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Acute liver failure in children: Etiology and evaluation

Acute liver failure in children: Etiology and evaluation
Authors:
James E Squires, MD, MS
Robert H Squires, Jr, MD, FAAP
Section Editor:
Elizabeth B Rand, MD
Deputy Editor:
Alison G Hoppin, MD
Literature review current through: Jun 2022. | This topic last updated: Jul 15, 2022.

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 [1-3]. The estimated frequency of ALF in all age groups in the United States is approximately 17 cases per 100,000 population per year, but the frequency in children is unknown. PALF accounts for approximately 8 percent of pediatric liver transplants (LTs) performed in the United States annually [4].

PALF is a rapidly evolving clinical condition. There are no adequately powered studies to inform diagnostic algorithms, assess markers of disease severity and trajectory, or 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 separately. (See "Acute liver failure in children: Management, complications, and outcomes".)

ALF in adults is addressed in separate 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 dysfunction in children is defined by the presence of all three of the following criteria [5,6]:

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 (AST) or alanine aminotransferase (ALT) >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 [7]. (See "Acute liver failure in children: Management, complications, and outcomes", section on 'Hepatic encephalopathy'.)

Patients meeting these criteria should be transferred to or evaluated in consultation with a Pediatric liver transplant center [6]. These criteria are the basis for entry into the pediatric acute liver failure (PALF) study group registry described below [8].

CLINICAL PRESENTATION — Pediatric acute liver failure (PALF) typically presents in a previously healthy patient with a nonspecific prodrome of variable duration with features that might include abdominal discomfort and malaise with or without fever. With the exception of acute ingestions (eg, mushrooms, acetaminophen), the precise onset of disease is rarely identified. Symptoms may persist or wax and wane for days or weeks before the child is brought to medical attention. In the absence of jaundice or other clinically evident signs of liver dysfunction, the child may receive empiric treatment to relieve symptoms, and some children undoubtedly recover before PALF is recognized. However, if there are clinical signs of liver injury or encephalopathy or if blood work is obtained that reveals hepatic dysfunction, the clinical syndrome of PALF can be recognized.

Common features at presentation of PALF were described in a study from a multicenter registry (likely with selection bias for children with more severe illness) [9]:

Encephalopathy – 53 percent (13 percent grade 3 or 4)

Seizure – 7 percent

Ascites – 22 percent

In addition to the 53 percent of patients with encephalopathy on admission, an additional 15 percent of patients developed encephalopathy within the next seven days [9]. Encephalopathy is less commonly observed among children younger than three years and those with acetaminophen-induced PALF. (See "Acute liver failure in children: Management, complications, and outcomes", section on 'Hepatic encephalopathy'.)

CAUSES OF PEDIATRIC ACUTE LIVER FAILURE — Specific etiologies of pediatric acute liver failure (PALF) can be broadly categorized as infectious, immunologic, metabolic, vascular, and toxin- or drug-related [6]. In earlier studies, more than 50 percent of patients did not have an identifiable etiology for PALF and were categorized as indeterminate. Improvements in diagnostic processes result in lower proportions of indeterminate diagnoses. As an example, integration of an age-specific diagnostic algorithm into the electronic medical record resulted in a reduction of indeterminate cases to 31 percent [8].

Worldwide, the causes of PALF vary depending on the age group and region. The causes of PALF in resource-rich countries are outlined in the figures (table 2), which is derived from a registry of PALF in children from 24 pediatric liver transplantation (LT) centers in the United States, Canada, and the United Kingdom between 2000 and 2012, known as the Pediatric Acute Liver Failure Study Group (PALFSG) [8]. In resource-limited countries, the etiologies are similar but are dominated by infectious etiologies, among which hepatitis A virus (HAV) is the most common (table 3).

Acetaminophen — Acetaminophen (N-acetyl-p-aminophenol [APAP]; paracetamol) is widely used in children for management of fever and pain. APAP is safe and well tolerated when dosing instructions are strictly followed. However, APAP has a low therapeutic index, and, in certain individuals or clinical scenarios, chronic administration of therapeutic doses of APAP can result in significant hepatotoxic effects [10,11]. Two clinical scenarios are associated with APAP hepatotoxicity:

Acute single ingestion of a hepatotoxic dose of APAP that is greater than 100 mg/kg (typically an intentional ingestion by an older child or adolescent or, rarely, an exploratory ingestion by a young child).

Chronic ingestion of inappropriately high doses of APAP (>90 mg/kg per day, ie, >15 mg/kg given every four hours) for more than one day may be associated with hepatotoxicity in some individuals. An accurate dose history is challenging in circumstances where chronic APAP administration is indicated to manage symptoms of fever and discomfort. Thus, the dose administered and the dose received may be inaccurate. Risk factors for developing hepatotoxicity include concomitant use of other medicines that alter hepatic metabolism, delayed medical care, younger age, and prolonged periods of fasting [10,12]. In the PALFSG registry, chronic APAP may have contributed to liver injury in approximately 10 percent of patients [13]. The clinical phenotype of chronic exposure to APAP in the setting of ALF is similar to that seen with acute APAP toxicity: marked elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), accompanied by a low total bilirubin. The pathophysiology of chronic exposure and its relationship, if any, to PALF remains poorly understood. A careful history of APAP administration should be obtained in patients with PALF.

In patients with PALF, acute or chronic APAP exposure typically is characterized by high ALT levels and relatively modest elevations in total bilirubin. In the PALFSG registry, children with chronic APAP exposure were younger than those with acute APAP exposure and also had worse 21-day outcomes [13]. Whether the difference in outcome was related to age, differences in treatment (eg, use of n-acetylcysteine), or other underlying contributors to liver disease remains to be determined. The pathophysiology, diagnosis, and management of APAP poisoning in children are discussed in detail in separate topic reviews. (See "Clinical manifestations and diagnosis of acetaminophen (paracetamol) poisoning in children and adolescents" and "Management of acetaminophen (paracetamol) poisoning in children and adolescents".)

Other medications or toxins — Liver injury caused by drugs and toxins other than acetaminophen was identified in approximately 3 percent of cases in the PALFSG registry; the vast majority of the cases occurred in children over 10 years of age [8]. The list of toxins associated with liver failure is extensive and expanding; a partial list is shown in the table (table 4) [1,14]. Details on specific medications and herbal therapies are available from the LiverTox website [15]. (See "Drug-induced liver injury".)

Intrinsic hepatotoxins — Agents with predictable dose-dependent hepatotoxicity are known as intrinsic hepatotoxins and include industrial solvents and mushroom toxin (as well as APAP, which is discussed above). The diagnosis of hepatotoxic liver injury is based upon the interval between drug ingestion and the onset of symptoms, the known hepatotoxicity of the offending agent, serum drug levels (if available), and liver biopsy findings [16]. (See "Amatoxin-containing mushroom poisoning (eg, Amanita phalloides): Clinical manifestations, diagnosis, and treatment".)

Idiosyncratic hepatotoxic effects — Many agents have idiosyncratic hepatotoxic effects, such that toxicity is not predictable or dose-dependent. (See "Drugs and the liver: Metabolism and mechanisms of injury", section on 'Idiosyncratic hepatotoxicity'.)

An idiosyncratic hepatotoxic effect is well established for each of the following drugs; if a patient with ALF was recently exposed to these drugs, a causal association is likely:

Isoniazid (see "Isoniazid hepatotoxicity")

Propylthiouracil (see "Thionamides: Side effects and toxicities", section on 'Hepatotoxicity')

Halothane

For many other drugs, idiosyncratic hepatotoxicity is less well established. If a patient with ALF was recently exposed to such a drug, a hepatoxic effect is possible, but other potential causes of the ALF should also be fully explored [11,17]. In children, idiosyncratic reactions causing PALF have been reported for the following drugs [9,18,19]:

Antiseizure medications – Valproate, phenytoin, carbamazepine, lamotrigine, and felbamate are among the most common drugs associated with PALF [19]. Patients with unsuspected mitochondrial disease (eg, Alpers-Huttenlocher disease) are particularly at risk for hepatotoxicity from valproate. (See 'Inherited metabolic disease' below.)

Antimicrobial agents – Isoniazid has well-established hepatotoxic effects, as described above. In addition, minocycline, amoxicillin-clavulanate, azithromycin, rifampin, roxithromycin, and nitrofurantoin, as well as a number of antiviral agents used in the treatment of human immunodeficiency virus (HIV), have been reported to cause PALF [18,19].

Chemotherapeutic agents – Cyclophosphamide and dacarbazine are associated with hepatic vein injury, resulting in veno-occlusive disease and PALF.

Other medications – Other potential medications that should be considered in the proper clinical setting include amiodarone (antiarrhythmic) and trazodone (antidepressant).

Recreational drugs – Recreational drug use, particularly cocaine and ecstasy (3,4-methylenedioxyamphetamine [MDMA]), is associated with PALF in teenagers and also in younger children who live in environments where these compounds are accessible. (See "MDMA (ecstasy) intoxication" and "Inhalant abuse in children and adolescents".)

Complementary or alternative medicines – Complementary or alternative medical therapies associated with liver failure include pyrrolizidine alkaloids, germander, Chinese herbal medicine, ma huang, chaparral, black cohosh root, pennyroyal, and kava [20]. (See "Hepatotoxicity due to herbal medications and dietary supplements".)

If drug-induced liver injury is suspected, rechallenge with that drug should be avoided [6].

Immune dysregulation

Autoimmune marker positive — The clinical significance of autoimmune markers in patients with PALF is not clear. In some cases, these markers are nonspecific since they can be found in patients with other known causes of liver failure, such as Wilson disease and drug-induced liver failure. In other cases of PALF, patients have a clinical picture consistent with autoimmune hepatitis (AIH), with markedly elevated autoimmune markers and/or total serum protein, characteristic histologic features, and apparent response to treatment with corticosteroids.

More than 25 percent of the cases in the PALFSG registry had positive autoimmune markers (antinuclear antibody, anti-smooth muscle antibody, and/or liver-kidney microsomal antibody) [21]. The true frequency of positive autoimmune markers in PALF is not known, because these tests are not consistently obtained in the patient population [22]. The frequency of autoimmune markers in PALF is similar across age groups, including in infants between 9 weeks and 12 months of age, and is evenly distributed among males and females [1]. Therefore, an autoimmune mechanism should be considered in all age groups outside of the neonatal period. This pattern is in contrast with chronic AIH, which is most frequent in adolescents and adults and has a female predominance.

Establishing an underlying diagnosis of AIH is challenging in patients with PALF and, in many cases, only a presumptive diagnosis can be made [21]. Isolated mild elevations of antinuclear antibody are common and are not diagnostic of AIH. Elevated serum immunoglobulin G (IgG) supports the diagnosis of AIH but is not always present. Similarly, the diagnosis can be supported by a liver biopsy if it reveals histologic features suggestive of AIH. The interpretation of autoimmune markers and other laboratory and histologic findings is discussed in detail in a separate topic review (see "Overview of autoimmune hepatitis", section on 'Diagnostic evaluation'). Of note, the simplified scoring system that is often used for diagnosis of AIH [23] may not be sufficiently sensitive for children presenting with ALF [24].

If AIH is suspected, patients are usually treated with corticosteroids because these drugs can interrupt the liver injury in many patients, but in cases where the diagnosis is uncertain, this can be a difficult decision. (See "Acute liver failure in children: Management, complications, and outcomes", section on 'Treat the underlying cause'.)

Immune dysregulation in PALF has been recognized for a number of years. Most, but not all, patients have negative autoimmune markers but histologic features of severe acute hepatitis with an inflammatory infiltrate dominated by CD8-positive lymphocytes [25]. Additional markers reflecting immune activation may include elevated soluble interleukin 2 (IL-2) receptor alpha [26], cytokine, and chemokine profiles [27,28]. Further characterization of this unique subset of PALF patients is needed. (See 'Indeterminate' below.)

Hemophagocytic lymphohistiocytosis — Hemophagocytic lymphohistiocytosis (HLH) is an enigmatic condition involving immune dysfunction. The disorder is most commonly diagnosed in the first five years of life but can present in adolescence or adulthood. It is characterized by fever, hepatosplenomegaly, marked elevation in serum aminotransferase levels, cytopenias, hypertriglyceridemia, hyperferritinemia (serum ferritin concentrations are often over 5000 ng/mL), hypofibrinogenemia, and elevated levels of soluble IL-2 receptor alpha (sCD25) [29,30]. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)

Up to 25 percent of HLH cases are familial, and mutations in genes affecting granule-dependent cytotoxicity are identified in approximately one-half of affected patients. The remainder of cases (and some of the genetic cases) may be triggered by acute viral infection, particularly Epstein-Barr virus [31,32]. Several other viruses were identified among patients with a final diagnosis of HLH in the PALFSG registry, but these viruses may not have been causal [33]. (See 'Infection with viruses other than hepatitis viruses' below.)

Gestational alloimmune liver disease (neonatal hemochromatosis) — Gestational alloimmune liver disease (GALD; previously known as neonatal hemochromatosis) is an alloimmune-mediated disorder affecting newborn infants. Although it is rare, it is responsible for a significant minority of PALF presenting in the neonatal period [34].

Clinical features – GALD presents with signs and symptoms of acute hepatic failure during the first few days of life. Characteristic clinical features include refractory hypoglycemia, severe coagulopathy, hypoalbuminemia, elevated serum ferritin (>1000 ng/mL), and ascites. Strikingly, serum aminotransferase levels are normal or near-normal, which helps to distinguish GALD from other causes of liver failure that present during the neonatal period. Extrahepatic iron deposition is a hallmark finding. Hemosiderin deposition in the minor salivary glands obtained by a buccal mucosal biopsy is often seen. Characteristic findings on magnetic resonance imaging (MRI) of the abdomen include reduced T2-weighted intensity of the pancreas relative to the spleen. MRI can also detect excess extramedullary iron deposition in the brain and heart.

Pathogenesis – The term GALD reflects the recognition that an alloimmune mechanism is responsible for the disorder. Maternal IgG appears to activate fetal complement that leads to the formation of membrane attack complex, resulting in liver cell injury [35]. The degree of liver injury can be profound, so that death from liver failure can occur within the first few weeks of life. Liver failure associated with GALD is technically a terminal event of a chronic intrauterine liver disease. However, the typical phenotype of the family's index case of GALD is one of ALF presenting during the neonatal period, so it is discussed here for clinical purposes.

Most cases of GALD would previously have been classified as neonatal hemochromatosis. However, the terms are not synonymous. GALD is an intrauterine disease process causing severe fetal liver injury, often but not always accompanied by the hepatic and extrahepatic iron deposition that characterizes neonatal hemochromatosis. Neonatal hemochromatosis is the phenotypic expression in the neonate of severe liver injury initiated in utero, most commonly caused by GALD.

Differential diagnosis – The differential diagnosis of GALD includes inborn errors of metabolism. As an example, a neonate with clinical and autopsy findings consistent with GALD was found to have a homozygous mutation in the DGUOK gene (deoxyguanosine kinase) [36]. Mutations in DGUOK can cause a mitochondrial depletion syndrome with hepatocerebral manifestations. (See 'Young infants' below.)

Management – Exchange transfusion and high-dose intravenous immune globulin (IVIG) is the preferred treatment for GALD [37]. For pregnant women with a previous pregnancy that resulted in an infant with GALD, treatment with high-dose IVIG beginning at 14 weeks gestation dramatically reduces the risk for recurrence of the disease. (See "Causes of cholestasis in neonates and young infants", section on 'Gestational alloimmune liver disease (neonatal hemochromatosis)'.)

Inherited metabolic disease — Metabolic diseases do not fit the definition of ALF precisely, as the condition was certainly present prior to presentation. However, a number of inherited metabolic diseases are diagnosed only after the child presents with ALF. Thus, these conditions are important considerations in the differential diagnosis of PALF. Overall, metabolic diseases account for at least 10 percent of PALF cases in North America and Europe [38,39]. While some conditions, such as mitochondrial disease, may present at any age, many metabolic conditions presenting as liver failure segregate within age groups. Metabolic conditions that should be considered in these age groups are listed in the table (table 5A). The conditions that have been associated with a presentation of ALF are outlined briefly below. Details of the specific conditions can be found in the linked topic reviews.

Young infants — Metabolic conditions affecting infants in the first few months of life include galactosemia, tyrosinemia, Niemann-Pick type C, mitochondrial hepatopathies, and urea cycle defects [34,40-42]:

Galactosemia (MIM #230400) should be considered in a child consuming breast milk or other lactose-containing formulas who develops liver failure associated with reducing substances in the urine; reducing substances are detected by a test for reducing sugars (such as Clinitest tablets). Galactosemia can present in association with gram-negative sepsis. Galactosemia is included in the newborn screen in all states in the United States, but if the condition is suspected, definitive testing should be performed even if the newborn screen is negative. (See "Galactosemia: Clinical features and diagnosis" and "Galactosemia: Management and complications".)

Hereditary tyrosinemia type 1 (MIM #276700) can present with a profound coagulopathy and normal or near-normal serum aminotransferase levels. Like galactosemia, tyrosinemia can present in association with gram-negative sepsis. Almost all states in the United States include tyrosinemia in the newborn screen. (See "Disorders of tyrosine metabolism", section on 'Hereditary tyrosinemia type 1' and "Newborn screening".)

Niemann-Pick type C (MIM #257220) is a lysosomal storage disease; marked splenomegaly is often noted. Although most individuals present with progressive neurologic disease in middle to late childhood, a minority of cases present during early infancy with severe hepatic disease and/or respiratory failure [43]. (See "Overview of Niemann-Pick disease", section on 'NPD type C'.)

Mitochondrial hepatopathies are increasingly recognized as an important cause of liver failure due to deficiencies in respiratory complexes I, III, or IV or mitochondrial deoxyribonucleic acid (DNA) depletion (table 6). These include mitochondrial DNA depletion syndrome 3 (MIM #251880), which is caused by mutations in the DGUOK gene, and mitochondrial DNA depletion syndrome 6 (MIM #256810), also known as Navajo neurohepatopathy, which is caused by mutations in the MPV17 gene [39,44-46].

With some exceptions, mitochondrial hepatopathies that present in infancy with PALF are associated with systemic mitochondrial dysfunction, characterized by progressive neurologic deficiencies, cardiomyopathy, and/or myopathy. Many affected infants have a history of intrauterine growth retardation and/or prematurity [44]. Lactic acidosis and an elevated molar ratio of lactate to pyruvate (>25 mol/mol) occur across all diagnostic categories in PALF and thus are not reliable to identify patients with a mitochondrial disorder [47]. Defects in fatty acid oxidation, a primary function of mitochondria, may become clinically apparent during a period of fasting as a consequence of anorexia associated with an acute illness or when the infant begins to sleep through the night. These patients are particularly vulnerable to hepatotoxic effects of valproate. (See "Mitochondrial myopathies: Clinical features and diagnosis" and "Causes of cholestasis in neonates and young infants", section on 'Mitochondrial disorders'.)

In such patients, hepatomegaly is often evident and serum aminotransferase levels usually are elevated, but only to a mild to moderate degree (usually <400 international units/L). Jaundice can be minimal (serum bilirubin concentration usually <10 mg/dL), which suggests that certain organelle functions remain intact and also that bilirubin production probably is not increased.

Recurrent PALF episodes have been associated with LARS1 or NBAS gene mutations. Importantly, acute liver failure in the neonatal period may be the initial presentation of these rare disorders and a high clinical suspicion is indicated to make the diagnosis [48,49].

Older infants and young children — In older infants and young children up to five years of age presenting with ALF, the following metabolic diseases are sometimes identified [9]:

Mitochondrial hepatopathies, particularly disorders of fatty acid oxidation, occur relatively commonly in this age group (table 6) [50]. Mitochondrial hepatopathy disorders presenting in this age group include Alpers-Huttenlocher disease (MIM #203700), caused by mutations of the POLG gene (mitochondrial DNA polymerase gamma) [39,44,46]. This disorder is characterized by developmental regression, seizures, and liver failure, which is often triggered by exposure to valproate. (See 'Young infants' above.)

Hereditary fructose intolerance presents only after the introduction of fructose and/or sucrose into an infant's diet and is characterized by recurrent hypoglycemia and vomiting. Therefore, most cases present at the age of weaning, when fructose or sucrose typically is added to the infant's diet. However, some infants may present earlier because many commercial formulas and medications contain sucrose [51]. (See "Causes of hypoglycemia in infants and children", section on 'Hereditary fructose intolerance'.)

Argininosuccinate synthetase deficiency (citrullinemia type 1, MIM #215700) and ornithine transcarbamylase deficiency (MIM #311250) have been associated with PALF [52,53], although the mechanism of liver injury is uncertain. Most other urea cycle defects present with hyperammonemia, mental status changes, and seizures, but without liver synthetic dysfunction. (See "Urea cycle disorders: Clinical features and diagnosis".)

LARS1 or NBAS gene mutations also may present in this age group.

Older children and adolescents

Wilson disease – Wilson disease is the most common metabolic condition associated with PALF in children over five years of age [9]. The presence of a Coombs-negative hemolytic anemia, marked hyperbilirubinemia, low serum ceruloplasmin, and a normal or subnormal low serum alkaline phosphatase should prompt consideration of Wilson disease [54]. Findings in a predominately adult population suggest that the combination of an alkaline phosphatase-to-total bilirubin ratio of less than 4 and an AST-to-ALT ratio of more than 2.2 provided a rapid and accurate method for diagnosis of Wilson disease presenting as ALF [55]. However, these findings have not yet been confirmed in a pediatric population. (See "Wilson disease: Diagnostic tests".)

Mitochondrial disease (fatty acid oxidation defects) occasionally present with PALF in older children and adolescents. (See "Inborn errors of metabolism: Classification", section on 'Fatty acid oxidation disorders'.)

Infectious diseases — A nonspecific prodrome consisting of fever, nausea, vomiting, and abdominal discomfort precedes many cases of ALF in children, regardless of etiology. Therefore, in the past, ALF often was attributed to a virus or infection. When rigorous techniques are applied in an attempt to identify specific infectious agents, the common hepatitis viruses have not often been found in ALF, except in association with a community outbreak or in regions in which the virus is endemic [56]. There is general agreement that HAV, hepatitis B virus (HBV), herpes simplex virus (HSV), parvovirus, and adenovirus are capable of causing ALF, as can enterovirus for infants less than seven months of age [34]. For other viruses, such as hepatitis C virus (HCV), cytomegalovirus, Epstein-Barr virus, human herpes virus 6, and HIV, there is less certainty that the presence of the virus is causally linked to the episode for ALF [33]. Many cases of PALF are not fully tested for a viral cause.

Hepatitis viruses — Less than 1 percent of children with symptomatic HAV develop ALF. Nonetheless, acute HAV accounts for up to 80 percent of PALF cases in resource-limited countries, reflecting high rates of HAV infection in the population [57]. In North America and Western Europe, HAV infection causes only 0.8 percent of cases of PALF, reflecting low rates of HAV infection, especially since the introduction of the HAV vaccine in the United States in 1995 [9]. (See "Overview of hepatitis A virus infection in children".)

Similarly, acute HBV infection resulting in ALF is uncommon in pediatric series from Western Europe and North America, where HBV is not endemic. Among the first 986 PALFSG patients, three (0.3 percent) were ultimately diagnosed with HBV [8]. However, in areas where HBV is endemic, it accounts for up to 20 percent of PALF cases. Death occurs more commonly in older patients and in individuals who acquired HBV following a blood transfusion rather than from perinatal infection. Mutations in the HBV genome appear to be a risk factor in the development of ALF [58]. (See "Clinical manifestations and diagnosis of hepatitis B virus infection in children and adolescents", section on 'Acute hepatitis B virus infection'.)

HCV infection has rarely been identified as the cause for ALF, and ALF has not been observed in large studies of transfusion-acquired HCV infection [59]. HCV ribonucleic acid (RNA) has not been detected in the serum of patients with sporadic fulminant hepatitis without defined cause [60]. (See "Hepatitis C virus infection in children", section on 'Management of acute hepatitis C virus'.)

Seroprevalence of hepatitis E virus (HEV) appears to be increasing. HEV remains a rare cause of ALF in the United States but is endemic in many developing countries. HEV appears to be a common cause of acute hepatitis and sometimes of ALF in these endemic areas, but the true incidence may be underestimated because serologic testing is not consistently performed [22]. Most experience with HEV comes from the Indian subcontinent, where 38 percent of PALF cases were attributed to HEV alone or in combination with HAV [61]. Pregnant women have a high risk of fulminant hepatitis, with a case fatality rate from ALF of 10 to 20 percent, with particularly high risk during the third trimester of pregnancy [1,62,63]. Among women with HEV infection during pregnancy, the risk of symptomatic hepatitis in the newborn is high. (See "Hepatitis viruses and the newborn: Clinical manifestations and treatment", section on 'Hepatitis E' and "Hepatitis E virus infection".)

Infection with viruses other than hepatitis viruses — Viruses in the herpes family are highly cytopathic and can cause severe hepatic necrosis, often in the absence of significant inflammation. Little is known about the incidence or case fatality rates among children with ALF secondary to herpesvirus infection. However, early detection utilizing newer diagnostic techniques, such as real-time polymerase chain reaction, and early institution of specific therapy may improve survival [64]. Each of the following has been reported to cause ALF in both immunocompromised and immunocompetent hosts [38]:

HSV – HSV most commonly affects infants and newborns but can affect all age groups [34]. Affected infants present with symptoms resembling sepsis and may or may not have lesions of the skin, eyes, or mouth. In a registry study from the United States, HSV was identified in 25 percent of young infants who underwent testing and was frequently fatal in this age group [33]. Because HSV is a sexually transmitted disease, it should also be considered in sexually active adolescents. HSV-associated hepatitis is rare in immunocompetent individuals; 30 percent of affected patients have skin lesions. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis" and "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Hepatitis'.)

Epstein-Barr virus – Epstein-Barr virus is the virus most frequently implicated in older children and adolescents with PALF in regions where hepatitis A and B are not endemic. (See "Clinical manifestations and treatment of Epstein-Barr virus infection", section on 'Primary infection'.)

Human herpesvirus 6 (HHV-6) – The role of HHV-6 in ALF is unclear. In a small series in adults, HHV-6 was detected in 80 percent of the explanted livers of patients who underwent LT for ALF of unknown cause [65]. However, HHV-6 is prevalent as a latent infection in humans, so the presence of HHV-6 does not prove that it caused the ALF. In a case series in children who underwent LT for unknown cause, HHV-6 was detected in 34 of 51 (67 percent) of explanted livers, compared with 19 of 51 (37 percent) of age-matched control patients receiving an LT for metabolic disease [66]. The association is strongest in children younger than three years. Given the small numbers, this association does not establish causality. However, a disordered immune response to the virus may have contributed to the clinical phenotype. Far more commonly, primary infection with HHV-6 causes a self-limited febrile illness, with or without rash (roseola infantum). (See "Human herpesvirus 6 infection in children: Clinical manifestations, diagnosis, and treatment", section on 'Less common manifestations'.)

Parvovirus B19 – Whether parvovirus B19 infection is associated with PALF is unclear. When detected, it may be an incidental finding or an exacerbating factor for another viral infection. This virus causes one of the common childhood exanthemas (erythema infectiosum, or fifth disease) [38]. It rarely can cause severe bone marrow depression and has been associated with mild hepatitis. A few studies suggest that the rate of parvovirus B19 infection among individuals with ALF and aplastic anemia are higher than among patients with ALF due to known causes [67,68]. However, in a large study in adults with ALF, there was no serologic evidence of parvovirus B19 infection [69]. (See "Clinical manifestations and diagnosis of parvovirus B19 infection", section on 'Unconfirmed disease associations'.)

Other viruses associated with ALF include adenovirus, dengue fever, members of the enterovirus family (including echovirus [16,34,50] and coxsackie A and B), and paramyxovirus. Adenovirus is under investigation as a possible cause of several clusters of acute hepatitis in young children in early 2022 (see 'Outbreak 2022' below and "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection"). Paramyxovirus infection (other than measles and mumps) was associated with a syncytial giant-cell hepatitis with ALF in a series from Toronto [70]. Several of the patients in this report had chronic progressive hepatitis or late-onset hepatic failure rather than ALF.

Nonviral infectious hepatitis — Infectious agents other than viruses only rarely have been recorded as producing ALF; however, they are generally accompanied by features of disseminated intravascular coagulation. Despite the rarity of occurrence, they should be considered carefully in every case because they are potentially treatable.

Systemic sepsis occasionally presents in a manner that is virtually indistinguishable from ALF. Reported infectious etiologies include Neisseria meningitides infection, septic shock and intraabdominal abscesses, and portal sepsis with enteric organisms. Spirochetal infection (syphilis) can affect liver function and produce severe hepatitis, even hepatic failure. ALF is a rare complication of congenital syphilis and also has been reported in adolescents and adults with acquired syphilis [71,72]. Leptospirosis very rarely causes hepatic failure. Finally, in endemic areas, brucellosis and Coxiella burnetii (Q fever), Plasmodium falciparum, and Entamoeba histolytica infections have presented as ALF.

Hypoperfusion — Hypoperfusion of the liver can result in ischemic hepatitis and ALF. Hypoperfusion typically results from systemic hypotension with multiorgan dysfunction due to neonatal shock, sepsis, cardiac dysfunction (eg, hypoplastic left heart syndrome, cardiomyopathy, cardiopulmonary bypass), or drugs. Hypoperfusion of the liver may also be seen with Budd-Chiari syndrome (hepatic vein thrombosis), veno-occlusive disease, or the use of vasoconstricting drugs such as cocaine and methamphetamine.

Other rare causes — Liver failure may be the presenting manifestation of the following systemic conditions:

Leukemia [9]

Celiac disease [73] – If recognized, this is potentially treatable following institution of a gluten-free diet

Indeterminate — A specific diagnosis is not identified in 30 to 50 percent of children with PALF [6,8,9]. If a specific diagnosis is not possible after a thorough evaluation, these cases should be classified as indeterminate PALF (I-PALF). It is important to monitor hemoglobin, white blood cells, and platelets in all indeterminate patients for at least four months, regardless of their transplant status, for evidence of aplastic anemia, which can develop following an episode of PALF.

One study reported that APAP-cysteine adducts (a biomarker of acetaminophen exposure) were found in 12 percent of children with I-PALF and no clear history of toxic exposure to acetaminophen [74]. This finding raises the possibility that unsuspected APAP toxicity may be present in some patients with I-PALF, but the relative importance of acetaminophen in the etiopathogenesis of PALF in those patients is uncertain.

I-PALF likely consists of multiple patient subgroups (figure 1). One subgroup reflects patients with an incomplete diagnostic evaluation, either because of variation in diagnostic prioritization or premature interruption of the planned diagnostic tests by death, LT, or clinical improvement. For example, in one series, the majority of patients classified as I-PALF were incompletely evaluated for AIH because only 79 percent underwent any testing for AIH and only 55 percent had all three autoantibodies determined [22]. Another subgroup of I-PALF likely comprises patients with a pathophysiologic injury that is not identified using our diagnostic strategies, including types of immune dysregulation or infection that are not captured by standard diagnostic methods. As an example, a subset of patients with PALF of indeterminate etiology has a dense CD103+, CD8+ T cell infiltrate, raising the possibility of immune-mediated injury [75]. PALF patients with this "activated" CD8 T cell hepatitis are more likely to receive LT than are patients with other causes of PALF. Based on these observations, there has been a growing trend toward treatment of PALF associated with activated CD8+ T cell hepatitis with immunosuppression. However, the therapeutic benefit of this practice remains unknown. (See 'Characteristics suggesting a specific diagnosis' below.)

At a symposium on I-PALF sponsored by the National Institutes of Health, evidence was presented identifying similarities between I-PALF, HLH, and macrophage activation syndrome, suggesting that an uncontrolled hyperinflammatory state may be present in some patients with I-PALF [76]. (See "Acute liver failure in children: Management, complications, and outcomes", section on 'Aplastic anemia'.)

"Recurrent" liver failure — In rare instances, a child will appear to recover completely from an episode of I-PALF, only to experience a second or even third episode. Conditions associated with recurrent PALF include an increasing number of genetic diseases, with fatty acid oxidation defects, neuroblastoma amplified sequence (NBAS) gene mutations [77,78], and LARS gene mutations [49,78,79] being the most common, but others have been identified [80-82]. Reexposure to an unsuspected drug or herbal remedy should also be considered. (See "Overview of fatty acid oxidation disorders".)

Outbreak 2022 — In early 2022, an outbreak of acute hepatitis was identified among young children (most <5 years) in the United Kingdom and Ireland and other clusters with similar characteristics were subsequently reported elsewhere in Europe and the United States [83-86]. Hypotheses about possible causes are summarized in a technical report from the United States Centers for Disease Control and Prevention as of June 16, 2022 [86]. Candidates under investigation are:

Adenovirus – Adenovirus (primarily type 41) has been detected in many cases, including 45 percent of those in the United States [87], and testing for adenovirus was suggested in preliminary communications [84,88,89]. However, adenovirus has not historically been a recognized cause of hepatitis in healthy children. Moreover, analysis of data in the United States through March 2022 showed no overall increase in hospitalizations for hepatitis of unknown cause compared with before the coronavirus disease 2019 (COVID-19) pandemic and no increase in adenovirus types 40/41 positivity [90]. Thus, it is unclear whether the case series in the United States represents a novel cause of acute hepatitis versus a previously existing phenomenon and whether there is a relationship with adenovirus infection. (See "Diagnosis, treatment, and prevention of adenovirus infection".)

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) – SARS-CoV-2 has been detected in a minority of cases (10 percent of United States cases [87]). Other patients have a history of past COVID-19 disease (26 percent of United States cases [87]). Thus, an association with active or past SARS-CoV-2 infection has not been established. (See "COVID-19: Clinical manifestations and diagnosis in children".)

There is no link with COVID-19 vaccine or hepatitis viruses (A, B, C, E, and D) [88,91,92], and no common exposures (eg, travel or toxins) have been identified [87].

ETIOLOGIC EVALUATION — Every effort should be made to rapidly identify a cause of pediatric acute liver failure (PALF), if possible. For some causes, an effective treatment is available that could alter the cause of the disease. For other disorders, the diagnosis gives important information about prognosis and informs decisions about liver transplantation (LT). However, the ability to do a complete diagnostic evaluation of children with ALF is limited by the volume of blood needed to complete diagnostic tests and sometimes by a rapid clinical trajectory ending in death or LT prior to a complete evaluation. Given the rarity of PALF, an algorithmic age-based diagnostic approach is useful to improve diagnostic yield. As an example, integration of an age-specific diagnostic algorithm into the electronic medical record improved the frequency of specific diagnosis and reduced the proportion of indeterminate cases of PALF (I-PALF) from 50 to 30 percent [8]. It was also associated with a reduction in LT without an increase in death.

History — A detailed history is essential [38]. Each of the following issues should be explored:

Time of onset of symptoms such as jaundice, change in mental status, easy bruising, vomiting, and fever.

Exposure to contacts with infectious hepatitis.

History of blood transfusions.

In adolescents, a history of depression, suicide attempts, and risk-taking behaviors.

A list of prescription and over-the-counter medications in the home, including complementary and alternative medicines, and whether these medications might have been ingested intentionally or accidentally (table 4).

Use of intravenous drugs or other recreational drugs that are hepatotoxins, including ecstasy, cocaine, or solvent-sniffing. Any exposure to hepatotoxic drugs or chemicals should be considered as possibly related to the liver injury. However, a history of exposure to a drug or toxin should not preclude a thorough search for other causes of liver injury. (See 'Idiosyncratic hepatotoxic effects' above.)

Family history of Wilson disease, infectious hepatitis, infant deaths or autoimmune conditions, which might lead to a specific diagnosis.

In neonates, review of maternal records for risks and tests for congenital infections, including syphilis and herpes simplex virus (HSV), or history of unexplained fetal loss or neonatal hepatitis. (See 'Infection with viruses other than hepatitis viruses' above and 'Nonviral infectious hepatitis' above and "Overview of TORCH infections".)

Evidence of developmental delay and/or seizures, which should prompt a careful assessment for metabolic disease. (See 'Inherited metabolic disease' above.)

Pruritus, ascites, splenomegaly, or growth failure, which might suggest a chronic liver condition with an acute presentation.

Physical examination — The physical examination should assess for each of the following:

Evaluation of growth, development, and nutrition status – Abnormal growth or development may suggest an underlying disorder, including metabolic disease.

Evidence of coagulopathy, including bruises, bleeding following venipuncture, and petechiae.

Findings related to liver function and blood flow, including jaundice, hepatomegaly alone or with splenomegaly, ascites, and peripheral edema.

Evidence of hepatic encephalopathy (HE) – Altered mental status should be assessed but may be difficult to assess in infants and young children. Fetor hepaticus is a sweet, distinctive aroma to the breath associated with HE but is rarely present. 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). Evaluation and management of HE are discussed in greater detail separately. (See "Acute liver failure in children: Management, complications, and outcomes", section on 'Hepatic encephalopathy'.)

Findings suggestive of chronic liver disease, including digital clubbing, palmar erythema, cutaneous xanthoma, and prominent abdominal vessels suggesting longstanding portal hypertension. If present, these findings suggest that the patient is experiencing a decompensation or complication of a chronic liver disease rather than a true ALF, and this helps to narrow the diagnostic considerations.

Slit-lamp examination for Kayser-Fleischer rings – This should be performed in older children and adolescents, if possible, to evaluate for Wilson Disease. However, the yield of the examination is low because this finding is common among patients with neurologic manifestations of Wilson Disease but is usually not present in patients with Wilson disease who present with ALF. (See "Wilson disease: Diagnostic tests".)

Laboratory testing — Careful coordination of laboratory and diagnostic tests is helpful to ensure that high-priority tests are performed expeditiously. Because more than 30 percent of children with ALF are younger than three years of age, limitations on the volume of blood that can be drawn require a knowledgeable prioritization of tests. Laboratory tests fall into the following categories, with different priorities depending on the needs of the individual patient:

Liver-specific tests — To assess the degree of inflammation, injury, and function and to guide transplant decisions. At a minimum, measure serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total and conjugated bilirubin, alkaline phosphatase, albumin, prothrombin time (PT), partial thromboplastin time (PTT), and ammonia.

General laboratory tests — To assess hematologic, renal, pancreatic, and electrolyte abnormalities and to guide management of these complications – At a minimum, perform a complete blood count with differential and measure electrolytes, blood glucose, blood urea nitrogen and creatinine, amylase, and lipase.

Diagnostic testing for the cause of PALF — Priorities for diagnostic testing should be guided by the frequency of a disorder within an age group and population [8]. While some conditions such as HSV can occur within all age categories, others such as gestational alloimmune liver disease (GALD) and Wilson disease are found within a more narrow age range. Therefore, age-based diagnostic prioritization enhances the likelihood of establishing a diagnosis as quickly as possible. The table lists diagnostic tests that would be most useful for children of different ages based upon the expected diagnoses (table 5B).

Priority should be given to identifying conditions that are amenable to specific therapy, would be relevant to subsequent pregnancies, or would be a contraindication to LT [38].

The following disorders should be specifically considered because they are amenable to specific therapy:

Acute acetaminophen toxicity – We suggest measuring the serum acetaminophen level in all adolescents presenting with unexplained ALF and in other children in whom an accidental ingestion or inadvertent overdose seems possible. (See 'Acetaminophen' above.)

HSV – We suggest routinely testing for HSV in blood by polymerase chain reaction in all young infants with PALF, as well as in patients who have been exposed to sexual activity (voluntarily or involuntarily), are immunosuppressed, have vesicular skin lesions, or have ulcerative lesions of the oral pharynx or genitalia. In these high-risk groups, we also suggest initiation of acyclovir treatment while awaiting results of testing. We also suggest viral cultures and/or direct immunofluorescence assays of any vesicular skin lesions or of liver tissue if a biopsy is performed. (See 'Infection with viruses other than hepatitis viruses' above.)

Hemophagocytic lymphohistiocytosis (HLH) – In patients younger than five years with fever and cytopenia in two or more cell lines, screen for this disorder by measuring ferritin, triglycerides, fibrinogen, and soluble interleukin 2 (IL-2) receptor alpha. (See 'Hemophagocytic lymphohistiocytosis' above.)

Autoimmune hepatitis (AIH) – Because AIH is a potentially treatable cause of ALF in children of all ages, it should be considered early in the evaluation process to enable prompt initiation of treatment. Screening requires testing serologic antinuclear antibody, anti-smooth muscle antibody, liver-kidney microsomal antibody, and total IgG, which can be estimated by subtracting the serum albumin (mg/dL) from the serum total protein (mg/dL). However, autoimmune markers are found in conditions other than AIH, thus necessitating subjective clinical judgment to influence the final diagnosis and treatment strategy [22]. (See 'Autoimmune marker positive' above.)

Wilson disease – Patients older than five years with PALF should be screened for Wilson disease by measuring serum ceruloplasmin. In addition to low serum ceruloplasmin, suggestive laboratory findings include a marked mixed or primarily unconjugated hyperbilirubinemia, a low serum alkaline phosphatase, and hemolytic anemia with negative test for direct antiglobulin (DAT [also known as the Coombs test]). (See 'Older children and adolescents' above.)

Metabolic defects – Certain metabolic defects related to carbohydrate, fatty acid, and protein metabolism are important to diagnose because they are responsive to dietary management. Selection of tests depends on the age and presentation of the patient (table 5A-B). At a minimum, tests should include measurements of serum glucose, lactate, pyruvate, ammonia, and creatinine kinase to screen for mitochondrial hepatopathies. Lactic acidosis and an elevated molar ratio of lactate to pyruvate (>25 mol/mol) are common in all causes of PALF, so these tests are not specific for a mitochondrial etiology [47]. In infants and younger children, serum amino acids and acylcarnitine/acylcarnitine profile should be included in the initial evaluation. Genetic mutation analysis has become increasingly available to detect mitochondrial and other inherited disorders, and next-generation sequencing may provide an important tool in the diagnosis of PALF [93]. However, results from these tests may not be available before medical decisions must be made to proceed with specific treatment or LT. (See 'Inherited metabolic disease' above.)

For neonates and young infants presenting with PALF, the newborn screen may help identify patients at risk or who have developed symptoms of PALF. However, the newborn screen should not be used as a "specific" test to diagnose a metabolic disease, nor should it be used to exclude a diagnosis should one be suspected. Some children will present before results of the newborn screen are available. Thus, the following tests should be performed in a newborn infant if the newborn screen is not available or if there is a reasonable clinical suspicion for these disorders (see 'Young infants' above):

Galactosemia – Screen by testing urine for reducing substances (eg, Clinitest tablet) and also perform specific testing of red blood cell galactose-1-phosphate uridyl transferase before the patient receives a blood transfusion. (See "Galactosemia: Clinical features and diagnosis".)

Tyrosinemia – Test urine for succinylacetone. (See "Disorders of tyrosine metabolism", section on 'Hereditary tyrosinemia type 1'.)

Hereditary fructose intolerance – For infants presenting with PALF after exposure to fructose or sucrose (in medications, juice, or formula), testing for hereditary fructose intolerance is essential. The diagnosis is made by sequencing the ALDOB (aldolase B, fructose-bisphosphate) gene. (See "Causes of hypoglycemia in infants and children" and "Causes of hypoglycemia in infants and children", section on 'Hereditary fructose intolerance'.)

GALD – GALD (also known as neonatal hemochromatosis) should be considered in any neonate presenting with ALF, particularly if there is a history of neonatal liver disease or death in older siblings and/or if the degree of coagulopathy is more severe than the aminotransferase elevation. (See 'Gestational alloimmune liver disease (neonatal hemochromatosis)' above.)

If there is a strong clinical suspicion of other disorders (such as exposure to hepatitis A virus [HAV]), specific testing is appropriate even if no specific treatment is available. This is because establishing the cause of PALF may reduce the need for other in-depth diagnostic testing and sometimes provides prognostic information that is useful when making transplant decisions. For example, a patient with a systemic mitochondrial disease presenting as ALF, either independent of or in association with valproate toxicity, will not benefit from LT, as outcome is uniformly poor. (See 'Young infants' above.)

Other — Other tests include:

Abdominal ultrasound with Doppler, to evaluate for vascular anomalies that may cause PALF and to determine hepatic and vascular anatomy in preparation for LT, as well as to assess liver contour (eg, nodular versus smooth) and size.

Other tests required in preparation for a LT. (See "Acute liver failure in children: Management, complications, and outcomes", section on 'Laboratory monitoring'.)

Liver biopsy — Establishing a pathologic diagnosis by liver biopsy has not been considered critical in the management of a patient with PALF, primarily due to the risk of bleeding following percutaneous biopsy. In addition, the histopathology analysis has been thought to have limited value in determining the treatment strategy or establishing the diagnosis. However, liver biopsies are increasingly performed by the transvenous (eg, transjugular) approach because this technique markedly reduces the risks of hemorrhage in this population [94]. The frequency of liver biopsy in PALF patients varies widely among institutions. Liver biopsy may be considered for those patients suspected to have Wilson disease if other diagnostic criteria are inconclusive or for patients with indeterminate or autoimmune marker-positive PALF for whom corticosteroid or other immunosuppressive therapy is being considered. (See "Transjugular liver biopsy".)

Nonspecific findings — Most causes of PALF result in diffuse hepatocellular necrosis. This pattern is typical of ALF resulting from viral infections, most toxic and ischemic injuries, and some metabolic diseases. The degree of hepatocellular necrosis and its histologic pattern vary by cause and by individual case. Most liver samples from children with ALF show massive confluent or multilobular necrosis, with or without a moderate inflammatory infiltrate and evidence of regeneration. Occasionally, there is a marked inflammatory infiltrate, consisting primarily of lymphocytes with a scattering of plasma cells, neutrophils, and eosinophils (picture 1). The inflammatory infiltrate is not limited to the portal tracts but can be found within the lobule and around the central vein. Characterization of the inflammatory infiltrate using immunohistochemical markers for T lymphocytes (CD4 and CD8), B lymphocytes (CD20), natural killer cells (CD56) and macrophages (CD163) may provide insight into the pathogenesis of PALF and, in the future, help direct therapy [95].

Occasionally, if orthotopic LT is performed early in the course of rapidly progressive ALF, the gross surgical and microscopic appearances of the liver are relatively normal. The lobular structure and framework may be intact, including a normal cord pattern, but the hepatocytes are necrotic. Inflammation is absent. This lesion suggests widespread, simultaneous lethal injury of hepatocytes.

Characteristics suggesting a specific diagnosis — The following histologic characteristics support a specific cause of ALF. However, these findings are not diagnostic and should be interpreted in the context of the patient's other clinical characteristics.

Steatosis – Diffuse hepatic steatosis is observed rarely in ALF in children. When present, the typical lesion is characterized by hepatocellular fat in a microvesicular (small fat droplet) pattern. The absence of cell necrosis in association with failure of liver function implies organelle failure as the cause. In adults, this pattern is seen most often in fatty liver of pregnancy. In children with ALF, the presence of steatosis suggests a mitochondrial disorder or other inborn error of metabolism (see 'Inherited metabolic disease' above). Alternatively, steatosis can be caused by toxins or drugs. Certain drugs (eg, valproate and amiodarone) tend to cause steatosis, whereas others (isoniazid, propylthiouracil, and halothane) do not. If the observed histology differs from that expected by the drug in question, another cause should be sought. (See "Drug-induced liver injury".)

Macrovesicular (large fat droplet) steatosis is seen in patients with nonalcoholic fatty liver disease (NAFLD). NAFLD is not known to be a cause of PALF, but given the increasing prevalence of NAFLD in the pediatric population, macrovesicular steatosis may be a coincidental finding in PALF. Whether NAFLD increases a patient's risk of liver injury from other insults such as infections or drugs/medications to the degree that PALF develops is not known. Macrovesicular steatosis also can be seen with Wilson disease.

Diffuse swelling of hepatocytes, with only spotty necrosis – This lesion is characterized by diffuse swelling of hepatocytes with condensation of organelles and cytoplasmic elements and is seen in association with some inborn errors of metabolism. Hepatocyte necrosis is spotty and usually not prominent. Macrovesicular fat with displacement of nuclei is seen in a variable proportion of hepatocytes, sometimes a majority. This lesion suggests organelle injury that is severe enough to cause the death of some hepatocytes. Aminotransferase levels and serum bilirubin levels are elevated moderately. Full histologic recovery can occur if the metabolic injury is controlled.

Central lobular necrosis – Diffuse central lobular necrosis is a characteristic of acetaminophen toxicity but can also be a nonspecific finding in multiple forms of ALF.

Characteristics suggesting AIH – Histologic features of AIH causing ALF include evidence of immune activation with the presence of a plasma cell-enriched infiltrate, central perivenulitis, and lymphoid follicles with evidence of massive hepatic necrosis [96]. Inflammation is often most intense at the limiting plate. (See "Overview of autoimmune hepatitis", section on 'Histology'.)

Dense infiltrate of CD8-positive T cells – This finding suggests immune dysregulation that may be amenable to immunosuppressive therapy [25]. (See 'Indeterminate' above.)

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".)

SUMMARY AND RECOMMENDATIONS

Clinical presentation – Pediatric acute liver failure (PALF) typically presents in a previously healthy patient with a nonspecific prodrome of variable duration with features that might include abdominal discomfort and malaise with or without fever. Jaundice, encephalopathy, and hepatomegaly are common. (See 'Clinical presentation' above.)

Diagnostic criteria – PALF is diagnosed when an infant or child with no previous evidence of chronic liver disease presents with biochemical evidence of acute liver injury (elevated aminotransferase activity) and hepatocyte dysfunction characterized by cholestasis (elevated bilirubin) as well as coagulopathy (elevated international normalized ratio [INR]) not corrected by vitamin K. (See 'Diagnostic criteria' above.)

Causes – The causes of PALF vary depending on the age group and region. The primary causes of PALF in resource-rich countries are outlined in the figures (table 2).

Acetaminophen (N-acetyl-p-aminophenol [APAP]) is an important cause of PALF, particularly among adolescents. It may be caused by an acute or chronic overdose and is potentially treatable if diagnosed rapidly. Other medications that can cause PALF are listed in the table (table 4). Antiseizure medications including valproate are the most common drugs associated with PALF, especially in patients with underlying mitochondrial disease. (See 'Acetaminophen' above and 'Other medications or toxins' above.)

Infectious causes of PALF, particularly hepatitis A virus (HAV), are far more common in countries in which these infections are endemic (table 3). Herpes simplex virus (HSV) can occur in all age groups, especially in young infants, and is an important and treatable cause of PALF. (See 'Infectious diseases' above.)

Autoimmune hepatitis (AIH) is most common among adolescents but is responsible for more than 5 percent of PALF in younger age groups beyond the neonatal period. (See 'Autoimmune marker positive' above and "Autoimmune hepatitis: Treatment".)

In newborn infants, important causes of PALF include gestational alloimmune liver disease (GALD [also known as neonatal hemochromatosis]), HSV, inborn errors of metabolism including tyrosinemia and galactosemia, and mitochondrial hepatopathies (table 6). In all young infants with PALF, we routinely test for HSV in blood by polymerase chain reaction and initiate acyclovir treatment while awaiting results of testing. (See 'Gestational alloimmune liver disease (neonatal hemochromatosis)' above and 'Young infants' above.)

Inborn errors of metabolism also may present with PALF during later infancy and early childhood. Causes include mitochondrial disorders such as fatty acid oxidation defects and urea cycle defects (table 5A and table 6). (See 'Inherited metabolic disease' above.)

Wilson disease is the most common metabolic condition associated with PALF in children over five years of age. It is characterized by a Coombs-negative hemolytic anemia, marked hyperbilirubinemia, low serum ceruloplasmin, and a low serum alkaline phosphatase. (See 'Older children and adolescents' above and "Wilson disease: Diagnostic tests".)

In 30 to 50 percent of patients, a specific cause is not discovered; in this case, the PALF is categorized as indeterminate. (See 'Indeterminate' above.)

Evaluation

Laboratory testing to evaluate liver function and manage the ALF include liver aminotransferases, bilirubin, coagulation tests, and ammonia, as well as general laboratory test to evaluate other organ function, and abdominal ultrasound (table 5B). (See 'Laboratory testing' above.)

Every effort should be made to rapidly identify a cause of PALF, if possible. A focused history and physical examination help to narrow the diagnostic possibilities. Careful coordination of laboratory and diagnostic tests is helpful to ensure that high-priority tests are performed expeditiously, with the highest priorities given to potentially treatable disorders. Tests needed for supportive care and transplant decisions necessarily compete with those needed for diagnosing the cause of the PALF. (See 'Etiologic evaluation' above.)

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Topic 16142 Version 40.0

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