The cause of acute hepatic failure is age-dependent. Usually, acute liver failure in patients in the pediatric intensive care unit is associated with viral hepatitis, drugs, or toxins. Viral hepatitis accounts for more than 80% of cases of acute hepatic failure in children of all age groups. Acute hepatic failure in the neonate may result from infection with viruses that characteristically do not cause severe hepatitis in older patients. Herpes simplex virus (HSV) infections usually are associated with systemic symptoms. Cytomegalovirus (CMV) hepatitis does not cause acute hepatic failure in this age group but rather a chronic or chronic progressive hepatitis; it is usually associated with other systemic features. Epstein-Barr virus (EBV) rarely causes acute hepatic failure in neonates.

Excepting neonates and immunocompromised patients, most cases of viral hepatitis resulting in acute hepatic failure are the result of infection with hepatitis virus type A or B or sporadic non-A-G hepatitis. Acute hepatitis type A is a relatively frequently diagnosed cause of acute hepatic failure, but the risk of hepatic failure developing in patients symptomatic with hepatitis A virus is very low. The prevalence of acute hepatitis B infection in a large series of acute hepatic failure ranges from 25% to 75%, rendering it the leading cause, overall. Hepatitis B is an uncommon finding in pediatric series in places where hepatitis B virus is not endemic. The overall rate of hepatic failure in hepatitis B infection is estimated to be approximately 1%. Hepatitis C is a very unusual cause of acute hepatic failure. Hepatitis D virus infection can be acquired as a coinfection with hepatitis B virus or as superinfection in patients previously infected with hepatitis B. Hepatitis D virus infection probably plays little role in the etiology of acute hepatic failure in children. No cases of hepatitis E virus involving children have been reported from western Europe or the United States. Sporadic non-A-G hepatitis is diagnosed if the patient has evidence of acute hepatitis in the absence of markers for hepatitis virus infection and in the absence of clinical or serologic evidence of systemic infection with other viral agents. Non–A-G hepatitis causes very severe hepatitis. It is the most important cause of acute hepatic failure in children in developed countries, comprising the majority of pediatric acute hepatic failure cases. Non-A-G hepatitis rarely is seen outside the setting of acute hepatic failure. A high case fatality rate is characteristic of acute hepatic failure secondary to non-A-G hepatitis.

HSV, varicella-zoster virus, CMV, and EBV have been reported to cause acute hepatic failure, almost always in immunocompromised hosts.

Drug-induced fulminant hepatic failure may be related to toxic effects or may be immune-related. Hepatic necrosis is associated with the ingestion of acetaminophen, phenytoin, valproic acid, isoniazid, halothane, or carbon tetrachloride. In children, the three most common drugs that cause acute hepatic failure are acetaminophen, isoniazid, and propylthiouracil. Halothane toxicity is seen more frequently in adults, but it has been observed in children. A systemic hypersensitivity reaction characterized by fever, rash, arthralgias, and hepatocellular damage may result from treatment with sulfamethoxazole, sulfasalazine, carbamazepine, and phenytoin. The ingestion of toxic amounts of iron and vitamin A also may cause acute hepatic failure.

Children who present with hepatic failure may have end-stage chronic liver disease or previously undiagnosed liver disease. Patients with biliary atresia may have hepatic failure before or after undergoing portoenterostomy. Metabolic diseases, such as tyrosinemia, alpha₁-antitrypsin deficiency, Wolman disease, errors in fatty oxidation defects, Wilson disease, Niemann-Pick disease, hereditary fructose intolerance, and cystic fibrosis, may result in hepatic failure.

Mild to moderate nausea, anorexia, and fatigue occur commonly with acute hepatitis. The presence of protracted vomiting, altered behavior, bruisability, or ascites alerts clinicians that the case may be associated with acute hepatic failure. Other associated symptoms include jaundice, abdominal pain, fever, and rash. Throughout the course of the illness, the degree of neurologic deterioration is one of the most reliable means of assessing and following the severity of the hepatic failure.

Monitored liver function tests include measurements of liver enzymes, alkaline phosphatase, bilirubin, albumin, and PT. The liver enzymes become elevated with altered hepatocellular integrity. The absolute height of their elevation does not correlate with the severity of the disease. The pattern of change in liver enzyme levels with time can be useful in following the activity of the disease, as long as the liver still can produce the enzymes. The destruction of hepatocytes may be so rapid that the enzymes can fall precipitously as a premorbid event.

Alkaline phosphatase is produced in the bile canaliculus in response to increased pressure within the canaliculus. Thus,
alkaline phosphatase of liver origin rises with any extrahepatic or intrahepatic obstruction to bile flow. An assay of 5′-nucleotidase may be useful to differentiate between bone and liver alkaline phosphatase.