Pediatric Fulminant Hepatic Failure

Fulminant hepatic failure (FHF) is usually defined as the severe impairment of hepatic functions or severe necrosis of hepatocytes in the absence of preexisting liver disease. However, unlike in adults, encephalopathy may be absent, late, or apparent in children only at the terminal stages. 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. At least several hundred children of all ages develop FHF each year in the United States, if all etiologies, including infections, drugs, inborn errors of metabolism, and unknown causes, are considered.

The exact etiology remains unidentified in many cases of pediatric FHF (see Etiology). Likewise, the pathophysiologic mechanism that leads to hepatic encephalopathy in children with FHF has not been fully defined ^[1] (see Pathophysiology).

FHF affects previously healthy children with no recognized risk factors for liver disease. Children usually present with a hepatitis-like clinical picture; jaundice is the presenting symptom in most patients. Children with FHF are critically ill, and symptoms and level of consciousness rapidly deteriorate. Over a few days to weeks, the condition progresses to coma, with development of ascites, cerebral edema, and decorticate and decerebrate posturing (see Presentation).

A range of laboratory studies is required to determine the etiology, severity, and prognosis in pediatric patients with FHF. Liver biopsy is usually an essential procedure to consider in the management of this condition (see Workup).

Symptomatic treatment and life support should be provided to patients. Direct treatment is toward the specific cause of FHF when an identifiable etiology is found. An intensive care unit (ICU) and pediatric hepatology setting with facilities for liver transplantation should be available for proper diagnosis and management. Orthotopic liver transplantation remains the only effective mode of treatment of FHF ^[2] (see Treatment).

Pharmacologic intervention is usually directed at causative agents or the treatment of complications (see Medication).

Increasing public awareness of potential hepatotoxins, including over-the-counter medications such as acetaminophen (ie, paracetamol) and ibuprofen, is essential. Despite an effective antidote, acetaminophen overdose remains a frequent cause of acute liver failure in children. ^[3]

See Acute Liver Failure for more information on this topic.

Fulminant hepatic failure (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. Decreased hepatic clearance of these neurotoxins and increased absorption may contribute to the encephalopathy. Serum ammonia levels may be normal or slightly elevated, even in patients who are deeply comatose, thus not the sole explanation of the impaired cerebral function.

Viral agents may cause damage to hepatocytes either by direct cytotoxic effect or as a result of hyperimmune response to viral antigens. 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.

The etiology of pediatric fulminant hepatic failure (FHF) differs significantly from adults in developed countries. Viral hepatitis and drug-induced hepatotoxicity are the two most common identifiable causes of FHF. The cause remains unknown (ie, idiopathic) in a large proportion of patients. ^[4]

Infectious Agents

In approximately 50% of patients, FHF is caused by acute viral hepatitis, commonly caused by hepatitis viruses A, B, C, D, or E. Acute viral hepatitis A and E are usually self-limiting diseases. However, acute liver failure, prolonged cholestasis, ascites, and hemolysis are common atypical manifestations of acute viral hepatitis A and E. ^[5] Many other viruses 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. ^[3]

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) and 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 infection is a recognized cause of FHF in individuals of all ages, with an estimated prevalence of 1.5-31%. All cases should therefore be followed up until complete recovery. ^[6] 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. Children with acute leukemia are at a high risk of hepatitis C infection, either by immunosuppression from therapy or from multiple transfusions of blood products. HCV in leukemia could be virtually eliminated by proper testing of the blood transfusion pool. ^[7]

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.

Hepatotoxic Drugs

These agents are the second most common cause of FHF, responsible for approximately 20% of cases. ^[8] Hepatotoxic drugs include acetaminophen (paracetamol), chlorinated hydrocarbons, salicylates, methanol, isoniazid, intravenous tetracycline, and sodium valproate. ^[9] 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. ^{[3, 10]}

Metabolic Disorders

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. In older children and adolescents with FHF, Wilson disease, which is the most common metabolic cause in that age group, should be considered. ^{[11, 12, 13, 14]}

Circulatory Conditions

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 Conditions

In more than 30% of cases of FHF, a diagnosis cannot be established. This condition is known as indeterminate pediatric acute liver failure (iPALF) and is diagnosed when other possible causes have been ruled out. iPALF has been found in a heterogeneous group of patients in both adult and pediatric series. Recent studies have shown that many patients with iPALF have evidence of immune-mediated liver injury. The underlying cause of such liver injury is attributed to hyper-inflammatory immune dysregulation with T-cell activation, which triggers a cascade of pro-inflammatory cytokines and chemokines, leading to hepatocyte damage. iPALF is characterized by its high fatality rate, low rate of spontaneous recovery, and unique complication of aplastic anemia, as compared with other causes of FHF. Based on these findings, there is a growing trend to treat iPALF related to immune dysregulation with immunosuppressive therapy; however, the therapeutic benefit of this practice remains unknown. ^{[15, 16, 17]}

Other conditions also include Hodgkin disease, leukemic infiltration, and autoimmune hepatitis.

Fulminant hepatic failure (FHF) is usually defined as the severe impairment of hepatic functions or severe necrosis of hepatocytes 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, which proposed a more detailed classification and definition of liver failure in children. ^[18] The group proposed the following definitions for hyperacute, acute, and subacute 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. ^{[11, 13, 14]}

Acute liver failure in children is a potentially devastating disease. ^[19] 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. The clinical course and progression of acute liver failure is variable and unpredictable, with the duration from initial symptoms to clinical outcome, recovery, transplant, or death ranging from only hours to several days, highlighting the importance of promptly identifying an underlying cause and initiating treatment.

Prognostic criteria include patient’s age, etiology of liver disease, degree and onset of encephalopathy, serum bilirubin level, prothrombin time (PT) or international normalized ratio (INR), serum creatinine level, factor V level, and arterial pH level.

Presence of jaundice for at least 1 week before the onset of encephalopathy is associated with a poor prognosis. Patients with illness lasting longer than 8 weeks before the onset of encephalopathy have a higher likelihood of developing portal hypertensive manifestations such as renal failure. Increased incidence of cerebral edema is associated with illness lasting fewer than 4 weeks before disease. Hemorrhagic diathesis and systemic collapse indicate a poor prognosis.

The maximum INR reached during the course of illness is a sensitive predictor of outcome. With an INR of 4 or more, the mortality rate reaches 86%; with an INR of less than 4, it is as low as 27%.

Children with fulminant hepatic failure (FHF) who have severe coagulopathy, prolonged duration of illness prior to the onset of encephalopathy, and lower alanine aminotransferase on admission are more likely to require liver transplantation. ^[20] Early referral to a specialized center for consideration of liver transplantation is vital in these patients. Shortage of organ donors affects survival rate.

Prognostic scoring systems still may fail to successfully establish an accurate prognosis in acute liver failure. Studies have been launched to evaluate the prognostic accuracy of the pediatric end-stage liver disease score in children with acute liver failure. Such a score may help establish the optimal timing for liver transplantation evaluation and listing. ^{[21, 22, 23]}