eMedicine Specialties > Pediatrics: General Medicine > Gastroenterology

Fulminant Hepatic Failure

Author: Hisham Nazer, MB, BCh, FRCP, DCh, DTM&H, Professor of Pediatrics, Consultant in Pediatric Gastroenterology, Hepatology and Clinical Nutrition, Bushnaq Medical Centre, University of Jordan
Coauthor(s): Dena Nazer, MD, Fellow, Child Protection Center, Children's Hospital of Michigan
Contributor Information and Disclosures

Updated: Nov 12, 2008

Introduction

Background

Fulminant hepatic failure (FHF) is usually defined as the severe impairment of hepatic functions in the absence of preexisting liver disease. However, unlike in adults, encephalopathy may be absent, late, or unrecognized in children. Thus, the emphasis in children is placed on the presence of significant coagulopathy in the absence of sepsis or disseminated intravascular coagulation that is not correctable by the administration of parenteral vitamin K within 8 hours. This leads to the updated definition by The Second World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition, who proposed a more detailed classification and definition of liver failure in children.¹ The group proposed the following definitions for liver failure in children (all definitions imply the absence of previous liver disease):

• Hyperacute liver failure is defined as coagulopathy due to acute liver dysfunction of up to 10 days total duration by clinical criteria (eg, acetaminophen toxicity). Jaundice is frequently clinically absent initially, and encephalopathy varies.
• Acute liver failure is defined as coagulopathy due to acute liver dysfunction of more than 10 days, but less than 30 days total duration by clinical criteria. Encephalopathy is absent or impossible to recognize, especially in younger patients. If encephalopathy is present, it tends to be preterminal.
• Subacute liver failure is defined as coagulopathy due to acute liver dysfunction of more than 31 days, but less than 6 months total duration by clinical criteria. Jaundice is almost always present, and encephalopathy often marks preterminal deterioration. It is seen in Wilson disease, autoimmune liver disease, and postmedications.

Pathophysiology

The pathogenesis of FHF usually begins with exposure of a susceptible person to an agent capable of producing severe hepatic injury, although the exact etiology remains unidentified in many cases of FHF. Likewise, the pathophysiologic mechanism that leads to hepatic encephalopathy in children with FHF has not been fully defined.

One theory highlights the effect of accumulation of neurotoxic or neuroactive substances as a consequence of hepatocellular failure. These substances include false neurotransmitters, ammonia, increased gamma-aminobutyric acid receptor activity, and increased circulating levels of endogenous benzodiazepine-like substances.

Viral agents may cause damage to hepatocytes either by direct cytotoxic effect or as a result of hyperimmune response. Apparently, the interaction between agent and host determines the incidence of FHF.

Hepatotoxic metabolites, which accumulate as a result of errors in metabolism or of taking hepatotoxic drugs, may cause injury to the hepatocytes. Serum ammonia levels may be normal or slightly elevated, even in patients who are deeply comatose.

Frequency

United States

FHF is a serious and fatal disease. In the pediatric age group, at least several hundred children are affected each year in the United States, if all etiologies including infectious, drugs, inborn errors of metabolism, and unknown causes are considered.

Mortality/Morbidity

FHF results are fatal for most affected children. The mortality rate may reach 80-90% in the absence of liver transplantation. In some pediatric series, survival rates of 50-75% have been reported.

Sex

Distribution of FHF is equal among males and females.

Age

Children of all ages may develop FHF. However, its atypical presentation in neonates and young infants accounts for the occasional delay in diagnosis or even in missed diagnosis in this age group.

Clinical

History

Fulminant hepatic failure (FHF) affects previously healthy children with no recognized risk factors for liver disease. Children usually present with a hepatitis like clinical picture and worsening of symptoms over a period of several days to a few weeks.

• Jaundice is the presenting symptom in most patients. A prodrome of flulike illness may precede jaundice. Fever, anorexia, vomiting, abdominal pain, and fetor hepaticus are associated clinical findings.
• Altered consciousness is also a sign in patients with FHF. Mental changes occur within 2 weeks of the onset of jaundice in most patients. The patient may become somnolent and/or confused and may respond slowly to painful stimuli.
• Infants initially may present with poor feeding, irritability, and disturbances in sleep rhythms, with frank features of encephalopathy manifesting only later.
• FHF may present in asymptomatic children with Wilson disease.

Physical

Children with FHF are critically ill, and symptoms and level of consciousness rapidly deteriorate.

• Over the next few days to weeks, the condition progresses to coma, with development of ascites, cerebral edema, and decorticate and decerebrate posturing.
• GI bleeding may occur because of severe coagulopathy.
• Liver size may be normal, small, or large, and the liver may shrink with deterioration of the overall general condition of the patient.
• Hemorrhagic diathesis and systemic collapse indicate a poor prognosis.
• Pay special attention to early symptoms and signs of cerebral edema. These include increased muscle tone, arterial hypertension, seizures, agitation, and sluggish pupillary response to light.

Causes

Infectious diseases, hepatotoxic drugs, toxins, metabolic diseases, and ischemia are the main causes of FHF in children, although the cause remains unknown (ie, idiopathic) in a large proportion of patients.

Viral hepatitis and drug-induced hepatotoxicity are the 2 most common causes of FHF. In the United States, acute viral hepatitis accounts for approximately 50% of cases, whereas acetaminophen toxicity accounts for approximately 20-35% of cases. However, in many patients, no specific viral etiology can be found.

• Infectious agents: In approximately 50% of patients, FHF is caused by acute viral hepatitis, commonly caused by hepatitis viruses A; B; non-A, non-B; D; or E. Many viruses other than hepatitis are also recognized causes of FHF in childhood, including Epstein-Barr virus; cytomegalovirus (CMV); paramyxovirus; varicella-zoster virus; herpesvirus types 1, 2, and 6; parvovirus; and adenovirus.
  • Hepatitis B virus (HBV) is the most common cause of FHF in endemic areas. Recognized sources of infection include women with positive anti-hepatitis B e antigen (HBe) who give birth and carriers of subdeterminants of hepatitis B surface antigen (HBsAg) who donate blood.
  • The presence of immunoglobulin M (IgM) antibody to HBV core antigen (IgM anti-HBcAg) or HBsAg in serum is supportive of the diagnosis of acute HBV infection. However, in patients with FHF caused by HBV infection, serum findings may be negative for hepatitis HBsAg. In more than one third of patients, no HBV DNA is detectable in the serum.
  • Hepatitis A virus (HAV) infection is a recognized cause of FHF in individuals of all ages, with an estimated prevalence rate of 1.5-31%. Diagnosis of HAV infection is made by the presence of anti-HAV IgM in the patient's serum.
  • Hepatitis C virus (HCV) infection is not a significant cause of FHF in children. HCV infection is diagnosed by detecting anti-HCV antibody or HCV RNA in the serum.
  • Hepatitis D virus (HDV) also is not a significant cause of FHF in children. The diagnosis of HDV is confirmed by the presence of anti-HDV antibody in serum. Superinfection with HDV can result in FHF in chronic carriers of HBV, with or without chronic hepatitis.
  • Hepatitis E virus mainly affects adolescents and young adults in endemic areas.
  • Non–A-E hepatitis is found in a heterogenous group of patients in both adult and pediatric series. Prevalence in American and European patients with FHF is approximately 24%. Patients usually present with symptoms similar to those found in other forms of hepatitis. They have the same biochemical and histologic manifestations, but no viral markers are detected, and no history of drug exposure or other cause of FHF is found.
  • Non–A-E hepatitis is characterized by its high fatality rate, low rate of spontaneous recovery, and unique complication of aplastic anemia compared to other causes of FHF.
• Hepatotoxic drugs: These agents are the second most common cause of FHF, responsible for approximately 25% of cases. Hepatotoxic drugs include acetaminophen (paracetamol), chlorinated hydrocarbons, salicylates, methanol, isoniazid, intravenous tetracycline, and sodium valproate. The most common drug involved is acetaminophen, and, in some locations, it is the most common cause of FHF. Overdose of acetaminophen causes direct hepatotoxicity and hepatocellular necrosis.
• Metabolic causes
  • These causes vary according to the age of the patient. Because patients with metabolic causes have preexisting liver disease, the inclusion of metabolic causes in the etiology of FHF in children is not uniformly approved.
  • In neonates, inborn errors of metabolism, including tyrosinemia, hereditary fructose intolerance, galactosemia, and neonatal hemochromatosis, are the major metabolic causes of FHF.
  • Consider Wilson disease in older children with FHF.
• Circulatory causes: Circulatory causes are uncommon in FHF. They include congestive heart failure, cardiomyopathy, sepsis, shock, cyanotic heart disease, obstructive lesions of the aorta, vascular occlusions, myocarditis, and severe asphyxia.
• Other causes: This category includes Hodgkin disease, leukemic infiltration, and autoimmune hepatitis.
• Idiopathic causes: Idiopathic FHF remains significant in children.

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