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.

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

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 (see Treatment and Management).[2]

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

See Acute Liver Failure for more information on this topic.

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 to 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. Etiology

The etiology of pediatric fulminant hepatic failure differs significantly from adults in developed countries. Viral hepatitis and drug-induced hepatotoxicity are the 2 most common identifiable causes of FHF. The cause remains unknown (ie, idiopathic) in a large proportion of patients.[3]

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.[4] 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.[5]

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 hepatitic 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.[5, 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

Non–A-E hepatitis has been found in a heterogeneous 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. Non–A-E hepatitis is a diagnosis of exclusion, assigned when other identifiable causes have been eliminated. Patients 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, as compared with other causes of FHF.

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

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.

Acute liver failure in children is a potentially devastating disease.[15] 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.

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 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.[16] 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.[17, 18, 19]

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.[5]

For patient education information, see the Hepatitis Center and the Liver, Gallbladder, and Pancreas Center, as well as Hepatitis A, Hepatitis B, Hepatitis C, and Cirrhosis.

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 rapid worsening of symptoms. FHF may present in asymptomatic children with Wilson disease.[11, 12, 13]

Jaundice is the presenting symptom in most pediatric FHF patients. A prodrome of flulike illness may precede jaundice. Fever, anorexia, vomiting, abdominal pain, and fetor hepaticus are associated clinical findings. Infants may present initially with poor feeding, irritability, and disturbances in sleep rhythms, with frank features of encephalopathy manifesting only later.

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.

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.

Gastrointestinal bleeding may occur because of severe coagulopathy. The liver size may be normal, small, or large; the liver may shrink with deterioration of the overall general condition of the patient.

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.

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.[20] 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]

A range of laboratory studies is required to determine the etiology, severity, and prognosis in patients with fulminant hepatic failure (FHF). Liver biopsy is usually an essential procedure to consider in the management of FHF.

Hepatic enzyme levels do not correlate well with the severity of the disease; they may be elevated, normal, or even decreased in patients with FHF. Levels are often markedly elevated in patients with metabolic disorders. With progressive necrosis of the liver, hepatic enzyme levels decrease.

Both direct and indirect serum bilirubin levels are usually elevated. Typically, conjugated hyperbilirubinemia is present.

Glucose level is decreased, especially in infants. Hyponatremia (see Serum Sodium), hyperkalemia (see Potassium), respiratory alkalosis, or metabolic acidosis (see Acid-Base Interpretation) may also be present.

Serum creatinine, phosphate, and other levels have been recognized recently as strong predictors of survival and the need for transplantation.

Prothrombin time (PT) is prolonged. However, administration of vitamin K typically has not been found to result in a satisfactory drop in prothrombin time (PT) in patients with FHF.

Hepatitis A virus (HAV), hepatitis B virus (HBV; see Hepatitis B Test), hepatitis C virus (HCV; see Hepatitis C Test), hepatitis D virus (HDV), hepatitis E virus and many other 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 immunoglobulin M (IgM) antibody to HBV core antigen (IgM anti-HBcAg) 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, cytomegalovirus (CMV), herpesviruses, and adenoviruses.

Liver biopsy may contribute to the working diagnosis and subsequent therapy. However, samples should be examined with caution because results correlate poorly with prognosis. In view of the presence of coagulopathy, weigh the risk of liver biopsy against its contribution to diagnosis and management.

Histologic Findings

Two types of histology have been recognized in patients with FHF. The first type is usually 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.

Reaching a diagnosis of fulminant hepatic failure (FHF) 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.[21]

Provide symptomatic treatment and life support. Direct treatment toward the specific cause of FHF when an identifiable etiology is found. Avoid nephrotoxic agents, benzodiazepines, and other sedative medications. An intensive care unit (ICU) and pediatric hepatology setting with facilities for liver transplantation should be available for proper diagnosis and management.

General supportive care includes correction of any fluid and electrolyte imbalances and management of hypoglycemia if present.

Correction of Fluid and Electrolyte Abnormalities

Avoid fluid overload (restrict hydration up to 2 mL/kg/h). Hemodynamic monitoring of central pressures is advised to assess volume depletion and overload.

Monitor electrolytes and correct any disturbances. Patients may require intravenous administration of calcium, phosphorus, or magnesium.

Management of Hypoglycemia

Monitor blood glucose regularly for possible complicating hypoglycemia, and treat with intravenous glucose administration. An infusion of 10-20% of glucose is usually required.

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.

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.

Hepatitis is treated with acyclovir for herpesvirus hepatitis and with prednisone and azathioprine for autoimmune hepatitis.

Acetaminophen overdose is treated with an antidote for hepatotoxicity (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).

Renal dysfunction with renal failure occurs in as many as 50% of patients. Kidneys are involved secondary to hepatorenal syndrome (HRS), acute tubular necrosis (ATN), drug-induced nephrotoxicity, or prerenal azotemia. Therefore, monitoring fluids and renal function tests is important.

Maintain urine output. Focus on management of renal impairment due to HRS or ATN.

Management of Hepatorenal Syndrome

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 levels in the serum, low plasma osmolarity, high urine osmolarity, and poor nutritional status. Avoid large-volume paracentesis without plasma volume replacement.[22]

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. Medical therapy is considered a temporary measure to improve renal function while the child with HRS is waiting for liver transplantation. Vasoconstrictors, such as the vasopressin analog terlipressin, have shown promising results in adult patients with HRS. Terlipressin administration results in splanchnic vasoconstriction and thus an increase in systemic and renal perfusion in HRS. Therapy with terlipressin constitutes a bridge towards liver transplantation and improves the prognosis after transplantation.

Cerebral edema occurs in as many as 80% of patients. It increases intracranial pressure (ICP), resulting in impaired cerebral perfusion. This can result in irreversible neurologic damage, 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 the patient with the head elevated and avoidance of any manipulations that increase ICP. Other preventive measures are the avoidance of hypothermia and hypercapnia, controlling agitation, and instituting moderate hyperventilation.

Continuously monitoring ICP 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.

Bacterial and fungal infections commonly occur. Use appropriate antibiotics to treat serious infections, septicemia, peritonitis, urinary tract infections, and pneumonia.

Use lactulose enemas to evacuate the bowel. Oral neomycin is indicated to decrease enteric bacteria that produce ammonia.

Orthotopic liver transplantation (OLT) remains the only effective mode of treatment of FHF. FHF is the indication for 11-13% of liver transplantations and carries an important prognostic implication. Consider OLT in any patient presenting with FHF, regardless of the etiology.[23] Consider urgent transplant when the international normalized ratio (INR) reaches 4, especially in very young children.[24, 25]

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 transplantation.[26, 27]

In an 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,[28, 29] xenograft, extracorporeal human liver, and artificial liver support devices, also are considered in emergency situations. 

Despite technical difficulties and a donor organ shortage, the results of OLT 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.[27, 7]

See Pediatric Liver Transplantation and Liver Transplants for more complete information on these topics.

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. Special formulas are available that are high in branched-chain amino acids and low in aromatic amino acids and electrolytes.

Consultations with the following specialists may be indicated:

• Gastroenterologist

• Neurosurgeon

• Hematologist

• Infectious disease specialist

• Transplantation surgeon

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

Class Summary

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

Phytonadione (AquaMEPHYTON, Mephyton)

Vitamin K is a fat-soluble vitamin absorbed by the gut and stored in the liver. It is necessary for function of clotting factors in the coagulation cascade and, thus, is used in coagulopathy resulting from liver failure.

Class Summary

Hyperosmotic agents such as lactulose work by increasing the amount of stool water content and softening the stool, allowing for an increased number of bowel movements per day. They also cause decreases in the blood ammonia concentration.

Lactulose (Cephulac)

Lactulose inhibits diffusion of NH3 into blood by producing an acidic pH that causes the conversion of NH3 to NH4, a nondiffusable form of ammonia. It is also used to evacuate the bowel and reduce intestinal stasis.

Class Summary

Aminoglycosides such as neomycin are used as adjunctive therapy to reduce the number of ammonia-forming intestinal bacteria.

Neomycin (Mycifradin)

Neomycin interferes with bacterial protein synthesis by binding to 30S ribosomal subunits, thus reducing the number of ammonia-producing bacteria in the intestine. The subsequent reduction in blood ammonia has resulted in neurologic improvement. Agents such as neomycin are used to prevent and treat portal systemic encephalopathy.

Class Summary

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

Mannitol (Osmitrol, Resectisol)

Mannitol is used to decrease intracranial pressure. Mannitol is used in patients with documented intracranial pressure greater than 30 mm Hg and can be considered in patients with progressive edema.

Class Summary

Antiviral 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.

Acyclovir (Zovirax)

Acyclovir is a synthetic purine nucleoside analogue. Hepatitis is treated with acyclovir for herpesvirus hepatitis.

Class Summary

These agents are used in the management of poisoning and overdose, for prevention of toxic effects, or for metabolic disorders. In 2012, the Pediatric Acute Liver Failure Study Group, in a placebo–controlled clinical trial, evaluated intravenous N-acetylcysteine in pediatric patients with non-acetaminophen acute liver failure. The study group concluded that such a regimen did not improve one-year survival in this group of patients. Further controlled pediatric drug trials may still be needed.

N-acetylcysteine (Mucomyst)

N-acetylcysteine is indicated in acetaminophen toxicity. It may provide a substrate for conjugation with a toxic metabolite of acetaminophen. All doses should be administered, even if the acetaminophen level has dropped below the toxic range.

Class Summary

These agents are used in autoimmune hepatitis for immunosuppression effect.

Prednisone (Deltasone, Orasone)

Prednisone is an immunosuppressant for treatment of autoimmune disorders; it may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte activity. It stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.

Azathioprine (Imuran)

Azathioprine antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. It may decrease proliferation of immune cells, which results in lower autoimmune activity.

Class Summary

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

Ranitidine (Zantac)

A parenteral H2-receptor blocker is administered prophylactically to prevent potential GI bleeding. Ranitidine is indicated in peptic ulcer disease and upper GI bleeding for both treatment and prophylaxis.