Accepted Article
Prior Decompensation is associated with Delayed Mortality in Patients with Acute-on-chronic Liver Failure
1
Yu Shi2#, Minghua Zheng3#, Yang Ying2, Wei Wu2, Qiao Yang4, Yihua Wu5, Huadong Yan1*
1.
Department of Hepatology, Ningbo No.2 Hospital, Ningbo 315010, China
2. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China 3.
Department of Infection and Liver Diseases, Liver Research Center, The First
Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
4. Department of Infectious Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China 5.
Department of Epidemiology and Health Statistics, Zhejiang University School of
Public Health, Hangzhou 310058, China # The authors contribute to the work equally ﹡Corresponding author: Dr. Huadong Yan, Department of Hepatology, Ningbo No.2 Hospital, 315010. Tel:86-0574-83870999, fax:86-0574-83870612, Email address: [email protected]. Short title: Distinct subgroups among ACLF
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences
between this version and the Version of Record. Please cite this article as doi: 10.1111/jgh.12787 This article is protected by copyright. All rights reserved.
Accepted Article
Abstract Background and aims: Patients with acute-on-chronic liver failure (ACLF) represent a complex population with differential prognosis. The aim of the study was to categorize ACLF according to the severity of underlying chronic liver diseases (CLD). Methods: A total of 540 ACLF patients were recruited, including 127 with prior decompensated cirrhosis and 413 without prior decompensation (PD) including 193 with underlying chronic hepatitis and 220 with prior compensated cirrhosis. The clinical characteristics and prognosis of subgroups were compared. Cox proportional hazard model and multinominal logistic regression analysis were performed to identify significant prognostic parameters. Results: The 28-day, 3-month and 1-year survival of ACLF patients with or without PD were 58.9% versus 61.4%, 36.2 versus 52.5% and 29.1% versus 49.6%, respectively. On multinominal logistic regression analysis or time-to-death analysis by Cox proportional hazard model, PD was significantly associated with post-28-day mortality but not within-28-day mortality. On multivariate time-to-death analysis, elder age, high INR and serum bilirubin, low levels of serum sodium and platelet count, and presence of hepatic
encephalopathy (HE), upper gastrointestinal bleeding, respiratory or circulation dysfunction were predictors of within-28-day mortality in patients without PD, whereas the risk factors in patients with PD were high INR, creatinine, presence of HE, respiratory or
circulation dysfunction.
This article is protected by copyright. All rights reserved.
Accepted Article
Conclusions: ACLF patients with or without PD had comparable short-term prognosis but differential 1-year mortality. ACLF patients with PD were distinct from those without PD in age, types of acute insults, severity of hepatic damage and distribution of complications and the former group was characterized by increased delayed mortality. Key words: acute-on-chronic liver failure; cirrhosis; decompensation; prognosis
Introduction Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome defined as “acute
deterioration of preexisting, chronic liver disease due to a precipitating event and associated with high short-term mortality”1. As the etiology of underlying chronic liver diseases (CLD) and the type of precipitating events are different throughout the world, the diagnosis criteria of ACLF are not standardised 2-4. Among the Asian population, the Asian
Pacific Association for the Study of the Liver (APSAL) defines the underlying chronic liver diseases as compensated cirrhosis, chronic hepatitis and other chronic liver diseases”, and liver failure as “serum bilirubin≥5 mg/dl and coagulopathy (INR≥1.5 or prothrombin activity < 40%), complicated with ascites and/or hepatic encephalopathy”2. However, in
clinical practice, it is more common that cirrhotic patients, who undergo a prior hepatic decompensation, present a rapid deterioration of preexisting chronic liver disease fulfilling the “liver failure” criteria after a recent acute insult. And those patients are treated in the same way as “APSAL-defined ACLF patients”1, 5-6. However, it is unclear whether those with a history of hepatic decompensation would have a poorer short-term outcome compared with patients with compensated CLD or the prior de-compensation would have
This article is protected by copyright. All rights reserved.
Accepted Article
significant impact on the long-term recovery from acute insults. The aim of this retrospective cohort study was to extend APASL criteria to cirrhotic patients with prior de-compensation and to compare disease course, short-term and long-term prognosis of ACLF patients according to the severity of pre-existing chronic liver disease.
Patients and methods Study population Patients who were suspected as having ACLF and were referred between January 3, 2007 and May 3, 2013 in Ningbo No.2 Hospital were screened. For patients with chronic hepatitis or compensated cirrhosis, the diagnosis of ACLF was based on the guidelines of APASL: (i) acute deterioration of chronic liver diseases expressed as jaundice (serum bilirubin ≥ 5 mg/dl [85µmol/L]) and coagulopathy (INR ≥ 1.5 or prothrombin activity < 40%); (ii) overt ascites (detected by physical examination) and/or hepatic encephalopathy (HE) occurring within 4 weeks2. For those with piror decompensation, a revised APASL criteria was used: (i) acute deterioration of chronic liver diseases expressed as jaundice (serum bilirubin ≥ 5 mg/dl [85µmol/L]) and coagulopathy (INR ≥ 1.5 or prothrombin activity < 40%); (ii) any type of extra-hepatic organ dysfunction [kideny dysfunction: serum creatinine > 1.5 mg dl-1 without the presence of chronic kidney diseases7; cerebral dysfunction: presence
of
hepatic encephalopathy;
respiratory dysfunction
was
defined
as
PaO2/FiO2≤200 or SpO2/FiO2≤214 or need for mechanical ventilation8; circulation
dysfunction was defined as MAP < 70 mm Hg despite adequate fluid resuscitation and need for vasopressors8). In addition, we excluded patients with human immunodeficiency This article is protected by copyright. All rights reserved.
Accepted Article
virus (HIV) infection, tumors, renal diseases, severe cardiopulmonary co-morbidity and those who had received a liver transplant. Among those undergoing liver transplantation, 10 were treated within 28 days after diagonosis of ACLF, 6 between 28 days and 3 months, and 2 after 3 months. The detailed information for those 18 patients is shown in
supplementary information. The study fulfilled the principles of the Declaration of Helsinki and was approved by the ethics committee of Ningbo No.2 Hospital. Written consent was obtained from each participant.
Diagnostic criteria for underlying liver diseases, acute precipitating events and complications The diagnostic criteria for cirrhosis included liver biopsy (whenever possible), endoscopic
signs of portal hypertension, radiological evidence of liver nodularity or clinical evidence of prior hepatic de-compensation in patient with chronic liver diseases9. Events of hepatic
decompensation included ascites, hepatic encephalopathy and upper gastrointestinal
bleeding. Various hepatic insults (i.e.flare-up of chronic hepatitis B [CHB], Hepatitis A virus[HAV] or Hepatitis E virus [HEV] infection, active drinking; or use of hepatotoxic drugs) and non-hepatic insults (i.e.surgery, variceal bleeding and non-hepatotropic infection) were screened to identify acute precipitating events as previously described10. Non-hepatic insults were classified as acute precipitating events only after hepatic acute events had been excluded. Overt ascites was diagnosed by clinical examination and ultrasonography as previously described11. Hepatic encephalopathy (HE) was defined as
an episode of neurological and neuropsychiatric abnormality12.
This article is protected by copyright. All rights reserved.
Accepted Article
Patient management, end-points and follow-up As previously described12, the general management of ACLF patients included resting, bowel washing, plasma transfusion and energy-supporting. Nucleos(t)ide analogs were used in ACLF patients with evidence of HBV replication and the following regimen have been used: lamivudine 100 mg daily, telbivudine 600 mg daily, entecavir 0.5 mg daily, and lamivudine 100 mg plus adefovir 10 mg daily. The treatment of hepatic de-compensation such as ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatic encephalopathy and variceal bleeding were based on relevant guidelines. For patients with circulation dysfunction, fluid replacement was performed and vasoactive drugs were used when necessary. Nasal catheter, mask or venturi mask oxygen inhalation or mechanical ventilation was chosen according to the severity of respiratory dysfunction.
The starting date of the follow-up was the date of diagnosis of ACLF and the planned follow-up in the study was 1-year. For patients discharged from hospital, prognostic information was obtained by checking medical records or by contacting the patients’ families. The primary endpoint of the study was mortality at 1-year, 28-day and post-28-day.
Statistical analysis Continuous variables were expressed as the mean standard deviation (SD) or the median with the interquartile range. Binary or nominal variables were expressed as a number and percentage of the total patient population. Groups were compared using
This article is protected by copyright. All rights reserved.
Accepted Article
Student’s t-test, the Mann-Whitney u-test or a Chi-square test. Survival curves were drawn to describe the prognosis of subgroups of ACLF patients; the cumulative incidence of death was compared using the Log-rank test. Mutlinomial logistical regression analysis was performed to identify factors associated with multiple outcomes (within 28-day death, post-28-day death and survival). In mutlinomial logistical regression analysis, all the continuous variables were dichotomized into binary variables and the cut-off point was chosen according to clinical practice. In addition, Cox proportional hazard model was also used to analyze the factors associated with mortality from a time-to-death perspective. In
Cox proportional hazard regression, it should be noted that only patients surviving after 28 days were considered when analyzing factors associated with post-28-day mortality. For all multivariate analyses, univariate analysis was performed to screen the potential risk factors of poor prognosis. Then, candidate variables (p-value
Prior Decompensation is associated with Delayed Mortality in Patients with Acute-on-chronic Liver Failure
1
Yu Shi2#, Minghua Zheng3#, Yang Ying2, Wei Wu2, Qiao Yang4, Yihua Wu5, Huadong Yan1*
1.
Department of Hepatology, Ningbo No.2 Hospital, Ningbo 315010, China
2. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China 3.
Department of Infection and Liver Diseases, Liver Research Center, The First
Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
4. Department of Infectious Diseases, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, China 5.
Department of Epidemiology and Health Statistics, Zhejiang University School of
Public Health, Hangzhou 310058, China # The authors contribute to the work equally ﹡Corresponding author: Dr. Huadong Yan, Department of Hepatology, Ningbo No.2 Hospital, 315010. Tel:86-0574-83870999, fax:86-0574-83870612, Email address: [email protected]. Short title: Distinct subgroups among ACLF
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences
between this version and the Version of Record. Please cite this article as doi: 10.1111/jgh.12787 This article is protected by copyright. All rights reserved.
Accepted Article
Abstract Background and aims: Patients with acute-on-chronic liver failure (ACLF) represent a complex population with differential prognosis. The aim of the study was to categorize ACLF according to the severity of underlying chronic liver diseases (CLD). Methods: A total of 540 ACLF patients were recruited, including 127 with prior decompensated cirrhosis and 413 without prior decompensation (PD) including 193 with underlying chronic hepatitis and 220 with prior compensated cirrhosis. The clinical characteristics and prognosis of subgroups were compared. Cox proportional hazard model and multinominal logistic regression analysis were performed to identify significant prognostic parameters. Results: The 28-day, 3-month and 1-year survival of ACLF patients with or without PD were 58.9% versus 61.4%, 36.2 versus 52.5% and 29.1% versus 49.6%, respectively. On multinominal logistic regression analysis or time-to-death analysis by Cox proportional hazard model, PD was significantly associated with post-28-day mortality but not within-28-day mortality. On multivariate time-to-death analysis, elder age, high INR and serum bilirubin, low levels of serum sodium and platelet count, and presence of hepatic
encephalopathy (HE), upper gastrointestinal bleeding, respiratory or circulation dysfunction were predictors of within-28-day mortality in patients without PD, whereas the risk factors in patients with PD were high INR, creatinine, presence of HE, respiratory or
circulation dysfunction.
This article is protected by copyright. All rights reserved.
Accepted Article
Conclusions: ACLF patients with or without PD had comparable short-term prognosis but differential 1-year mortality. ACLF patients with PD were distinct from those without PD in age, types of acute insults, severity of hepatic damage and distribution of complications and the former group was characterized by increased delayed mortality. Key words: acute-on-chronic liver failure; cirrhosis; decompensation; prognosis
Introduction Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome defined as “acute
deterioration of preexisting, chronic liver disease due to a precipitating event and associated with high short-term mortality”1. As the etiology of underlying chronic liver diseases (CLD) and the type of precipitating events are different throughout the world, the diagnosis criteria of ACLF are not standardised 2-4. Among the Asian population, the Asian
Pacific Association for the Study of the Liver (APSAL) defines the underlying chronic liver diseases as compensated cirrhosis, chronic hepatitis and other chronic liver diseases”, and liver failure as “serum bilirubin≥5 mg/dl and coagulopathy (INR≥1.5 or prothrombin activity < 40%), complicated with ascites and/or hepatic encephalopathy”2. However, in
clinical practice, it is more common that cirrhotic patients, who undergo a prior hepatic decompensation, present a rapid deterioration of preexisting chronic liver disease fulfilling the “liver failure” criteria after a recent acute insult. And those patients are treated in the same way as “APSAL-defined ACLF patients”1, 5-6. However, it is unclear whether those with a history of hepatic decompensation would have a poorer short-term outcome compared with patients with compensated CLD or the prior de-compensation would have
This article is protected by copyright. All rights reserved.
Accepted Article
significant impact on the long-term recovery from acute insults. The aim of this retrospective cohort study was to extend APASL criteria to cirrhotic patients with prior de-compensation and to compare disease course, short-term and long-term prognosis of ACLF patients according to the severity of pre-existing chronic liver disease.
Patients and methods Study population Patients who were suspected as having ACLF and were referred between January 3, 2007 and May 3, 2013 in Ningbo No.2 Hospital were screened. For patients with chronic hepatitis or compensated cirrhosis, the diagnosis of ACLF was based on the guidelines of APASL: (i) acute deterioration of chronic liver diseases expressed as jaundice (serum bilirubin ≥ 5 mg/dl [85µmol/L]) and coagulopathy (INR ≥ 1.5 or prothrombin activity < 40%); (ii) overt ascites (detected by physical examination) and/or hepatic encephalopathy (HE) occurring within 4 weeks2. For those with piror decompensation, a revised APASL criteria was used: (i) acute deterioration of chronic liver diseases expressed as jaundice (serum bilirubin ≥ 5 mg/dl [85µmol/L]) and coagulopathy (INR ≥ 1.5 or prothrombin activity < 40%); (ii) any type of extra-hepatic organ dysfunction [kideny dysfunction: serum creatinine > 1.5 mg dl-1 without the presence of chronic kidney diseases7; cerebral dysfunction: presence
of
hepatic encephalopathy;
respiratory dysfunction
was
defined
as
PaO2/FiO2≤200 or SpO2/FiO2≤214 or need for mechanical ventilation8; circulation
dysfunction was defined as MAP < 70 mm Hg despite adequate fluid resuscitation and need for vasopressors8). In addition, we excluded patients with human immunodeficiency This article is protected by copyright. All rights reserved.
Accepted Article
virus (HIV) infection, tumors, renal diseases, severe cardiopulmonary co-morbidity and those who had received a liver transplant. Among those undergoing liver transplantation, 10 were treated within 28 days after diagonosis of ACLF, 6 between 28 days and 3 months, and 2 after 3 months. The detailed information for those 18 patients is shown in
supplementary information. The study fulfilled the principles of the Declaration of Helsinki and was approved by the ethics committee of Ningbo No.2 Hospital. Written consent was obtained from each participant.
Diagnostic criteria for underlying liver diseases, acute precipitating events and complications The diagnostic criteria for cirrhosis included liver biopsy (whenever possible), endoscopic
signs of portal hypertension, radiological evidence of liver nodularity or clinical evidence of prior hepatic de-compensation in patient with chronic liver diseases9. Events of hepatic
decompensation included ascites, hepatic encephalopathy and upper gastrointestinal
bleeding. Various hepatic insults (i.e.flare-up of chronic hepatitis B [CHB], Hepatitis A virus[HAV] or Hepatitis E virus [HEV] infection, active drinking; or use of hepatotoxic drugs) and non-hepatic insults (i.e.surgery, variceal bleeding and non-hepatotropic infection) were screened to identify acute precipitating events as previously described10. Non-hepatic insults were classified as acute precipitating events only after hepatic acute events had been excluded. Overt ascites was diagnosed by clinical examination and ultrasonography as previously described11. Hepatic encephalopathy (HE) was defined as
an episode of neurological and neuropsychiatric abnormality12.
This article is protected by copyright. All rights reserved.
Accepted Article
Patient management, end-points and follow-up As previously described12, the general management of ACLF patients included resting, bowel washing, plasma transfusion and energy-supporting. Nucleos(t)ide analogs were used in ACLF patients with evidence of HBV replication and the following regimen have been used: lamivudine 100 mg daily, telbivudine 600 mg daily, entecavir 0.5 mg daily, and lamivudine 100 mg plus adefovir 10 mg daily. The treatment of hepatic de-compensation such as ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, hepatic encephalopathy and variceal bleeding were based on relevant guidelines. For patients with circulation dysfunction, fluid replacement was performed and vasoactive drugs were used when necessary. Nasal catheter, mask or venturi mask oxygen inhalation or mechanical ventilation was chosen according to the severity of respiratory dysfunction.
The starting date of the follow-up was the date of diagnosis of ACLF and the planned follow-up in the study was 1-year. For patients discharged from hospital, prognostic information was obtained by checking medical records or by contacting the patients’ families. The primary endpoint of the study was mortality at 1-year, 28-day and post-28-day.
Statistical analysis Continuous variables were expressed as the mean standard deviation (SD) or the median with the interquartile range. Binary or nominal variables were expressed as a number and percentage of the total patient population. Groups were compared using
This article is protected by copyright. All rights reserved.
Accepted Article
Student’s t-test, the Mann-Whitney u-test or a Chi-square test. Survival curves were drawn to describe the prognosis of subgroups of ACLF patients; the cumulative incidence of death was compared using the Log-rank test. Mutlinomial logistical regression analysis was performed to identify factors associated with multiple outcomes (within 28-day death, post-28-day death and survival). In mutlinomial logistical regression analysis, all the continuous variables were dichotomized into binary variables and the cut-off point was chosen according to clinical practice. In addition, Cox proportional hazard model was also used to analyze the factors associated with mortality from a time-to-death perspective. In
Cox proportional hazard regression, it should be noted that only patients surviving after 28 days were considered when analyzing factors associated with post-28-day mortality. For all multivariate analyses, univariate analysis was performed to screen the potential risk factors of poor prognosis. Then, candidate variables (p-value
