Acute liver failure in children_ Etiology and evaluation - UpToDate

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Acute liver failure in children: Etiology and evaluation - UpToDate

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Acute liver failure in children: Etiology and evaluation Author: Robert H Squires, Jr, MD, FAAP Section Editor: Elizabeth B Rand, MD Deputy Editor: Alison G Hoppin, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Mar 2020. | This topic last updated: Jan 13, 2020.

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 acute liver failure (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 10 percent of pediatric liver transplants (LT) performed in the United States annually. 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, or 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. The pressing clinical questions faced when children with PALF first present are: ●

Does the patient have a condition that is treatable?

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What is the risk of deterioration or improvement on each day the child is alive with his or her native liver?

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Is an LT necessary for patient survival?

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Are associated morbidities reversible?

An organized approach to answering these questions, including an overview of the causes of PALF, will be outlined in this topic review. 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".)

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

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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 [4]: ●

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

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Seizure – 7 percent

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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 [4]. 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, and toxin- or drug-related. 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 [5]. Worldwide, the causes of PALF vary depending on the age group and region. The causes of PALF in developed countries are outlined in the table (table 1), 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) [5]. In developing countries, the etiologies are similar but are dominated by infectious etiologies, among which hepatitis A is the most common (table 2). 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 [6,7]. 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).

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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 [6,8]. In the PALFSG registry, chronic APAP may have contributed to liver injury in approximately 10 percent of patients [9]. 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 https://www.uptodate.com/contents/acute-liver-failure-in-children-etiology-and-evaluation/print

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those with acute APAP exposure, and also had worse 21-day outcomes [9]. 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 less than 3 percent of cases in the PALFSG registry; the vast majority of the cases occurred in children over 10 years of age [4]. The list of toxins associated with liver failure is extensive and expanding; a partial list is shown in the Table (table 3) [2,10]. (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 [11]. (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 reactions'.) 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")

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

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Halothane (see "Halothane hepatitis")

For many other drugs, idiosyncratic hepatotoxicity is less well established. If a patient with ALF was recently exposed to such a drug, a degree of skepticism should be maintained regarding the role of drug exposure in causing the hepatic injury [7,12]. In children, idiosyncratic reactions causing PALF have been reported for the following drugs [4,13,14]: ●

Anticonvulsant drugs – Valproate, phenytoin, carbamazepine, lamotrigine, and felbamate are among the most common drugs associated with PALF [14]. Patients with unsuspected mitochondrial disease (eg, AlpersHuttenlocher disease) are particularly at risk for hepatotoxicity from valproate. (See 'Inherited metabolic disease' below.)

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Antimicrobial agents – Minocycline, amoxicillin-clavulanate, azithromycin, roxithromycin, and nitrofurantoin, as well as a number of antiviral agents used in the treatment of HIV, have been reported to cause PALF (as well as isoniazid, for which the hepatotoxic effect is well established) [13,14].

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

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

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Recreational drugs – Recreational drug use, particularly cocaine and ecstasy (3,4-methylenedioxyamphetamine [MDMA]), is associated with PALF in teenagers and even younger children who live in environments where these

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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 [15]. (See "Hepatotoxicity due to herbal medications and dietary supplements".)

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 (WD) 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 [ANA], anti-smooth muscle antibody [SMA], and/or liver-kidney microsomal antibody [LKM]) [16]. The true frequency of positive autoimmune markers in PALF is not known because these tests are not consistently obtained in the patient population [17]. 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 [2]. Therefore, an autoimmune mechanism should be considered in all age groups outside of the neonatal period. This pattern is in contrast to chronic AIH, which is most frequent in adolescents and adults and has a female predominance. Establishing a firm diagnosis for AIH is challenging in patients with PALF and, in many cases, only a presumptive diagnosis can be made [16]. Isolated mild elevations of ANA 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. Of note, the simplified scoring system that is often used for diagnosis of AIH [18] may not be sufficiently sensitive for children presenting with ALF [19]. (See "Overview of autoimmune hepatitis", section on 'Diagnostic evaluation'.) 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'.) Hemophagocytic lymphohistiocytosis — Hemophagocytic lymphohistiocytosis (HLH) is an enigmatic condition involving immune dysfunction. Up to 25 percent of cases are familial, and mutations in genes affecting granuledependent 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 [20,21]. 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 [22]. (See 'Infection with viruses other than hepatitis viruses' below.) 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) [23,24]. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".) Gestational alloimmune liver disease (neonatal hemochromatosis) — Gestational alloimmune liver disease (GALD, previously known as neonatal hemochromatosis) is a rare disorder characterized by clinical and biochemical features of acute hepatic failure and hepatic and extrahepatic iron accumulation (hemosiderosis) during the neonatal period. The new name reflects the recognition that an alloimmune mechanism is responsible for the disorder. Maternal https://www.uptodate.com/contents/acute-liver-failure-in-children-etiology-and-evaluation/print

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IgG appears to activate fetal complement that leads to the formation of membrane attack complex, resulting in liver cell injury [25]. 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. Characteristic clinical features of GALD 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 of the abdomen include reduced T2-weighted intensity of the pancreas relative to the spleen. Magnetic resonance imaging can also detect excess extramedullary iron deposition in the brain and heart. 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 deoxyguanosine kinase (DGUOK) [26]. Mutations in DGUOK can cause a mitochondrial depletion syndrome with hepatocerebral manifestations. (See 'Young infants' below.) Exchange transfusion and high-dose intravenous immune globulin is the preferred treatment for GALD [27]. For pregnant women with a previous pregnancy that resulted in an infant with GALD, treatment with high-dose immune globulin 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 [1,28]. 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 4A). 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 (MH), and urea cycle defects [29]: ●

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".)

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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".)

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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 [30]. (See "Overview of Niemann-Pick disease", section on 'NPD type C'.)

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MH are increasingly recognized as an important cause of liver failure due to deficiencies in respiratory complexes I, III, or IV or mitochondrial DNA depletion (table 5). These include mitochondrial DNA depletion syndrome 3 (MIM #251880), which is caused by mutations in the deoxyguanosine kinase (DGUOK) gene; and mitochondrial DNA depletion syndrome 6 (MIM #256810), also known as Navajo neurohepatopathy, which is caused by mutations in the MPV17 gene [28,31-33]. With rare exceptions, MH 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 [31]. 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 [34]. 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 2). (See 'Diagnosis of acute liver failure' above.)

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The causes of PALF vary depending on the age group and region. The primary causes of PALF in developed countries are outlined in the Table (table 1). In more than 50 percent of patients, a specific cause is not discovered, and in this case, the PALF is categorized as indeterminate.

• 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 in a dose-related manner include isoniazid, halothane, and propylthiouracil. Many other medications and recreational drugs have idiosyncratic hepatotoxic effects (table 3). Anticonvulsant drugs including valproate are the most common drugs associated with PALF. Patients with unsuspected mitochondrial disease (eg, Alpers-Huttenlocher disease) are particularly at risk for hepatotoxicity from valproate. (See 'Acetaminophen' above and 'Other medications or toxins' above.)

• Infectious causes of PALF, particularly hepatitis A, are far more common in countries in which these infections are endemic (table 2). 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.)

• During the neonatal period, important causes of PALF include gestational alloimmune liver disease (GALD [also known as neonatal hemochromatosis]), HSV, and inborn errors of metabolism, including tyrosinemia and galactosemia, and mitochondrial hepatopathies (MH) (table 5). In all young infants with PALF, we routinely test for HSV in blood by polymerase chain reaction (PCR), 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 4A and table 5). (See 'Inherited metabolic disease' above.)

• Wilson disease (WD) 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".)

• An indeterminate diagnosis occurs commonly, particularly among children between 1 and 10 years of age. (See 'Indeterminate' 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

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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.) ●

Laboratory testing to evaluate liver function and manage the acute liver failure (ALF) include serum aspartate aminotransferase (AST); alanine aminotransferase (ALT); total and conjugated bilirubin, alkaline phosphatase; albumin; prothrombin time (PT); partial thromboplastin time (PTT); ammonia; complete blood count (CBC); electrolytes; glucose; blood urea nitrogen (BUN); creatinine; amylase; lipase; serum ammonia, and abdominal ultrasound (table 4B). (See 'Laboratory testing' above.)

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33. McKiernan P, Ball S, Santra S, et al. Incidence of Primary Mitochondrial Disease in Children Younger Than 2 Years Presenting With Acute Liver Failure. J Pediatr Gastroenterol Nutr 2016; 63:592. 34. Feldman AG, Sokol RJ, Hardison RM, et al. Lactate and Lactate: Pyruvate Ratio in the Diagnosis and Outcomes of Pediatric Acute Liver Failure. J Pediatr 2017; 182:217. 35. Shneider BL, Rinaldo P, Emre S, et al. Abnormal concentrations of esterified carnitine in bile: a feature of pediatric acute liver failure with poor prognosis. Hepatology 2005; 41:717. 36. Li H, Byers HM, Diaz-Kuan A, et al. Acute liver failure in neonates with undiagnosed hereditary fructose intolerance due to exposure from widely available infant formulas. Mol Genet Metab 2018; 123:428. 37. Gallagher RC, Lam C, Wong D, et al. Significant hepatic involvement in patients with ornithine transcarbamylase deficiency. J Pediatr 2014; 164:720. 38. Korman JD, Volenberg I, Balko J, et al. Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests. Hepatology 2008; 48:1167. 39. Moreira-Silva SF, Frauches DO, Almeida AL, et al. Acute liver failure in children: observations in Vitória, Espírito Santo State, Brazil. Rev Soc Bras Med Trop 2002; 35:483. 40. Bartholomeusz A, Locarnini S. Hepatitis B virus mutants and fulminant hepatitis B: fitness plus phenotype. Hepatology 2001; 34:432. 41. Farci P, Alter HJ, Shimoda A, et al. Hepatitis C virus-associated fulminant hepatic failure. N Engl J Med 1996; 335:631. 42. Liang TJ, Jeffers L, Reddy RK, et al. Fulminant or subfulminant non-A, non-B viral hepatitis: the role of hepatitis C and E viruses. Gastroenterology 1993; 104:556. 43. Poddar U, Thapa BR, Prasad A, Singh K. Changing spectrum of sporadic acute viral hepatitis in Indian children. J Trop Pediatr 2002; 48:210. 44. Hamid SS, Jafri SM, Khan H, et al. Fulminant hepatic failure in pregnant women: acute fatty liver or acute viral hepatitis? J Hepatol 1996; 25:20. 45. Khuroo MS, Teli MR, Skidmore S, et al. Incidence and severity of viral hepatitis in pregnancy. Am J Med 1981; 70:252. 46. Verma A, Dhawan A, Zuckerman M, et al. Neonatal herpes simplex virus infection presenting as acute liver failure: prevalent role of herpes simplex virus type I. J Pediatr Gastroenterol Nutr 2006; 42:282. 47. Härmä M, Höckerstedt K, Lautenschlager I. Human herpesvirus-6 and acute liver failure. Transplantation 2003; 76:536. 48. Yang CH, Sahoo MK, Fitzpatrick M, et al. Evaluating for Human Herpesvirus 6 in the Liver Explants of Children With Liver Failure of Unknown Etiology. J Infect Dis 2019; 220:361. 49. Tung J, Hadzic N, Layton M, et al. Bone marrow failure in children with acute liver failure. J Pediatr Gastroenterol Nutr 2000; 31:557. 50. Karetnyi YV, Beck PR, Markin RS, et al. Human parvovirus B19 infection in acute fulminant liver failure. Arch Virol 1999; 144:1713.

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51. Lee WM, Brown KE, Young NS, et al. Brief report: no evidence for parvovirus B19 or hepatitis E virus as a cause of acute liver failure. Dig Dis Sci 2006; 51:1712. 52. Phillips MJ, Blendis LM, Poucell S, et al. Syncytial giant-cell hepatitis. Sporadic hepatitis with distinctive pathological features, a severe clinical course, and paramyxoviral features. N Engl J Med 1991; 324:455. 53. Listernick R. Liver failure in a 2-day-old infant. Pediatr Ann 2004; 33:10. 54. Lo JO, Harrison RA, Hunter AJ. Syphilitic hepatitis resulting in fulminant hepatic failure requiring liver transplantation. J Infect 2007; 54:e115. 55. Stevens FM, McLoughlin RM. Is coeliac disease a potentially treatable cause of liver failure? Eur J Gastroenterol Hepatol 2005; 17:1015. 56. Umemura T, Tanaka E, Ostapowicz G, et al. Investigation of SEN virus infection in patients with cryptogenic acute liver failure, hepatitis-associated aplastic anemia, or acute and chronic non-A-E hepatitis. J Infect Dis 2003; 188:1545. 57. James LP, Alonso EM, Hynan LS, et al. Detection of acetaminophen protein adducts in children with acute liver failure of indeterminate cause. Pediatrics 2006; 118:e676. 58. Alonso EM, Horslen SP, Behrens EM, Doo E. Pediatric acute liver failure of undetermined cause: A research workshop. Hepatology 2017; 65:1026. 59. Rivera-Penera T, Moreno J, Skaff C, et al. Delayed encephalopathy in fulminant hepatic failure in the pediatric population and the role of liver transplantation. J Pediatr Gastroenterol Nutr 1997; 24:128. 60. Lee WS, McKiernan P, Kelly DA. Etiology, outcome and prognostic indicators of childhood fulminant hepatic failure in the United kingdom. J Pediatr Gastroenterol Nutr 2005; 40:575. 61. Chapin CA, Mohammad S, Bass LM, et al. Liver Biopsy Can Be Safely Performed in Pediatric Acute Liver Failure to Aid in Diagnosis and Management. J Pediatr Gastroenterol Nutr 2018; 67:441. 62. Chapin C, Meijome T, Loomes KM, et al. Indeterminate pediatric acute liver failure is characterized by dense polyclonal CD8+ hepatic infiltration (conference paper). Hepatology 2016; 64:143A. 63. Stravitz RT, Lefkowitch JH, Fontana RJ, et al. Autoimmune acute liver failure: proposed clinical and histological criteria. Hepatology 2011; 53:517.

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GRAPHICS Etiology of acute liver failure in children in North America and Europe (final diagnosis as percent of cases in each age group) Percent of cases in age group (n) Diagnosis

All ages (n = 986)

0 to 90 days (n = 181)

91 days to 3 years (n = 274)

4 to 17 years (n = 531)

Indeterminate

45 (444)

35 (64)*

59 (162)*

41 (218)*

APAP

12 (123)

1 (1)

4 (12)

21 (110)*

Metabolic

10 (100)

17 (31)*

11 (30)*

7 (39)*

1 (9)

2 (3)

2 (6)

0 (0)

Wilson disease

4 (36)

0 (0)

0 (0)

7 (36)*

Fatty acid oxidation