Acute liver failure in children: Management, complications, and outcomes

INTRODUCTION — Pediatric acute liver failure (PALF) is a complex, rapidly progressive clinical syndrome that is the final common pathway for many disparate conditions, some known and others yet to be identified [1,2]. The estimated frequency of ALF in all age groups is between one and six cases per million people every year [3], but the frequency in children is unknown. PALF accounts for approximately 9 percent of pediatric liver transplants (LT) performed in the United States annually [4].

PALF is a rapidly evolving clinical condition. There are no adequately powered studies to inform diagnostic algorithms, to assess markers of disease severity and trajectory, and to guide decisions about LT. The clinician must construct an individualized diagnostic approach and management strategy. Management requires a multidisciplinary team involving the hepatologist, critical care specialist, and LT surgeon.

Management of PALF and its complications in children are discussed here. An organized approach to diagnosing the cause of PALF is presented separately. (See "Acute liver failure in children: Etiology and evaluation".)

ALF in adults is addressed in separate topic reviews. (See "Acute liver failure in adults: Etiology, clinical manifestations, and diagnosis" and "Acute liver failure in adults: Management and prognosis".)

DIAGNOSTIC CRITERIA — Acute liver failure in children is defined by the presence of all three of the following criteria [1,2]:

●Acute onset – Onset of hepatic failure within eight weeks of onset of clinical liver disease in a patient with no previous evidence of chronic liver disease.

●Biochemical evidence of acute liver injury (one or both):

•Hepatocellular injury – Aspartate aminotransferase or alanine aminotransferase >100 IU/L (unless explained by myopathy)

•Biliary dysfunction – Total bilirubin >5 mg/dL (85.5 micromol/L), direct or conjugated bilirubin >2 mg/dL (34.2 micromol/L), and/or gamma-glutamyl transpeptidase >100 IU/L

●Coagulopathy – That persists after vitamin K administration, defined as:

•Prothrombin time (PT) ≥15 seconds or international normalized ratio (INR) ≥1.5 with evidence of hepatic encephalopathy (table 1A-B).

•PT ≥20 seconds or INR ≥2.0, with or without encephalopathy. Hepatic encephalopathy is not required if the coagulopathy is severe, because it can be difficult to assess in children and may not be clinically apparent until the terminal stages of the disease process [5]. (See 'Hepatic encephalopathy' below.)

Patients meeting these criteria should be transferred to or managed in consultation with a pediatric liver transplant center [2].

GENERAL MANAGEMENT PRINCIPLES — After the initial characterization of the patient presentation, proper patient management needs to be conducted along multiple parallel paths [2,6]:

●Evaluate the cause of pediatric acute liver failure (PALF) (figure 1A-B), guided by the patient's age and prioritizing the diagnosis of treatable disorders (see 'Treat the underlying cause' below and "Acute liver failure in children: Etiology and evaluation", section on 'Diagnostic testing for the cause of PALF')

●Monitor the function of each organ system

●Identify and treat complications

●Provide medical support to maximize health and survival

Clinical setting — Children with PALF have potential for rapid clinical deterioration and should be cared for by a team of pediatric specialists with experience in the diagnosis and management of PALF. This includes pediatric intensivists, gastroenterologists/hepatologists, liver transplant (LT) specialists, and skilled nurses and ancillary personnel. This core care team may be supplemented by additional subspecialists, including neurologists, nephrologists, geneticists, neurosurgeons, immunologists, and others based on the underlying disease process driving PALF or the multisystemic complications that can accompany PALF.

For patients initially seen in the outpatient setting, once PALF is recognized, transfer should be arranged to the nearest emergency department. Thereafter, most patients with PALF should initially be monitored in a pediatric intensive care unit. This will allow for careful clinical and neurologic assessment of the patient. Frequent bedside assessment by an experienced nurse or clinician is essential and should be performed multiple times during the day and night to assess evidence of changing mental status or hepatic encephalopathy (HE), increased respiratory effort, changing heart rate or changes in blood pressure that might be signs of infection, increasing cerebral injury (cerebral edema), or electrolyte imbalance. Fluid balance (input and output) should be strictly monitored. For patients with advancing encephalopathy or neurologic symptoms, consulting a neurologist should be considered.

Severity assessment — There are no reliable tools to predict survival or death in patients with PALF. Prognostic tools that incorporate biochemical tests (lactate, total bilirubin, phosphorous, international normalized ratio [INR], prothrombin time [PT], ammonia, Gc-globulin), clinical features (encephalopathy, cerebral edema), diagnosis (eg, acetaminophen), or combinations of the three have been tried without reliable success.

Development of a reliable model to predict death remains a challenge, given that LT interrupts the natural history of PALF [7,8]. Existing liver failure scoring systems, including the Clichy score, Model for End-Stage Liver Disease (MELD) score, and Pediatric End-Stage Liver Disease (PELD) score, are not adequate prognostic tools, because they are only weakly associated with outcome [9]. The Kings College Hospital Criteria is commonly used to predict prognosis and need for LT in adults with ALF and is stratified by whether the ALF is caused by acetaminophen toxicity. However, this score is not useful in PALF [10]. (See "Acute liver failure in adults: Management and prognosis", section on 'King's College Criteria'.)

The Liver Injury Unit score has been developed specifically for PALF and includes factors for peak total bilirubin, PT or INR, and ammonia [11]. A study tested the validity of the Liver Injury Unit score using data from the Pediatric Acute Liver Failure Study Group and, after optimization, sensitivity and specificity were 74 and 80 percent, respectively [12]. While this represents an improvement compared with the other scoring systems mentioned above, the Liver Injury Unit score is not sufficient to make critical decisions about LT. We believe that the ideal scoring system should reflect the dynamic nature of PALF and incorporate periodic clinical and biochemical changes into deriving the likelihood of death or survival [13]. Indeed, more contemporary prognostic scores seek to incorporate change in markers over time as a way to predict outcomes [14]. More work is needed to optimize and validate such strategies.

Treat the underlying cause — Causes of PALF that are amenable to specific treatments include:

●Acetaminophen ingestion. (See "Acetaminophen (paracetamol) poisoning: Management in adults and children".)

●Herpes simplex virus. (See "Neonatal herpes simplex virus infection: Management and prevention" and "Treatment and prevention of herpes simplex virus type 1 in immunocompetent adolescents and adults".)

●Autoimmune hepatitis. Establishing a firm diagnosis for autoimmune hepatitis is challenging in patients with PALF, and, in many cases, only a presumptive diagnosis can be made. (See "Acute liver failure in children: Etiology and evaluation", section on 'Autoimmune marker positive'.)

If autoimmune hepatitis is suspected, patients are usually treated with corticosteroids because these drugs can interrupt the liver injury in many patients. Among children who respond to corticosteroids, some children appear to tolerate weaning of the corticosteroids without recurrence of their disease. Recurrent disease appears to be somewhat less common in children with autoimmune-mediated ALF as compared with adults. Initiation of steroid therapy in the setting of PALF is a difficult decision. Steroid treatment may be the only option for a critically ill, deteriorating child and can be valuable if the patient does have an immune-mediated etiology of disease [15]. On the other hand, steroids also may cause mental status changes that interfere with assessments of encephalopathy and also increase risk for sepsis, a frequent cause of death in this population. (See "Management of autoimmune hepatitis".)

●Wilson disease. (See "Wilson disease: Management".)

●Certain inborn errors of metabolism. (See "Acute liver failure in children: Etiology and evaluation", section on 'Inherited metabolic disease'.)

●Hemophagocytic lymphohistiocytosis. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)

●Gestational alloimmune liver disease. (See "Causes of cholestasis in neonates and young infants", section on 'Gestational alloimmune liver disease (neonatal hemochromatosis)' and "Acute liver failure in children: Etiology and evaluation", section on 'Gestational alloimmune liver disease (neonatal hemochromatosis)'.)

Laboratory monitoring

●Routine tests to assess disease severity and progression – Routine laboratory monitoring should include a complete blood count, electrolytes, renal function tests, glucose, calcium, phosphorous, ammonia, PT, INR, and total and direct/conjugated bilirubin [2]. The frequency of laboratory monitoring should be at least daily, but multiple tests obtained regularly throughout the day may be necessary to monitor the dynamic changes that can occur in PALF. Management of patients with abnormal results is discussed below. (See 'Coagulopathy' below and 'Metabolic' below.)

Blood cultures should be obtained if a systemic infection is suspected (eg, fever, elevated white blood cell count) or if there is evidence of clinical deterioration (eg, worsening encephalopathy, cardiovascular instability), with or without fever, as infection may precipitate clinical decline.

For measurement of ammonia, arterial samples are ideal but not always clinically practical. For children with stage 0 to II HE, ammonia can generally be monitored with venous samples obtained from a free-flowing catheter and promptly placed on ice and transported to the laboratory. Children with more advanced HE often require elective intubation and ventilatory support, accompanied by placement of an arterial catheter. If available, ammonia samples should be obtained from the arterial catheter, but the arterial catheter should not be placed solely for ammonia testing. (See 'Hepatic encephalopathy' below.)

●Tests for transplant evaluation – Not all patients admitted with clinical and biochemical features of PALF will require an LT evaluation. However, if an evaluation is warranted, most of the biochemical tests necessary for evaluation are included in the initial and daily monitoring tests described above. Additional tests include blood typing (ABO and Rh; these need to be obtained/confirmed with two separate blood draws), human leukocyte antigens (HLA) antibodies, acute hepatitis panel, and cytomegalovirus and Epstein-Barr virus serologies. Consultations from anesthesia, neurology, cardiology, and social work should be sought for most patients. Evaluation of a child for LT is outlined in a clinical practice guideline prepared jointly by several societies [16]; some details may vary among centers. (See "Liver transplantation in adults: Patient selection and pretransplantation evaluation", section on 'Pretransplantation evaluation'.)

●Tests to diagnose the cause of PALF – Laboratory studies for diagnosing the cause of the PALF are also important and should be planned based on the patient's age and presentation, prioritizing those diagnoses that may be amenable to specific treatment. (See "Acute liver failure in children: Etiology and evaluation", section on 'Diagnostic testing for the cause of PALF'.)

Fluid management — Patients with PALF are sensitive to fluid volume. Overhydration can lead to pulmonary and peripheral edema, while underhydration can precipitate renal dysfunction including hepatorenal syndrome and contribute to encephalopathy and hypotension. Therefore, intravenous and oral fluid intake should be modestly restricted for most patients with PALF. An effort should be made to restrict total daily fluid intake (including medications and blood products) to between 90 and 95 percent of the maintenance fluid requirement [2].

Initial fluids should be 10 percent dextrose (D10) one-half normal saline (or similar to avoid sodium overload), with 15 mEq of potassium (K⁺)/L as potassium chloride alone or a combination of potassium chloride and potassium phosphate [2]. Glucose and electrolytes can be adjusted as needed based upon monitoring laboratory tests and renal function. Fluids with "fixed" concentrations of electrolytes, such as Lactated Ringer (which includes 28 mEq lactate/L and does not have glucose), should be avoided for use as maintenance fluids. However, if the child is hemodynamically unstable, additional fluid resuscitation and pressor support may be needed to stabilize cardiovascular status.

Serum glucose should be maintained between 90 and 120 mg/dL (5 to 6.7 mmol/L), since both hypoglycemia and hyperglycemia may affect critical homeostatic mechanisms and liver regeneration [2,17]. Some patients may require higher concentrations of intravenous dextrose, administered by central venous catheter. (See 'Metabolic' below.)

Nutrition — Nutrition support should be maintained to avoid a catabolic state. There is little evidence to support the use of enteral formulas designed for hepatic disease (eg, formulas enriched in branched-chain amino acids and low in aromatic amino acids), and these formulas are expensive. Limited evidence from studies in adults suggest that such formulas may have some benefit for HE but not for mortality [18]. (See "Overview of enteral nutrition in infants and children", section on 'Specialty formulas' and "Hepatic encephalopathy in adults: Treatment", section on 'Branched-chain amino acids'.)

If it is not safe for the child to receive oral or enteral feeding, intravenous alimentation (parenteral nutrition) should be initiated. (See "Parenteral nutrition in infants and children".)

We suggest the following parameters for parenteral nutrition in patients with PALF:

●Total fluid input including parenteral nutrition, blood products, and medications should generally be limited to between 85 to 95 percent of the maintenance fluid requirement to avoid excessive hydration.

●Protein input should initially be 1 g/kg/day. This input may be advanced above this threshold if ammonia is normal but may need to be reduced to 0.5 g/kg/day for patients with elevated serum ammonia levels. Intravenous administration of branched-chain amino acids have been reported to paradoxically increase ammonia production and cannot be recommended without further study [19].

●Trace metals (trace elements) should generally be eliminated or reduced. This is because copper and manganese are metabolized in the liver and may accumulate in patients with ALF. Moreover, chromium, molybdenum, and selenium should be eliminated or reduced if renal disease is also present.

Liver support — A number of approaches are being developed to perform some functions of the liver in an attempt to delay or avoid the need for LT. These extracorporeal liver support systems can be broadly divided into artificial liver support, including the membrane-adsorbent recirculating system and plasma exchange (with or without hemodialysis), and bioartificial liver support, which uses both human and/or animal cellular components within various systems [20]. To date, none has been established as a definitive treatment for acute hepatic failure. (See "Acute liver failure in adults: Management and prognosis", section on 'Artificial hepatic assist devices'.)

Plasmapheresis or plasma exchange is not generally recommended as standard of care for management of children or adults with ALF. An exception is that for patients with ALF due to Wilson disease, plasma exchange can be valuable as a temporizing measure because it rapidly removes large amounts of copper. (See "Wilson disease: Management", section on 'Patients with acute liver failure'.)

The rationale for plasmapheresis for ALF is that it might facilitate removal of suspected toxins in the blood to facilitate a milieu in which the liver might recover or regenerate. Most case series in children or adults with ALF suggest that plasma exchange might improve coagulation profiles, vasopressor requirements, and encephalopathy grade scores but not patient survival and neurologic outcome [21-23]. By contrast, one study in adults with ALF suggested that high-volume plasma exchange may improve outcome [24]. Results of this study may not be applicable to children, because the causes of ALF vary with age. For example, acetaminophen toxicity accounted for 60 percent of the enrolled participants in this adult study, while it accounts for only 12 percent of patients with PALF.

A number of other interventions have been studied but are unhelpful for ALF and should generally not be used. These include glucocorticoids (except in the setting of autoimmune hepatitis), hepatic "regeneration therapy" using insulin and glucagon, charcoal hemoperfusion, and prostaglandin E. Furthermore, a randomized, doubly masked, controlled trial in PALF demonstrated that intravenous N-acetylcysteine was not beneficial in children with non-acetaminophen-induced ALF [25]. One-year survival with native liver was significantly worse for those receiving N-acetylcysteine than placebo, particularly for those children younger than two years of age. (See "Acute liver failure in adults: Management and prognosis", section on 'Unhelpful treatments'.)

COMPLICATIONS

Central nervous system

Hepatic encephalopathy — Hepatic encephalopathy (HE) is a neuropsychiatric syndrome associated with hepatic dysfunction [26]. In a large registry of patients with pediatric acute liver failure (PALF), some degree of encephalopathy was present on admission in 50 percent of patients and developed within the next seven days in an additional 15 percent [27]. HE is uncommon in patients with acetaminophen toxicity [27,28].

●Clinical features and evaluation – HE is determined by serial clinical evaluations of behavior, cognition, neurologic examination, and, occasionally, electroencephalogram (EEG) to categorize the patient into one of five clinical stages of encephalopathy, ranging from stage 0 (minimal or no evidence of neurologic dysfunction) to stage IV (coma) [29]. Stages of encephalopathy are defined slightly differently in infants and children up to 36 months of age (table 1A) compared with older children and adolescents (table 1B and figure 2). The scoring system has been found to have important clinical and prognostic implications in adults and children with ALF. The pathogenesis and diagnosis of HE in adults is discussed in separate topic reviews. (See "Hepatic encephalopathy in adults: Clinical manifestations and diagnosis" and "Hepatic encephalopathy: Pathogenesis".)

The roles of other modalities to assess neurologic function in children, such as visual evoked potentials, transcranial Doppler, cerebral near-infrared spectroscopy, optic nerve sheath diameter [30], and biomarkers [31], in the detection of HE or cerebral injury are areas for investigation. While neurologic morbidity remains a major determinant of outcome following PALF, further studies are needed to improve early detection of neurologic injury, standardize management of seizures and HE, and determine whether such interventions improve outcomes.

HE is not always clinically apparent in infants and young children. Distinguishing hepatic-based encephalopathy from other causes of an altered mental status such as sepsis, hypotension, electrolyte disturbances, hypoglycemia, anxiety, steroid psychosis (if being treated with glucocorticoids), or "intensive care unit psychosis" is difficult for all age groups.

Hyperammonemia plays a central role in the development of HE in most cases. Cerebral injury (cerebral edema) rarely develops if the ammonia level remains <75 micromol/L [2], whereas an ammonia level >100 micromol/L on admission is a strong predictor of hepatic encephalopathy and cerebral injury (based on studies in adults) [32]. An ammonia level at or above 200 micromol/L has been associated with increased mortality [33].

●Management – Our approach to initial treatment of HE in children includes the following [2].

•General measures:

-Minimize stimulation; the room should be as quiet as possible. Minimize elective/routine tracheal suctioning if intubated.

-Elevate the head of bed to 30°.

-Address other contributing factors that might affect mental status (eg, treat suspected sepsis, identify electrolyte abnormalities, treat hypoglycemia, and remove or reduce sedative medications, if possible).

-Take measures to prevent injury if the patient becomes agitated or combative (eg, pads on bed rails).

-Some clinicians restrict protein intake to no more than 1 g/kg/day, to help reduce ammonia production. There is little evidence to support the use of enteral formulas designed for hepatic disease. (See 'Nutrition' above.)

•Medication:

-For patients with progressive HE associated with hyperammonemia, w suggest medical therapy with lactulose. Lactulose is used empirically, although the evidence supporting this practice is limited and its use in adults is controversial. (See "Acute liver failure in adults: Management and prognosis", section on 'Hepatic encephalopathy'.)

The starting dose of lactulose is 0.5 mL/kg per dose, up to maximum 30 mL per dose (equivalent of 0.3 g/kg per dose, maximum 20 g per dose). Give one dose every two hours by mouth or via nasogastric tube, and adjust the dose as needed to produce two to three soft stools daily [34]. We do not treat with lactulose for patients without hyperammonemia.

-If the response to lactulose is inadequate, bowel "decontamination" with rifaximin can be used as a second-tier treatment, although the benefit of this therapy may not be appreciated for several days following initiation.

•Other – Continuous renal replacement therapy has been used successfully to remove ammonia and/or manage fluid balance in adults [35] and children with ALF [36]. In children, a reduction in ammonia within 48 hours of renal replacement therapy initiation was associated with significant improvement in survival [36]. This modality should be considered if other treatment options are not successful.

Medical management of HE has not been well studied in children, and clinical practice has been extrapolated from the clinical experience in adults. (See "Acute liver failure in adults: Management and prognosis", section on 'Hepatic encephalopathy'.)

Ammonia scavengers are sometimes used for adults with HE due to chronic liver disease but have not been adequately studied and are rarely used in ALF. In a randomized, double-masked, placebo-controlled study in adults with ALF, the ammonia scavenger L-ornithine L-aspartate did not lower ammonia or improve survival [37]. (See "Hepatic encephalopathy in adults: Treatment", section on 'L-ornithine-L-aspartate'.)

Cerebral injury (cerebral edema) — Some patients with HE develop a clinically important increase in intracranial pressure (ICP), which can have devastating consequences, leading to ischemic and hypoxic brain injury or brainstem herniation and death [38,39].

●Clinical features and evaluation – Cerebral injury (cerebral edema) occurs in up to 80 percent of those with advanced HE (stage III or IV) and can progress rapidly [38,40]. Detection of cerebral injury in the early stages is difficult because noninvasive monitoring with clinical assessment or radiographic studies lacks sensitivity. Cerebral injury should be suspected in a patient with PALF with worsening mental status, severe headache with vomiting, coma, hypertension with bradycardia or tachycardia, or papilledema. Neuroimaging with computed tomography can be performed rapidly, sometimes at the bedside in some intensive care units, and can be used to assess features of cerebral injury (eg, obscuration of cortical sulci and basal cisterns, loss of grey/white matter differentiation) or evidence of intracranial hemorrhage, which is another potential cause for changes in neurologic status. Preliminary studies suggest that ultrasonographic measurement of the optic nerve sheath diameter may serve as a noninvasive approach to assessment of increased ICP [41,42]. (See "Elevated intracranial pressure (ICP) in children: Clinical manifestations and diagnosis", section on 'Noninvasive detection of elevated ICP'.)

●Invasive measurement of ICP – In patients with stage III or IV encephalopathy, neurosurgical evaluation for possible placement of an ICP monitor should be considered. This device is the most sensitive measure of ICP and permits constant monitoring of ICP in an intubated and comatose patient, but this advantage must be balanced against the risk of bleeding, which is high due to the coexisting coagulopathy [2]. Intracranial bleeding occurs in 10 to 20 percent of patients, although the amount of bleeding is often minimal [40,43].

Monitoring of ICP in children remains controversial due to associated complications of the procedure and lack of evidence that monitoring improves survival [44]. Decisions about whether to place a monitor should be made with consultation from specialists in pediatric neurology and neurosurgery, and practice varies among institutions. (See "Elevated intracranial pressure (ICP) in children: Clinical manifestations and diagnosis", section on 'Invasive measurement of ICP'.)

Once an ICP monitor is in place and properly functioning, it can be a valuable tool to continually assess response to ICP and its treatment [40]. The ICP monitor is also felt to be valuable during surgical procedures, including liver transplantation (LT), to gauge fluid and medical management of the unconscious patient.

The indications, types, and complications of ICP pressure monitoring in adults with ALF are discussed in a separate topic review. (See "Acute liver failure in adults: Management and prognosis", section on 'Intracranial pressure monitoring'.)

●Pathogenesis – The pathogenesis of cerebral injury is complex and likely involves the interaction among ammonia, cerebral blood flow, and inflammation [45,46]. Elevated levels of ammonia are generated as a consequence of the failing liver, which leads to increased intracerebral concentrations. Ammonia enters the astrocyte, which is rich in glutamine synthetase. Conversion of ammonia and glutamate to glutamine, a potent intracellular osmolyte, creates an osmotic gradient that favors astrocyte swelling and contributes to cerebral injury and intracranial hypertension. Changes in the inflammatory milieu, sepsis, fluid or blood product administration, and other factors can result in a sudden and often unanticipated increase in ICP.

●Management – Management of cerebral injury in children is discussed in a separate topic review. (See "Elevated intracranial pressure (ICP) in children: Management".)

Seizures — Children with ALF may experience generalized or focal seizures or nonconvulsive (electrographic) seizures. Phenytoin is often used for initial treatment of seizures because prophylactic phenytoin was found to be safe and effective in reducing seizure activity in adults with ALF and cerebral injury [47]. However, practices are variable and there is no definitive standard of care. Valproate should be avoided, given its association with acute liver injury (see "Acute liver failure in children: Etiology and evaluation", section on 'Idiosyncratic hepatotoxic effects'). For seizures that are refractory to phenytoin, therapeutic options may include midazolam infusion, phenobarbital, levetiracetam, or topiramate. The selection of drug depends on the patient's mental status, physiologic stability, availability of EEG monitoring to titrate drug infusions, and institutional experience.

Hematologic

Coagulopathy

●Evaluation – Patients with PALF should be monitored for laboratory evidence of coagulopathy and for clinical symptoms of bleeding. The primary purpose of laboratory monitoring is to monitor the course of synthetic dysfunction, including decisions about LT. Treatment of the coagulopathy is based primarily on clinical bleeding symptoms and need for invasive procedures.

The prothrombin time (PT) and international normalized ratio (INR) are used to assess the severity of liver dysfunction in the setting of ALF because these tests reflect hepatic production of clotting factors, particularly factors V and VII, which have the shortest half-lives [2]. However, the PT and INR are not good markers for the risk of bleeding in patients with ALF. This is because ALF reduces both procoagulant proteins (eg, factors V, VII, and X and fibrinogen) and anticoagulant proteins (eg, antithrombin, protein C, and protein S) [9,48]. (See "Hemostatic abnormalities in patients with liver disease".)

This balanced reduction in the procoagulant and anticoagulant proteins, as well as increased clot strength reflected by a normal thromboelastography [49], may account for the relative infrequency of clinically important bleeding in PALF in the absence of a provocative event such as infection or increased portal hypertension.

●Treatment – When laboratory evidence of coagulopathy is first recognized, a single parenteral dose of vitamin K (eg, 1 mg for infants or 5 mg for adolescents) should be administered once for empiric correction of vitamin K deficiency [2]. If the coagulation profile does not significantly improve after vitamin K administration, this confirms that the coagulopathy is caused by liver failure rather than vitamin K deficiency. Repeat administration of vitamin K is generally unnecessary.

Blood product therapy should not be given prophylactically in an attempt to normalize the coagulation profile, as it is unnecessary and may contribute to volume overload [2]. However, blood product therapy is generally warranted for patients with active bleeding (typically, gross bleeding from the mucosa or gastrointestinal tract) or in preparation for a surgical procedure, such as placement of an ICP monitor. The treatment is tailored to the laboratory abnormalities and includes efforts to normalize the PT/INR with fresh frozen plasma or other procoagulation products, such as recombinant factor VII, and/or platelet transfusion. Aggressive correction of the coagulopathy just prior to transplant is not necessary.

Aplastic anemia — Bone marrow failure, characterized by a spectrum of features ranging from mild pancytopenia to aplastic anemia, occurs in a significant minority of children with ALF [50-52]. It is identified most commonly in the setting of indeterminate PALF and may not be clinically evident until after emergent LT or recovery without transplantation. (See "Acute liver failure in children: Etiology and evaluation".)

Treatment includes immunomodulatory medications that include steroids, cyclosporine A, and antilymphocyte or antithymocyte globulin, as well as hematopoietic stem cell transplant. (See "Treatment of acquired aplastic anemia in children and adolescents".)

Gastrointestinal

Ascites — Ascites develops in a minority of patients with ALF. Precipitating factors include hypoalbuminemia, excessive fluid administration, and infection. The primary treatment is moderate fluid restriction and/or correction of serum albumin using 25 percent albumin infusion [2]. Diuretics should be reserved for patients with respiratory compromise or generalized fluid overload. Overly aggressive diuresis may precipitate hepatorenal syndrome. (See 'Kidney injury' below.)

Gastrointestinal bleeding — Gastrointestinal bleeding is surprisingly infrequent, given the degree of coagulopathy. This is probably because of a balanced reduction in the procoagulant and anticoagulant proteins, as described above. (See 'Coagulopathy' above.)

Many centers routinely use acid-suppressing agents as prophylaxis against gastrointestinal bleeding, but the utility of this strategy has not been established [53].

Causes for bleeding include gastric erosions or ulcers due to nonsteroidal antiinflammatory drugs, or idiopathic gastroduodenal ulceration. Infection can precipitate bleeding in this vulnerable population, so blood cultures and initiation of antibiotics should also be considered when bleeding develops. Administration of platelets, blood, and plasma is necessary if bleeding is hemodynamically significant.

Pancreatitis — Biochemical and clinical evidence of pancreatitis is associated with multisystem failure in critically ill children. In patients who develop pancreatitis in the setting of ALF, glucose and fluid management may become even more challenging. (See "Management of acute pancreatitis".)

Kidney injury — Kidney injury in a patient with ALF may be caused by:

●Drugs or toxins – Patients presenting with kidney function impairment in the setting of ALF should be carefully assessed for evidence of a medication or toxin as the precipitating cause (including acetaminophen, inhaled solvents, mushrooms, recreational drugs, or medication-induced ALF).

●Hypovolemia – Kidney function impairment can be caused by hypovolemia (prerenal azotemia) if fluid restriction is too stringent.

●Shock – Acute deterioration of renal function after presentation with ALF may result from systemic hypotension due to sepsis or hemorrhage.

●Hepatorenal syndrome – Hepatorenal syndrome is a feared renal complication associated with ALF, although it occurs more commonly in the setting of chronic liver disease with established cirrhosis. The diagnosis is suspected when there is evidence of deteriorating renal function in the absence of bleeding, hypotension, sepsis, or nephrotoxic medications. Unlike prerenal azotemia, the urine sodium typically is low and there is no improvement with volume expansion. Hepatorenal syndrome can progress rapidly over the course of two weeks (type 1 hepatorenal syndrome) or more slowly (type II hepatorenal syndrome) [9]. Renal replacement therapy with continuous venovenous hemofiltration or dialysis may be necessary in some cases, but only LT can reverse hepatorenal syndrome. Management of hepatorenal syndrome in adults is discussed separately. (See "Hepatorenal syndrome".)

Metabolic — Metabolic abnormalities often seen in patients with ALF include [2,29]:

●Hypoglycemia – Hypoglycemia is caused by impaired hepatic gluconeogenesis and depleted glycogen stores. Hypoglycemia is treated with continuous infusion of glucose, which is infused via a central venous catheter to accommodate the hypertonic solution. Glucose infusion rates of 10 to 15 mg/kg/minute may be required to achieve stable serum glucose levels (target 90 to 120 mg/dL [5 to 6.7 mmol/L]). A central venous catheter may be required if concentrations of intravenous glucose over 12.5 percent are needed to maintain the serum glucose while restricting fluid volume.

Severe and refractory hypoglycemia suggests the possibility of an inborn error of metabolism as a cause for the liver failure. (See "Acute liver failure in children: Etiology and evaluation", section on 'Inherited metabolic disease'.)

●Hypokalemia – Hypokalemia may be caused by dilution from volume overload, ascites, or renal wasting. (See "Hypokalemia in children".)

●Hypophosphatemia – Serum phosphorus should be monitored frequently since hypophosphatemia can be profound [2]. While the mechanism is unknown, hypophosphatemia is presumed to result from increased needs due to active liver cell regeneration. If possible, maintain serum phosphate at >3 mg/dL [2]. Hyperphosphatemia, often associated with kidney function impairment, is a poor prognostic sign [54]. (See "Acute kidney injury in children: Clinical features, etiology, evaluation, and diagnosis".)

●Acid-base disturbances – Acid-base disturbances are caused by a variety of mechanisms, including respiratory alkalosis from hyperventilation; respiratory acidosis from respiratory failure; metabolic alkalosis from hypokalemia; and metabolic acidosis from hepatic necrosis, shock, and increased anaerobic metabolism or as the result of inborn errors of metabolism. (See "Approach to the child with metabolic acidosis".)

Infectious — Patients with ALF are susceptible to bacterial infection and sepsis because of immune system dysfunction [9]. Evidence of infection may be subtle, such as tachycardia, gastrointestinal bleeding, reduced urine output, or changes in mental status. Fever may or may not be present. (See "Septic shock in children in resource-abundant settings: Rapid recognition and initial resuscitation (first hour)".)

Thus, blood cultures should be obtained if there is any evidence of clinical deterioration, and antibiotics should be initiated to cover both gram-positive and gram-negative organisms [55].

Cardiopulmonary — Excessive fluid administration contributes to pulmonary edema and should be avoided. For patients who develop pulmonary edema, careful fluid restriction and discrete use of diuretics may be needed in some instances but should be used with caution because these interventions can reduce organ perfusion and precipitate renal failure. Central venous pressure monitoring may assist in assessing volume needs for the child.

Inotropic support (eg, norepinephrine, sometimes with low-dose vasopressin) may be needed to maintain perfusion of vital organs [2]. (See "Shock in children in resource-abundant settings: Initial management".)

LIVER TRANSPLANT

Liver transplant decisions — In the era before liver transplantation (LT) was available, the natural history of pediatric acute liver failure (PALF) was for children to either survive or die. LT interrupts the natural course of PALF and can save the life of a patient with ALF if they have a condition that is not amenable to treatment or fails to respond to treatment (figure 3). However, because the cause of PALF often is not known and the course of PALF is difficult to predict, it is likely that some patients may receive LT in situations in which spontaneous recovery would have occurred.

The first decision is whether and when to initiate an evaluation for LT. Listing for LT has become more selective over time, without adversely affecting outcomes. This was shown in a report of more than 1000 participants in the PALF study from 2000 to 2015 [8], in which time to listing (median one day) remained constant over the 15-year study period, while frequency of listing and receiving an LT decreased over time, and there was no association with an increase in the frequency of death. Clinical characteristics differed between those listed for LT and those not listed, for reasons of being "not sick enough" or "medically unsuitable." Patients who were listed for LT were more likely to be male and have clinical evidence of encephalopathy and higher bilirubin levels compared with those "not sick enough." They were also more likely to have an indeterminate diagnosis, to be older, and have higher values for alanine aminotransferase, bilirubin, and platelet count compared with those who were deemed "medically unsuitable."

As discussed above, none of the scoring systems are adequate to direct decisions about LT for patients with PALF [2] (see 'Severity assessment' above). A more reliable modeling scheme is needed to readily and effectively distinguish the patient who would die from the one who would survive without LT and recognize when it would be futile to proceed with LT. Until then, the best solution is a global clinical assessment by a team of clinicians with experience in PALF and LT, incorporating the prognosis associated with the cause of the ALF, and the patient's dynamic course, based on repeated assessments of the probability of survival with native liver from one time interval to the next.

LT decisions are particularly challenging for patients with PALF caused by a mitochondrial disease. Multisystem mitochondrial dysfunction is a contraindication to LT because the long-term prognosis is poor [16]. However, patients with certain mitochondrial diseases (such as those caused by defects in the TRMU or DGUOK genes), who do not have extrahepatic manifestations of disease may have isolated hepatic mitochondrial dysfunction and could be candidates for LT [56-58]. Unfortunately, multisystem involvement may not be apparent at the time of LT, placing the child at risk for developing symptoms in the future. Moreover, patients whose ALF was triggered by valproate have a very poor prognosis after LT due to a high likelihood of mitochondrial disease (especially POLG gene mutations) and extrahepatic disease progression [16,59,60]. (See "Acute liver failure in children: Etiology and evaluation", section on 'Older infants and young children'.)

Organ allocation in acute liver failure — Organ allocation for children with ALF remains an evolving process. Organ allocation in the United States is managed by the United Network for Organ Sharing and is based largely on disease severity scores for adults (Model for End-Stage Liver Disease, version 3.0 [MELD 3.0]) and children (Pediatric End-Stage Liver Disease [PELD]) to support organ allocation for patients with chronic liver disease. In 2023, PELD was revised to include serum creatinine (PELD-Cr) and the score adjusted to better align pediatric and adult scores with true mortality risk [61]. PELD-Cr can be calculated using this calculator (calculator 1) or this online calculator for PELD-Cr. MELD 3.0 is used for patients 12 years and older and is discussed in detail separately. (See "Model for End-stage Liver Disease (MELD)".)

Further details about organ allocation are summarized in this article on pediatric liver transplant prioritization [62].

Importantly, PELD-Cr and MELD are most useful when allocating organs for patients with chronic liver disease and they were not designed for use in ALF. The urgency of LT for children with PALF is typically not reflected by their PELD-Cr/MELD score. Therefore, patients with ALF who are in need of LT are given priority over those listed with a PELD-Cr/MELD score and are listed as status 1A, the category with the highest priority status.

To assign a candidate pediatric status 1A, the candidate's transplant hospital must submit a Liver Status 1A Justification Form to the Organ Procurement Transplantation Network. The candidate's transplant program may assign the candidate pediatric status 1A if all the following conditions are met [63]:

●<18 years of age

●Has a diagnosis of acute liver failure

●Must not have a preexisting diagnosis of liver disease

●Must meet at least one of the following conditions:

•Is ventilator dependent

•Requires dialysis, continuous veno-venous hemofiltration, or continuous veno-venous hemodialysis

•International normalized ratio (INR) ≥1.5 and <2.0 and a diagnosis of hepatic encephalopathy developing within 56 days of the first signs or symptoms of liver disease

•INR ≥2.0

Children who are classified as status 1A require reassessment of their listing status after seven days. At any time, children can be removed from the transplantation list if they become too ill to undergo transplantation or recover to a point that transplantation is not necessary. If a child is still on the list after seven days, options would be to continue to list the patient as status 1A by providing supportive clinical information, remove the child from the list, or reduce the urgency by changing the listing status from status 1A to the calculated PELD-Cr score.

Types of grafts — LT has improved overall survival for children with ALF. Because the supply of appropriately sized organs from deceased donors is inadequate, some children with PALF die while waiting for LT and pretransplant mortality is worse than for patients with chronic liver failure. As a result, technical variants to whole grafts such as split and living donors have been introduced.

Donor organs are made available to a child with ALF in one of three ways [64]:

●Deceased donor, whole organ

●Deceased donor, cut down to accommodate the child's abdominal cavity or "split" with the right lobe going to an adult and all or part of the left lobe going to the child

●Living donor (either related or unrelated), with all or part of the left lobe going to the child

The availability of deceased donor livers varies significantly depending upon the location of the transplant center. Because patients are typically listed for LT within a day or two of hospital admission, the risk of dying before a liver becomes available is increased in areas where liver availability is scarce. In the early years of LT for PALF, living donor transplant was initially not pursued, due to a number of ethical concerns such as whether informed consent could genuinely be obtained given the short time allotted for the evaluation, coercion, and other competing interests. However, many pediatric transplant centers have worked through these important ethical issues and now offer a living donor option for patients with PALF, with good outcomes [64,65]. (See "Living donor liver transplantation in adults".)

Auxiliary LT is an alternative approach that consists of placement of a graft adjacent to the patient's native liver (auxiliary heterotopic LT) or in the hepatic bed after a portion of the native liver (auxiliary orthotopic LT) has been removed. This technique has been used as a "bridge" to provide needed time for the native liver to regenerate, but challenges remain as to the timing for withdrawal of immunosuppression, which leads to involution of the transplanted graft [66]. (See "Acute liver failure in adults: Management and prognosis", section on 'Auxiliary liver transplantation'.)

Hepatocyte transplant — The role of hepatocyte transplantation in PALF is yet to be determined and may be an opportunity for investigation in the future [16,67-69]. Hepatocyte transplantation may serve as a bridge to transplant or perhaps a "cure" for some children with metabolic diseases. It has been used in a small number of children with ALF. However, technical challenges as well as lack of a readily available source for hepatocytes have limited the opportunity for this procedure at most centers. A study that demonstrated the feasibility and safety of transplanting microencapsulated human hepatocytes in alginate extends the utility of this approach [70]. (See "Hepatocyte transplantation".)

OUTCOMES — In the pre-liver transplantation (LT) era, mortality for children with pediatric acute liver failure (PALF) approached 85 percent. While selection criteria for identifying PALF patients differ from that used in the pretransplant era, improvement in medical management and intensive care as well as introduction of LT as a surgical option have contributed to significantly improved patient outcomes, such that 21-day mortality is now approximately 11 percent [28]. However, this change in mortality may also reflect differences in the patient population listed for LT. Moreover, all studies of outcomes are affected by decisions about LT because LT interrupts the natural course of PALF. Some children who receive LT might have recovered spontaneously if they had not undergone LT, and some die as a consequence of LT rather than of the underlying PALF. Patient outcome depends on a number of factors including the etiology, disease severity, supportive management, and treatment. However, outcomes vary among children with seemingly similar etiology, disease severity, and treatment. Additional factors are likely involved to explain these variations, perhaps including the inflammatory milieu, end-organ damage, immune activation, and potential for liver regeneration.

Data from the Pediatric Acute Liver Failure Study Group in North America and Europe revealed that the 21-day outcome varied by diagnosis, age, and degree of encephalopathy [27,28,71]. Spontaneous survival (survival with the native liver) varies with the underlying cause of the PALF. Spontaneous survival was highest amongst those with liver failure due to acetaminophen (94 percent) and was lower for those with liver failure due to metabolic disease (44 percent), for those with non-acetaminophen drug-induced disease (41 percent), and for those with an indeterminate diagnosis (45 percent) [27]. For children with an established diagnosis, between 20 to 33 percent received an LT, and of those with acetaminophen-induced PALF, only 2 percent received an LT. In comparison, among patients with a diagnosis of indeterminant PALF, 46 percent underwent LT. Therefore, children who do not have a specific diagnosis are more likely to receive an LT. The major causes of death for children with PALF who do not receive LT are multiorgan system failure, cerebral edema and herniation, and sepsis.

In the Pediatric Acute Liver Failure Study Group cohort, patients with higher stages of encephalopathy had lower spontaneous survival, as might be expected [27,28]. Excluding patients with acetaminophen toxicity, spontaneous survival was 79 percent among those who never developed encephalopathy, versus 45 percent among those with encephalopathy at study enrollment, and 25 percent among those who developed encephalopathy during the first seven days after enrollment [28]. However, it is notable that 4 percent of those who never developed encephalopathy died and 17 percent had LT, suggesting that hepatic encephalopathy (HE) is not a reliable predictor of outcome. PALF participants whose encephalopathy was observed to either progress from one stage to another or persist during the seven days that encephalopathy was recorded had a high likelihood of receiving an LT. Patients presenting without HE were typically younger and less likely to have presented with fever or seizures.

Both early and late graft loss and death are higher among children who undergo LT for ALF than for those with chronic liver disease [72]. Reasons for these findings are uncertain, but one possibility includes immune dysregulation that may be associated with PALF, which could lead to increased susceptibility to infection or graft rejection. Use of living donor LT appears to mitigate this risk. In a cohort of older PALF patients who underwent LT (most of which were from a living donor), graft survival was 81.9 percent at one year post-transplant and 79.2 percent at five years; patient survival was 87.9 percent at both time points [73]. Comparable results for living donor LT were reported from Poland, with better outcomes in patients receiving a living donor LT compared with a deceased donor LT [74]. However, in a separate study, similar success with living donor LT was not achieved in infants under one year of age with an indeterminate cause for PALF, with five-year patient and graft survival of 26.7 percent and 17.8 percent, respectively [75]. For many children, a clinical benefit from living donor LT becomes more apparent over time for reasons that have not been fully delineated [76].

A cross-sectional analysis of neuropsychologic functioning and health-related quality of life outcomes among long-term PALF survivors demonstrate an average intelligence quotient and visual spatial ability, but impairments in motor skills, attention, executive function, health-related quality of life, and fatigue were noted [77]. Prospective studies are needed to better understand the impact of PALF on neuropsychologic and health-related quality of life outcomes in children.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pediatric liver disease" and "Society guideline links: Acute liver failure".)

SUMMARY AND RECOMMENDATIONS

●Overview – Pediatric acute liver failure (PALF) is a complex, rapidly progressive clinical syndrome of disparate etiology that precipitates complications and failure in most other organ systems. Treatment of PALF requires identification of the underlying etiology (with specific treatment where appropriate), management of each of these complications, supportive care, and informed decisions about liver transplantation (LT).

●Laboratory monitoring – Laboratory monitoring should include a complete blood count, glucose, electrolytes, renal function tests, calcium, phosphorous, ammonia, coagulation profile (prothrombin time [PT] and international normalized ratio [INR]), total and direct bilirubin, and blood cultures. (See 'Laboratory monitoring' above.)

●Fluid management – Patients with PALF are sensitive to fluid volume. In the absence of the hemodynamic instability, we suggest modest restriction of intravenous fluids, typically to between 90 to 95 percent of the maintenance fluid requirement (Grade 2C). (See 'Fluid management' above.)

●Complications

•Hepatic encephalopathy – Hepatic encephalopathy (HE) develops in the majority of patients with PALF and is identified by serial clinical evaluations. For patients with HE associated with hyperammonemia, we suggest treatment with lactulose, in addition to nonpharmacologic measures (Grade 2C). (See 'Hepatic encephalopathy' above.)

•Cerebral injury – Management of cerebral injury (cerebral edema) requires meticulous supportive care. Practice varies regarding surgical placement of an intracranial pressure (ICP) monitor. (See 'Cerebral injury (cerebral edema)' above and "Elevated intracranial pressure (ICP) in children: Management".)

•Coagulopathy – The PT and INR reflect hepatic production of clotting factors and are used to assess the severity of liver dysfunction in the setting of PALF. However, the PT or INR are not good markers for the risk of bleeding in patients with PALF, because PALF reduces both procoagulant proteins and anticoagulant proteins. (See 'Coagulopathy' above.)

-For all patients with coagulopathy, we suggest empiric administration of parenteral vitamin K (Grade 2C). A single dose is sufficient; repeat administration of vitamin K is unnecessary. Vitamin K is routinely administered to these patients because it helps to correct any component of the coagulopathy that is caused by vitamin K deficiency and is very low risk. Furthermore, if the coagulation profile does not significantly improve after vitamin K administration, this suggests that the coagulopathy is caused by liver failure rather than vitamin K deficiency.

-Plasma transfusions or other procoagulation products should be reserved for patients with active bleeding or in anticipation of an invasive surgical procedure.

•Kidney injury – Several mechanisms can cause kidney function impairment in PALF. The most severe is hepatorenal syndrome, which is characterized by low urine sodium and lack of improvement with volume expansion. (See 'Kidney injury' above.)

•Metabolic – Metabolic disturbances often seen in patients with PALF include hypoglycemia, hypokalemia, hypophosphatemia, and acid-base disturbances. (See 'Metabolic' above.)

•Infection – Patients with PALF are susceptible to bacterial infection and sepsis because of immune system dysfunction. Evidence of infection may be subtle, and fever may not be present. Thus, blood cultures should be obtained with any evidence of clinical deterioration, and antibiotics should be initiated if there are signs or symptoms of sepsis. (See 'Infectious' above.)

●Liver transplantation – Decisions about whether and when to perform an LT for a patient with PALF are difficult because of uncertainty regarding the patient's outcome without LT and the potential morbidity and mortality of the LT procedure. No prognostic tool is adequate to direct decisions about LT. (See 'Severity assessment' above and 'Liver transplant decisions' above.)

●Outcomes – Outcomes for patients with PALF vary substantially by diagnosis. Survival without LT is highest for patients with acetaminophen-related PALF (94 percent). Other important prognostic factors include age, timing of diagnosis for treatable disorders, and degree of encephalopathy. (See 'Outcomes' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert H Squires, Jr, MD, FAAP, who contributed to earlier versions of this topic review.