Acute liver failure is a serious liver disease syndrome with a very high morbidity and mortality rate, and in 2005, the American Academy of Liver Diseases issued recommendations for the management of acute liver failure. In order to meet the needs of clinical work and to standardize the diagnosis and treatment of liver failure in China, the Infection Disease Branch of the Chinese Medical Association and the Hepatology Branch of the Chinese Medical Association organized domestic experts to formulate China’s first “Guidelines for the Diagnosis and Treatment of Liver Failure” in 2006. However, the above recommendations and guidelines were formulated for adult liver failure, while the etiology and clinical manifestations of liver failure in children are quite different from those in adults.On August 28-30, 2008, the Ninth National Academic Conference on Pediatric Liver Diseases was held in Shanghai, which was organized by the Chinese Medical Association Infectious Diseases Branch and the Chinese Medical Association Hepatology Branch. The meeting was sponsored by the Infectious Diseases Branch of the Chinese Medical Association, co-organized by Shanghai Liver Disease Society and Shanghai Infectious Diseases Society of the Shanghai Medical Association, and hosted by Pediatric Liver Diseases and Infections Group of the Infectious Diseases Branch of the Chinese Medical Association and Pediatrics Hospital affiliated with Fudan University. In order to improve the diagnosis and treatment of acute liver failure in children, academician Li Lanjuan, Chairman of the Infectious Diseases Branch of the Chinese Medical Association, and Prof. Anil Dhawan, Director of the Department of Paediatric Hepatology at King’s College Hospital and Chairman of the European Committee of Paediatric Liver Disease (ECLD), were invited to give presentations on the relevant issues. The latest progress on childhood liver failure in that meeting is summarized here. Definition of liver failure in children Acute liver failure was initially defined as massive hepatic necrosis with hepatic encephalopathy within 8 weeks of onset in patients without chronic liver disease. Later, it was suggested that some patients with previously asymptomatic chronic liver disease, including hepatomegaly, vertically acquired HBV infection, or autoimmune hepatitis, may already have cirrhosis, and that those with an acute onset of disease should still be included in the category of acute liver failure. In addition, some scholars do not use the earliest time of symptom onset, but the time from the appearance of jaundice to the progression of hepatic encephalopathy to categorize. 2005, the American Academy of Liver Diseases defined acute liver failure as the development of coagulation dysfunction (INR ≥ 1.5) and varying degrees of mental disorders (hepatic encephalopathy) within 26 weeks of the onset of the disease in patients without cirrhosis, including the acute onset of manifestations of hepatic legionnaires’ disease, etc. In China, the term acute liver failure is used to refer to patients with liver cirrhosis. In the past, China referred to liver failure as severe hepatitis, but the nomenclature, categorization, and definition were not consistent with the international term for liver failure. Liver failure is defined in the Guidelines for the Diagnosis and Treatment of Liver Failure as a clinical syndrome in which severe damage to hepatocytes is caused by a variety of factors, leading to dysfunction in synthesis, detoxification, and biotransformation, with jaundice, coagulation dysfunction, hepatic encephalopathy, and ascites as the main clinical manifestations. Clinically, it can be categorized into 4 types: acute liver failure, subacute liver failure, slow plus acute liver failure and chronic liver failure. Acute liver failure is defined as liver failure within 2 weeks of disease onset, and subacute liver failure is defined as liver failure within 15 days to 24 weeks of disease onset, which is equivalent to previous acute or subacute severe hepatitis, respectively. Slow plus acute liver failure is the development of acute or subacute liver failure on the basis of chronic liver disease, which is new in this liver failure criteria. Chronic liver failure is progressive decompensation of liver function or resulting in decompensation on the basis of chronic liver disease and is the result of chronic cirrhosis, which is the same as the international definition. The common feature of the above definitions is that hepatic encephalopathy is a requirement for the diagnosis of liver failure. However, in recent years, many scholars have recognized that hepatic encephalopathy appears late in children with liver failure, and some infants and younger children even go directly to end-stage without hepatic encephalopathy. Some data show that only 51% of children with acute liver failure develop hepatic encephalopathy. Secondly, the diagnosis of hepatic encephalopathy in children is difficult, especially in young children or infants. Therefore, the currently more accepted definition of acute liver failure in children is a multisystem disorder with severe acute hepatic impairment in a child without known chronic liver disease, with or without encephalopathy associated with hepatocellular necrosis. According to this definition, encephalopathy is not a requirement for acute liver failure in children, and the absence of known chronic liver disease means that acute onset of hepatomegaly, autoimmune hepatitis, or hepatitis B of unknown duration of infection can be included. 2, the etiology of acute liver failure in children and the importance of etiologic diagnosis There is a big difference in etiology between acute liver failure in adults and acute liver failure in children. Data from the United Kingdom show that about 53% of adult patients are caused by acetaminophen (APAP) overdose, while only 9% and 17% are caused by hepatitis B and non-A-E hepatitis, respectively; in children, APAP overdose accounts for a smaller proportion. In a multicenter study in Europe and the Americas, APAP overdose was responsible for less than 20% of 331 children with acute liver failure, and the cause of the disease was unknown in 50% of the children; other more common causes included metabolic diseases, autoimmune disorders, infectious hepatitis, and primary herpesvirus infection in infants. It is important to define the cause of acute liver failure, as the entire course of the disease may be altered as a result. The clinical presentation of acute liver failure in children, especially infants, is less typical than in adults, making the diagnosis difficult and a comprehensive evaluation is warranted. History inquiries include symptoms of morbidity (e.g., jaundice, mental changes, bleeding tendencies, vomiting, and fever), history of exposure to hepatitis, history of blood transfusions, use of prescription and over-the-counter medications, history of intravenous medications, and a family history of hepatoblastoid nucleus pulposus, alpha-1 antitrypsin deficiency, infectious hepatitis, infant mortality, and autoimmune disorders. Early evaluation for metabolic disease should be performed if there is evidence of growth retardation or seizures. Accompanying pruritus, ascites, or growth retardation should be considered as a possibility of chronic liver disease. Laboratory tests should include a complete blood panel, electrolytes, renal function tests, blood glucose, blood calcium, blood phosphorus, amino acids, coagulation profile, total bilirubin, direct bilirubin, and blood cultures. Liver transplantation is the most important treatment for acute liver failure, but it is not suitable for children with acute liver failure caused by certain pathologies, such as hemophagocytic lymphohistiocytosis, leukemia, lymphoma, certain types of storage diseases, mitochondrial disease, etc. These diseases must be treated for the primary pathology rather than liver transplantation. 3, intestinal microecology and liver failure The First Hospital Affiliated to Zhejiang University School of Medicine, academician Li Lanjuan, led by a group of researchers on the relationship between intestinal microecological imbalance and liver failure conducted a series of studies. Microecological balance is an important symbol of human health, and is an indispensable “organ” that provides nutrition, regulates epithelial development and innate immunity. In pediatrics, the misuse of antimicrobial drugs is the most important cause of intestinal microecological imbalance. Animal experiments and clinical studies at the cellular, molecular and metabolomic levels have found that in liver failure, the beneficial bacteria in the intestinal tract of patients are significantly reduced, the harmful bacteria are significantly increased, and the barrier effect of the intestinal mucosa is destroyed, thus increasing the level of endotoxin in the blood and aggravating the liver injury through a series of cytokine pathways. Therefore, liver damage can be reduced to a certain extent by adjusting the microecological environment in the body. Metabolomics is a newly developed technology in recent years, combining genomics, proteomics and environmental science research methods, and has been used for the study of metabolic profile of liver failure patients, which can be used as an important means for biomarker discovery, clinical diagnosis, prognosis judgment and mechanism research. 4.Value of liver biopsy in the etiological diagnosis of acute liver failure In order to clarify the etiology of acute liver failure, many centers perform liver biopsy under open abdominal vision (liver biopsy) or transjugular hepatic perforation biopsy on the basis of transfusion of fresh lyophilized plasma (FFP) or Factor VII and other agents to correct the abnormalities of coagulation, and obtain specimens for pathological examination. Some scholars believe that liver biopsy is not helpful in defining the etiology of acute liver failure, the reason is that in acute liver failure, the patient’s liver appears as mass necrosis, and on the bulk specimen, some parts are nodules, some parts are collapsed, liver biopsy can not view the whole picture of the liver, and according to the different parts of the biopsy, it will be shown under the microscope with different characteristics. Some foreign scholars conducted a retrospective study of 211 cases of children with acute liver failure from 1989 to 2004. 111 of the 211 cases had stored liver tissue specimens, mainly diseased livers resected at the time of transplantation in cases undergoing liver transplantation therapy. Without providing clinical information, the films were read blindly by a pathologist to give a diagnostic recommendation. According to the clinical data, the clinical etiology could be diagnosed in about 53% of the cases, and the cause was unknown in only 47%, whereas the pathologist only gave a suggestive etiologic diagnosis in 32% of the cases, and the etiology was not suggested in 68% of the cases. The cases in which the pathologist gave a diagnosis suggestive of an etiologic factor were those in which the etiologic factor was suggested only by other clinical data. Liver tissue resected during liver transplantation is more informative than liver biopsy. Since pathologic examination of such large pieces of liver tissue does not provide more information for the etiologic diagnosis of acute liver failure, liver biopsy in cases of acute liver failure will provide even less help in the diagnosis and management of the case. Considering that liver biopsy increases the risk of bleeding, many pediatric hepatologists do not currently recommend liver biopsy in children with acute liver failure. 5 TREATMENT OF ACUTE LIVER FAILURE IN CHILDREN 5.1 GENERAL MANAGEMENT AND TREATMENT OF THE CAUSE The management of acute liver failure in children includes general measures, treatment related to the cause of the disease, management of specific complications, and consideration of the indications for liver transplantation. The treatment plan should be tailored to the specific situation of the child, taking into account local medical resources and the need for referral to a transplant center, and especially taking into account the etiology of the disease, as the prognosis varies greatly depending on the etiology. In terms of general treatment, the patient should be admitted to the intensive care unit to ensure a quiet environment and avoid unnecessary stimuli. Closely monitor input and output. Avoid hypoglycemia and electrolyte disorders. Nursing staff must examine the child several times around the clock to assess for changes in mental status or evidence of hepatic encephalopathy, such as increased respiration and heart rate, and changes in blood pressure, which may be signs of infection, worsening cerebral edema, or electrolyte disturbances. Cardiopulmonary function and oxygen saturation are monitored. Assisted ventilation is required if So2 <95%, G3-4 coma, G1-2 coma with agitation, or if long distance transport is being considered. Nutrition of the child is also very important. The traditional view is that protein should be given sparingly in patients with hepatic failure, but several days on a protein-free diet will result in negative nitrogen balance and cause organism failure, so the current view is that at least 1 g/kg body weight per day should be guaranteed as a supply of high-quality protein. If the patient develops constipation, it can be treated with lactulose. The use of aluminum thioglycollate (Sucralfate) and ranitidine is currently thought to prevent stress ulcers and peptic hemorrhage, but this still needs to be supported by evidence from evidence-based medicine. Measures such as liver biopsy and sedation (unless mechanical ventilation) should be avoided if possible. Some cases with a clear etiology can be treated by targeting the cause: N-acetylcysteine (NAC) can be used for acute poisoning by APAP; penicillin G and silymarin can be given for acute liver failure due to definite or suspected mushroom poisoning; 2-(2-nitro-1,4-trifluorophenylmethyl)-1,3 cyclohexanone (NTBC) can be used for tyrosinemia; and lactose-free diets can be used for galactosemia; Herpesvirus infection can be treated with acyclovir; acute liver failure due to autoimmune hepatitis can be treated with glucocorticoids, etc. 5.2 Management of coagulation disorders Patients with acute liver failure have impaired coagulation mechanisms, with reduced procoagulant and anticoagulant proteins. However, a balanced reduction in procoagulant and anticoagulant proteins rarely leads to severe bleeding in the absence of provocative factors such as infection or elevated hepatic portal pressure. PT/INR was found to be unrelated to the risk of bleeding, although it reflects a reduction in liver-derived coagulation factors. Patients with active bleeding or preparing for invasive surgical procedures should have plasma or other procoagulant products such as recombinant coagulation factor VII entered to correct plasma PT/INR. Prophylactic use of fresh frozen plasma (FFP) or recombinant coagulation factor VII to correct coagulation disorders is not recommended. The benefit of prophylactic use of FFP is that it reduces bleeding and infection; however, controlled studies have shown that it does not improve patient survival. Since PT/INR is an important indicator of hepatic synthetic function, prophylactic use of FFP interferes with monitoring of liver function, and its use can also cause fluid overload and hyperviscosity syndrome. The use of complex plasminogen complexes should also be avoided in hepatic failure. Complex plasminogen complex preparations contain a small amount of activated thrombin, which can induce the development of diffuse intravascular coagulation (DIC) due to liver dysfunction that does not allow for its timely and effective removal. 5.3 Management of elevated intracranial pressure Increased intracranial pressure is common in patients with acute liver failure and is a major cause of death. 80% of patients who die from acute liver failure have cerebral edema. Because of severe coagulation disorders, placement of an intracranial pressure monitor is risky. plasma exchange can be performed to correct coagulation disorders before placement of an intracranial pressure monitor. Children presenting with increased intracranial pressure should have their cranial pressure lowered and cerebral perfusion maintained. Hypothermia has been shown to be beneficial in reducing elevated intracranial pressure in animal studies and is now being tried in children. 5.4 Artificial liver supportive therapy Large liver necrosis in liver failure, drug treatment is often difficult to be effective, artificial liver technology can temporarily replace the liver function, can make part of the acute or subacute liver failure liver cells have a chance to regenerate, at the same time, can also be used for liver transplantation for those who can not regenerate liver cells to buy time. There are 3 main types of artificial livers: abiotic, biologic, and hybrid. The abiotic technology is well established and includes hemoperfusion, plasma adsorption, and plasma exchange. Selective plasma exchange can reduce the amount of plasma used and avoid hypoproteinemia. Different technologies can be used in combination to personalize treatment according to different conditions. Non-biological artificial liver can remove toxic substances and supplement biologically active substances, which has been commonly used in adult liver failure patients, but the application in children with liver failure needs further research. Biological artificial liver is a hot spot of research at home and abroad, by using exogenous hepatocyte bioreactors can replace the functions of the liver in a more comprehensive way, including metabolism and secretion, etc. It has been applied in animal models and other applications, and the preliminary results are encouraging. Hybrid artificial liver, which combines abiotic and biotic types, is also in the research stage. Continuous hemodiafiltration dialysis (CHDF) and molecular adsorption recirculation system (MARS) are new blood purification techniques successively used in the treatment of acute liver failure in recent years, which can comprehensively remove protein-bound toxins and water-soluble toxins, reduce intracranial pressure, improve renal function, and help to prevent and control cerebral edema, hepatorenal syndrome, and multi-organ failure. The Molecular Adsorbent Recirculation System (MARS) utilizes membranes with albumin-associated binding sites to separate the patient's blood from the albumin dialysate. Albumin-bound substances, such as bilirubin, aromatic amino acids, and endogenous benzodiazepine products, are transferred to the membrane binding sites and subsequently removed into the albumin dialysate. However, there is very limited information on the application of this technique in children and it is still in the clinical research phase. 5.5 Liver Transplantation and Hepatocyte Transplantation Liver transplantation techniques play an important role in the treatment of acute liver failure. In recent years, the development of techniques such as living liver transplantation, split liver transplantation and partially-assisted liver transplantation has effectively alleviated the shortage of liver sources and increased the number of patients who can receive liver transplantation. Currently, liver transplantation has one of the highest survival rates after solid organ transplantation in pediatric patients. In Western countries, 10% to 15% of children with acute liver failure undergo liver transplantation. The survival rate after liver transplantation in patients with acute liver failure depends on three factors: the age of the recipient, the age at which the operation was performed, and the appropriate size of the graft.The 10-year survival rate after liver transplantation is 65% in children less than 1 year of age and 79% in older children.The survival rate of those who underwent liver transplantation after 1993 is higher than that of those who underwent transplantation before 1993.The survival rate of liver cell transplantation is higher than that of those who underwent transplantation before 1993. Hepatocyte transplantation is a cell engineering technique developed in the 1970s. Increasing the number of surviving or functional hepatocytes through HT can also be used as a transitional measure before liver transplantation or for the recovery of the liver itself. In addition, attention has been focused on stem cell transplantation. Hepatocyte transplantation and stem cell transplantation can be an important means of treating acute liver failure in the future. 6. Prognosis The near-term prognosis of children with acute liver failure depends on the etiology, age, and extent of encephalopathy, among other things. Among patients without liver transplantation, children with acute liver failure caused by APAP have the highest survival rate of 94%, compared with 41% for other drugs, 44% for metabolic diseases, and 43% for unspecified causes. The mortality rate increased as the degree of encephalopathy worsened. Another study found that 20% of children without encephalopathy died or eventually underwent liver transplantation. In conclusion, the etiologic spectrum and clinical features of acute liver failure in children are different from those of adults, and treatment must be guided by a multidisciplinary and comprehensive approach to etiology, as well as monitoring, prediction, and treatment of multisystem complications. Overall, the short-term outcome of acute liver failure in children is superior to that of adults, but this also depends on correct and timely diagnosis and the severity of encephalopathy.