Definition and Epidemiology
Acute liver failure (ALF) is a rare but devastating result of hepatic necrosis in previously healthy individuals. Hepatic function rapidly declines within days to weeks and is often complicated by coagulopathy, hepatic encephalopathy (HE), hypoglycemia, acute renal failure, sepsis, and gastrointestinal bleeding. These complications can lead to death with mortality rates up to 40% in the United States.1
Children who develop ALF by definition have no previous history of liver disease. Traditionally, the criteria for defining ALF included the development of HE within 8–12 weeks of the first signs of illness. This definition has since been revised due to the difficultly in assessing HE in infants and younger children and the variability in initial presentation.
In 1999 the Pediatric Acute Liver Failure Study Group (PALFSG) was formed to better understand the pathogenesis and treatment of ALF. An important initial task included defining ALF in childhood and creating a scale to assess encephalopathy in children younger than 4 years of age. The definition of ALF in children included four major criteria: (1) the absence of prior liver disease; (2) serum biochemical markers showing evidence of acute liver injury; (3) coagulopathy not correctable with vitamin K administration; (4) international normalized ratio (INR) ≥1.5 in the setting of HE or ≥2.0 without HE.2 A scale was created to help assess HE in children under the age of 4 years (Table 30–1).
|Stage||Clinical Presentation||Reflexes/Asterixis||Neurological Signs|
|Children 3 years and younger|
|I||Mood changes, confused||Normal/none||Tremor, apraxia|
|II||Decreased inhibitions, drowsy, inappropriate behavior|
Hyper-reflexic, possible asterixis
Babinski sign/asterixis present
|III||Stuporous, able to follow simple commands, arousable|
Decerebrate or decorticate
|IV||Comatose, arouse to painful stimuli (IV a) or no response to stimuli (IV b)|
|Early (I and II)||Crying inconsolable, inattention to task, sleep reversal||Normal or hyper-reflexic/unreliable||Untestable|
|Mid (III)||Somnolence, stupor, combativeness||Hyper-reflexic/unreliable||Most likely untestable|
|Late (IV)||Comatose, arouse to painful stimuli (IV a) or no response to stimuli (IV b)||Absent||Decerebrate or decorticate|
The overall incidence of pediatric ALF is low, but the rate of devastating complications and mortality is high. The primary causes of ALF in children include viral hepatitis, drug-induced liver failure, metabolic causes, autoimmune disease, and idiopathic causes. Approximately 50% of cases of pediatric ALF have no known cause.2 Regardless of the cause, ALF is a medical emergency and early recognition affects outcome. Prior to liver transplantation becoming an available treatment option, death rates approached 100%.1 Currently, short-term survival with liver transplantation is >65%.3
The pathologic features of ALF include rapid and massive hepatocyte death, with failure of the remaining hepatocytes to regenerate. The mechanism of this severe hepatic necrosis is unknown. Although approximately 50% of cases of ALF have no identifiable etiology, we know that there is variability with age (Table 30–2).2,4,5 In neonates, inborn errors of metabolism and infections are often found to be the predominant causes of ALF, while in older children toxins, drugs, and autoimmune disorders are more common causes.4–7
|Infectious||Herpes simplex virus, cytomegalovirus, hepatitis B, adenovirus, echovirus, coxsackie, syphilis, bacterial infections (leading to sepsis and shock)|
|Metabolic||Galactosemia, type I tyrosinemia, hereditary fructose intolerance, urea cycle disorders, respiratory chain defects, mitochondrial disorders, neonatal hemochromatosis, Niemann–Pick disease type C, Zellweger syndrome, inborn errors of bile acid synthesis|
|Vascular/ischemic||Congestive heart failure—as a result of congenital heart disease, hypoperfusion|
|Hematologic||Hemophagocytic lymphohistiocytosis (HLH)|
|Infectious||Epstein–Barr virus, hepatitis A, B, non-A, non-B, non-C hepatitis, herpes virus, sepsis|
|Toxins||Amanita phalloides, carbon tetrachloride|
|Drugs||Acetaminophen, halothane, antituberculous medications (isoniazid, rifampicin, pyrazinamide), antimicrobials (beta-lactams, tetracycline, macrolides, sulfonamides), ketoconazole, antiepileptics (carbamazepine, valproate)|
|Autoimmune||Types 1 and 2|
|Vascular/ischemic||Congestive heart failure, Budd–Chiari syndrome|
|Malignancies||Hepatoblastoma, leukemia, non-Hodgkin lymphoma|
Multiple factors must be considered in neonates who develop ALF including maternal exposures, infant exposures, perinatal infections, metabolic disorders, genetic disorders, hypotension/shock, and hematologic disorders.5 Identifying the cause allows for an improved determination of probable prognosis and treatment options. Neonatal infections can be severe and generalized. Perinatal infections with herpes virus, hepatitis B virus, adenovirus, cytomegalovirus, and echovirus in addition to others have been known to cause ALF in neonates. Herpes simplex virus (HSV), in particular, is the most common viral etiology and a high cause of mortality.2,5 Skin lesions are not necessarily present, but patients often have a significant serum transaminitis and coagulopathy. Intravenous acyclovir should be instituted immediately if HSV is suspected. Bacterial infections from group B Streptococcus, Escherichia coli, and Listeria monocytogenes are the most frequent causes of sepsis in neonates that can also progress to ALF from hypoperfusion and shock.
Metabolic disorders must be considered in the neonatal period as a cause of ALF and must be investigated promptly since dietary changes and disease-specific treatments can be life saving. Metabolic disorders to consider in this age group include galactosemia, type I tyrosinemia, hereditary fructose intolerance, urea cycle disorders, respiratory chain defects, mitochondrial disorders, and neonatal hemochromatosis (NH). In galactosemia and hereditary fructose intolerance, the treatment is removal of the offending dietary agent that is life saving. Type I tyrosinemia is treated by giving a low-phenylalanine and low-tyrosine diet along with 2(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexenedione (NTBC) that prevents the formation of fumarylacetoacetate, the toxic metabolite of tyrosine. Since the introduction of NTBC, patients with type I tyrosinemia have improved survival rates. Patients may still require liver transplantation if they do not respond to NTBC or are at high risk for the development of malignant hepatocellular carcinoma nodules.8 Mitochondrial disorders have many different clinical presentations, with ALF seen in the context of multiorgan failure. Transmission is through maternal DNA. Liver transplantation is not indicated since the disease is progressive and not localized only to the liver. In NH, ALF occurs at birth. Massive iron deposition is seen both intra- and extrahepatically, but spares the reticuloendothelial system. The exact pathogenesis is unknown but it is thought to be related to maternal alloimmune injury and there is a high recurrence rate in families of affected infants. Diagnosis is made by excluding other causes of liver failure, finding elevated levels of serum ferritin, near complete saturation of iron-binding capacity, MRI demonstration of extrahepatic iron deposition, and biopsy confirmation of elevated iron stores. Treatment with an antioxidant cocktail consisting of vitamin E, N–acetylcysteine (NAC), selenium, desferoxamine, and prostaglandin E1 may be helpful but often NH requires liver transplantation for cure.9 An article published in 2009 showed newborn infants with NH treated with a combination of high-dose IVIG and exchange transfusion were four times as likely to improve and not require liver transplantation.10 Additionally, the experimental use of gamma-globulin infusions to pregnant mothers of previously affected infants has had very promising results in preventing recurrence with subsequent pregnancies.11 Unfortunately, presently there is no way to diagnose NH in a first pregnancy.
In children over the age of 3 years, the most common causes in the United States of pediatric ALF are from acetaminophen ingestion, non-acetaminophen toxins, viral infections, and metabolic derangements. Acetaminophen ingestions, intentional or accidental, account for 21% of pediatric ALF.2 This is much different from the younger age group where only 2% of ALF in children under the age of 3 years is from acetaminophen overdose. Acetaminophen ingestion fortunately also has the highest rate of spontaneous recovery without the need for liver transplant. Non-acetaminophen, drug-induced liver failure accounts for approximately 7% of PALF in this older age group and is usually caused by antimicrobials, antiepileptics, or antituberculous medications, though multiple drugs can cause hepatotoxicity and can lead to ALF.12 Ingested toxins from poisonous mushrooms (Amanita phalloides) also referred to as the “death cap” can also cause ALF. Infectious causes of hepatitis, leading to fulminant hepatic failure, occur less frequently and are mostly caused by Epstein–Barr virus. Another major cause of ALF in the older age group is Wilson disease. In Wilson disease, there are low serum copper and serum ceruloplasmin levels; elevated urinary copper excretion and hemolysis are present. Wilson disease can cause chronic liver disease that can be treated with d–penicillamine or triene therapy, but if the presentation is as ALF, liver transplantation is often required for survival (see Chapter 25). Autoimmune hepatitis, which usually presents as a chronic liver disease, can also present as ALF. It causes approximately 6% of all ALF cases and when presenting as ALF often needs liver transplantation for survival. Autoimmune hepatitis is more frequently seen in the older age group, but is also seen in children <3 years old.2
The characteristic findings in ALF include the abrupt onset of jaundice, encephalopathy, and elevated biochemical markers of liver injury. These include a prolonged prothrombin time (PT) and elevated serum transaminases in a previously healthy child. Initial symptoms of jaundice, abdominal pain, nausea, and vomiting may be non-specific. Clinical presentation may vary with age and etiology of liver failure, so a detailed history is important in determining the next steps in therapy. Symptoms may progress rapidly within days or may take weeks to develop, depending on the etiology of the liver failure.