102 Korea Digestive Disease Week Definition and Treatment of Liver Failure Seung Kak Shin, M.D. Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea INTRODUCTION Liver failure can be divided into acute liver failure (ALF) due to acute liver injury without previous history of liver disease or liver cirrhosis, and chronic liver failure (also called end stage liver disease) resulting in gradual progression of chronic liver disease. Recently, the new concept of acute on chronic liver failure (ACLF) has emerged. DEFINITION OF LIVER FAILURE 1. Definition of ALF The most widely accepted definition of ALF includes evidence of coagulation abnormality, usually an INR ≥ 1.5, and any degree of mental alteration (hepatic encephalopathy, HEP) in a patient without preexisting cirrhosis and with an illness of <26 weeks’ duration.(1- 2) In the absence of any alteration of consciousness, the patient who develop coagulopathy was defined as acute liver injury (ALI), not liver failure. If there is no primary liver insult, these patients should be considered to have a secondary liver injury and not ALF; management should focus on the treatment of any underlying disease processes. (3) Previously, O’Grady et al. classified ALF according to the period from jaundice (or symptom onset) to HEP – hyperacute liver failure (< 1 week), acute liver failure (1-4 weeks) and, subacute liver failure (4-12 weeks) because the prognosis was considered to be different. (4) However, it is known that such classification has no prognostic significance distinct from the causes of the liver failure. Therefore, in 2005, American Association for the Study of Liver Diseases (AASLD) guideline suggested that all patients with HEP within 26 weeks of symptom onset should be unified to acute liver failure.(5) 2. Definition of ACLF The concept of ACLF was introduced by Jalan and Williams to describe the acute deterioration in liver function over 2 to 4 weeks in a patient with well-compensated cirrhosis associated with a precipitating event (hepatotoxic: superimposed hepatitis viral infection, drug-induced liver injury, hepatotoxins, or excessive alcohol consumption; extrahepatic: variceal bleeding or sepsis), leading to severe deterioration in clinical status with jaundice and HEP and/or hepatorenal syndrome (HRS). (6) Since then, the definition of the Asian-Pacific Association for the Study of the Liver (APASL)-ACLF Research Consortium (AARC) and the definition of the European Liver Association (EASL) Chronic Liver Failure Consortium (CLIF-C) have been most widely used, although they have not yet reached a fully uniform definition throughout the world. In European multicenter study (CANONIC study), bacterial infection and active alcoholism, which are important mechanisms of systemic inflammation, were the most frequent precipitating events. (7) In Korean multicenter study (KACLif study), bacterial infection and gastrointestinal bleeding were more frequent in ACLF patients according to the EASL-CLIF definition, while active alcoholism and use of toxic material were more frequent in ACLF patients according to the AARC definition.(8) TREATMENT OF LIVER FAILURE 1. Treatment of ALF In patients with severe acute liver injury, screen intensively for any signs of HEP is required. The presence of cirrhosis, alcohol induced liver injury or malignant infiltration of the liver should be distinguished. It is important to find the cause of acute liver failure because urgent treatment for causes can determine the prognosis if it is due to acetaminophen poisoning, mushroom poisoning, or hepatitis B infection. Then, prognostic stratification is needed. Early referral of patients with a poor prognosis (an INR >1.5 and onset of HEP or other poor prognostic features) to a liver transplant center is essential to optimize clinical outcomes. Even if the patient does not need transfer at that time point, early discussion with a transplant unit is needed. (3) When acute liver failure occurs due to acute liver injury, various complications such as cerebral edema, elevated intracranial pressure, hepatic coma, infection, blood clotting disorder, gastrointestinal bleeding, hemodynamic instability, renal failure, and metabolic complications may occur. Appropriate prevention and treatment is needed. Even if any degree of consciousness alteration occurs, rapid symptom exacerbation may occur, requiring intensive care unit treatment and preparation of liver transplantation. The most commonly used prognostic system is the King’s College Hospital criteria. Recent study demonstrated that administration of N-Acetylcysteine could improve transplant-free survival in early stage non-acetaminophen ALF.(9) The liver assist therapies to either support the patient until the native liver has had time to recover, or to bridge the patient to liver
Definition and Treatment of Liver Failure
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Definition and Treatment of Liver Failure
Seung Kak Shin, M.D.
Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea
INTRODUCTION
Liver failure can be divided into acute liver failure (ALF) due to acute liver injury without previous history of liver disease or liver cirrhosis, and chronic liver failure (also called end stage liver disease) resulting in gradual progression of chronic liver disease. Recently, the new concept of acute on chronic liver failure (ACLF) has emerged.
DEFINITION OF LIVER FAILURE
1. Definition of ALF
The most widely accepted definition of ALF includes evidence of coagulation abnormality, usually an INR ≥ 1.5, and any degree of mental alteration (hepatic encephalopathy, HEP) in a patient without preexisting cirrhosis and with an illness of <26 weeks’ duration.(1- 2) In the absence of any alteration of consciousness, the patient who develop coagulopathy was defined as acute liver injury (ALI), not liver failure. If there is no primary liver insult, these patients should be considered to have a secondary liver injury and not ALF; management should focus on the treatment of any underlying disease processes. (3) Previously, O’Grady et al. classified ALF according to the period from jaundice (or symptom onset) to HEP – hyperacute liver failure (< 1 week), acute liver failure (1-4 weeks) and, subacute liver failure (4-12 weeks) because the prognosis was considered to be different. (4) However, it is known that such classification has no prognostic significance distinct from the causes of the liver failure. Therefore, in 2005, American Association for the Study of Liver Diseases (AASLD) guideline suggested that all patients with HEP within 26 weeks of symptom onset should be unified to acute liver failure.(5)
2. Definition of ACLF
The concept of ACLF was introduced by Jalan and Williams to describe the acute deterioration in liver function over 2 to 4 weeks in a patient with well-compensated cirrhosis associated with a precipitating event (hepatotoxic: superimposed hepatitis viral infection, drug-induced liver injury, hepatotoxins, or excessive alcohol consumption; extrahepatic: variceal bleeding or sepsis), leading to severe deterioration in clinical status with jaundice and HEP and/or hepatorenal syndrome (HRS). (6) Since then, the definition of the Asian-Pacific Association for the Study of the Liver (APASL)-ACLF Research Consortium (AARC) and
the definition of the European Liver Association (EASL) Chronic Liver Failure Consortium (CLIF-C) have been most widely used, although they have not yet reached a fully uniform definition throughout the world. In European multicenter study (CANONIC study), bacterial infection and active alcoholism, which are important mechanisms of systemic inflammation, were the most frequent precipitating events. (7) In Korean multicenter study (KACLif study), bacterial infection and gastrointestinal bleeding were more frequent in ACLF patients according to the EASL-CLIF definition, while active alcoholism and use of toxic material were more frequent in ACLF patients according to the AARC definition.(8)
TREATMENT OF LIVER FAILURE
1. Treatment of ALF
In patients with severe acute liver injury, screen intensively for any signs of HEP is required. The presence of cirrhosis, alcohol induced liver injury or malignant infiltration of the liver should be distinguished. It is important to find the cause of acute liver failure because urgent treatment for causes can determine the prognosis if it is due to acetaminophen poisoning, mushroom poisoning, or hepatitis B infection. Then, prognostic stratification is needed. Early referral of patients with a poor prognosis (an INR >1.5 and onset of HEP or other poor prognostic features) to a liver transplant center is essential to optimize clinical outcomes. Even if the patient does not need transfer at that time point, early discussion with a transplant unit is needed. (3) When acute liver failure occurs due to acute liver injury, various complications such as cerebral edema, elevated intracranial pressure, hepatic coma, infection, blood clotting disorder, gastrointestinal bleeding, hemodynamic instability, renal failure, and metabolic complications may occur. Appropriate prevention and treatment is needed. Even if any degree of consciousness alteration occurs, rapid symptom exacerbation may occur, requiring intensive care unit treatment and preparation of liver transplantation. The most commonly used prognostic system is the King’s College Hospital criteria. Recent study demonstrated that administration of N-Acetylcysteine could improve transplant-free survival in early stage non-acetaminophen ALF.(9) The liver assist therapies to either support the patient until the native liver has had time to recover, or to bridge the patient to liver
PG Course 1. (KASL) Recent Update on Liver Diseases 103
www.kddw.org November 23 (Thu)-25 (Sat), 2017, Seoul, Korea
transplantation were studied. In recent RCT study, plasma exchange has been shown to improve transplant-free survival in patients with ALF, and to modulate immune dysfunction.(10)
2. Treatment of ACLF
The causes of ACLF such as acute exacerbation of chronic hepatitis B or infection should be promptly identified and treated. In patients with ACLF and suspected bacterial infection, broad spectrum antibiotics should be initiated as early as possible. Acute kidney injury is common in patients with ACLF. Acute tubular necrosis should be differentiated from HRS, which justifies vasoconstrictive agents.(11) Liver-specific scores such as the CLIF-SOFA(7), CLIF-OF and the CLIF-C ACLF score(12) have been developed to more precisely assess the prognosis of patients with ACLF. Development or increase in the number of organ failures needs early or emergency liver transplantation. Recent trials on extracorporeal liver support failed to demonstrate a survival benefit.(13-14)
CONCLUSIONS
ALF and ACLF are serious diseases with a high risk of mortality. To improve prognosis, the causes of liver failures should be promptly identified, and the development of complications or multiple organ failures should be prevented and intensively managed. Liver transplantation is the most definitive step for patients who fail to demonstrate recovery.
REFERENCES
1. Trey C, Davidson CS. The management of fulminant hepatic fail- ure. Prog Liver Dis 1970;3:282-298.
2. Lee WM, Stravitz RT, Larson AM. Introduction to the revised
American Association for the Study of Liver Diseases Position Pa- per on acute liver failure 2011. Hepatology 2012;55:965-967.
3. EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure. J Hepatol. 2017;66:1047–1081.
4. O’Grady JG, Schalm SW, Williams R. Acute liver failure: redefining the syndromes. Lancet 1993;342:273–275.
5. Polson J, Lee WM, AASLD position paper: The management of acute liver failure. Hepatology 2005;41:1179-1197.
6. Jalan R, Williams R. Acute-on-chronic liver failure: pathophysi- ological basis of therapeutic options. Blood Purif 2002;20:252– 261.
7. Moreau R, Jalan R, Gines P et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompen- sation of cirrhosis. Gastroenterology. 2013;144:1426-1437.
8. 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:e0146745.
9. Lee WM, Hynan LS, Rossaro L et al. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetamino- phen acute liver failure. Gastroenterology. 2009;137:856–864.
10. Larsen FS, Schmidt LE, Bernsmeier C et al. High-volume plasma exchange in patients with acute liver failure: An open randomised controlled trial. J Hepatol. 2016;64:69-78.
11. Durand F, Nadim MK. Management of acute-on-chronic liver fail- ure. Semin Liver Dis 2016;36:141–152.
12. Jalan R, Saliba F, Pavesi M, et al. Development and validation of a prognostic score to predict mortality in patients with acute on- chronic liver failure. J Hepatol 2014;61:1038–1047.
13. Bañares R, Nevens F, Larsen FS, et al. Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure: the RELIEF trial. Hepatology 2013;57:1153–1162.
Seung Kak Shin, M.D.
Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea
INTRODUCTION
Liver failure can be divided into acute liver failure (ALF) due to acute liver injury without previous history of liver disease or liver cirrhosis, and chronic liver failure (also called end stage liver disease) resulting in gradual progression of chronic liver disease. Recently, the new concept of acute on chronic liver failure (ACLF) has emerged.
DEFINITION OF LIVER FAILURE
1. Definition of ALF
The most widely accepted definition of ALF includes evidence of coagulation abnormality, usually an INR ≥ 1.5, and any degree of mental alteration (hepatic encephalopathy, HEP) in a patient without preexisting cirrhosis and with an illness of <26 weeks’ duration.(1- 2) In the absence of any alteration of consciousness, the patient who develop coagulopathy was defined as acute liver injury (ALI), not liver failure. If there is no primary liver insult, these patients should be considered to have a secondary liver injury and not ALF; management should focus on the treatment of any underlying disease processes. (3) Previously, O’Grady et al. classified ALF according to the period from jaundice (or symptom onset) to HEP – hyperacute liver failure (< 1 week), acute liver failure (1-4 weeks) and, subacute liver failure (4-12 weeks) because the prognosis was considered to be different. (4) However, it is known that such classification has no prognostic significance distinct from the causes of the liver failure. Therefore, in 2005, American Association for the Study of Liver Diseases (AASLD) guideline suggested that all patients with HEP within 26 weeks of symptom onset should be unified to acute liver failure.(5)
2. Definition of ACLF
The concept of ACLF was introduced by Jalan and Williams to describe the acute deterioration in liver function over 2 to 4 weeks in a patient with well-compensated cirrhosis associated with a precipitating event (hepatotoxic: superimposed hepatitis viral infection, drug-induced liver injury, hepatotoxins, or excessive alcohol consumption; extrahepatic: variceal bleeding or sepsis), leading to severe deterioration in clinical status with jaundice and HEP and/or hepatorenal syndrome (HRS). (6) Since then, the definition of the Asian-Pacific Association for the Study of the Liver (APASL)-ACLF Research Consortium (AARC) and
the definition of the European Liver Association (EASL) Chronic Liver Failure Consortium (CLIF-C) have been most widely used, although they have not yet reached a fully uniform definition throughout the world. In European multicenter study (CANONIC study), bacterial infection and active alcoholism, which are important mechanisms of systemic inflammation, were the most frequent precipitating events. (7) In Korean multicenter study (KACLif study), bacterial infection and gastrointestinal bleeding were more frequent in ACLF patients according to the EASL-CLIF definition, while active alcoholism and use of toxic material were more frequent in ACLF patients according to the AARC definition.(8)
TREATMENT OF LIVER FAILURE
1. Treatment of ALF
In patients with severe acute liver injury, screen intensively for any signs of HEP is required. The presence of cirrhosis, alcohol induced liver injury or malignant infiltration of the liver should be distinguished. It is important to find the cause of acute liver failure because urgent treatment for causes can determine the prognosis if it is due to acetaminophen poisoning, mushroom poisoning, or hepatitis B infection. Then, prognostic stratification is needed. Early referral of patients with a poor prognosis (an INR >1.5 and onset of HEP or other poor prognostic features) to a liver transplant center is essential to optimize clinical outcomes. Even if the patient does not need transfer at that time point, early discussion with a transplant unit is needed. (3) When acute liver failure occurs due to acute liver injury, various complications such as cerebral edema, elevated intracranial pressure, hepatic coma, infection, blood clotting disorder, gastrointestinal bleeding, hemodynamic instability, renal failure, and metabolic complications may occur. Appropriate prevention and treatment is needed. Even if any degree of consciousness alteration occurs, rapid symptom exacerbation may occur, requiring intensive care unit treatment and preparation of liver transplantation. The most commonly used prognostic system is the King’s College Hospital criteria. Recent study demonstrated that administration of N-Acetylcysteine could improve transplant-free survival in early stage non-acetaminophen ALF.(9) The liver assist therapies to either support the patient until the native liver has had time to recover, or to bridge the patient to liver
PG Course 1. (KASL) Recent Update on Liver Diseases 103
www.kddw.org November 23 (Thu)-25 (Sat), 2017, Seoul, Korea
transplantation were studied. In recent RCT study, plasma exchange has been shown to improve transplant-free survival in patients with ALF, and to modulate immune dysfunction.(10)
2. Treatment of ACLF
The causes of ACLF such as acute exacerbation of chronic hepatitis B or infection should be promptly identified and treated. In patients with ACLF and suspected bacterial infection, broad spectrum antibiotics should be initiated as early as possible. Acute kidney injury is common in patients with ACLF. Acute tubular necrosis should be differentiated from HRS, which justifies vasoconstrictive agents.(11) Liver-specific scores such as the CLIF-SOFA(7), CLIF-OF and the CLIF-C ACLF score(12) have been developed to more precisely assess the prognosis of patients with ACLF. Development or increase in the number of organ failures needs early or emergency liver transplantation. Recent trials on extracorporeal liver support failed to demonstrate a survival benefit.(13-14)
CONCLUSIONS
ALF and ACLF are serious diseases with a high risk of mortality. To improve prognosis, the causes of liver failures should be promptly identified, and the development of complications or multiple organ failures should be prevented and intensively managed. Liver transplantation is the most definitive step for patients who fail to demonstrate recovery.
REFERENCES
1. Trey C, Davidson CS. The management of fulminant hepatic fail- ure. Prog Liver Dis 1970;3:282-298.
2. Lee WM, Stravitz RT, Larson AM. Introduction to the revised
American Association for the Study of Liver Diseases Position Pa- per on acute liver failure 2011. Hepatology 2012;55:965-967.
3. EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure. J Hepatol. 2017;66:1047–1081.
4. O’Grady JG, Schalm SW, Williams R. Acute liver failure: redefining the syndromes. Lancet 1993;342:273–275.
5. Polson J, Lee WM, AASLD position paper: The management of acute liver failure. Hepatology 2005;41:1179-1197.
6. Jalan R, Williams R. Acute-on-chronic liver failure: pathophysi- ological basis of therapeutic options. Blood Purif 2002;20:252– 261.
7. Moreau R, Jalan R, Gines P et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompen- sation of cirrhosis. Gastroenterology. 2013;144:1426-1437.
8. 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:e0146745.
9. Lee WM, Hynan LS, Rossaro L et al. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetamino- phen acute liver failure. Gastroenterology. 2009;137:856–864.
10. Larsen FS, Schmidt LE, Bernsmeier C et al. High-volume plasma exchange in patients with acute liver failure: An open randomised controlled trial. J Hepatol. 2016;64:69-78.
11. Durand F, Nadim MK. Management of acute-on-chronic liver fail- ure. Semin Liver Dis 2016;36:141–152.
12. Jalan R, Saliba F, Pavesi M, et al. Development and validation of a prognostic score to predict mortality in patients with acute on- chronic liver failure. J Hepatol 2014;61:1038–1047.
13. Bañares R, Nevens F, Larsen FS, et al. Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure: the RELIEF trial. Hepatology 2013;57:1153–1162.
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