In 2005, the American College of Hepatology issued recommendations for the management of acute liver failure, which is a serious liver disease syndrome with a high mortality rate. In order to meet the needs of clinical work and standardize the diagnosis and treatment of liver failure in China, the Infectious Diseases Branch of the Chinese Medical Association and the Hepatology Branch of the Chinese Medical Association organized relevant domestic experts to develop the first “Guidelines for the Treatment of Liver Failure” in China in 2006. The 9th National Pediatric Liver Disease Conference was held in Shanghai from August 28-30, 2008. The conference was sponsored by the Infectious Diseases Branch of the Chinese Medical Association, co-organized by the Shanghai Hepatology Society and the Infectious Diseases Society of the Shanghai Medical Association, and organized by the Pediatric Liver Disease and Infection Group of the Infectious Diseases Branch of the Chinese Medical Association and the Pediatric Hospital of Fudan University. In order to improve the diagnosis and treatment of acute liver failure in children, the conference invited academician Li Lanjuan, Chairman of the Infectious Diseases Branch of the Chinese Medical Association, and Professor Anil Dhawan, Director of the Pediatric Hepatology Unit of King’s College Hospital and Chairman of the European Pediatric Hepatology Special Committee, to give presentations on relevant issues. The latest progress of liver failure in children in that meeting is summarized.
1. Definition of liver failure in children
Acute liver failure was initially defined as massive hepatic necrosis with hepatic encephalopathy within 8 weeks of presentation in patients without chronic liver disease. Subsequently, it has been suggested that some patients with previously asymptomatic chronic liver disease, including hepatomegaly, vertically acquired HBV infection, or autoimmune hepatitis, may already have cirrhosis, of which those with acute onset should still be included in the category of acute liver failure. In 2005, the American College of Hepatology defined acute liver failure as coagulopathy (INR ≥ 1.5) and varying degrees of mental impairment (hepatic encephalopathy) in patients without cirrhosis within 26 weeks of onset, including acute onset manifestations of hepatomegaly. Previously, China referred to liver failure as severe hepatitis, but the naming, classification and definition are not consistent with the international term liver failure. The Guidelines for the Treatment of Liver Failure define liver failure as a clinical syndrome in which multiple factors cause severe damage to hepatocytes, resulting in dysfunction of their synthesis, detoxification and biotransformation, with jaundice, coagulation dysfunction, hepatic encephalopathy and ascites as the main clinical manifestations. It can be clinically classified into 4 types: acute liver failure, subacute liver failure, slow plus acute liver failure and chronic liver failure. Acute liver failure refers to the onset of liver failure within 2 weeks, while subacute liver failure refers to the onset of liver failure between 15 days and 24 weeks, corresponding to previous acute or subacute severe hepatitis, respectively. Chronic plus acute liver failure is the appearance of acute or subacute liver failure on top of chronic liver disease, which is newly proposed in the current liver failure criteria. Chronic liver failure is the development of progressive decompensation of liver function or causing loss of compensation on the basis of chronic liver disease, as a result of chronic cirrhosis, and is the same as the international definition.
The common feature of the above definitions is that hepatic encephalopathy is a necessary condition 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 the end stage without hepatic encephalopathy. Some data show that only 51% of children with acute liver failure present with hepatic encephalopathy. Second, the diagnosis of hepatic encephalopathy in children is difficult, especially in young children or infants. Therefore, a more accepted definition of acute liver failure in children is a multisystem disorder of severe acute hepatic impairment with or without encephalopathy associated with hepatocellular necrosis in children without known chronic liver disease. 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 hepatomegaly, autoimmune hepatitis, or hepatitis B of unknown duration of infection can be included.
2. The importance of etiology and etiologic diagnosis of acute liver failure in children
There is a major difference in the etiology of acute liver failure in adults and acute liver failure in children. In the UK, it has been shown that about 53% of adult patients are affected by acetaminophen (APAP) overdose, while only 9% and 17% are caused by hepatitis B and non-A-E; in children, APAP overdose accounts for a smaller proportion. In a multicenter study in Europe and the Americas, less than 20% of 331 children with acute liver failure were caused by APAP overdose, and the cause was unknown in 50% of the children, while other more common causes included metabolic diseases, autoimmune diseases, infectious hepatitis, and primary herpesvirus infection in infants.
It is important to identify the cause of acute liver failure, and the entire course of the disease may be altered as a result. The clinical presentation of acute liver failure in children, especially in infants, is less typical than in adults, making diagnosis difficult, and a comprehensive evaluation should be performed. History taking includes symptoms of onset (e.g., jaundice, psychiatric changes, bleeding tendencies, vomiting, and fever), history of hepatitis exposure, history of blood transfusion, use of prescription and over-the-counter medications, history of intravenous medications, and family history of hepatomegaly, alpha-1 antitrypsin deficiency, infectious hepatitis, infant death, and autoimmune disease. Early evaluation for metabolic disease should be performed if there is evidence of growth retardation or seizures. The presence of pruritus, ascites, or growth retardation should be considered as a possibility of chronic liver disease.
Laboratory tests should include complete blood count, 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 children with acute liver failure caused by certain etiologies, such as phagocytic lymphohistiocytic hyperplasia, leukemia, lymphoma, certain types of storage diseases, and mitochondrial disease, should not undergo liver transplantation, as these diseases must be treated for the primary cause rather than liver transplantation.
3. Intestinal Microecology and Liver Failure
A group led by academician Lanjuan Li of the First Hospital of Zhejiang University School of Medicine has conducted a series of studies on the relationship between intestinal microecological imbalance and liver failure. Microecological balance is an important sign of human health, and is an indispensable “organ” for providing nutrition, regulating 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 shown that in liver failure, the beneficial bacteria in the intestinal tract are significantly reduced, the harmful bacteria are significantly increased, and the barrier role of the intestinal mucosa is disrupted, resulting in increased levels of endotoxins in the blood and exacerbating liver damage through a series of cytokine pathways. Therefore, liver damage can be reduced to a certain extent by adjusting the microecological environment in the human body. Metabolomics is a newly developed technique in recent years, combining research methods of genomics, proteomics and environmental science, which has been used to study the metabolic profile of patients with liver failure and can be an important tool for biomarker discovery, clinical diagnosis, prognosis judgment and mechanism research.
4. The value of liver biopsy in the diagnosis of the etiology of acute liver failure
In order to clarify the etiology of acute liver failure, many centers perform liver biopsy (liver biopsy) under open direct vision or transjugular vein hepatic puncture biopsy to obtain specimens for pathological examination on the basis of transfusion of fresh lyophilized plasma (FFP) or agents such as factor VII to correct coagulation abnormalities. Some scholars also believe that liver biopsy is not helpful in clarifying the etiology of acute liver failure, on the grounds that in acute liver failure the patient’s liver appears as a mass of necrosis, nodular in some areas and collapsed in others on the gross specimen, and liver biopsy cannot be viewed in its entirety, and will show different features under the microscope depending on the site of the biopsy. A retrospective study of 211 children with acute liver failure from 1989-2004 was conducted by a foreign scholar. 111 of the 211 cases had stored liver tissue specimens, mainly diseased livers removed during transplantation in cases treated with liver transplantation. The pathologists were blinded to read the films without clinical information and gave diagnostic recommendations. Based on the clinical data, a clinical etiological diagnosis could be made in about 53% of the cases and only 47% of the cases were of unknown cause, while the pathologist gave a suggestive etiological diagnosis in only 32% of the cases and 68% of the cases were not suggestive. Most of the cases in which the pathologist gave a diagnosis suggestive of an etiology were those in which the etiology had been suggested only by other clinical data. Liver tissue removed during liver transplantation is more informative than liver biopsy. Since such pathological examination of large pieces of liver tissue does not provide more information for the diagnosis of the etiology 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. Given the increased risk of bleeding associated with liver biopsy, many pediatric hepatologists currently do not recommend liver biopsy in children with acute liver failure.
5. Treatment of acute liver failure in children
(1) General management and etiological treatment
The management of acute liver failure in children includes general measures, treatment related to the etiology, management of specific complications, and consideration of indications for liver transplantation. The treatment plan should be tailored to the specific circumstances of the child, requiring consideration of local medical resources and the need for referral to a transplant center, especially considering the etiology, as the prognosis varies greatly depending on the cause.
In terms of general treatment, the patient should be admitted to the intensive care unit to ensure a quiet environment and avoid unnecessary stimulation. Closely monitor input and output. Avoid hypoglycemia and electrolyte disturbances. Caregivers must check the child several times around the clock to assess for altered mental status or evidence of hepatic encephalopathy, such as increased respiration and heart rate, and altered blood pressure, which may be a sign of infection, increased cerebral edema, or electrolyte disturbances. Monitor cardiopulmonary function and oxygen saturation. Assisted ventilation is required if So2 is <95%, G3-4 coma, G1-2 coma with agitation, or if long-distance transport is being considered. The nutrition of the child is also very important. The traditional view is that protein should be given sparingly in patients with liver failure, but a protein-free diet for several days will cause a negative nitrogen balance and cause organismal failure, so the current view is to ensure at least 1 g/kg body weight per day of high-quality protein supply. If patients develop constipation, they can be treated with lactulose. It is currently believed that the use of aluminum thioglycollate (Sucralfate) and ranitidine may prevent stress ulcers and gastrointestinal bleeding, but this still needs to be supported by evidence from evidence-based medicine. In contrast, measures such as liver biopsy and sedation (unless mechanically ventilated) should be avoided if possible.
Some cases with a clear etiology can be treated for that etiology: N-acetylcysteine (NAC) for acute APAP poisoning; penicillin G and silymarin for acute liver failure due to definite or suspected mushroom poisoning; tyrosinemia with 2-(2-mononitro-4-trifluoro-monophenylmethyl)-1,3 cycloethanone (NTBC); galactosemia with a lactose-free diet. Herpes virus infection can be treated with acyclovir; acute liver failure due to autoimmune hepatitis can be treated with glucocorticoids, etc.
(2) Management of coagulation disorders
Patients with acute liver failure have impaired coagulation mechanisms with reduced procoagulant and anticoagulant proteins. However, in the absence of provoking factors such as infection or elevated hepatic portal pressure, a balanced reduction in procoagulant and anticoagulant proteins rarely leads to severe bleeding. PT/INR was found to be independent of the risk of bleeding, although it reflects a reduction in hepatic-derived coagulation factors. Patients who have active bleeding or are preparing for invasive surgery should be given plasma or other procoagulant products such as recombinant coagulation factor VII to correct the plasma PT/INR.
Prophylactic use of fresh frozen plasma (FFP) or recombinant coagulation factor VII to correct clotting disorders is not recommended. Prophylactic use of FFP has the benefit of reducing bleeding and infection; however, controlled studies have shown that it does not improve patient survival. Because PT/INR is an important indicator of hepatic synthetic function, prophylactic use of FFP can interfere with monitoring of liver function, and its use can also cause fluid overload and hyperviscosity syndrome. The use of complex prothrombin complexes should also be avoided in the presence of liver failure. Complex prothrombin complex preparations contain a small proportion of activated thrombin, which cannot be removed effectively in a timely manner due to liver dysfunction, and therefore can induce the development of diffuse intravascular coagulation (DIC).
(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. Due to severe coagulation dysfunction, placement of an intracranial pressure detector is risky and may be followed by plasma exchange to correct coagulation dysfunction before placement of an intracranial pressure detector. Children with increased intracranial pressure should have their intracranial pressure lowered and cerebral perfusion maintained. Hypothermia has been shown in animal studies to be beneficial in reducing increased intracranial pressure and is now being tried in children.
(4) Artificial liver support therapy
Artificial liver technology can temporarily replace the liver function and give the hepatocytes a chance to regenerate in some acute or subacute liver failure, and also buy time for liver transplantation for those whose hepatocytes cannot be regenerated. There are 3 main types of artificial livers: non-biological, biological and hybrid. The non-biologic types are well established and include blood perfusion, plasma adsorption, and plasma exchange. Selective plasma exchange can reduce the amount of plasma used and avoid hypoproteinemia. Combination of different techniques can be used to personalize the treatment according to the condition. Non-biologic artificial liver can remove toxic substances and replenish biologically active substances, and has been commonly used in adult liver failure patients, but further research is needed for its application in pediatric liver failure patients. Biologic artificial liver is a hot topic of research both at home and abroad. By using exogenous hepatocyte bioreactors, the functions of the liver can be replaced more comprehensively, including metabolism and secretion, and has been applied in animal models and other applications, with encouraging preliminary results. 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 that have been successively used in the treatment of acute liver failure in recent years. They can comprehensively remove protein-bound and water-soluble toxins, lower intracranial pressure, improve renal function, and contribute to the prevention and treatment of cerebral edema, hepatorenal syndrome and multi-organ failure.
The Molecular Adsorption Recirculation System (MARS) uses membranes with albumin-related 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, information on the application of this technique to children is very limited and is still in the clinical research phase.
(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 partial-assist 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 surgery was performed, and the appropriate graft size. 10-year survival rates after liver transplantation are 65% for children less than 1 year old and 79% for older children. survival rates are higher for those transplanted after 1993 than for those transplanted before 1993.
Hepatocyte transplantation is a cell engineering technique developed in the 1970s. Increasing the number of viable or functional hepatocytes through HT can also be used as a transitional measure prior to liver transplantation or for the liver’s own recovery. In addition, attention has been focused on stem cell transplantation. Hepatocyte transplantation and stem cell transplantation could be an important tool for the future treatment of acute liver failure.
6. Prognosis
The immediate prognosis of children with acute liver failure depends on the etiology, age, and degree of encephalopathy. Among patients without liver transplantation, the survival rate of children with acute liver failure due to APAP is the highest, at 94%, compared with 41% due to other drugs, 44% due to metabolic disease, and 43% for unknown causes. The mortality rate increases as the degree of encephalopathy increases. Another study found that 20% of children who did not develop encephalopathy died or eventually received liver transplantation.
In conclusion, the etiologic spectrum and clinical features of acute liver failure in children are different from those of adults, and treatment requires a multidisciplinary and comprehensive approach guided by etiology and the monitoring, prediction, and treatment of multisystem complications. Overall, the short-term outcome of acute liver failure in children is better than in adults, but it also depends on the correct and timely diagnosis and the severity of the encephalopathy.