AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 a recent update of the 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. 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 is variable.
• 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 is 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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

FHF affects previously healthy children with no recognized risk factors for liver disease. Children usually present with a hepatitislike 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 flu-like illness may precede jaundice. Fever, anorexia, vomiting, abdominal pain, and fetor hepaticus are associated clinical findings.
• Altered consciousness also is 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.
• Gastrointestinal (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 also are 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 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, IV 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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Liver function studies
• • Levels of hepatic enzymes do not correlate well with the severity of the disease; they may be elevated, normal, or even decreased in patients with FHF.
  • Levels often are markedly elevated in patients with metabolic disorders.
  • With progressive necrosis of the liver, hepatic enzyme levels decrease.
• Serum bilirubin: Both direct and indirect serum bilirubin levels usually are elevated. Typically, conjugated hyperbilirubinemia is present.
• Biochemistry: Glucose level is decreased, especially in infants. Hyponatremia, hyperkalemia, respiratory alkalosis, or metabolic acidosis also may be present.
• Renal function: Serum creatinine, phosphate, and other levels have been recognized recently as strong predictors of survival and the need for transplantation.
• Coagulation profile: Prothrombin time (PT) is prolonged. However, it does not respond well to the administration of vitamin K.
• Viral studies
• • HAV, HBV, non-A, non-B hepatitis, HDV, and hepatitis E viruses account for approximately 50% of cases. Many viruses other than hepatitis also are recognized causes of FHF in childhood.
  • HBV is the most common cause of FHF in endemic areas. Presence of IgM anti-HBcAg or HBsAg in serum supports the diagnosis of acute HBV infection.
  • HAV infection is a recognized cause of FHF in individuals of all ages. Diagnosis of HAV infection is made by the presence of anti-HAV IgM in the patient's serum.
  • HCV infection is diagnosed with detection of anti-HCV antibody or HCV RNA in the serum.
  • HDV is diagnosed by the presence of anti-HDV RNA in the serum.
  • Other causative viruses include Epstein-Barr virus, CMV, herpesviruses, and adenoviruses.

Procedures

• Liver biopsy
• • Liver biopsy is usually an essential procedure to consider in the management of FHF. It contributes to the working diagnosis and subsequent therapy. However, samples should be examined with caution because results correlate poorly with prognosis. Liver biopsy mostly is required to further assist in reaching a likely diagnosis or in preparation for liver transplantation.
  • In view of the presence of coagulopathy, weigh the risk of liver biopsy against its contribution to diagnosis and management. Administration of vitamin K typically has not been found to result in a satisfactory drop in PT in FHF. Transvenous biopsy is not uncommonly used as a relatively safe route in such a clinical situation.

Histologic Findings

Two types of histology have been recognized in patients with FHF. The first type usually is observed in cases that stem from drug reactions or viral hepatitis. This type is characterized by extensive necrosis of the peripheral hepatocytes, with little or no regeneration.

Hepatocyte necrosis with microvascular fat accumulation may be observed, especially in patients with FHF secondary to inborn errors of metabolism.

The second type of histology, observed in valproate toxicity, Reye syndrome, and other metabolic liver disease, is characterized by microvesicular steatosis and centrilobular necrosis.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Reaching a diagnosis is of vital importance so that appropriate and early treatment can be initiated. Unfortunately, in most patients, no definitive therapy that can result in regeneration of hepatocytes or reversal of injury is available. Increasing public awareness of potential hepatotoxins, including over the counter medications such as paracetamolas paracetamol and ibuprofen, is essential.

• General concerns include the following:
• • An intensive care unit (ICU) and pediatric hepatology setting with facilities for liver transplantation should be available for proper diagnosis and management.
  • Maintain urine output, and correct hypoglycemia and any associated electrolyte disturbances.
  • Patients may require IV administration of calcium, phosphorous, magnesium, factor concentrate, and platelets.
  • An infusion of 10-20% of glucose usually is required.
  • Avoid fluid overload (restrict hydration up to 2 mL/kg/h). Hemodynamic monitoring of central pressures is advised to assess volume depletion and overload.
  • Parenteral vitamin K and plasmapheresis are needed to correct coagulopathy and prevent its serious sequelae. However, unless acute hemorrhage is present or an invasive procedure is performed, empiric transfusion with fresh frozen plasma (FFP) is not warranted. It can present a significant volume challenge to the kidneys. It also normalizes PT, reducing the prognostic importance of this variable in respect to prognosis.
  • Platelet transfusion may be indicated in severe cases of FHF with coagulopathy and thrombocytopenia. It occasionally is required to maintain a platelet count of greater than 50,000.
  • A parenteral H2-receptor blocker is administered prophylactically to prevent potential GI bleeding.
  • Avoid nephrotoxic agents, benzodiazepines, and other sedative medications.
  • Despite an effective antidote, paracetamol overdose remains a frequent cause of acute liver failure in children.
• Direct treatment toward the specific cause of FHF when an identifiable etiology is found. Provide symptomatic treatment and life support. Use appropriate antibiotics to treat serious infections, septicemia, peritonitis, and pneumonia.
• • Focus on management of renal impairment due to hepatorenal syndrome (HRS) or acute renal tubular necrosis.
  • Pay special attention to management of cerebral edema. Proper positioning and avoidance of manipulations that increase intracranial pressure (ICP) can help prevent cerebral edema. Monitoring ICP continuously in severe illness is of vital importance, especially in stage 3 or 4 of hepatic encephalopathy. Mannitol is used in patients with documented ICP greater than 30 mm Hg and is considered in patients with progressive edema.
  • Restrict protein intake to 0.5 g/kg/d or less.
  • Use lactulose enemas to evacuate the bowel.
  • Oral neomycin is indicated to decrease enteric bacteria that produce ammonia.
  • Monitor blood glucose regularly for possible complicating hypoglycemia, and treat with IV glucose administration.
• Specific treatment is as follows
• • Hepatitis is treated with acyclovir for herpesvirus hepatitis and with prednisone and azathioprine for autoimmune hepatitis.
  • Acetaminophen overdose is treated with hepatotoxic drugs (ie, N-acetylcysteine).
  • Galactosemia and fructosemia are treated with dietary elimination. Hereditary tyrosinemia type I is treated with dietary elimination and 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC).

Surgical Care

Orthotopic liver transplantation remains the only effective mode of treatment of FHF. Consider this in any patient presenting with FHF, regardless of the etiology. FHF is the indication for 11-13% of liver transplantations and carries an important prognostic implication.

• Consider urgent transplant when international normalized ratio (INR) reaches 4, especially in very young children.
• A more recent approach is to try using liver-assist devices, such as matrices of cultured hepatocytes, to support the patient's liver until hepatic regeneration occurs or a suitable donor is made available for liver transplant.
• In acute emergency, segment liver transplant or living related donor transplant is performed to spare the child with FHF the potentially fatal outcome of rapidly progressive liver necrosis.
• Innovative approaches, such as auxiliary hepatic transplantation, xenograft, extracorporeal human liver, and artificial liver support devices, also are considered in emergency situations. Their role holds promise but requires further investigation.
• Despite technical difficulties and a donor organ shortage, the results of liver transplantation in the pediatric age group with end-stage liver disease have demonstrated promising results. Therefore, early referral to a specialized center for liver transplantation is vital.

Consultations

• Gastroenterologist
• Neurosurgeon
• Hematologist
• Infectious disease specialist
• Transplantation surgeon

Diet

Special attention to diet is indicated. Patients require high calories, high carbohydrates, and moderate fat. Total parenteral nutrition (TPN) may be needed to ensure adequate nutrition, especially when enteral feeding is not possible.

• Monitor glucose carefully, and avoid volume overload.
• Special formulas exist that are high in branched-chain amino acids and low in aromatic amino acids and electrolytes.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

No definite treatment is available for FHF. Medical treatment usually is directed at causative agents or at minimizing morbidity or mortality caused by serious complications (see Treatment).

Drug Category: Vitamins

Organic substances required by the body in small amounts for various metabolic processes. Vitamins may be synthesized in small or insufficient amounts in the body or not synthesized at all, thus requiring supplementation.

Drug Category: Ammonia inhibitors

These agents are used to prevent and treat portal systemic encephalopathy. Lactulose may be used to inhibit diffusion of ammonia into the blood and enhance diffusion from the blood into the gut. Neomycin is used to decrease ammonia-producing bacteria in the gut. The subsequent reduction in blood ammonia has resulted in neurologic improvement.

Drug Category: Osmotic diuretics

These agents may reduce subarachnoid space pressure by creating osmotic gradient between cerebrospinal fluid in arachnoid space and plasma. They are not for long-term use.

Drug Category: Antiviral agents

These agents inhibit activity of herpesvirus types 1 and 2. They have affinity for viral thymidine kinase and, once phosphorylated, cause DNA chain termination when acted on by DNA polymerase.

Drug Category: Antidotes

These agents are used in the management of poisoning and overdose, for prevention of toxic effects, or for metabolic disorders when toxic substances accrue.

Drug Category: Immunosuppressive agents

These agents are used in autoimmune hepatitis for immunosuppression effect.

Drug Category: Histamine H2 antagonists

These agents inhibit histamine stimulation of the H2 receptor in gastric parietal cells, which, in turn, reduces gastric acid secretion, gastric volume, and reduced hydrogen concentrations. These agents are used to prevent stress ulcer development and potential GI bleeding.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Transfer

• An ICU and pediatric hepatology setting with facilities for liver transplantation should be available for proper diagnosis and management.

Deterrence/Prevention

• Preventive methods to avoid cerebral edema and renal failure should be performed.

Complications

• Infections: Bacterial and fungal infections commonly occur, leading to the development of peritonitis, pneumonia, urinary tract infections, or septicemia.
• Cerebral edema
• • Cerebral edema occurs in as many as 80% of patients. It increases ICP, resulting in impaired cerebral effusion. This can result in irreversible neurologic damage, uncal herniation, and death.
  • Cytotoxic and vasogenic edema are present, presumably caused by release of neurotoxins in the circulation.
  • Insertion of an ICP monitor in patients with grade 3 encephalopathy is advisable to detect cerebral edema early in its course.
  • Preventive measures include positioning patient with head elevated, avoiding hypothermia and hypercapnia, controlling agitation, and instituting moderate hyperventilation.
• GI bleeding
• Electrolytes imbalance
• Renal dysfunction with renal failure: This occurs in as many as 50% of patients. Therefore, monitoring fluids and renal function tests is important.
• • Kidneys are involved secondary to HRS, acute tubular necrosis, drug-induced nephrotoxicity, or prerenal azotemia.
  • HRS is defined as functional renal failure occurring in patients with severe liver disease in the absence of any other underlying cause of renal disease. A decrease in blood flow to the kidneys has been suggested as the underlying pathophysiology.
  • Pay special attention to risk factors leading to development of HRS, including low sodium and high potassium in the serum, low plasma osmolarity, high urine osmolarity, and poor nutritional status. Avoid large-volume paracentesis without plasma volume replacement.
  • Liver transplantation is the treatment of choice for HRS; however, some patients continue to require dialysis following the transplant.
  • Peritoneal dialysis, hemodialysis, and hemofiltration have limited benefit and, thus, remain controversial in HRS.
  • Systemic vasoconstricting agents and renal vasodilators are used but have limited value, although one has been shown to reverse HRS.
• Acid-base disturbances
• Pulmonary and cardiovascular problems
• Coagulopathy caused by decreased synthesis of clotting factors by the liver, thrombocytopenia, and abnormal platelet function

Prognosis

• Prognostic criteria include patient's age, etiology of liver disease, degree and onset of encephalopathy, serum bilirubin level, PT or INR, serum creatinine, 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.
• 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%.

Patient Education

• For excellent patient education resources, visit eMedicine's Hepatitis Center and Liver, Gallbladder, and Pancreas Center. Also, see eMedicine's patient education articles, Hepatitis A, Hepatitis B, Hepatitis C, and Cirrhosis.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Atypical presentation of FHF in neonates and young infants accounts for the occasional delay in diagnosis or even in missed diagnosis.

Special Concerns

• FHF remains a serious disease with a high mortality rate, especially among infants and young children. Special concerns arise because of the following:
• • The exact etiology of FHF remains unknown in a high percentage of patients, especially among infants and young children.
  • An urgent need still exists to understand the exact mechanism of FHF in children resulting in massive hepatic necrosis and to provide measures to prevent the progress of the disease.
  • Shortage of organ donors affects survival rate.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Baccarani U, Adani GL, Sainz M, et al. Human hepatocyte transplantation for acute liver failure: state of the art and analysis of cell sources. Transplant Proc. Jul-Aug 2005;37(6):2702-4. [Medline].
• Baker A, Alonso ME, Aw MM, et al. Hepatic failure and liver transplant: Working Group report of the second World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr. Jun 2004;39 Suppl 2:S632-9. [Medline].
• Caraceni P, Van Thiel DH. Acute liver failure. Lancet. Jan 21 1995;345(8943):163-9. [Medline].
• Dhawan A, Cheeseman P, Mieli-Vergani G. Approaches to acute liver failure in children. Pediatr Transplant. Dec 2004;8(6):584-8. [Medline].
• Goss JA, Shackleton CR, Maggard M, et al. Liver transplantation for fulminant hepatic failure in the pediatric patient. Arch Surg. Aug 1998;133(8):839-46. [Medline].
• Hattori H, Higuchi Y, Tsuji M, et al. Living-related liver transplantation and neurological outcome in children with fulminant hepatic failure. Transplantation. Mar 15 1998;65(5):686-92. [Medline].
• Lee WM. Acute liver failure. N Engl J Med. Dec 16 1993;329(25):1862-72. [Medline].
• Lee WS, McKiernan P, Kelly DA. Etiology, outcome and prognostic indicators of childhood fulminant hepatic failure in the United kingdom. J Pediatr Gastroenterol Nutr. May 2005;40(5):575-81. [Medline].
• Suchy FJ. Fulminant hepatic failure in children. Saudi Journal of Gastroenterology. 1996;2(1):34-43.
• Treem WR. Fulminant hepatic failure in children. J Pediatr Gastroenterol Nutr. 2002;35 Suppl 1:S33-8. [Medline].
• Whittington PF. Fulminant hepatic failure in children. In: FJ Suchy, ed. Liver Disease in Children. Philadelphia: Mosby;. 1994:180-213.

Article Last Updated: Jun 27, 2006