu Y , et al. . Acute-on-chronic liver failure precipitated by hepatic injury is distinct from that precipitated by extrahepatic insults . Hepatology . 2015 ; 62 ( 1 ): 232 – 242 . Google Scholar CrossRef Search ADS PubMed 6 Allen AM , Kim WR , Moriarty JP , et al. . Time trends in the health care burden and mortality of acute on chronic liver failure in the United States . Hepatology . 2016 ; 64 ( 6 ): 2165 – 2172 . Google Scholar CrossRef Search ADS PubMed 7 Shawcross DL , Austin MJ , Abeles RD , et al. . The impact of organ dysfunction in cirrhosis: survival at a cost? J Hepatol . 2012 ; 56 ( 5 ): 1054 – 1062 . Google Scholar CrossRef Search ADS PubMed 8 Olson JC , Wendon JA , Kramer DJ , et al. . Intensive care of the patient with cirrhosis . Hepatology . 2011 ; 54 ( 5 ): 1864 – 1872 . Google Scholar CrossRef Search ADS PubMed 9 Chan AC , Fan ST . Criteria for liver transplantation in ACLF and outcome . Hepatol Int . 2015 ; 9 ( 3 ): 355 – 359 . Google Scholar CrossRef Search ADS PubMed 10 Li H , Chen HS , Nyberg SL . Extracorporeal liver support and liver transplant for patients with acute-on-chronic liver failure . Semin Liver Dis . 2016 ; 36 ( 2 ): 153 – 160 . Google Scholar CrossRef Search ADS PubMed 11 Clària J , Stauber RE , Coenraad MJ , et al. . Systemic inflammation in decompensated cirrhosis: characterization and role in acute-on-chronic liver failure . Hepatology . 2016 ; 64 ( 4 ): 1249 – 1264 . Google Scholar CrossRef Search ADS PubMed 12 Li H , Chen LY , Zhang NN , et al. . Characteristics, diagnosis and prognosis of acute-on-chronic liver failure in cirrhosis associated to Hepatitis B . Sci Rep . 2016 ; 6 : 25487 . Google Scholar CrossRef Search ADS PubMed 13 Sarin SK , Kedarisetty CK , Abbas Z , et al. . Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL) 2014 . Hepatol Int . 2014 ; 8 ( 4 ): 453 – 471 . Google Scholar CrossRef Search ADS PubMed 14 Sarin SK , Kumar A , Almeida JA , et al. . Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL) . Hepatol Int . 2009 ; 3 : 269 – 282 . Google Scholar CrossRef Search ADS PubMed 15 Maiwall R , Sarin SK , Kumar S , et al. . Development of predisposition, injury, response, organ failure model for predicting acute kidney injury in acute on chronic liver failure . Liver Int . 2017 ; 37 ( 10 ): 1497 – 1507 . Google Scholar CrossRef Search ADS PubMed 16 Choudhury A , Jindal A , Maiwall R , et al. . Liver failure determines the outcome in patients of acute-on-chronic liver failure (ACLF): comparison of APASL ACLF research consortium (AARC) and CLIF-SOFA models . Hepatol Int . 2017 ; 11 ( 5 ): 461 – 471 . Google Scholar CrossRef Search ADS PubMed 17 Choudhury A , Kumar M , Sharma BC , et al. . Systemic inflammatory response syndrome in acute-on-chronic liver failure: relevance of ”golden window”: a prospective study . J Gastroenterol Hepatol . 2017 ; 32 ( 12 ): 1989 – 1997 . Google Scholar CrossRef Search ADS PubMed 18 Duseja A , Singh SP . Toward a better definition of acute-on-chronic liver failure . J Clin Exp Hepatol . 2017 ; 7 ( 3 ): 262 – 265 . Google Scholar CrossRef Search ADS PubMed 19 Durand F , Nadim MK . Management of acute-on-chronic liver failure . Semin Liver Dis . 2016 ; 36 ( 2 ): 141 – 152 . Google Scholar CrossRef Search ADS PubMed 20 Jalan R , Yurdaydin C , Bajaj JS , et al. . Toward an improved definition of acute-on-chronic liver failure . Gastroenterology . 2014 ; 147 ( 1 ): 4 – 10 . Google Scholar CrossRef Search ADS PubMed 21 Aubé C , Bazeries P , Lebigot J , et al. . Liver fibrosis, cirrhosis, and cirrhosis-related nodules: imaging diagnosis and surveillance . Diagn Interv Imaging . 2017 ; 98 ( 6 ): 455 – 468 . Google Scholar CrossRef Search ADS PubMed 22 Kim TY , Song DS , Kim HY , et al. . Characteristics and discrepancies in acute-on-chronic liver failure: need for a unified definition . PLoS One . 2016 ; 11 ( 1 ): e0146745 . Google Scholar CrossRef Search ADS PubMed 23 Shalimar , Saraswat V , Singh SP , et al. . Acute-on-chronic liver failure in India: The Indian National Association for Study of the Liver consortium experience . J Gastroenterol Hepatol . 2016 ; 31 ( 10 ): 1742 – 1749 . Google Scholar CrossRef Search ADS PubMed 24 Wu T , Li J , Shao L , et al. . Development of diagnostic criteria and a prognostic score for hepatitis B virus-related acute-on-chronic liver failure [Published online ahead of print September 19, 2017]. Gut . (doi: 10.1136/gutjnl-2017-314641 ). 25 Singer M , Deutschman CS , Seymour CW , et al. . The third international consensus definitions for sepsis and septic shock (Sepsis-3) . JAMA . 2016 ; 315 ( 8 ): 801 – 810 . Google Scholar CrossRef Search ADS PubMed 26 Wasmuth HE , Kunz D , Yagmur E , et al. . Patients with acute on chronic liver failure display “sepsis-like” immune paralysis . J Hepatol . 2005 ; 42 ( 2 ): 195 – 201 . Google Scholar CrossRef Search ADS PubMed 27 Alam A , Chun Suen K , Ma D . Acute-on-chronic liver failure: recent update . J Biomed Res . 2017 ; 31 ( 3 ): 1 – 18 . Google Scholar PubMed 28 World Health Organization . Guidelines for the Prevention, Care and Treatment of Persons with Chronic Hepatitis B Infection . Geneva, Swtizerland : WHO ; 2015 . (WHO guidelines approved by the guidelines review committee). 29 Nah H , Lee SG , Lee KS , et al. . Evaluation of bilirubin interference and accuracy of six creatinine assays compared with isotope dilution-liquid chromatography mass spectrometry . Clin Biochem . 2016 ; 49 ( 3 ): 274 – 281 . Google Scholar CrossRef Search ADS PubMed 30 Vaishya R , Arora S , Singh B , et al. . Modification of Jaffe’s kinetic method decreases bilirubin interference: a preliminary report . Indian J Clin Biochem . 2010 ; 25 ( 1 ): 64 – 66 . Google Scholar CrossRef Search ADS PubMed 31 Owen LJ , Keevil BG . Does bilirubin cause interference in Roche creatinine methods? Clin Chem . 2007 ; 53 ( 2 ): 370 – 371 . Google Scholar CrossRef Search ADS PubMed 32 Moreau R . The pathogenesis of ACLF: the inflammatory response and immune function . Semin Liver Dis . 2016 ; 36 ( 2 ): 133 – 140 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png American Journal of Epidemiology Oxford University Press

Acute-on-Chronic Liver Failure in China: Rationale for Developing a Patient Registry and Baseline Characteristics

Loading next page...
 
/lp/ou_press/acute-on-chronic-liver-failure-in-china-rationale-for-developing-a-3L0vzHpC53
Publisher
Oxford University Press
Copyright
© The Author(s) 2018. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
ISSN
0002-9262
eISSN
1476-6256
D.O.I.
10.1093/aje/kwy083
Publisher site
See Article on Publisher Site

Abstract

Abstract Definitions and descriptions of acute-on-chronic liver failure (ACLF) vary between Western and Eastern types, and alcoholism and hepatitis B virus (HBV) are, respectively, the main etiologies. To determine whether there are unified diagnostic criteria and common treatment programs for different etiologies of ACLF, a multicenter prospective cohort with the same inclusion criteria and disease indicators as those used in the European Consortium Acute-on-Chronic Liver Failure in Cirrhosis Study is urgently needed in Asia, where the prevalence of HBV is high. A multicenter prospective cohort of 2,600 patients was designed, drawing from 14 nationwide liver centers from tertiary university hospitals in China, and 2,600 hospitalized patients with chronic liver disease (both cirrhotic and noncirrhotic) of various etiologies with acute decompensation or acute hepatic injury were continuously recruited from January 2015 to December 2016. Data were collected during hospitalization, and follow-ups were performed once a month, with plans to follow all patients until 36 months after hospital discharge. Of these patients, 1,859 (71.5%) had HBV-related disease, 1,833 had cirrhotic disease, and 767 had noncirrhotic disease. The numbers and proportions of enrolled patients from each participating center and the baseline characteristics of the patients with or without cirrhosis are presented. acute decompensation, acute liver injury, acute-on-chronic liver failure, cirrhosis, noncirrhotic chronic liver disease, outcome, protocol design Acute-on-chronic liver failure (ACLF) is a distinct condition characterized by acute deterioration of liver function in both cirrhotic and noncirrhotic patients, successive multiple-organ failure, and high short-term (28-day) mortality (15%) (1, 2). Alcoholism is the main etiology of Western-type ACLF, with cirrhosis as the primary cause of almost all alcoholism-related ACLF (3). However, hepatitis B virus (HBV) is the main cause of Eastern-type ACLF (4, 5). The predisposition to HBV-related ACLF may affect both cirrhotic and noncirrhotic patients. The prevalence of ACLF has increased in recent decades. For instance, in the United States, it increased from 1.5% of hospitalizations for cirrhosis in 2001 to 5% in 2011 (6), and ACLF inpatient costs increased 5-fold from 2001 to 2011 (6). The economic burden of the treatment of this disease is very high, exceeding £50,000 (US $67,000) per patient in the United Kingdom (7) and over $3 billion in the United States annually (8). Liver transplantation (LT) is the only curative treatment for ACLF (9, 10). In 2013, the European Association for the Study of the Liver–Chronic Liver Failure (EASL-CLIF) Consortium conducted the prospective multicenter EASL-CLIF Acute-on-Chronic Liver Failure in Cirrhosis (CANONIC) Study at 29 liver units in 8 European countries, and they proposed the Chronic Liver Failure–Sequential Organ Failure Assessment (CLIF-SOFA) score as a clinical diagnostic criterion for alcoholism- and HBV-related ACLF. The 90-day mortality of ACLF patients according to CLIF-SOFA scores was as high as 51%, compared with 10% for non-ACLF patients (3). The European CANONIC study also identified systemic inflammatory responses as the primary drivers of multiple-organ failure, which is a typical pathogenesis in Western cirrhotic ACLF patients (3, 11). Submassive hepatic necrosis, as a critical histological feature, has recently been identified in HBV-related cirrhotic ACLF patients, and systemic inflammatory responses by necrotic parenchymal hepatocytes, which cause multiple-organ failure in HBV patients, have a mechanism similar to that in alcoholism-related ACLF (4, 12). However, the lack of multicenter, prospective studies on HBV-related ACLF in Asia has slowed the development of evidence-based diagnostic criteria for Eastern ACLF patients. The current Asian ACLF diagnostic criteria are the Asian Pacific Association for the Study of the Liver (APASL) criteria, which were created by consensus in 2009. The content was improved in 2014 (13, 14), but the criteria are still not supported by multicenter, prospective evidence-based data. The current APASL criteria (also known as the APASL ACLF research consortium (AARC) criteria) for ACLF are based on total bilirubin and the international normalized ratio of prothrombin time, which represent acute liver deterioration or single-organ liver failure (15–17). There is a sharp East-West divide with respect to the definition and diagnostic criteria for ACLF, and the key point is whether ACLF is acute, deteriorated, hepatic single-organ failure, or multiple-organ failure. In addition, the East and West are divided on some key elements of ACLF, such as the exact duration between acute insult and ACLF, what qualifies as the underlying chronic liver disease, organ failure in the definition of ACLF, and how to use mortality to define ACLF (18). Due to the current lack of universally accepted diagnostic criteria for ACLF of distinct etiologies and because the potential risk factors that affect its prognosis remain unclear, the optimal treatment for patients cannot be determined (19). Therefore, a prospective, multicenter study must be conducted to clarify the Eastern type of ACLF and the differences between the Eastern and Western types. Moreover, the inclusion criteria for the Eastern prospective study should be similar to those in the European CANONIC study, to allow comparison and validation of the data (20). Above all, data from a prospective, multicenter cohort in the East and exploration of the characteristics of the disease are urgently required, and the findings will facilitate the development of unified global diagnostic criteria through collaboration with a Western cohort to identify predisposing conditions, identify potential risk factors or biomarkers, and ultimately prevent ACLF. Finally, uniform diagnostic criteria could be used to develop and validate new treatments for ACLF. MATERIALS Aim and study protocol The overall aim was to build a prospective, multicenter, clinical patient cohort representing Eastern-type ACLF in patients with chronic liver disease (cirrhotic and noncirrhotic) of various etiologies, accompanied by acute decompensation (AD) or acute liver injury (ALI), to characterize disease progression and establish appropriate diagnostic criteria. The protocol included the following: Exploration of the epidemiology of inpatients with severe chronic liver disease and a high short-term risk of mortality in hospitals nationwide, including the prevalence of acute deterioration, the disease burden, and the clinical features of patients with short-term mortality. Exploration of the clinical course of patients with short-term mortality, determination of the time interval from acute insults to different endpoints (including AD, organ failure, and death), and identification of the distribution and regularity of mortality within a 1-year follow-up. Implementation of a statistical approach to determine cutoff values for vital organ dysfunction and failure, to establish diagnostic criteria for ACLF patients based on an evidence-based definition of organ failure, to quantify the severity of the disease and establish a prognosis model, to define high–disease risk patients, to determine whether there are universally accepted diagnostic criteria for both Eastern and Western types of the disease, and to distinguish early-stage ACLF patients (pre-ACLF) from non-ACLF patients with AD or ALI. 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 using DNA samples extracted from peripheral blood mononuclear cells; and exploration of the mechanism of ACLF disease progression by studying DNA levels (genome-wide association study), protein levels (proteomic analysis), and metabolite levels (metabolomic analysis). Overview A multicenter, prospective cohort design was used to observe hospitalized patients with AD or ALI at risk of developing ACLF, which leads to rapid deterioration and high mortality. Liver-cirrhotic or noncirrhotic patients with AD or ALI were consecutively recruited from 14 tertiary university hospitals in China. Data were collected according to case-report forms. The follow-up is ongoing and will last for 36 months. Death from any cause is considered the endpoint, and LT is considered a censoring event. Figure 1 shows a flow chart of the study design. Figure 1. View largeDownload slide Flow chart of the study design, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, 2015–2019. In the first stage, chronic liver disease patients with acute hepatic injury (alanine aminotransferase or aspartate aminotransferase >3 × upper limit of normal or total bilirubin >2 × upper limit of normal within 1 week before enrollment) or acute decompensation (ascites, hepatic encephalopathy, bacterial infection, or gastrointestinal bleeding within 1 month before enrollment) were chosen as candidates. In the enrollment stage, we collected measurements and biospecimens for days 1, 4, 7, 14, 21, and 28 as well as 24 hours before death or liver transplantation. Final number for each outcome or censored data will not be available until 2019, when monthly follow-up by clinic visit or phone call is completed. Figure 1. View largeDownload slide Flow chart of the study design, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, 2015–2019. In the first stage, chronic liver disease patients with acute hepatic injury (alanine aminotransferase or aspartate aminotransferase >3 × upper limit of normal or total bilirubin >2 × upper limit of normal within 1 week before enrollment) or acute decompensation (ascites, hepatic encephalopathy, bacterial infection, or gastrointestinal bleeding within 1 month before enrollment) were chosen as candidates. In the enrollment stage, we collected measurements and biospecimens for days 1, 4, 7, 14, 21, and 28 as well as 24 hours before death or liver transplantation. Final number for each outcome or censored data will not be available until 2019, when monthly follow-up by clinic visit or phone call is completed. The study initiated enrollment in January 2015, and enrollment ended in December 2016. Eligibility criteria The inclusion criteria included the following (Web Appendix 1, available at https://academic.oup.com/aje): Inpatients (hospitalization >1 day), including patients in emergency observation wards; and Chronic liver disease patients, including non–alcoholism-related fatty-liver disease patients, chronic liver hepatitis patients without cirrhosis, compensated cirrhosis patients, and decompensated cirrhosis patients; or Patients with ALI (alanine aminotransferase or aspartate aminotransferase >3 × upper limit of normal or total bilirubin >2 × upper limit of normal within 1 week before enrollment) or AD (ascites, hepatic encephalopathy, bacterial infection, or gastrointestinal bleeding within 1 month before enrollment). Patients were excluded if any of the following criteria were met: pregnancy, hepatocellular carcinoma or other liver malignancies, malignancy of other organs, severe chronic extrahepatic disease, and receipt of immunosuppressive drugs for reasons other than chronic liver disease Selection of centers The centers participating in this study met all qualifications (Web Appendix 2). Ultimately, 14 centers from 12 different provinces (Shanghai, Chongqing, Hubei, Beijing, Guangdong, Hunan, Jilin, Fujian, Tianjin, Shandong, Henan, and Xinjiang) participated; their locations are shown in Figure 2. Of the 14 centers, 13 are located in eastern China, in which 94% of the Chinese population resides. One liver center is in western China, in which 6% of the population resides. Figure 2. View largeDownload slide The 14 recruitment centers, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, 2015–2019. Approximately 6% of the total population in China resides west of the dividing line in the figure, and 94% of the total population in China resides east of the line; 13 centers are located in Eastern China, and 1 is located in Western China. Figure 2. View largeDownload slide The 14 recruitment centers, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, 2015–2019. Approximately 6% of the total population in China resides west of the dividing line in the figure, and 94% of the total population in China resides east of the line; 13 centers are located in Eastern China, and 1 is located in Western China. Follow-up The patients were followed for 28 days during hospitalization and regularly after discharge. All-cause mortality was considered the endpoint. LT and loss to follow-up were considered censoring events. During hospitalization, data were collected at 1, 4, 7, 14, 21, and 28 days (or the last day if the patient was hospitalized for less than 28 days) as well as 24 hours prior to death or LT (if the patient died or had LT), with a focus on the following aspects: evaluation of organ failure, laboratory examinations, and biospecimen retention. The status of patient discharge was then recorded, and the recorded information included whether the patient was discharged, died, or had LT, and whether the patient died within 28 days of admission. The time of death and the main cause of death or the time of LT and the results of hepatic pathology were also noted. Any other information considered important for the patient, particularly hospitalization expenses and duration, was also noted. After discharge, follow-up was performed by clinical visit or telephone call depending on whether the patient could attend the clinic. All patients had a home phone, mobile phone, or WeChat number (a popular mobile phone texting and voice messaging communication service; Tencent Inc., Shenzhen, China). To date, we have been unable to contact only approximately 5% of patients by phone, for reasons including not answering the phone, wrong number, refusal to answer questions, a number not in service, and other reasons. Telephone follow-ups were performed at 28 days and monthly, with a planned follow-up of 3 years, and then every 6 months to reinforce telephone follow-ups. At the follow-up contact, if the patient has died, then the time of death and the main cause of death are recorded. If the patient is alive, then the manifestation of new complications (e.g., gastrointestinal bleeding, hepatic encephalopathy, ascites, or bacterial infection) or hepatocellular carcinoma is determined. Antiviral therapy and alcohol intake are monitored (if applicable). If a patient has undergone LT, then the LT time, results of hepatic pathology, and hospital name are recorded. If a patient is lost to follow-up, then the day and reason are noted. Data collection Clinical data All measures for the study are listed in Table 1. The research included hospitalized patients’ data and outpatients’ follow-up data. Overall, 2,600 inpatients were enrolled continuously during January 2015 to December 2016 (ClinicalTrials.gov: NCT02457637). Only cirrhotic or noncirrhotic patients, of various etiologies, with AD or ALI were enrolled. Cirrhosis or absence of cirrhosis was then diagnosed by imaging according to the definition published in Aubé et al. (21). Demographic data, disease history, baseline data, follow-up data after admission, and follow-up data after discharge were recorded. During hospitalization, biochemical parameters, organ failure evaluation, imaging results, and applied treatments were recorded and followed up at days 1, 4, 7, 14, 21, and 28 (or the last day, if hospitalized for less than 28 days) after enrollment, according to the case report forms (Web Appendix 3–5 and Web Table 1). If patients died or underwent LT, then their data at 24 hours prior to death or LT were also recorded. After discharge, the patients were followed. For each discharged patient, a 36-month follow-up is conducted (ongoing) (Web Appendix 6). Table 1. Broad Categories for Each Follow-up Phase, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, 2015–2019 Phase Measurements Demographic data Name, age, sex, identification number, telephone number, e-mail address, WeChata (similar to WhatsAppb) number, family address, and degree of education. History of disease Etiology of liver disease, antiviral therapy, history of cirrhosis and previous acute decompensation, predisposing factors, main cause of admission, and other chronic disease. Baseline (day 1) Organ failure; bacterial infection, systemic inflammatory reactive syndrome, sepsis, severe sepsis, and septic shock; laboratory examinations: routine blood, urine, and stool tests; liver and renal function tests; blood electrolytes; blood-gas analysis; blood glucose; coagulation test; CRP; PCT; HBV antibodies and antigens; antihepatitis A (IgM); HBV-DNA, antihepatitis E (IgM); antihepatitis C; immunoglobulins (IgA, IgG, IgM, and IgG-4); autoantibody measurement; blood culture (if a patient exhibited fever and shivering), sputum culture (for suspected pulmonary infection), middle urine culture (for suspected urinary tract infection), and ascites culture (for suspected spontaneous bacterial peritonitis); imaging: thoracic x-ray or CT; MRI; B-ultrasound, and FibroScanc or other elastography; treatment with diuretics and paracentesis; whether ascites and hepatic encephalopathy could be medically controlled; plasma, PBMC DNA, urine, and liver tissues stored at −80°C. Follow-up after admission (4, 7, 14, 21, and 28 days (or the last day if the patient was hospitalized for less than 28 days) and 24 hours prior to death or LT (if the patient died or had LT)) Organ failure; bacterial infection, systemic inflammatory reactive syndrome, sepsis, severe sepsis, and septic shock; laboratory examinations: routine blood, urine, and stool tests; liver and renal function tests; blood electrolytes; blood glucose; coagulation test; and CRP and PCT. Optional tests during hospitalization included autoantibody measurement, blood culture (if a patient exhibited fever and shivering), sputum culture (for suspected pulmonary infection), middle urine culture (for suspected urinary tract infection), and ascites culture (for suspected spontaneous bacterial peritonitis); treatment with diuretics and paracentesis; whether ascites and hepatic encephalopathy could be medically controlled; status upon discharge.Plasma, PBMC DNA, urine, and liver tissues were stored at −80°C. Follow-up after discharge (monthly for 36 months) Death: the time of death and the main cause of death;Alive: new complications and hepatocellular carcinoma identification; LT: time of LT and hospital name; or loss to follow-up: the time and reason for loss to follow-up. Phase Measurements Demographic data Name, age, sex, identification number, telephone number, e-mail address, WeChata (similar to WhatsAppb) number, family address, and degree of education. History of disease Etiology of liver disease, antiviral therapy, history of cirrhosis and previous acute decompensation, predisposing factors, main cause of admission, and other chronic disease. Baseline (day 1) Organ failure; bacterial infection, systemic inflammatory reactive syndrome, sepsis, severe sepsis, and septic shock; laboratory examinations: routine blood, urine, and stool tests; liver and renal function tests; blood electrolytes; blood-gas analysis; blood glucose; coagulation test; CRP; PCT; HBV antibodies and antigens; antihepatitis A (IgM); HBV-DNA, antihepatitis E (IgM); antihepatitis C; immunoglobulins (IgA, IgG, IgM, and IgG-4); autoantibody measurement; blood culture (if a patient exhibited fever and shivering), sputum culture (for suspected pulmonary infection), middle urine culture (for suspected urinary tract infection), and ascites culture (for suspected spontaneous bacterial peritonitis); imaging: thoracic x-ray or CT; MRI; B-ultrasound, and FibroScanc or other elastography; treatment with diuretics and paracentesis; whether ascites and hepatic encephalopathy could be medically controlled; plasma, PBMC DNA, urine, and liver tissues stored at −80°C. Follow-up after admission (4, 7, 14, 21, and 28 days (or the last day if the patient was hospitalized for less than 28 days) and 24 hours prior to death or LT (if the patient died or had LT)) Organ failure; bacterial infection, systemic inflammatory reactive syndrome, sepsis, severe sepsis, and septic shock; laboratory examinations: routine blood, urine, and stool tests; liver and renal function tests; blood electrolytes; blood glucose; coagulation test; and CRP and PCT. Optional tests during hospitalization included autoantibody measurement, blood culture (if a patient exhibited fever and shivering), sputum culture (for suspected pulmonary infection), middle urine culture (for suspected urinary tract infection), and ascites culture (for suspected spontaneous bacterial peritonitis); treatment with diuretics and paracentesis; whether ascites and hepatic encephalopathy could be medically controlled; status upon discharge.Plasma, PBMC DNA, urine, and liver tissues were stored at −80°C. Follow-up after discharge (monthly for 36 months) Death: the time of death and the main cause of death;Alive: new complications and hepatocellular carcinoma identification; LT: time of LT and hospital name; or loss to follow-up: the time and reason for loss to follow-up. Abbreviations: CRP, C-reactive protein; CT, computed tomography; HBV, hepatitis B virus; IgA, immunoglobulin A; IgG, immunoglobulin G; IgG-4, immunoglobulin G4; IgM, immunoglobulin M; LT, liver transplantation; MRI, magnetic resonance imaging; PBMC, peripheral blood mononuclear cells; PCT, procalcitonin. a Wechat (Tencent Inc., Shenzhen, China). b WhatsApp (WhatsApp Inc., Mountain View, California). c Fibroscan (Echosens Inc., Paris, France). Table 1. Broad Categories for Each Follow-up Phase, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, 2015–2019 Phase Measurements Demographic data Name, age, sex, identification number, telephone number, e-mail address, WeChata (similar to WhatsAppb) number, family address, and degree of education. History of disease Etiology of liver disease, antiviral therapy, history of cirrhosis and previous acute decompensation, predisposing factors, main cause of admission, and other chronic disease. Baseline (day 1) Organ failure; bacterial infection, systemic inflammatory reactive syndrome, sepsis, severe sepsis, and septic shock; laboratory examinations: routine blood, urine, and stool tests; liver and renal function tests; blood electrolytes; blood-gas analysis; blood glucose; coagulation test; CRP; PCT; HBV antibodies and antigens; antihepatitis A (IgM); HBV-DNA, antihepatitis E (IgM); antihepatitis C; immunoglobulins (IgA, IgG, IgM, and IgG-4); autoantibody measurement; blood culture (if a patient exhibited fever and shivering), sputum culture (for suspected pulmonary infection), middle urine culture (for suspected urinary tract infection), and ascites culture (for suspected spontaneous bacterial peritonitis); imaging: thoracic x-ray or CT; MRI; B-ultrasound, and FibroScanc or other elastography; treatment with diuretics and paracentesis; whether ascites and hepatic encephalopathy could be medically controlled; plasma, PBMC DNA, urine, and liver tissues stored at −80°C. Follow-up after admission (4, 7, 14, 21, and 28 days (or the last day if the patient was hospitalized for less than 28 days) and 24 hours prior to death or LT (if the patient died or had LT)) Organ failure; bacterial infection, systemic inflammatory reactive syndrome, sepsis, severe sepsis, and septic shock; laboratory examinations: routine blood, urine, and stool tests; liver and renal function tests; blood electrolytes; blood glucose; coagulation test; and CRP and PCT. Optional tests during hospitalization included autoantibody measurement, blood culture (if a patient exhibited fever and shivering), sputum culture (for suspected pulmonary infection), middle urine culture (for suspected urinary tract infection), and ascites culture (for suspected spontaneous bacterial peritonitis); treatment with diuretics and paracentesis; whether ascites and hepatic encephalopathy could be medically controlled; status upon discharge.Plasma, PBMC DNA, urine, and liver tissues were stored at −80°C. Follow-up after discharge (monthly for 36 months) Death: the time of death and the main cause of death;Alive: new complications and hepatocellular carcinoma identification; LT: time of LT and hospital name; or loss to follow-up: the time and reason for loss to follow-up. Phase Measurements Demographic data Name, age, sex, identification number, telephone number, e-mail address, WeChata (similar to WhatsAppb) number, family address, and degree of education. History of disease Etiology of liver disease, antiviral therapy, history of cirrhosis and previous acute decompensation, predisposing factors, main cause of admission, and other chronic disease. Baseline (day 1) Organ failure; bacterial infection, systemic inflammatory reactive syndrome, sepsis, severe sepsis, and septic shock; laboratory examinations: routine blood, urine, and stool tests; liver and renal function tests; blood electrolytes; blood-gas analysis; blood glucose; coagulation test; CRP; PCT; HBV antibodies and antigens; antihepatitis A (IgM); HBV-DNA, antihepatitis E (IgM); antihepatitis C; immunoglobulins (IgA, IgG, IgM, and IgG-4); autoantibody measurement; blood culture (if a patient exhibited fever and shivering), sputum culture (for suspected pulmonary infection), middle urine culture (for suspected urinary tract infection), and ascites culture (for suspected spontaneous bacterial peritonitis); imaging: thoracic x-ray or CT; MRI; B-ultrasound, and FibroScanc or other elastography; treatment with diuretics and paracentesis; whether ascites and hepatic encephalopathy could be medically controlled; plasma, PBMC DNA, urine, and liver tissues stored at −80°C. Follow-up after admission (4, 7, 14, 21, and 28 days (or the last day if the patient was hospitalized for less than 28 days) and 24 hours prior to death or LT (if the patient died or had LT)) Organ failure; bacterial infection, systemic inflammatory reactive syndrome, sepsis, severe sepsis, and septic shock; laboratory examinations: routine blood, urine, and stool tests; liver and renal function tests; blood electrolytes; blood glucose; coagulation test; and CRP and PCT. Optional tests during hospitalization included autoantibody measurement, blood culture (if a patient exhibited fever and shivering), sputum culture (for suspected pulmonary infection), middle urine culture (for suspected urinary tract infection), and ascites culture (for suspected spontaneous bacterial peritonitis); treatment with diuretics and paracentesis; whether ascites and hepatic encephalopathy could be medically controlled; status upon discharge.Plasma, PBMC DNA, urine, and liver tissues were stored at −80°C. Follow-up after discharge (monthly for 36 months) Death: the time of death and the main cause of death;Alive: new complications and hepatocellular carcinoma identification; LT: time of LT and hospital name; or loss to follow-up: the time and reason for loss to follow-up. Abbreviations: CRP, C-reactive protein; CT, computed tomography; HBV, hepatitis B virus; IgA, immunoglobulin A; IgG, immunoglobulin G; IgG-4, immunoglobulin G4; IgM, immunoglobulin M; LT, liver transplantation; MRI, magnetic resonance imaging; PBMC, peripheral blood mononuclear cells; PCT, procalcitonin. a Wechat (Tencent Inc., Shenzhen, China). b WhatsApp (WhatsApp Inc., Mountain View, California). c Fibroscan (Echosens Inc., Paris, France). Biospecimens All biospecimens containing DNA, including plasma (1 mL–1.5 mL in total) and urine (1 mL–1.5 mL in total), were collected during hospitalization for as long as possible. All samples were stored at −80°C. Quality control Electronic data-capture functions Electronic data-capture functions included electronic case-report form development, data retention and audit trails, logical verification, management of data-related questions, source data validation, database locking, and data storage and export. Personnel training Before the electronic data-capture system was implemented, complete and timely training of personnel was carried out, and then access to the corresponding system rights was granted. Verification by regulatory authorities Internal verification: 1) A telephone check-in was conducted weekly. 2) A principal investigator meeting was conducted every 4 months. 3) Annual on-site verification of the criteria for inclusion, extreme value verification, logical verification, review of critical medical records (such as records regarding infection and hepatitis B reactivation), and verification of critical missing values was performed. External verification: 1) A third-party biological company (BC-BIOSTAT Co. Ltd., Beijing, China) was responsible for data management and data inventory. 2) A statistical plan was developed before the study. 3) The database was sent to the European CLIF data center for third-party quality verification. Archiving of traceable raw data Copies were made of medical records, including medical history records, physical examination data, clinical laboratory examination data, imaging pathology, medication orders. All data were stored on a hard disk and were sent to all the managing centers quarterly, and 3 copies were retained. Cold chain (−70°C) transport Cold chain (−70°C) transport of biochemical samples to the oversight center was carried out to ensure quality and unified management. RESULTS In total, 2,600 patients, including 1,833 patients with cirrhosis and 767 noncirrhotic patients, were enrolled from 14 centers based on imaging tests according to the study design shown in the flow chart (Figure 3). The numbers and proportions of patients from each center are presented in Figure 4. The top 6 centers with the largest numbers of enrolled patients were Ren Ji Hospital, Southwest Hospital, Wuhan Union Hospital, Nanfang Hospital, Beijing Ditan Hospital, and Xiangya Hospital. The numbers of patients enrolled, according to month, in 2015 and 2016 are shown in Figure 5A and 5B. On average, 90 patients per month were enrolled in 2015, and 127 patients per month were enrolled in 2016. Figure 3. View largeDownload slide Enrollment campaign flow diagram, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, 2015–2019. Phase I: recruitment; phase II: hospitalization follow-up at days 1, 4, 7, 14, 21, and 28 as well as 24 hours before death or liver transplantation (LT); phase III: outpatient follow-up every month for 36 months. For phase III, data will not be available until 2019, when monthly follow-up by clinic visit or phone call is completed. Figure 3. View largeDownload slide Enrollment campaign flow diagram, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, 2015–2019. Phase I: recruitment; phase II: hospitalization follow-up at days 1, 4, 7, 14, 21, and 28 as well as 24 hours before death or liver transplantation (LT); phase III: outpatient follow-up every month for 36 months. For phase III, data will not be available until 2019, when monthly follow-up by clinic visit or phone call is completed. Figure 4. View largeDownload slide The number of patients enrolled from each of the 14 centers, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, 2015–2019. Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai; Southwest Hospital, Third Military Medical University, Chongqing; Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei; Nanfang Hospital, Southern Medical University, Guangzhou; Beijing Ditan Hospital, Capital Medical University, Beijing; Xiangya Hospital, Central South University, Hunan; First Hospital of Jilin University (JU), Jilin; Taihe Hospital, Hubei University of Medicine, Hubei; Shanghai Public Health Clinical Centre (SPHCC), Fudan University, Shanghai; Second Hospital of Shandong University (SDU), Shandong; First Affiliated Hospital of Xinjiang Medical University (XMU), Xinjiang; Henan Provincial People’s Hospital, Henan; Tianjin, Affiliated Hospital of Logistics University of People’s Armed Police Force, Tianjin; and Fuzhou General Hospital of Nanjing Military Command, Fujian. Figure 4. View largeDownload slide The number of patients enrolled from each of the 14 centers, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, 2015–2019. Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai; Southwest Hospital, Third Military Medical University, Chongqing; Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei; Nanfang Hospital, Southern Medical University, Guangzhou; Beijing Ditan Hospital, Capital Medical University, Beijing; Xiangya Hospital, Central South University, Hunan; First Hospital of Jilin University (JU), Jilin; Taihe Hospital, Hubei University of Medicine, Hubei; Shanghai Public Health Clinical Centre (SPHCC), Fudan University, Shanghai; Second Hospital of Shandong University (SDU), Shandong; First Affiliated Hospital of Xinjiang Medical University (XMU), Xinjiang; Henan Provincial People’s Hospital, Henan; Tianjin, Affiliated Hospital of Logistics University of People’s Armed Police Force, Tianjin; and Fuzhou General Hospital of Nanjing Military Command, Fujian. Figure 5. View largeDownload slide The number of patients enrolled from each of the 14 centers, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, in 2015 (A) and in 2016 (B). Figure 5. View largeDownload slide The number of patients enrolled from each of the 14 centers, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, in 2015 (A) and in 2016 (B). We collected the patients’ plasma, urine, and peripheral blood mononuclear cell DNA and stored these samples at −80°C. Of the 2,600 patients enrolled, plasma samples were obtained at least once from 1,992 patients, and 2 or more samples were obtained from 692 patients; peripheral blood mononuclear cell DNA was obtained from 2,077 patients. The baseline clinical characteristics on the first day of admission for all enrolled patients with or without cirrhosis are summarized in Table 2. Overall, 74% of the patients were male, and the mean age of the patients was 48 years. In addition, 1,859 patients had HBV-associated ACLF (71.5%), accounting for the vast majority of the etiologies, and only 741 (28.50%) patients had other etiologies. The rates of loss to follow-up at 28, 90, and 180 days and at 1 year were 0.81%, 1.35%, 1.85%, and 5.12%, respectively (Table 3). The numbers of patients lost to follow-up at each center are shown in Table 3. The numbers of patients who underwent transplantation at 28, 90, and 180 days were 131, 171, and 177, respectively, as shown in Table 2. Table 2. Baseline Characteristics and Liver Transplantation Rates of Patients With and Without Cirrhosis on Admission (Day 1) and During Follow-up, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, 2015–2016a Characteristic Enrolled Patients (n = 2,600) Mean (SD) No. % Male sex 1,915 73.65 Age, years 48.34 (12.28) Etiology  Related to HBV 1,859 71.50  Not related to HBV 741 28.50 Laboratory data  Leukocyte count (× 109/L) 5.90 (4.64)  Platelet count (× 109/L) 109 (78)  Serum bilirubin, mg/dL 9.30 (10.32)  INR 1.64 (0.78)  Alanine aminotransferase, U/L 328.21 (515.93)  Aspartate aminotransferase, U/L 262.07 (98.69)  γ-Glutamyltransferase, U/L 127.78 (182.83)  Alkaline phosphatase, U/L 153.13 (126.70)  Serum creatinine, mg/dL 0.87 (0.63)  Serum sodium, mmol/L 137.38 (5.94) Liver transplantation, days  28 131 5.0  90 171 6.5  180 177 6.8 Characteristic Enrolled Patients (n = 2,600) Mean (SD) No. % Male sex 1,915 73.65 Age, years 48.34 (12.28) Etiology  Related to HBV 1,859 71.50  Not related to HBV 741 28.50 Laboratory data  Leukocyte count (× 109/L) 5.90 (4.64)  Platelet count (× 109/L) 109 (78)  Serum bilirubin, mg/dL 9.30 (10.32)  INR 1.64 (0.78)  Alanine aminotransferase, U/L 328.21 (515.93)  Aspartate aminotransferase, U/L 262.07 (98.69)  γ-Glutamyltransferase, U/L 127.78 (182.83)  Alkaline phosphatase, U/L 153.13 (126.70)  Serum creatinine, mg/dL 0.87 (0.63)  Serum sodium, mmol/L 137.38 (5.94) Liver transplantation, days  28 131 5.0  90 171 6.5  180 177 6.8 Abbreviations: HBV, hepatitis B virus; INR, international normalized ratio; SD, standard deviation. a The planned study completion date is 2019. Enrollment took place during 2015–2016. Table 2. Baseline Characteristics and Liver Transplantation Rates of Patients With and Without Cirrhosis on Admission (Day 1) and During Follow-up, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, 2015–2016a Characteristic Enrolled Patients (n = 2,600) Mean (SD) No. % Male sex 1,915 73.65 Age, years 48.34 (12.28) Etiology  Related to HBV 1,859 71.50  Not related to HBV 741 28.50 Laboratory data  Leukocyte count (× 109/L) 5.90 (4.64)  Platelet count (× 109/L) 109 (78)  Serum bilirubin, mg/dL 9.30 (10.32)  INR 1.64 (0.78)  Alanine aminotransferase, U/L 328.21 (515.93)  Aspartate aminotransferase, U/L 262.07 (98.69)  γ-Glutamyltransferase, U/L 127.78 (182.83)  Alkaline phosphatase, U/L 153.13 (126.70)  Serum creatinine, mg/dL 0.87 (0.63)  Serum sodium, mmol/L 137.38 (5.94) Liver transplantation, days  28 131 5.0  90 171 6.5  180 177 6.8 Characteristic Enrolled Patients (n = 2,600) Mean (SD) No. % Male sex 1,915 73.65 Age, years 48.34 (12.28) Etiology  Related to HBV 1,859 71.50  Not related to HBV 741 28.50 Laboratory data  Leukocyte count (× 109/L) 5.90 (4.64)  Platelet count (× 109/L) 109 (78)  Serum bilirubin, mg/dL 9.30 (10.32)  INR 1.64 (0.78)  Alanine aminotransferase, U/L 328.21 (515.93)  Aspartate aminotransferase, U/L 262.07 (98.69)  γ-Glutamyltransferase, U/L 127.78 (182.83)  Alkaline phosphatase, U/L 153.13 (126.70)  Serum creatinine, mg/dL 0.87 (0.63)  Serum sodium, mmol/L 137.38 (5.94) Liver transplantation, days  28 131 5.0  90 171 6.5  180 177 6.8 Abbreviations: HBV, hepatitis B virus; INR, international normalized ratio; SD, standard deviation. a The planned study completion date is 2019. Enrollment took place during 2015–2016. Table 3. Enrolled Number and Percentages of Patients Lost to Follow-up at 28 Days, 90 Days, and 180 Days in Total and at Each Center, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, 2015–2017 Center No. of Patients Enrolled Lost to Follow-up 28 Days, % 90 Days, % 180 Days, % 1 Year, % Total 2,600 0.81 1.35 1.85 5.12 Centera  Ren Ji Hospital 487 0.21 0.21 0.41 1.44  Southwest Hospital 348 0.00 1.15 2.01 7.47  Wuhan Union Hospital 326 2.15 2.76 2.76 5.83  Nanfang Hospital 291 0.00 0.00 0.34 5.15  Beijing Ditan Hospital 281 2.85 4.27 5.69 12.81  Xiangya Hospital 255 0.39 0.39 1.18 4.70  First Hospital of JU 146 0.00 0.68 2.05 4.12  Taihe Hospital 131 0.00 0.00 0.00 0.76  SPHCC 97 0.00 0.00 0.00 0.00  Second Hospital of SDU 76 2.63 3.95 3.95 5.26  First Hospital of XMU 68 0.00 0.00 0.00 0.00  Henan 48 2.08 4.17 4.17 6.25  Tianjin 27 0.00 3.70 3.70 3.70  Fuzhou 19 5.26 5.26 5.26 15.79 Center No. of Patients Enrolled Lost to Follow-up 28 Days, % 90 Days, % 180 Days, % 1 Year, % Total 2,600 0.81 1.35 1.85 5.12 Centera  Ren Ji Hospital 487 0.21 0.21 0.41 1.44  Southwest Hospital 348 0.00 1.15 2.01 7.47  Wuhan Union Hospital 326 2.15 2.76 2.76 5.83  Nanfang Hospital 291 0.00 0.00 0.34 5.15  Beijing Ditan Hospital 281 2.85 4.27 5.69 12.81  Xiangya Hospital 255 0.39 0.39 1.18 4.70  First Hospital of JU 146 0.00 0.68 2.05 4.12  Taihe Hospital 131 0.00 0.00 0.00 0.76  SPHCC 97 0.00 0.00 0.00 0.00  Second Hospital of SDU 76 2.63 3.95 3.95 5.26  First Hospital of XMU 68 0.00 0.00 0.00 0.00  Henan 48 2.08 4.17 4.17 6.25  Tianjin 27 0.00 3.70 3.70 3.70  Fuzhou 19 5.26 5.26 5.26 15.79 Abbreviations: JU, Jilin University; SDU, Shandong University; SPHCC, Shanghai Public Health Clinical Centre; XMU, Xinjiang Medical University. a The full names and locations of the centers are as follows: Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai; Southwest Hospital, Third Military Medical University, Chongqing; Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei; Nanfang Hospital, Southern Medical University, Guangzhou; Beijing Ditan Hospital, Capital Medical University, Beijing; Xiangya Hospital, Central South University, Hunan; First Hospital of Jilin University, Jilin; Taihe Hospital, Hubei University of Medicine, Hubei; Shanghai Public Health Clinical Centre, Fudan University, Shanghai; Second Hospital of Shandong University, Shandong; First Affiliated Hospital of Xinjiang Medical University, Xinjiang; Henan Provincial People’s Hospital, Henan; Tianjin, Affiliated Hospital of Logistics University of People’s Armed Police Force, Tianjin; and Fuzhou General Hospital of Nanjing Military Command, Fujian. Table 3. Enrolled Number and Percentages of Patients Lost to Follow-up at 28 Days, 90 Days, and 180 Days in Total and at Each Center, Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis, 2015–2017 Center No. of Patients Enrolled Lost to Follow-up 28 Days, % 90 Days, % 180 Days, % 1 Year, % Total 2,600 0.81 1.35 1.85 5.12 Centera  Ren Ji Hospital 487 0.21 0.21 0.41 1.44  Southwest Hospital 348 0.00 1.15 2.01 7.47  Wuhan Union Hospital 326 2.15 2.76 2.76 5.83  Nanfang Hospital 291 0.00 0.00 0.34 5.15  Beijing Ditan Hospital 281 2.85 4.27 5.69 12.81  Xiangya Hospital 255 0.39 0.39 1.18 4.70  First Hospital of JU 146 0.00 0.68 2.05 4.12  Taihe Hospital 131 0.00 0.00 0.00 0.76  SPHCC 97 0.00 0.00 0.00 0.00  Second Hospital of SDU 76 2.63 3.95 3.95 5.26  First Hospital of XMU 68 0.00 0.00 0.00 0.00  Henan 48 2.08 4.17 4.17 6.25  Tianjin 27 0.00 3.70 3.70 3.70  Fuzhou 19 5.26 5.26 5.26 15.79 Center No. of Patients Enrolled Lost to Follow-up 28 Days, % 90 Days, % 180 Days, % 1 Year, % Total 2,600 0.81 1.35 1.85 5.12 Centera  Ren Ji Hospital 487 0.21 0.21 0.41 1.44  Southwest Hospital 348 0.00 1.15 2.01 7.47  Wuhan Union Hospital 326 2.15 2.76 2.76 5.83  Nanfang Hospital 291 0.00 0.00 0.34 5.15  Beijing Ditan Hospital 281 2.85 4.27 5.69 12.81  Xiangya Hospital 255 0.39 0.39 1.18 4.70  First Hospital of JU 146 0.00 0.68 2.05 4.12  Taihe Hospital 131 0.00 0.00 0.00 0.76  SPHCC 97 0.00 0.00 0.00 0.00  Second Hospital of SDU 76 2.63 3.95 3.95 5.26  First Hospital of XMU 68 0.00 0.00 0.00 0.00  Henan 48 2.08 4.17 4.17 6.25  Tianjin 27 0.00 3.70 3.70 3.70  Fuzhou 19 5.26 5.26 5.26 15.79 Abbreviations: JU, Jilin University; SDU, Shandong University; SPHCC, Shanghai Public Health Clinical Centre; XMU, Xinjiang Medical University. a The full names and locations of the centers are as follows: Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai; Southwest Hospital, Third Military Medical University, Chongqing; Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei; Nanfang Hospital, Southern Medical University, Guangzhou; Beijing Ditan Hospital, Capital Medical University, Beijing; Xiangya Hospital, Central South University, Hunan; First Hospital of Jilin University, Jilin; Taihe Hospital, Hubei University of Medicine, Hubei; Shanghai Public Health Clinical Centre, Fudan University, Shanghai; Second Hospital of Shandong University, Shandong; First Affiliated Hospital of Xinjiang Medical University, Xinjiang; Henan Provincial People’s Hospital, Henan; Tianjin, Affiliated Hospital of Logistics University of People’s Armed Police Force, Tianjin; and Fuzhou General Hospital of Nanjing Military Command, Fujian. DISCUSSION Although investigators in 2 Asian countries, South Korea and India (16, 22, 23), have published prospective studies on ACLF, more than 50% of the patients in those studies had alcoholism-related ACLF and could not represent Eastern-type ACLF. Because China has a high prevalence of HBV, a Chinese cohort is more representative of the Eastern type of ACLF. In 2017, Wu et al. (24) published a multicenter study on HBV-related ACLF, but the inclusion criteria for the study were predefined as severe liver injury (total bilirubin ≥5 mg/dL and international normalized ratio ≥1.5) or AD of cirrhosis in chronic HBV-infected patients. Consequently, those whose disease was less severe (total bilirubin <5 mg/dL or international normalized ratio <1.5) at admission but who progressed rapidly and had transitioned into the progressive phase of ACLF within 28 days were likely to be missed. The same inclusion bias might be seen in patients who had extrahepatic organ failure at admission but without liver or coagulation failure. In our study, there was no prior definition of ACLF, allowing more accurate descriptions of the disease, which includes all the chronic liver-disease inpatients at high risk of death. The present study includes the largest multicenter, prospective cohort for investigating ACLF patients in China. This is also, to our knowledge, the first study of a high-risk population of ACLF patients with eligibility criteria and natural disease courses similar to those of the European CANONIC study. This cohort is also the largest cohort of Eastern-type (HBV) ACLF cases in the world, and the data collection has been designed to enable results to be compared with those from European studies to determine the similarities and differences between these types of ACLF. Fourteen Chinese liver centers were included nationwide; all but 1 were located in eastern China, a region representing 94% of the Chinese population, and 1 was in western China, which represents approximately 6% of the total population. In this cohort, 71.5% of the patients had HBV-related ACLF, which is typically representative of Eastern-type ACLF. The patient registry has several methodological strengths. First, compared with the European CANONIC Study and Chinese Group on the Study of Severe Hepatitis B (COSSH) from China, both of which included about 1,300 patients, this registry represents the largest multicenter, prospective cohort of ACLF patients in the world (3, 9, 24). Second, we used rigorous methods for the patient registry, including the registration of the study protocol at ClinicalTrials.gov, prespecification of data items, the use of central and electronic data collection through an electronic data capture system, annual on-site data verification, and archiving of traceable raw data through central storage to ensure quality control in various ways. This approach enabled us to maintain adherence to the study protocol and achieve a relatively high quality of data collection. Moreover, we have accomplished adequate and timely follow-up via active patient follow-up and physician-oriented outpatient on-site visits. The availability of good follow-up data can empower us to address varieties of clinical questions, not just the diagnostic issues. To our knowledge, this is the first large-scale study in China to explore the burden of chronic liver disease in terms of disease progression and deterioration. In addition to addressing the diagnostic criteria of ACLF and disease prediction through biomarkers, new biomarkers of the disease can be explored through multiomics to identify potential intervention targets. Most European studies of ACLF are based on cirrhosis patients. As demonstrated in clinical work conducted in China, researchers agree that noncirrhotic chronic liver disease patients can also develop ACLF despite the absence of supporting evidence. In our cohort, noncirrhotic HBV patients (who are common in Asia) and patients with liver cirrhosis (who are common in Western countries) were included. Therefore, these data can be used to investigate whether ACLF can develop in noncirrhotic patients and whether the disease characteristics of noncirrhotic ACLF patients are consistent with those of cirrhosis patients. European ACLF occurs mainly in patients with decompensated alcoholism-related cirrhosis combined with bacterial infection. These patients’ characteristics and disease durations are very similar to those of severe sepsis patients; thus, the course of the disease is complete in 28 days or less (25, 26). However, the pathology of HBV-related ACLF includes submassive hepatic necrosis (4) or sterile inflammation, both of which are considerable contributors to clinical death later than 28 days. Therefore, this study provides an opportunity to compare the different pathophysiological characteristics of the Eastern and Western types of ACLF to determine their respective natural courses. The present prospective, multicenter clinical patient cohort was developed to establish diagnostic criteria for Eastern-type ACLF by observing and exploring the early characteristics of the disease. More importantly, the study aims to distinguish pre-ACLF patients from non-ACLF patients with AD or ALI, thus providing evidence for timely intervention and improved survival of ACLF patients. This study further focuses on collaborating with the European Association for the Study of the Liver–Chronic Liver Failure Consortium to validate the results of both studies to achieve globally standardized diagnostic criteria, to identify important factors that influence prognosis and to manage them consistently. In the published European CANONIC Study and other Western ACLF studies, the etiology of ACLF is clearly different from that in our study cohort. The main cause of ACLF in the European CANONIC study patients was alcoholism-related liver disease, whereas hepatitis B patients accounted for approximately 70% of our cohort (1, 3, 27). In addition, the European CANONIC Study of multiple organ failure mainly evaluated renal failure, whereas in our cohort, the baseline data analysis showed that liver failure and coagulation abnormalities accounted for most cases (3). Moreover, due to the distinct etiology and characteristics of ACLF, the definitions and thresholds of liver, kidney, and coagulation system damage and failure in the Eastern and Western types of ACLF are not exactly the same. These criteria will need to be reevaluated in a follow-up study. Compared with Western-type ACLF, respiratory failure and circulatory failure are relatively rare in Eastern-type ACLF. Consequently, due to the different proportions of organ failure, 4 of these organs (excluding the respiratory and circulatory systems) can be used as standards for diagnosing ACLF in our subsequent analysis. Nevertheless, the main distinguishing features of Eastern and Western ACLF—namely, failure of different organs due to multiple organ failure and high mortality—are basically the same. The present study lacked liver biopsy specimens, and the diagnosis of cirrhosis was based on both clinical data and imaging. Although FibroScan (Echosens Inc., Paris, France) examination is disturbed by high levels of bilirubin and transaminase and therefore cannot accurately determine cirrhosis, patients without cirrhosis as diagnosed by computed tomography may be found to have early cirrhosis by pathology. In the future, the diagnosis of these noncirrhotic patients will involve the “FIB4” index for estimating hepatic fibrosis, aspartate aminotransferase-to-platelet ratio index (28), and other noninvasive indicators to qualify the disease. Second, it has been reported that hyperbilirubinemia affects the determination of serum creatinine values (29). To minimize this impact, we retested the patients with suspect creatinine levels and calibrated samples using reagents from Roche Diagnostics (Risch-Rotkreuz, Switzerland) (30, 31). Moreover, some data has supported the notion that systemic inflammation may be the primary driver of ACLF pathogenesis in cirrhosis (11, 32). Therefore, in cases of infection, which played a vital role in this study, the presence of bacterial DNA in peripheral blood will be analyzed through next-generation sequencing to identify infection in patients with clinically suspected infection but without a diagnosis of infection or a clear infection site. In summary, our Chinese cohort is the largest multicenter, prospective cohort for investigating ACLF patients in China. This study aims to build a prospective, multicenter clinical patient registry representative of Eastern-type ACLF in patients with chronic liver disease (cirrhotic and noncirrhotic) of various etiologies, accompanied by AD or ALI, to characterize disease progression and establish appropriate diagnostic criteria. ACKNOWLEDGMENTS Author affiliations: Department of Gastroenterology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China (Wen-yi Gu, Hai Li); Shanghai Institute of Digestive Disease, Shanghai, China (Wen-yi Gu, Hai Li); Key Laboratory of Gastroenterology and Hepatology, Chinese Ministry of Health (Shanghai Jiao Tong University), Shanghai, China (Wen-yi Gu, Hai Li); Department of Infectious Diseases, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China (Bao-yan Xu); Chinese Chronic Liver Failure Consortium, China (Bao-yan Xu, Xin Zheng, Jinjun Chen, Xian-bo Wang, Yan Huang, Yan-hang Gao, Zhong-ji Meng, Zhi-ping Qian, Feng Liu, Xiao-bo Lu, Hai Li); Department of Infectious Diseases, Institute of Infection and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (Xin Zheng); Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China (Jinjun Chen); Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University, Beijing, China (Xian-bo Wang); Department of Infectious Disease, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Hunan, China (Yan Huang); Department of Hepatology, First Hospital of Jilin University, Jilin, China (Yan-hang Gao); Department of Infectious Disease, Taihe Hospital, Hubei University of Medicine, Hubei, China (Zhong-ji Meng); Department of Liver Intensive Care Unit, Shanghai Public Health Clinical Centre, Fudan University, Shanghai, China (Zhi-ping Qian); Department of Infectious Diseases and Hepatology, Second Hospital of Shandong University, Shandong, China (Feng Liu); Liver Disease Center, First Affiliated Hospital of Xinjiang Medical University, Xinjiang, China (Xiao-bo Lu); Department of Infectious Disease, Henan Provincial People’s Hospital, Henan, China (Jia Shang); Infectious Disease Center, Affiliated Hospital of Logistics University of People’s Armed Police Force, Tianjin, China (Hai Li); Department of Infectious Disease, Fuzhou General Hospital of Nanjing Military Command, Fujian, China (Shao-yang Wang); and Chinese Evidence-Based Medicine Center and Clinical Research, Evaluation and Translation Group (CREAT) Group, West China Hospital, Sichuan University, Sichuan, China (Xin Sun). W.-Y.G., B.-Y.X., X.Z., J.C., X.-B.W., Y.H., contributed equally and share first authorship. This work was supported by the National Science and Technology Major Project (grants 2018ZX10723203 and 2018ZX10302206) and Shanghai Municipal Education Commission–Gaofeng Clinical Medicine and Shanghai Municipal Government Funding (grant 16CR1024B). This study was partly supported by the National Natural Science Foundation of China (grants GZ1263, 81470869, 81670576, 81330038, 81401665, 81270533, 81470038, 81271884, and 81461130019) and the Chongqing Natural Science Foundation (grant cstc2014jcyjA10118). We thank the Chinese Study of Acute-on-Chronic Liver Failure in Cirrhosis members and participants for the contributions to this study: Department of Gastroenterology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University—Zeng Bo, Chen Liuying, Yin Shan, Wang Shijin, Zhang Yan; Department of Infectious Diseases, Southwest Hospital, Third Military Medical University (Army Medical University)—Deng Guohong, Sun Shuning, Tan Wenting, Xiang Xiaomei, Dan Yunjie; Department of Infectious Diseases, Institute of Infection and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology—Xiong Shue, Xiong Yan, Zou Congcong; Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University—Li Beiling, Zhu Congyan; Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University—Zhang Qun, Hou Yixin, Li Yuxin, Huang Yunyi; Department of Infectious Disease, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University—Liu Xiaoxiao, Chen Jun; Department of Hepatology, First Hospital of Jilin University—Wen Xiaoyu, Gao Na, Liu Chunyan; Department of Infectious Disease, Taihe Hospital, Hubei University of Medicine—Lei Qing, Luo Sen; Department of Liver Intensive Care Unit, Shanghai Public Health Clinical Centre, Fudan University—Wang Jiefei, Ji Liujuan; Department of Infectious Diseases and Hepatology, Second Hospital of Shandong University—Li Jing, Wang Ziyu; Liver Disease Center, First Affiliated Hospital of Xinjiang Medical University—Jie Fangrong, Li Nan; Department of Infectious Disease, Henan Provincial People’s Hospital—Liu Junping; Infectious Disease Center, Affiliated Hospital of Logistics University of People’s Armed Police Force—Zhang Qing, Zheng Xuequn; and Department of Infectious Disease, Fuzhou General Hospital of Nanjing Military Command—Lin Taofa. Conflict of interest: none declared. Abbreviations ACLF acute-on-chronic liver failure AD acute decompensation ALI acute hepatic injury APASL Asian Pacific Association for the Study of the Liver CANONIC European Association for the Study of the Liver–Chronic Liver Failure Consortium Acute-on-Chronic Liver Failure in Cirrhosis HBV hepatitis B virus LT liver transplantation. REFERENCES 1 Bernal W , Jalan R , Quaglia A , et al. . Acute-on-chronic liver failure . Lancet . 2015 ; 386 ( 10003 ): 1576 – 1587 . Google Scholar CrossRef Search ADS PubMed 2 Arroyo V , Moreau R , Jalan R , et al. . Acute-on-chronic liver failure: a new syndrome that will re-classify cirrhosis . J Hepatol . 2015 ; 62 ( 1 suppl ): S131 – S143 . Google Scholar CrossRef Search ADS PubMed 3 Moreau R , Jalan R , Gines P , et al. . Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis . Gastroenterology . 2013 ; 144 ( 7 ): 1426 – 1437 . Google Scholar CrossRef Search ADS PubMed 4 Li H , Xia Q , Zeng B , et al. . Submassive hepatic necrosis distinguishes HBV-associated acute on chronic liver failure from cirrhotic patients with acute decompensation . J Hepatol . 2015 ; 63 ( 1 ): 50 – 59 . Google Scholar CrossRef Search ADS PubMed 5 Shi Y , Yang Y , Hu Y , et al. . Acute-on-chronic liver failure precipitated by hepatic injury is distinct from that precipitated by extrahepatic insults . Hepatology . 2015 ; 62 ( 1 ): 232 – 242 . Google Scholar CrossRef Search ADS PubMed 6 Allen AM , Kim WR , Moriarty JP , et al. . Time trends in the health care burden and mortality of acute on chronic liver failure in the United States . Hepatology . 2016 ; 64 ( 6 ): 2165 – 2172 . Google Scholar CrossRef Search ADS PubMed 7 Shawcross DL , Austin MJ , Abeles RD , et al. . The impact of organ dysfunction in cirrhosis: survival at a cost? J Hepatol . 2012 ; 56 ( 5 ): 1054 – 1062 . Google Scholar CrossRef Search ADS PubMed 8 Olson JC , Wendon JA , Kramer DJ , et al. . Intensive care of the patient with cirrhosis . Hepatology . 2011 ; 54 ( 5 ): 1864 – 1872 . Google Scholar CrossRef Search ADS PubMed 9 Chan AC , Fan ST . Criteria for liver transplantation in ACLF and outcome . Hepatol Int . 2015 ; 9 ( 3 ): 355 – 359 . Google Scholar CrossRef Search ADS PubMed 10 Li H , Chen HS , Nyberg SL . Extracorporeal liver support and liver transplant for patients with acute-on-chronic liver failure . Semin Liver Dis . 2016 ; 36 ( 2 ): 153 – 160 . Google Scholar CrossRef Search ADS PubMed 11 Clària J , Stauber RE , Coenraad MJ , et al. . Systemic inflammation in decompensated cirrhosis: characterization and role in acute-on-chronic liver failure . Hepatology . 2016 ; 64 ( 4 ): 1249 – 1264 . Google Scholar CrossRef Search ADS PubMed 12 Li H , Chen LY , Zhang NN , et al. . Characteristics, diagnosis and prognosis of acute-on-chronic liver failure in cirrhosis associated to Hepatitis B . Sci Rep . 2016 ; 6 : 25487 . Google Scholar CrossRef Search ADS PubMed 13 Sarin SK , Kedarisetty CK , Abbas Z , et al. . Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL) 2014 . Hepatol Int . 2014 ; 8 ( 4 ): 453 – 471 . Google Scholar CrossRef Search ADS PubMed 14 Sarin SK , Kumar A , Almeida JA , et al. . Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL) . Hepatol Int . 2009 ; 3 : 269 – 282 . Google Scholar CrossRef Search ADS PubMed 15 Maiwall R , Sarin SK , Kumar S , et al. . Development of predisposition, injury, response, organ failure model for predicting acute kidney injury in acute on chronic liver failure . Liver Int . 2017 ; 37 ( 10 ): 1497 – 1507 . Google Scholar CrossRef Search ADS PubMed 16 Choudhury A , Jindal A , Maiwall R , et al. . Liver failure determines the outcome in patients of acute-on-chronic liver failure (ACLF): comparison of APASL ACLF research consortium (AARC) and CLIF-SOFA models . Hepatol Int . 2017 ; 11 ( 5 ): 461 – 471 . Google Scholar CrossRef Search ADS PubMed 17 Choudhury A , Kumar M , Sharma BC , et al. . Systemic inflammatory response syndrome in acute-on-chronic liver failure: relevance of ”golden window”: a prospective study . J Gastroenterol Hepatol . 2017 ; 32 ( 12 ): 1989 – 1997 . Google Scholar CrossRef Search ADS PubMed 18 Duseja A , Singh SP . Toward a better definition of acute-on-chronic liver failure . J Clin Exp Hepatol . 2017 ; 7 ( 3 ): 262 – 265 . Google Scholar CrossRef Search ADS PubMed 19 Durand F , Nadim MK . Management of acute-on-chronic liver failure . Semin Liver Dis . 2016 ; 36 ( 2 ): 141 – 152 . Google Scholar CrossRef Search ADS PubMed 20 Jalan R , Yurdaydin C , Bajaj JS , et al. . Toward an improved definition of acute-on-chronic liver failure . Gastroenterology . 2014 ; 147 ( 1 ): 4 – 10 . Google Scholar CrossRef Search ADS PubMed 21 Aubé C , Bazeries P , Lebigot J , et al. . Liver fibrosis, cirrhosis, and cirrhosis-related nodules: imaging diagnosis and surveillance . Diagn Interv Imaging . 2017 ; 98 ( 6 ): 455 – 468 . Google Scholar CrossRef Search ADS PubMed 22 Kim TY , Song DS , Kim HY , et al. . Characteristics and discrepancies in acute-on-chronic liver failure: need for a unified definition . PLoS One . 2016 ; 11 ( 1 ): e0146745 . Google Scholar CrossRef Search ADS PubMed 23 Shalimar , Saraswat V , Singh SP , et al. . Acute-on-chronic liver failure in India: The Indian National Association for Study of the Liver consortium experience . J Gastroenterol Hepatol . 2016 ; 31 ( 10 ): 1742 – 1749 . Google Scholar CrossRef Search ADS PubMed 24 Wu T , Li J , Shao L , et al. . Development of diagnostic criteria and a prognostic score for hepatitis B virus-related acute-on-chronic liver failure [Published online ahead of print September 19, 2017]. Gut . (doi: 10.1136/gutjnl-2017-314641 ). 25 Singer M , Deutschman CS , Seymour CW , et al. . The third international consensus definitions for sepsis and septic shock (Sepsis-3) . JAMA . 2016 ; 315 ( 8 ): 801 – 810 . Google Scholar CrossRef Search ADS PubMed 26 Wasmuth HE , Kunz D , Yagmur E , et al. . Patients with acute on chronic liver failure display “sepsis-like” immune paralysis . J Hepatol . 2005 ; 42 ( 2 ): 195 – 201 . Google Scholar CrossRef Search ADS PubMed 27 Alam A , Chun Suen K , Ma D . Acute-on-chronic liver failure: recent update . J Biomed Res . 2017 ; 31 ( 3 ): 1 – 18 . Google Scholar PubMed 28 World Health Organization . Guidelines for the Prevention, Care and Treatment of Persons with Chronic Hepatitis B Infection . Geneva, Swtizerland : WHO ; 2015 . (WHO guidelines approved by the guidelines review committee). 29 Nah H , Lee SG , Lee KS , et al. . Evaluation of bilirubin interference and accuracy of six creatinine assays compared with isotope dilution-liquid chromatography mass spectrometry . Clin Biochem . 2016 ; 49 ( 3 ): 274 – 281 . Google Scholar CrossRef Search ADS PubMed 30 Vaishya R , Arora S , Singh B , et al. . Modification of Jaffe’s kinetic method decreases bilirubin interference: a preliminary report . Indian J Clin Biochem . 2010 ; 25 ( 1 ): 64 – 66 . Google Scholar CrossRef Search ADS PubMed 31 Owen LJ , Keevil BG . Does bilirubin cause interference in Roche creatinine methods? Clin Chem . 2007 ; 53 ( 2 ): 370 – 371 . Google Scholar CrossRef Search ADS PubMed 32 Moreau R . The pathogenesis of ACLF: the inflammatory response and immune function . Semin Liver Dis . 2016 ; 36 ( 2 ): 133 – 140 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

American Journal of EpidemiologyOxford University Press

Published: May 14, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off